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1f1e76c92b9e53e0083ea57b4bfee73472f84086	nice	Percutaneous ultrasound-guided microwave ablation for symptomatic benign thyroid nodules	Percutaneous ultrasound-guided microwave ablation for symptomatic benign thyroid nodules Evidence-based recommendations on percutaneous ultrasound-guided microwave ablation for symptomatic benign thyroid nodules . This involves inserting a thin wire into the nodule under local anaesthetic and guiding it into position using ultrasound. Microwaves from the wire heat the nodule to destroy it (ablation). The aim is to make the nodule smaller, relieve symptoms and improve appearance. # Recommendations Evidence on the safety of percutaneous ultrasound-guided microwave ablation for symptomatic benign thyroid nodules shows some well-recognised complications. Evidence on efficacy is adequate. Therefore, this procedure can be used provided standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page. Patient selection should be done by a multidisciplinary team. This procedure should only be done by a clinician with experience in the procedure and specific training in thyroid ultrasound. Patients should be assessed to exclude thyroid cancer before the procedure. Immediate support should be available to deal with airway complications.# The condition, current treatments and procedure # The condition Thyroid nodules may be cystic, colloid, hyperplastic, adenomatous, or cancerous. Most are benign and often asymptomatic. They may be single (solitary nodule) or multiple (multinodular goitre). Some thyroid nodules produce thyroxine or triiodothyronine and cause thyrotoxicosis. These are called hyperfunctioning or toxic thyroid nodules. # Current treatments Benign thyroid nodules may need treatment if they are symptomatic or causing cosmetic problems. Conventional treatment includes surgery. Less invasive alternatives to surgery include ethanol ablation, percutaneous laser ablation, high intensity focused ultrasound ablation and radiofrequency ablation. # The procedure Ultrasound-guided percutaneous microwave ablation for symptomatic benign thyroid nodules is a minimally invasive procedure done in an outpatient setting using local anaesthesia. The aim is to reduce symptoms and improve cosmetic appearance by making the nodule smaller while preserving thyroid function and with fewer complications than surgery. The patient is placed in the supine position with moderate neck extension. A microwave antenna is inserted into the nodule using ultrasound guidance to visualise the electrode during the procedure. Once in position, the microwave antenna is activated to heat and destroy the tissue by coagulative necrosis. The antenna may be repositioned to ensure that most of the nodule is ablated.	{'Recommendations': 'Evidence on the safety of percutaneous ultrasound-guided microwave ablation for symptomatic benign thyroid nodules shows some well-recognised complications. Evidence on efficacy is adequate. Therefore, this procedure can be used provided standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nPatient selection should be done by a multidisciplinary team.\n\nThis procedure should only be done by a clinician with experience in the procedure and specific training in thyroid ultrasound.\n\nPatients should be assessed to exclude thyroid cancer before the procedure.\n\nImmediate support should be available to deal with airway complications.', 'The condition, current treatments and procedure': '# The condition\n\nThyroid nodules may be cystic, colloid, hyperplastic, adenomatous, or cancerous. Most are benign and often asymptomatic. They may be single (solitary nodule) or multiple (multinodular goitre). Some thyroid nodules produce thyroxine or triiodothyronine and cause thyrotoxicosis. These are called hyperfunctioning or toxic thyroid nodules.\n\n# Current treatments\n\nBenign thyroid nodules may need treatment if they are symptomatic or causing cosmetic problems. Conventional treatment includes surgery. Less invasive alternatives to surgery include ethanol ablation, percutaneous laser ablation, high intensity focused ultrasound ablation and radiofrequency ablation.\n\n# The procedure\n\nUltrasound-guided percutaneous microwave ablation for symptomatic benign thyroid nodules is a minimally invasive procedure done in an outpatient setting using local anaesthesia. The aim is to reduce symptoms and improve cosmetic appearance by making the nodule smaller while preserving thyroid function and with fewer complications than surgery.\n\nThe patient is placed in the supine position with moderate neck extension. A microwave antenna is inserted into the nodule using ultrasound guidance to visualise the electrode during the procedure. Once in position, the microwave antenna is activated to heat and destroy the tissue by coagulative necrosis. The antenna may be repositioned to ensure that most of the nodule is ablated.'}	https://www.nice.org.uk/guidance/ipg743	Evidence-based recommendations on percutaneous ultrasound-guided microwave ablation for symptomatic benign thyroid nodules . This involves inserting a thin wire into the nodule under local anaesthetic and guiding it into position using ultrasound. Microwaves from the wire heat the nodule to destroy it (ablation). The aim is to make the nodule smaller, relieve symptoms and improve appearance.
7ab0f9e41bdc1c1eef9baabdd04fecd1503825ac	nice	Extracorporeal shockwave therapy for calcific tendinopathy in the shoulder	Extracorporeal shockwave therapy for calcific tendinopathy in the shoulder Evidence-based recommendations on extracorporeal shockwave therapy for calcific tendinopathy in the shoulder. This involves placing a device on the skin that delivers short pulses of sound into the shoulder. The aim is to reduce pain and improve shoulder function. # Recommendations Evidence on the safety of extracorporeal shockwave therapy for calcific tendinopathy in the shoulder shows no major safety concerns in the short term. Evidence on efficacy is inadequate. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. Further research should include randomised controlled trials comparing the procedure with current best practice. It should report details of patient selection, including site and density of calcification, duration of symptoms, and other treatments used at the same time. It should also report details of the technique, including dose and number of treatments, and long-term safety outcomes.# The condition, current treatments and procedure # The condition Calcific tendinopathy (also known as calcific tendonitis) is a disorder of the shoulder characterised by the formation of deposits of calcium crystals in 1 or more of the rotator cuff tendons. It can cause symptoms such as pain in the upper arm and shoulder, reduced range of movement, stiffness and weakness. The exact cause is unknown. # Current treatments Most cases of calcific tendinopathy resolve in time without treatment. In the early stages, symptom management includes painkillers and anti-inflammatory medication. If symptoms persist, physiotherapy may be needed. Other treatment options include steroid injection, percutaneous lavage or barbotage (using a needle to suck up or break up the calcium deposits), or surgery. # The procedure Extracorporeal shockwave therapy (ESWT) is a non-invasive treatment in which a device is used to pass controlled, short-duration acoustic shockwaves through the skin to the affected area. This produces transient pressure disturbances, which break up calcium deposits. There are 2 different types of ESWT. In focused ESWT the energy generated converges at a selected depth in the body tissues where the maximal pressure is reached. In radial ESWT the maximal pressure is at the skin surface and then diverges as it penetrates deeper. Local anaesthesia is sometimes used for pain relief during the procedure and ultrasound guidance can be used to assist with positioning the device. Treatment protocols for ESWT vary according to the energy density and frequency of shockwaves.	{'Recommendations': 'Evidence on the safety of extracorporeal shockwave therapy for calcific tendinopathy in the shoulder shows no major safety concerns in the short term. Evidence on efficacy is inadequate. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should include randomised controlled trials comparing the procedure with current best practice. It should report details of patient selection, including site and density of calcification, duration of symptoms, and other treatments used at the same time. It should also report details of the technique, including dose and number of treatments, and long-term safety outcomes.', 'The condition, current treatments and procedure': '# The condition\n\nCalcific tendinopathy (also known as calcific tendonitis) is a disorder of the shoulder characterised by the formation of deposits of calcium crystals in 1 or more of the rotator cuff tendons. It can cause symptoms such as pain in the upper arm and shoulder, reduced range of movement, stiffness and weakness. The exact cause is unknown.\n\n# Current treatments\n\nMost cases of calcific tendinopathy resolve in time without treatment. In the early stages, symptom management includes painkillers and anti-inflammatory medication. If symptoms persist, physiotherapy may be needed. Other treatment options include steroid injection, percutaneous lavage or barbotage (using a needle to suck up or break up the calcium deposits), or surgery.\n\n# The procedure\n\nExtracorporeal shockwave therapy (ESWT) is a non-invasive treatment in which a device is used to pass controlled, short-duration acoustic shockwaves through the skin to the affected area. This produces transient pressure disturbances, which break up calcium deposits. There are 2 different types of ESWT. In focused ESWT the energy generated converges at a selected depth in the body tissues where the maximal pressure is reached. In radial ESWT the maximal pressure is at the skin surface and then diverges as it penetrates deeper.\n\nLocal anaesthesia is sometimes used for pain relief during the procedure and ultrasound guidance can be used to assist with positioning the device.\n\nTreatment protocols for ESWT vary according to the energy density and frequency of shockwaves.'}	https://www.nice.org.uk/guidance/ipg742	Evidence-based recommendations on extracorporeal shockwave therapy for calcific tendinopathy in the shoulder. This involves placing a device on the skin that delivers short pulses of sound into the shoulder. The aim is to reduce pain and improve shoulder function.
56948141c8ac6666cc22065f580c8df761b48284	nice	Advocacy services for adults with health and social care needs	Advocacy services for adults with health and social care needs This guideline covers advocacy for people using health and social care services in all adult settings (including young people under 18 using adult services). It describes how to commission and deliver effective advocacy, as well as identifying who should be offered advocacy (including who is legally entitled to it). It also covers monitoring and improving advocacy services, and training and skills for advocates and practitioners. # Context Advocacy helps to ensure that people's voices, wishes and preferences are heard, their rights are upheld and their needs are met, particularly when they have difficulty in speaking up for themselves or are concerned that they are not being heard. An advocate helps someone with health and social care needs to express their needs and wishes, and to weigh up and take decisions about options available to them. Advocates can help people find services, make sure correct procedures are followed and challenge decisions made by councils, health services and other relevant health-based organisations. Advocacy helps protect human rights and plays a critical part in safeguarding. The advocate is there to represent the person's interests, which they can do by supporting them to speak, or by speaking on their behalf, including when the person is unable to instruct the advocate. (Adapted from the Think Local, Act Personal Care and Support Jargon Buster.) This guideline covers advocacy delivered by a trained person whose sole engagement is to support the person and help ensure that their voice, needs and preferences are heard (referred to in law as 'independent advocacy'). Family members and friends play a vital role in the lives of people who draw on support, for example ensuring that the person's voice and concerns are heard. However, the focus of this guidance is on a trained person whose sole involvement is as an advocate. Several Acts of Parliament specify the local authority's responsibility to ensure the provision of independent advocates and the situations in which they must make an advocate available. But many more people at certain points in their lives could benefit from access to the services of a trained advocate. Little information is available about how many people access independent advocacy or how many independent advocates are currently operating. There is a widely held view that there is a shortage of advocates. The commissioning of advocacy services, their availability and the ongoing training and support of advocates varies significantly across the country, although the National Qualification in Independent Advocacy is widely recognised. This guideline aims to help advocates and those who train and manage them, as well as those who commission their services and health and social care practitioners who interact with them, by setting out key aspects of service quality. It will also be of interest to people who use advocacy services and their families and carers. This guideline is relevant to people who need advocacy regardless of their condition or life circumstance. For more specific guidance about conditions or circumstances where advocacy is likely to be helpful, see the NICE guidelines on decision making and mental capacity, people growing older with learning disabilities, people experiencing homelessness and safeguarding adults in care homes.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The recommendations in this guideline apply to both instructed and non-instructed advocacy. When providing non-instructed advocacy, advocates will need to take additional steps to determine as far as possible what the person's wishes, feelings and desired outcomes are likely to be, to best represent the person. If the person lacks the capacity to instruct an advocate, advocates will need to act based on the person's likely wishes, feelings and desired outcomes. # Legal right to advocacy Advocacy must be offered according to the relevant legislation. The criteria for when and to whom to offer it are described in the: Care Act 2014 and the Care and Support statutory guidance for independent advocates for people using social care services Mental Capacity Act 2005 and its Code of Practice for independent mental capacity advocates Mental Health Act 1983 and its Code of Practice for independent mental health advocates. Local authorities must make appropriate arrangements for independent advocacy services to provide assistance to people making or intending to make complaints as described in the Health and Social Care Act 2012. For a summary, see box 1 on the legal entitlement to advocacy, as well as supporting information and resources on the Social Care Institute for Excellence's information on advocacy. For more guidance on helping people to make complaints, see the NICE guidelines on patient experience in adult NHS services and service user experience in adult mental health. Adapted from the Care Act 2014 statutory guidance, the Mental Capacity Act Code of Practice, the Mental Health Act 1983: Code of Practice and the Health and Social Care Act 2012. Care Act 2014 From the point of first contact, the local authority must appoint an independent advocate if an adult would experience substantial difficulty in any of these 4 areas: understanding the information provided retaining the information using or weighing up the information as part of the process of being involved communicating the person's views, wishes or feelings. And There is thought to be no one appropriate and independent to support and represent the person, for the purpose of facilitating their involvement. This applies to adults taking part in: a needs assessment a carer's assessment preparing a care and support or support plan revising a care and support or support plan a child's needs assessment a child's carer's assessment a young carer's assessment a safeguarding enquiry a safeguarding adult review an appeal against a local authority decision under Part 1 of the Care Act (subject to further consultation). Care and Support (Independent Advocacy Support) (No. 2) Regulations 2014 The Care and Support (Independent Advocacy Support) (No. 2) Regulations is a Statutory Instrument, which adds to the Care Act 2014 section 67(2). It extends the circumstances in which a person is entitled to an independent advocate to where an assessment or plan is likely to result in a hospital stay of more than 28 days or a stay in a care home for more than 8 weeks (although there are some exceptions). Mental Capacity Act 2005 An independent mental capacity advocate (IMCA) must be instructed, and then consulted, for people lacking capacity who have no one else to support them (other than paid staff), whenever: an NHS body is proposing to provide serious medical treatment or an NHS body or local authority is proposing to arrange accommodation (or a change of accommodation) in hospital or a care home. And the person will stay in hospital longer than 28 days or they will stay in the care home for more than 8 weeks. An IMCA may be instructed to support someone who lacks capacity to make decisions concerning: care reviews, if no one else is available to be consulted adult protection cases, whether or not family, friends or others are involved. Mental Health Act 1983 People are eligible for support from an independent mental health advocate, irrespective of their age, if they are: detained under the Mental Health Act 1983 (excluding certain short-term sections) liable to be detained even if not actually detained, including those who are currently on leave of absence from hospital or absent without leave, or those for whom an application or court order for admission has been completed conditionally discharged restricted patients subject to guardianship subject to a community treatment order being considered for treatment under section 57 of the Act or, for under‑18s, any treatment under section 58A. Health and Social Care Act 2012 The 2012 Health and Social Care Act amendment to the 2007 Local Government and Public Involvement in Health Act. The local authority must make arrangements for independent advocacy services to provide assistance to people making or intending to make a complaint: under a procedure operated by a health service body or independent provider section 113(1) or (2) of the Health and Social Care (Community Health and Standards) Act 2003 to the Health Service Commissioner for England to the Public Services Ombudsman for Wales, which relates to a Welsh health body under section 73C(1) of the National Health Service Act 2006 to a Local Commissioner under Part 3 of the Local Government Act 1974 about a matter which could be the subject of a complaint under section 73C(1) of the National Health Service Act 2006 -f such description as the Secretary of State may by regulations prescribe which relates to the provision of services as part of the health service and is made under a procedure of a description prescribed in the regulations, or gives rise, or may give rise, to proceedings of a description prescribed in the regulations. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on legal right to advocacy . Full details of the evidence and the committee's discussion are in: evidence review A: who has a legal right to advocacy? evidence review E: enabling and supporting effective advocacy. Loading. Please wait. # Who else may benefit from advocacy Offer advocacy to people who are not covered by the legal entitlement but who would otherwise not be able to express their views or sufficiently influence decisions that are likely to have a substantial impact on their wellbeing or the wellbeing of someone they have caring or parental responsibility for. For a short explanation of why the committee made this recommendation and how it might affect practice or services, see the rationale and impact section on who else may benefit from advocacy . Full details of the evidence and the committee's discussion are in evidence review B: who else would benefit from advocacy and how do we identify them? Loading. Please wait. # Information about effective advocacy and signposting to services Local authorities must meet the requirement of the Care Act 2014 to make information and advice publicly available about care and support services for adults in their area. This should include advocacy services. Local authorities, health authorities, NHS trusts, health and social care providers and advocacy services should provide everyone legally entitled to advocacy (including young people who are using adult services) with information about their entitlement to advocacy and what this means. There should be proactive signposting to the information using accessible formats. Local authorities, health authorities, NHS trusts, health and social care providers and advocacy services should provide everyone who would benefit from advocacy (whether or not they are legally entitled to it) with information about: what advocacy services are available to them how an advocate could help them how to access and contact advocacy services. Local authorities, health authorities, NHS trusts, health and social care providers and advocacy services should ensure that all information about advocacy is provided in a variety of ways to suit people's needs (including for family, friends and carers), using accessible formats where relevant. Examples include using interpreters, sign language and versions such as Easy Read, large print, braille and audio. For more guidance on communicating and providing information, see the NICE guideline on patient experience in adult NHS services and the NHS Accessible Information Standard. Local authorities, health authorities, NHS trusts, health and social care providers and advocacy services should repeat information about advocacy and how to access it at each key point in the person's interaction with health and social care. If a person is offered healthcare, care or support out of their home area, the organisation arranging the placement should give them (and their family, friends or carers, as appropriate) information about the advocacy support available and help them to access it. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on information about effective advocacy and signposting to services . Full details of the evidence and the committee's discussion are in: evidence review C: information about effective advocacy and signposting to services evidence review F: what does effective advocacy look like? Loading. Please wait. # Improving access to advocacy This section should be read alongside the section on training and skills for health and social care practitioners who work with advocates. Health and social care providers should ensure that advocates can meet people in person to support them to make initial contact with advocacy services. Health and social care providers in all settings, including hospitals, care homes and prisons, should ensure that policies and procedures do not act as an obstacle to people accessing advocacy. This includes finding alternative methods to mitigate any risks, for example from infection. If a person has been detained under the Mental Health Act 1983 and has legal representation, they still have a legal right to advocacy and therefore mental health services must continue to facilitate access to independent mental health advocacy (IMHA) support. See the section on legal right to advocacy. Commissioners and advocacy providers should make it easy for people to access advocacy by having: flexible ways to make contact, including by self-referral a simple process that directs people to the right advocacy support without them needing to know what type of advocacy they need (for example, a universal point of access). Advocacy providers should aim to support continuity by offering people the same advocate for different types of advocacy (for example, statutory advocacy in line with the Care Act 2014, IMHA, independent mental capacity advocate and non-statutory advocacy). If this is not possible, they should ensure that systems for handover are in place that are not reliant on a new referral. Independent mental health advocates should make regular visits to inpatient settings to identify people who would benefit from advocacy and help them to access it. This includes taking all necessary steps to ensure that people who would otherwise be unable to instruct an advocate, or who would find it particularly difficult, do not miss out on statutory advocacy services. Particular efforts should also be made to facilitate access to advocacy for people in isolation, seclusion or segregation. Advocacy providers, hospital and health trusts and commissioners should offer IMHA on an opt-out basis so that everyone who is eligible meets an advocate and is offered the service. Advocacy organisations should ensure that IMHA is offered at the earliest opportunity and then regularly afterwards to people who are eligible. This includes people who have initially declined support. For these people, advocacy organisations should explore, where appropriate, the reasons why the support was declined and what could be done to help them access advocacy. IMHA services should raise awareness of disabled people's organisations and user-led organisations, self-advocacy groups or patient participation forums and promote peer advocacy and self-advocacy options. Advocacy organisations should have a plan for how to ensure that their services are taken up by the people with the greatest need, who may not be able to ask for them. Local authorities and advocacy providers should collaborate to make it clear how people can access advocacy and how they can provide support to help them to do so if they: are supported outside of their home area or are carers who care for someone outside their area. Health and social care practitioners should ensure that people who are unable to ask for an advocate get advocacy when they are entitled to it. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on improving access to advocacy . Full details of the evidence and the committee's discussion are in: evidence review D: improving access to advocacy evidence review E: enabling and supporting effective advocacy evidence review G: partnership working and relationships with families and carers, commissioners and providers evidence review H: planning and commissioning services for advocacy. Loading. Please wait. # Enabling and supporting effective advocacy Health and social care practitioners and other referrers should: identify the need for advocacy as early as possible and make a referral to an advocacy service without delay. When the need for advocacy is identified, allow enough time: to appoint an advocate if the person does not have one to make any other arrangements, for example if the person needs an interpreter for the advocate to help the person prepare before any meetings or discussions, and to ensure they understand the outcome afterwards. Service providers should accommodate the availability of the advocate when planning and scheduling meetings, ward rounds or other situations where decisions are being made, including rearranging meetings where needed and practicable. If people have not had enough time to prepare with their advocate before a meeting, their advocate should support them in requesting to rearrange the meeting. Advocacy organisations should ensure that there is adequate time for the advocate and person to build relationships and trust according to their individual needs. Service providers should ensure that people can have discussions with their advocates in a private area where they can talk in confidence without being overheard. Health and social care practitioners should involve a person's advocate in all discussions with the person until a decision has been made and explained to the person, and they have had a chance to challenge the decision if they want to. Health and social care practitioners should facilitate advocacy, for example by: respecting the advocate's independence sharing information appropriately with advocates supporting the person and building good working relationships with them encouraging and supporting ongoing contact between the person and their advocate giving the person privacy to talk to their advocate supporting people to understand about advocacy and to ask for the advocacy that they would want, or ask for it on their behalf if appropriate responding to advocates in a timely manner supporting any communication needs, such as arranging for an interpreter. Health and social care providers should offer practical support to help people to communicate with their advocate remotely. This may include providing: access to computers, the internet and phones support to use technology help to schedule and remember meeting times. Advocacy providers should use digital platforms to communicate with the person when necessary or the person prefers it, and only when it is safe, effective and appropriate to do so. Health and social care practitioners responsible for decisions should ensure that all formal and informal concerns that are raised, by either the person or the advocate on their behalf, are understood, responded to and recorded. Health and social care providers should periodically audit cases to assess whether referrals have been made to advocacy services in line with statutory duties. If gaps in compliance (for example, people not being informed of their right to an advocate) are identified by audits, or otherwise, health and social care providers should develop action plans to improve compliance. Local authorities and health and social care providers should consider including the numbers of referrals they make to advocacy services as a part of their corporate performance information. Advocacy services should ensure that advocacy staff know when and how to report and act on safeguarding concerns. Advocacy services should ensure that their advocacy staff are delivering effective safeguarding by: having robust internal guidance keeping detailed, accurate records that are written at the time of the discussion or event appointing a safeguarding lead developing systems for tracking and monitoring concerns training, supervision and reflective practice providing input to local Safeguarding Adults Boards learning from adverse events continuing to advocate for the person throughout the process.For more guidance on communicating and discussing complex information, see the NICE guidelines on people's experience in adult social care services, patient experience in adult NHS services and shared decision making. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on enabling and supporting effective advocacy . Full details of the evidence and the committee's discussion are in: evidence review D: improving access to advocacy evidence review E: enabling and supporting effective advocacy evidence review F: what does effective advocacy look like? Loading. Please wait. # Effective advocacy Advocacy providers should ensure that their advocacy service is accessible, for example by: making face-to-face advocacy available unless this is not possible using remote advocacy if the person prefers this and it is effective -perating outside normal working hours if possible as well as during them making referral processes simple, flexible and clear making referral forms easily available online ensuring that meeting places are accessible in all aspects clearly describing available services producing policies, procedures and publicity materials in accessible formats, including Easy Read meeting people's communication needs providing advocacy free of charge for people who are eligible making efforts (directly and indirectly through other organisations) to reach under-represented and underserved communities providing non-instructed advocacy. Advocacy providers should ensure that their advocacy service is person centred, for example by: ensuring that advocates are directed by the wishes and interests of the person they are advocating for being non-judgemental and respectful of the person's needs, views, values, culture and experiences avoiding and challenging stereotyping supporting and helping the person to self-advocate as much as possible supporting the person to choose their own level of involvement and the way they and their advocate work together to progress matters enabling the person to lead and be involved in addressing the advocacy issue or decision-making processes clearly agreeing with the person their advocacy needs, their impact and desired outcomes -nly consulting, meeting or accepting information and documentation from third parties with the consent of the person, or if the person is unable to consent and it is in their best interests -ffering a choice of advocate (for example, gender and culture) for people seeking support. Advocates should work with the person they are supporting to develop a shared understanding of what the person wants to achieve. They should discuss and agree with the person whether they have achieved the outcome they wanted and what to do if this does not happen, and review regularly. When people lack capacity to instruct their advocate, advocacy providers should ensure that the advocacy remains person led and involves people with an interest in the person's welfare. Advocacy providers should include people with lived experience of health inequalities or using health and social care or advocacy services in their organisation, for example, as paid advocates or as part of management committees or boards. Advocacy providers must promote equality throughout their services for everyone with protected characteristics under the Equality Act 2010. Advocacy providers should deliver effective advocacy in relation to safeguarding by supporting their advocates to: be sensitive and alert to what the person is telling them and to observe the person's communications and circumstances to identify any safeguarding concerns respond to concerns about poor practice that fall below the threshold for safeguarding challenge decisions if safeguarding concerns have been raised but the local authority has decided they do not meet the threshold for action continue to advocate for a person throughout any safeguarding processes take action if they observe other safeguarding issues while they are advocating for a person provide non-instructed advocacy. Advocacy providers should ensure that the same advocate works with a person throughout the advocacy process, if possible and the person prefers it. Advocacy providers should maintain independence from any other organisations the person is in contact with, to avoid any conflict of interest. Ways to do this include: establishing themselves as a free-standing organisation with governance documents that promote and protect their independence ensuring that their independence is clearly reflected in all publicity material, including on their website ensuring that their service is structurally independent of any other services offered developing an organisational culture that encourages advocates to challenge freely and as directed by the people they are working with having a conflict of interests policy, keeping a register of conflicts that might influence board members, staff and volunteers, and ensuring that advocates are free from any conflicts of interest actively seeking funding from more than 1 source ensuring that funders, commissioners and external health and social care practitioners are not involved in organisational decisions such as how or by whom advocacy is delivered putting in place engagement protocols that govern the organisation's interaction with other organisations. Advocacy providers should, wherever possible, have advocates specialising in different types of advocacy and multi-skilled advocates who can provide different types of advocacy to the same person. Advocacy services should ensure that they can provide access to interpretation and translation services when the person needs them. Advocacy services should ensure that advocacy is culturally appropriate by respecting and taking into account the person's cultural needs, preferences, customs or religious beliefs and experience of health inequalities. Advocacy services should support their staff to develop cultural competence to meet the needs of the populations in their local areas, for example by training, supervision and reflective practice. Advocates should maintain confidentiality, and explain the principles and the limitations of confidentiality in advance to people they are supporting. This should include: what information will be shared, who with, and when and when confidentiality may need to be breached, for example, to make a child or adult safeguarding alert or when required by law. Advocacy providers should work together to promote best practice and consistency. This could be done, for example, by sharing learning, insight and tools, and developing joint publications, guidance and resources. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on effective advocacy . Full details of the evidence and the committee's discussion are in evidence review F: what does effective advocacy look like? Loading. Please wait. # Partnership working and relationships with families, friends and carers, commissioners and providers Advocates should liaise with family members, friends and carers when the person wants them to or when the person cannot express a view about this but it is in their best interests. This includes, for example, and where appropriate: seeking information from family members, friends and carers to help understand the person's circumstances, communication preferences, views and wishes sharing information with family members, friends and carers about the work that they are doing on the person's behalf. Advocacy providers should be familiar with local support services, such as health, social care, education, employment support and community action, and what these services offer so that they can give up-to-date and accurate information to people accessing advocacy. Safeguarding Adults Boards should ensure that they have input from advocacy providers, for example by having them as board members and giving them the opportunity to give feedback about services. Commissioners should support advocacy providers to ensure that information is available to people who may use advocacy services, for example ensuring there is enough time in contracts to develop and provide the information in accessible formats. Advocacy providers should work with commissioners and service providers to develop protocols that facilitate effective advocacy (for example, referrals, engagement and dispute resolution). Commissioners of advocacy services should work with other local commissioners and commissioning bodies, and those in other geographical areas, to: identify and address any current gaps in services develop a long-term view of what advocacy services are needed and plan how to achieve this. Practitioners should share relevant elements of individual risk assessments and safety plans with advocates to ensure their safety, and the safety of the people they support. Health and social care providers and advocacy providers should ensure that their staff understand when and how advocates can access a person's records, in line with legislation. Commissioners of IMHA services should work in partnership with commissioners of mental health services to understand and maximise the impact of IMHA provision on mental health service development. Advocacy providers and commissioners should work in partnership with other organisations to ensure culturally appropriate advocacy that meets local needs. For example, by: providing advocacy as an integral part of wider Black community and voluntary sector mental health service working closely with a south Asian community group to share insights and improve access to advocacy providing mental health advocacy as a discrete casework advocacy service managed by a Black community and voluntary sector service increasing the diversity of staff within advocacy services to reflect the local population co-locating different types of advocacy services, for example, an African and Caribbean advocacy service located in the same community centre as a mental health advocacy service. Advocacy providers should liaise with and facilitate the regulator in carrying out their role, including in inspecting regulated services. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on partnership working and relationships with families, friends and carers, commissioners and providers . Full details of the evidence and the committee's discussion are in evidence review G: partnership working and relationships with families and carers, commissioners and providers. Loading. Please wait. # Planning and commissioning services for advocacy Commission advocacy services based on an assessment of local need, building on the Joint Strategic Needs Assessment and taking into account the effects of structural, systemic and health inequalities on the population, in co-production with people who use health and social care services. Commissioning bodies in a locality should work together to agree and publish a long-term plan for advocacy based on the assessment of need. Commissioners should take into account the broad range of advocacy needs when planning and commissioning advocacy. This includes the need for statutory and non-statutory advocacy, peer advocacy and self-advocacy. Consider commissioning advocacy services that can also be used by people who do not meet the criteria for statutory advocacy but could benefit from using them (see the section on who else may benefit from advocacy). Consider taking into account wider public policies, strategy, legislation and guidance to inform advocacy commissioning decisions. Local authorities and commissioners should engage with health and social care service providers and community stakeholders to help them understand and address gaps in advocacy provision, including their duty to develop the market under the Care Act 2014. Commissioners and local authorities should involve people who use advocacy services in planning and designing advocacy services, including in monitoring contracts. For more guidance on involving people who use services, see the NICE guideline on community engagement. Commissioners must ensure that sufficient advocacy services are available to meet statutory duties for people who are detained or deprived of their liberty in independent hospitals. Commissioners should ensure that contracts support advocacy providers to maintain their independence and operate in line with advocacy principles, for example by avoiding caps on the number of hours an advocate can spend supporting someone. When drafting contracts and specifications for advocacy services, commissioners should take account of the overall resources needed, so that providers have enough time and funding for advocates to undertake continuing professional development and training. Consider the benefits of advocacy providers having an external quality accreditation, such as the Quality Performance Mark. Commissioners should ensure that service specifications, service costs and contracts with advocacy service providers specify that the service should be person centred and based on the relationship between the person and their advocate. For example, specify that advocacy services: allow the person to receive advocacy on issues that have a major impact on their health and social care needs ensure adequate and long-term support for people in situations that place them at high risk (for example, risk of exclusion or abuse). When planning and providing support, commissioners and advocacy providers should consider whether reasonable adjustments can be made to protect against or help the person deal with discrimination or inequalities arising from a person's protected characteristics as defined by the Equality Act 2010, or from other life circumstances and experiences such as health inequalities (see box 2). Protected characteristics of the Equality Act 2010 age disability gender reassignment marriage and civil partnership pregnancy and maternity race religion or belief sex sexual orientation. Examples of life circumstances and experiences that could lead to discrimination or inequalities transitioning from children's to adult care services communication impairment learning difficulties learning disability poor literacy refugee status English not being a first language being an offender homelessness being from a Gypsy, Roma or Traveller community coercive control health inequalities. Note: Some people could have multiple protected characteristics or life circumstances and experiences listed here and intersectionality may occur. Commissioners and advocacy providers should consider working with local organisations that have the skills, knowledge and networks to help promote access to advocacy for underserved groups (for example, people with refugee status and people from Gypsy, Roma and Traveller communities). When commissioning advocacy services, consider commissioning flexibility in services and a range of services so that: providers can have multidisciplinary advocates or specific ones, depending on the needs of clients services tailored to the local population are made available, for example, peer advocacy, family advocacy, group advocacy, statutory advocacy and non-statutory advocacy. Commissioners should ensure that the role of advocates in safeguarding is included in specifications when commissioning, developing policy and practice, and by promoting the value of advocacy in safeguarding people. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on planning and commissioning services for advocacy . Full details of the evidence and the committee's discussion are in: evidence review D: improving access to advocacy evidence review F: what does effective advocacy look like? evidence review H: planning and commissioning services for advocacy evidence review I: training, skills and support for advocates evidence review K: monitoring services and collecting data for quality improvement. Loading. Please wait. # Training, skills and support for advocates Commissioners and advocacy providers should work with public bodies and providers to increase investment in training for advocates so that they are trained and competent to support people from a variety of backgrounds and with a variety of needs. Advocacy providers should ensure that training, skills development and support for advocates covers the health, social care, housing, welfare and justice processes that are relevant to their role, so they can support people to navigate these services. These could include: NHS continuing healthcare and other health-funded support adult social care personal budgets, personal health budgets and integrated personal budgets personal independence payments mental health services section 117 aftercare under the Mental Health Act 1983 safeguarding procedures. Advocacy services should provide training, skills development and support including induction, to their advocacy staff. Training could include: core advocacy principles, for example those laid out in the Advocacy Charter anti-oppressive practice and culturally appropriate advocacy training communication, including specialised communication skills, for example communicating with people with a learning disability identifying abuse or neglect understanding human rights and how to promote them health inequalities making information available to people about how to make complaints, for example about health and social care services or local authorities social skills, for example being approachable and building rapport perseverance and tenacity time management managing expectations confidence to challenge decisions consistency maintaining General Data Protection Regulation (GDPR) compliance, report writing and record keeping understanding structural inequalities and intersectionality equity, diversity and inclusion. Advocates should complete the National Qualification in Independent Advocacy. Advocacy organisations should ensure arrangements are in place for the regular support and supervision of all advocates. Training for advocacy staff should include when and how to use non-instructed advocacy. Consider giving advocates who deliver non-instructed advocacy increased access to support, supervision and reflective practice to ensure their advocacy remains person led, independent and outcome focused. Advocacy services should ensure any volunteer advocates are trained and given adequate support and supervision. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on training, skills and support for advocates . Full details of the evidence and the committee's discussion are in: evidence review I: training, skills and support for advocates evidence review J: training and skills for practitioners who work with advocates evidence review K: monitoring services and collecting data for quality improvement. Loading. Please wait. # Training and skills for health and social care practitioners who work with advocates Providers and commissioners should ensure that information about advocacy is included in training for all health and social care practitioners at induction, with refresher training every 2 to 3 years or as needed, so that they understand: what advocacy is who is entitled to advocacy support under current legislation what advocacy support services are available locally in addition to those required by law when and how to request advocacy how to facilitate advocacy the role of the advocate in different settings and situations. Providers and commissioners should ensure that staff who may be the first point of contact for people using health and social care services that regularly work with advocacy services (for example receptionists) understand: who is entitled to advocacy support under current legislation what additional advocacy is available locally when and how to request advocacy. Providers and commissioners should ensure that staff in organisations working with advocacy services (including social workers, members of Safeguarding Adults Board members and commissioners of advocacy) have training in the role and function of advocates. This includes understanding that advocates: help people to get the support they need from services, for example by offering to attend meetings, writing letters and emails, and making phone calls support the person to make decisions, for example by providing information about available support services, making sure people understand their options and exploring the potential outcomes of the possible options represent only the views of the person they are supporting ensure the person's voice is heard and their rights are respected in all discussions aim to empower the person to develop personal agency, self-advocacy and confidence are independent of any provider service share information they receive with the person they are supporting challenge decisions and poor practice know what to do about safeguarding have a role in protecting a person's rights and promoting wellbeing are involved in non-instructed advocacy and know what this is. Providers of training on advocacy should: tailor training to practitioners' roles and responsibilities include people with lived experience of using advocacy services when designing and delivering training be able to deliver training in different formats, including face-to-face, digitally (for example, as e‑modules) and self-paced. Health and social care providers should check that practitioners are using the knowledge and understanding of advocacy obtained through training, in their day-to-day practice, for example through supervision and reflective practice. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on training and skills for health and social care practitioners who work with advocates . Full details of the evidence and the committee's discussion are in: evidence review D: improving access to advocacy evidence review F: what does effective advocacy look like? evidence review J: training and skills for practitioners who work with advocates. Loading. Please wait. # Monitoring services and collecting data for quality improvement ## Agreeing outcomes Advocacy service providers, commissioners, people who use advocacy services and other stakeholders should work together to agree: what service-level outcomes should be achieved (for example, making sure people's voices are heard, improving people's experience of safeguarding, empowerment and reducing health inequalities) how these outcomes will be reported (for example, information on outcomes could be separated out based on protected characteristics or other disadvantaged groups, such as those experiencing health inequalities). Advocacy service providers and commissioners should work together to agree how they will record their progress against the service-level outcomes. When monitoring advocacy services, advocacy providers and commissioners should measure outcomes that show the impact of advocacy on: people using an advocate (for example, to what extent they feel, or are, protected from harm, and the effects on their voice being heard, personal control and independence, their opportunities, challenging injustice and having their rights upheld) the health and care system (for example, the effects on the quality-of-service response and experience of people using it, person-led decision making and health inequalities) communities (for example, the effects on social inclusion; access to community services; and opportunities for people to contribute positively to society and get involved in their local community and engage with local forums, such as partnership boards and Safeguarding Adults Boards) the way advocacy services are run (for example, the effects on access to advocacy, governance and best practice; co‑production; and how advocacy is delivered). ## What data to collect Commissioners should ensure that measuring outcomes or monitoring activity does not compromise the independence or integrity of the advocacy provider, or individual privacy. Advocacy providers, in partnership with commissioners, should record anonymised information on people who use advocacy services, including: protected characteristics in the Equality Act 2010 the main subject of advocacy support identified health inequalities communication need and preferences reasons for referral type of location or residence (such as urban, rural, care home or independent accommodation) whether the advocacy provided is instructed or non-instructed. Advocacy providers should collect information about the impact of their services. Types of information include: survey data (such as satisfaction with the service provided) examples or short case studies describing how outcomes have changed as a result of advocacy the number of people reporting a particular outcome or the proportion of people who achieved a particular outcome detailed feedback on the experiences and views of people using advocacy services. Local authorities and commissioners should monitor: whether health and social care providers are telling people about advocacy and the criteria for accessing it and take steps where there are gaps in this access to advocacy and take up of it by different populations in the local community. Commissioners should check that advocacy providers have a robust method of quality assurance that monitors and reports on their quality of service. ## How to collect data Advocacy providers, in partnership with commissioners, should develop shared, consistent, practical and robust methods to record and collect information and data. Advocacy providers, in partnership with commissioners, should tailor the formats and methods of seeking feedback about advocacy support to the person's communication needs and preferences. Advocacy providers should find ways of gathering feedback that maximise the person's ability to provide that feedback anonymously and without the input of the advocacy provider. ## Evaluating and sharing data Commissioners should use the outcomes, data and information on user demographics and the impact of advocacy services to evaluate the effectiveness and quality of current advocacy services and to plan future services. Commissioners, advocacy providers and health and social care providers should work together to evaluate data they have collected on advocacy services. They should use this to make any changes that are needed to health, social care or advocacy services so that they meet the needs of all communities within the local population, including under-represented groups, those with protected characteristics or those experiencing health or other inequalities. Commissioners and advocacy providers should share insights and key information on common trends and themes from data they have collected on advocacy services and issues affecting people using advocacy services with relevant stakeholders. For example, health and social care providers, voluntary and community sector organisations, the Care Quality Commission, Safeguarding Adults Boards, integrated care partnerships and boards and local Healthwatch. ## Monitoring advocacy in safeguarding Local authorities and commissioners should monitor how advocates are involved in supporting people experiencing safeguarding concerns. Safeguarding Adults Boards should be assured that local authorities have auditing processes in place to monitor how people and their advocates are included in safeguarding processes. Advocacy providers should report to Safeguarding Adults Boards on the extent to which partner organisations fulfil statutory duties for advocacy and safeguarding. ## Adhering to statutory duties Commissioners and health and social care providers should ensure that they: consistently adhere to and monitor the statutory duties to refer to and involve advocacy address failures in the duty to refer to statutory advocacy. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on monitoring services and collecting data for quality improvement . Full details of the evidence and the committee's discussion are in: evidence review F: what does effective advocacy look like? evidence review G: partnership working and relationships with families and carers, commissioners and providers evidence review K: monitoring services and collecting data for quality improvement. Loading. Please wait.# Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster. # Anti-oppressive practice The phrase describes a critical examination of the impact of power, inequality and oppression on people. This could include examining an organisational structure while taking into account the wider social, cultural and political context. Anti-oppressive practice seeks to lessen the exclusion of certain social groups from social equality, rights and social justice. Anti-oppressive practice may include: recognising the barriers that people might face, such as personal, cultural or structural barriers recognising a person's place in a structure or culture and how this might affect other people working to understand people's experience of oppression recognising people's attributes and contribution empowering people to realise their rights. # Cultural competence Cultural competence is the ability to understand and respond to a person's particular religious, cultural or language needs and experiences. # Digital platforms This describes digital spaces where communication can occur, or information can be exchanged, securely. This could include some social media. # Health inequalities Systematic, unfair and avoidable differences in health across the population and between different groups within society. They arise because of the conditions in which we are born, grow, live, work and age. These conditions influence our opportunities for good mental and physical health. # Intersectionality The interconnection of social categorisations such as age, disability, gender reassignment, pregnancy and maternity, marriage or civil partnership, race, religion or belief, sex and sexual orientation and other characteristics or experiences listed in box 2, creating unique overlapping and interdependent systems of discrimination or disadvantage. # Non-instructed advocacy When a person cannot communicate their views or wishes in a way that can be understood by other people, then advocates may use recognised approaches to ensure that what may matter most to the person is represented. Advocates will need to take additional steps to determine as far as possible what the person's likely wishes, feelings and desired outcomes are likely to be, to best represent the person. The advocate's role in non-instructed advocacy may include: upholding the person's rights; making sure that their likely concerns are recognised and responded to; ensuring access to support; and encouraging decisions to be taken based on what is important for the person, and challenging any that appear not to be. A person's ability to communicate what is important to them might fluctuate and advocates may move between using non-instructed advocacy and using instructed advocacy. # Opt-out Opt-out is when a person is automatically referred to the advocacy service unless they opt out of the referral. The opt-out system is designed to ensure that people who are eligible for advocacy are made aware of independent mental health advocacy services and have the opportunity to access them. An opt-out measure may overcome barriers to access. # Peer advocacy Peer advocates have lived experience and can support others with a similar disability or experience. # Reflective practice A process for staff to: reflect on previous practice talk about why they made the decisions they made, and why they acted or behaved in particular ways talk about their emotional responses to their actions and the actions of others engage in continuous learning. Reflective practice may also provide insight into personal values and beliefs, and help staff understand how these influence action and decision making. # Self-advocacy The action of representing oneself or one's views or interests. This may be with respect to the care and support that people receive or the way that services are organised locally. # Structural inequalities The phrase refers to the inequalities that are systemically rooted in the normal operations of social institutions, in which different categories of people may not be seen as having equal status. This can result in the marginalisation of, or discrimination against, certain categories of people and manifest itself in areas such as unequal access to healthcare, housing or education. # Wellbeing The Care Act 2014 defines 'wellbeing' as a broad concept, relating to the following areas in particular: personal dignity (including treatment of the individual with respect) physical and mental health and emotional wellbeing protection from abuse and neglect control by the individual over day-to-day life (including over care and support provided and the way it is provided) participation in work, education, training or recreation social and economic wellbeing domestic, family and personal suitability of living accommodation the individual's contribution to society.# Recommendations for research The guideline committee has made the following recommendation for research. # Ways of providing advocacy services What is the effectiveness and acceptability of providing advocacy through different approaches? For a short explanation of why the committee made this recommendation for research, see the rationale section on monitoring services and collecting data for quality improvement . Full details of the evidence and the committee's discussion are in evidence review K: monitoring services and collecting data for quality improvement. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect services. # Legal right to advocacy Recommendations 1.1.1 and 1.1.2 ## Why the committee made the recommendations For more information about how these recommendations were developed, see the section on developing the recommendations. The committee agreed that the legislation covering statutory entitlement to advocacy is complex and can be difficult to understand. Referring to guidance in legislation would make it easier for advocacy providers, health and social care practitioners and other referrers to find the information they need and help them to understand when they are legally required to offer advocacy. ## How the recommendations might affect practice The recommendations bring together statutory guidance. Any change in practice would be a result of becoming compliant with current legal requirements. Return to recommendations # Who else may benefit from advocacy Recommendation 1.2.1 ## Why the committee made the recommendation For more information about how this recommendation was developed, see the section on developing the recommendations. The committee noted that advocacy was often mentioned in NICE guidance. In their experience, the reasons that a person may benefit from advocacy are related to their circumstances or situation rather than their personal characteristics. Therefore, the committee focused on defining these circumstances. ## How the recommendation might affect practice or services The provision of non-statutory advocacy services varies widely across areas and service providers. Many areas have little or no provision beyond what is legally required. Therefore, investment is needed to expand the scope and range of services. Although there was no economic evidence included in the evidence review for this topic, several published NICE guidelines recommended the use of non-statutory advocacy as it was considered both effective and cost effective in the populations they covered, because it reduced or prevented the need for medical or other interventions. The populations considered in those guidelines had a substantial overlap with the population covered here, so the results are likely to be generalisable to this guideline. If people who would benefit from non-statutory advocacy do not receive it, their needs often eventually escalate to a point at which they meet the threshold for statutory provision. So, providing non-statutory advocacy often does not represent new costs, but rather costs incurred sooner. Given the lower level of need for this group, the time needed for advocacy is likely to be substantially lower than for statutory advocacy. It is likely to reduce unplanned hospital admissions and the need for residential care. This should also lead to a higher quality of life by addressing needs earlier and preventing escalation. This reduction in time needed should also free up capacity in the statutory advocacy system, although this may take a few years. This will reduce or remove the need for longer-term investment in services, especially in employing new advocates. Return to recommendation # Information about effective advocacy and signposting to services Recommendations 1.3.1 to 1.3.6 ## Why the committee made the recommendations For more information about how these recommendations were developed, see the section on developing the recommendations. Local authorities have a legal duty to make information available about the care and support services in their area, but the committee were aware that this does not always happen. In the committee's experience, advocacy services are not widely known about and people are often unaware of their entitlement to advocacy. So, they do not access services. The committee agreed that providing this information should help to ensure that those with a legal entitlement to advocacy know about these services and can access them. They also agreed that awareness of non-statutory advocacy services is particularly low. So, giving information to people who are not legally entitled to advocacy, but could benefit from it, is equally important. In their experience, if a publicly funded service is provided, there is also a duty to give people information to help them access it. The committee agreed that providing information about non-statutory advocacy would increase knowledge and uptake. The Accessible Information Standard requires information to be given in accessible formats. The committee's experience is that this often does not happen for information about advocacy services. So, there is a risk of inequalities in access to both statutory and non-statutory advocacy. For example, people with communication difficulties might be less able to access services. In the committee's experience, some people who initially decline an advocate later change their minds. Repeating information at different times means that the person has the knowledge and opportunity to use an advocate when they want to. In the committee's experience, there is often confusion about who should provide information about advocacy services if someone is offered an out-of-area placement. They agreed that this responsibility needs to be clear. ## How the recommendations might affect practice or services There is a legal requirement for all advocacy services to provide information and signposting. But there are inconsistencies in how well this is met in different areas. There may be some change in practice for those not fully compliant with statutory requirements. For example, information is not always given in a range of formats, so there will be a cost for areas not currently adhering to this requirement. Providing information and signposting to people using out-of-area services will be a change in practice, because there is currently variation and confusion about who should do this. But implementing this recommendation is not expected to need extra resources. Providing information about non-statutory advocacy services is currently not a legal requirement. But it will not need any additional resource use because it can be included on existing information sources, such as printed leaflets or online. There may be an increase in resource use from more people using non-statutory advocacy services. Return to recommendations # Improving access to advocacy Recommendations 1.4.1 to 1.4.12 ## Why the committee made the recommendations For more information about how these recommendations were developed, see the section on developing the recommendations. In the committee's experience, meeting in person was routine practice before the COVID‑19 pandemic. But to reduce costs, many services have continued with remote meetings after restrictions have lifted. The committee discussed the benefits of advocates meeting with people in person to help them start using advocacy services. These include being able to see each other's body language, which is an important way of getting to know and understand each other, and it can speed up the process of developing trust. This is particularly important when people are accessing advocacy services for the first time. Furthermore, advocates physically being in the same space with the person can help them to raise issues that are usually unspoken or non-verbalised, for example safeguarding issues. They agreed that in-person meetings for the first contact would improve access for people who would otherwise be unwilling to use advocacy services. But they also noted that although in-person meetings were optimal, there are situations for which remote meetings using digital platforms could still be effective and some people may prefer them. The committee were aware that advocates experienced difficulties accessing certain settings due to blanket restrictions. These increased during the COVID‑19 pandemic (for example, limits on hospital and care home visiting). The committee agreed that access to an advocate was an essential part of upholding people's rights. Having legal representation does not fulfil, or negate, the legal entitlement to advocacy. But in the committee's experience, there are often misconceptions that people do not need an independent mental health advocate if they have legal representation. From their knowledge and experience, the committee were aware of difficulties with referrals, which are often sent back when the right information is not included. This delays access to services and may reduce service engagement. Based on the evidence and their experience, the committee agreed that making access easier may help hard-to-reach groups and improve empowerment and self-advocacy. The evidence indicated that there can be problems with continuity and access when people transition between different types of advocacy. Effective advocacy depends on developing trust and mutual understanding between the advocate and the person receiving support, so keeping the same advocate (for example, by having multi-skilled advocates) is important. But when this is not possible, ensuring that systems are in place for handover will make it less likely that people are lost to services. Healthcare practitioners should refer people for non-instructed advocacy if they need it, but in the committee's experience, this does not routinely happen. If independent mental health advocates are regularly present in inpatient settings, people are less likely to miss out on their statutory right to advocacy. The committee agreed that this could also have an important safeguarding effect, because it will give the advocates a comprehensive view of people's circumstances and environment. The expert testimony highlighted barriers to access, such as lack of awareness or understanding and negative attitudes, and stated that an opt-out system for independent mental health advocacy (IMHA) could help to overcome these barriers. Based on their experience, the committee agreed that referrals are not always made when they should be and that offering advocacy on an opt-out basis is an effective way of ensuring access to statutory advocacy. In the committee's experience, late referrals to IMHA services do not give people enough time to arrange advocacy support or meet their advocates before key meetings or events. This means that they cannot participate fully and effectively in decision making. Ensuring that people are offered IMHA early will help to avoid this. The committee agreed that repeating the offer of an advocate would give people more opportunities to take up advocacy support if they need it, especially if they had declined the original offer. For example, people who were too unwell when advocacy was first offered or people whose circumstances changed. Based on their own experience and evidence from the expert testimony, the committee agreed that raising awareness of service user groups and supporting peer and self-advocacy is important, because some people may prefer to seek advocacy from a peer rather than from a professional. People may feel better understood by, or more trusting of, people who have had similar experiences. Self-advocacy can also help the person to develop skills such as communication or decision making. This is in line with the advocacy ethos of supporting independence. In the committee's experience, people with the greatest need for advocacy services may not be able to ask for them, and so they do not get the support they are entitled to. Based on the evidence, the committee agreed it was therefore important for advocacy organisations to have a plan to proactively offer support to people who may want to use the service. Based on the evidence and the committee's experience, it is often unclear who is responsible for providing advocacy services when someone is supported out of their home area. This can form a barrier to accessing services and cause delays, potentially leading to ineffective advocacy. Under the Care Act 2014, local authorities have a duty to make information available about the care and support services in their area. This includes advocacy services. The committee agreed that, as part of this, it would be sensible to provide information about access to advocacy for people supported out of their home area. This would need collaboration with advocacy providers. In the committee's experience, people who are unable to ask for an advocate often are not offered advocacy services, despite being entitled to them. They agreed that it was the responsibility of healthcare and social care practitioners to ensure that advocacy is provided for everyone who needs it, even if they are not able to ask. ## How the recommendations might affect practice or services During the COVID‑19 pandemic, most meetings with advocates were by phone or videoconference. Increasing the number of in-person meetings, especially initial meetings, is likely to increase the average time of a meeting. It will also increase the need for advocate travel to levels at or near to those before the pandemic. In‑person meetings may also increase the uptake of advocacy, again increasing costs. But there would be likely cost savings in the long term because greater uptake, and improvement in the quality of interactions, would result in identifying problems earlier. This would avoid costly medical interventions, such as unplanned admissions to hospital, and prevent duplicate or inappropriate referrals. Remote meetings are likely to be less expensive, but if the added convenience increases uptake those cost savings will be reduced. The removal of blanket restrictions should not increase resource use, apart from the effect of in-person meetings restarting. Most new places that advocates would visit would not need substantially more travel or time than existing venues. Although extra time may be needed for visiting prisons, to clear security protocols, this will only be relevant to a small percentage of visits. Providing a simple process to access advocacy services will need some resources. But this is likely to mean shifting existing resources to fewer access points, rather than providing new ones. Cost savings should also occur from the economies of scale of having fewer access points, and a reduction in repeated or inappropriate referrals. Regular visits to inpatient settings by independent mental health advocates will be a change in practice in most places. The committee agreed that providing continuity of access could have some upfront costs to employ multi-skilled advocates where these are not currently used, but this should be offset in part through more effective use of resources. There is likely to be an increase in resource use from IMHA services making regular visits to hospital wards, both from the visits and from an increase in people using the service. Healthcare practitioners should already be making referrals for non-instructed advocacy, but in many places, this does not happen. Although it is likely to increase costs, savings are also likely to be made through improved safeguarding practices and through advocates obtaining a better understanding of peoples' needs. This should allow for better management of needs, improving quality of life and preventing costly unplanned hospitalisations. Providing an IMHA to people who are eligible for one is a legal requirement. But making access to IMHA opt-out rather than opt-in will mean that more people are aware of their right to access independent mental health advocates, and barriers to access (whether from process, lack of understanding or negative attitudes) will be substantially reduced. This is likely to increase access to those most in need of IMHA services, who may have had difficulty opting in, and to increase the number of meetings between advocates and people using their service. Although there is likely to be a significant resource impact in the short term, it will lead to improved access to advocacy services, and the benefits of these could offset costs in the longer term. Return to recommendations # Enabling and supporting effective advocacy Recommendations 1.5.1 to 1.5.16 ## Why the committee made the recommendations For more information about how these recommendations were developed, see the section on developing the recommendations. The committee noted that the Care Act 2014 sets out who is legally entitled to have an advocate but that there is variation in how quickly this is currently determined. In the committee's experience, referrals to advocacy services are often made too late. This can mean the service does not have time to tailor meetings to the person's needs, for example communication needs. The committee also agreed that timely appointments mean the advocate can help the person prepare for meetings. They noted that delays to this would have a detrimental effect on the outcomes because advocacy helps people to take part effectively in decision making. From their knowledge and experience, the committee were aware that the inconsistency is partly because it is difficult to specify how much time is needed. This depends on the person's individual circumstances and needs, for example if they need an interpreter. Many people who use an advocate have a statutory right to be represented at meetings. This is also crucial for non-statutory advocacy, so that people have their voices heard when decisions are being made. But in the committee's experience, the availability of the advocate is often not taken into account when arranging meetings. This may be because of other urgent commitments, competing demands and service pressures. The committee noted that checking advocate availability will make planning more efficient by reducing the need to reschedule meetings. From their knowledge and experience, the committee were aware that delays in appointing advocates or not checking the availability of the advocate also put the person under time pressure. Lack of preparation time has a negative impact on the outcomes of meetings. So, the committee agreed it was important to give people the chance to rearrange meetings if they think that the time with their advocate was insufficient. The committee agreed that building relationships and trust is a fundamental aspect of advocacy services. In their experience, effective advocacy is only possible when advocates have adequate time to build this relationship, so people feel comfortable sharing personal information and what is important to them. The committee were aware that the time it can take to build a trusting relationship could vary greatly based on individual needs, communication styles and personalities. Their experience was that this is often not factored in sufficiently when advocacy services are arranged. The committee agreed on the importance of privacy and ensuring that people can talk to their advocate in private spaces, without being overheard. This promotes a trusting relationship and allows people to talk frankly about their goals, wishes and needs. The committee discussed involving advocates in all discussions with the person. This promotes continuity of care, allowing the person using advocacy services to feel supported throughout the process. In the committee's experience, advocates are often only used during the decision-making process and less so after decisions have been made. But they noted that the discussions in meetings may sometimes be hard for the person to take in. This means that they may misinterpret what they have agreed to. The committee therefore decided that an advocate should be involved in all discussions (before and after meetings) to ensure that the person has understood fully what decisions have been made and the impact they may have, so that they have opportunities to challenge decisions and to raise any concerns. The committee agreed that health and social care practitioners need to work collaboratively with advocacy services. This could facilitate decision making with the person in many ways. In the committee's experience, health and social care practitioners are often busy and sometimes assume that once they have made a referral, that their job is completed. But their ongoing support is necessary to enable effective advocacy to take place. Based on their experience, the committee provided examples of how to facilitate advocacy effectively. They agreed that it is important to encourage practitioners and advocates to build good relationships from the start so that they can work together effectively and in the best interests of the person. The committee agreed that for advocacy services to be effective, advocates need to be able to meet the person and resources need to be used efficiently. They also noted that virtual meetings have become common and that people may need support with the software to access such meetings. From their knowledge and experience, they were aware that more practical support is needed to help people communicate remotely with their advocate or help them access virtual meetings that may otherwise not go ahead or be postponed. The committee discussed that this could include access to the internet, support to use technology, and help when scheduling meetings. The committee were aware of a person's need for privacy while communicating remotely with their advocates. The committee discussed that digital platforms could help advocacy services to engage with people and therefore ensure they are regularly contacted, get timely updates and are informed and empowered. The committee agreed on the vital role of advocates in supporting a person to have their voice heard. This includes ensuring that concerns raised by the person (or on their behalf) are not only listened to but are also interpreted in the way they are intended, are acted on and are noted in records. This can then be referred to in any future meetings and followed up for a response if necessary. In the committee's experience, there is wide variation in referrals for statutory advocacy, and non-compliance with legal duties is common. They highlighted the need to audit and monitor advocacy services to identify gaps in service delivery. The committee recognised that if health and social care practitioners developed action plans, this would help to improve compliance, by having clear steps that need to be taken to bring advocacy services up to the standard required by the legislation. The committee also agreed that including the numbers of referrals in corporate performance information would help to highlight discrepancies between the amount of advocacy commissioned and the number of people supported. The committee noted that advocacy services commonly deal with vulnerable people who may experience discrimination or abuse. If an advocate has reasonable cause to suspect a person has experienced, is experiencing or is at risk of abuse or neglect, they must follow local safeguarding policies as set out in the Care Act (2014). But in the committee's experience, there is variation in advocates' knowledge of the actions required in these situations. Not acting in accordance with statutory safeguarding processes could have serious consequences. The committee agreed that in their experience, the quality of safeguarding from advocacy providers varies and guidance is needed to ensure that safeguarding is effective, consistent and in line with legislation. They agreed that robust internal guidance would ensure providers consistently work to the required standard. Having effective governance, leadership, lines of communication and responsibilities also ensures that these processes are followed. The committee were aware that a safeguarding lead is already part of many local safeguarding policies but emphasised the need for this role to maintain good practice. The committee agreed on other examples that would ensure that staff know the relevant actions to take, so that they can prove that concerns have been raised and that actions have been taken. The committee also noted that safeguarding situations and related legislation are complex, and that training and supervision can help advocates feel confident in what to do if issues arise. The committee noted that guidance on communicating and discussing complex information is covered by the NICE guidelines on people's experience in adult social care services, patient experience in adult NHS services and service user experience in adult mental health. ## How the recommendations might affect practice or services There is variation in how effectively advocacy is enabled and supported in different areas, so the impact on practice will vary. More advocacy hours will be needed to allow time and availability to help a person prepare before any meeting and ensure adequate arrangements are made, such as providing an interpreter if needed. Services may need to employ additional advocates. It may be possible to reallocate staff from other roles as services are streamlined and fewer meetings are repeated or decisions challenged. Ensuring that service providers consider the availability of the advocate when planning and scheduling meetings is expected to lead to more productive meetings with less revisiting of decisions. This could lead to cost savings or free up resources. Involving advocates until decisions have been communicated will need a reorganisation of resources but is not expected to lead to additional cost or need for advocacy hours. There might also be some resources associated with rearranging meetings. But this might mean that meeting time is used more effectively, resulting in fewer decisions being challenged and resources being used more efficiently. The type of information that gets audited may change, but this is not expected to need additional time or costs and will make data collection compliant with statutory requirements. The guideline will reinforce best practice for health and social care workers facilitating advocacy and ensuring that advocates know how and when to act on safeguarding concerns. Digital platforms are already in almost universal use since COVID‑19. It is unlikely that further changes would be needed to this part of the service. Return to recommendations # Effective advocacy Recommendations 1.6.1 to 1.6.15 ## Why the committee made the recommendations For more information about how these recommendations were developed, see the section on developing the recommendations. The committee agreed that people were more likely to access advocacy if organisations provided accessible services. Based on their knowledge and experience, they agreed on ways that advocacy providers could make their services more accessible, for example by making efforts to reach underserved communities. The committee agreed that access needs are not just physical but also involve the environment and location and the person's sensory needs. They also drew on their knowledge of the Advocacy Charter and Quality Performance Mark (QPM), to agree on ways to improve accessibility and tailor advocacy to the person's individual needs, for example physical or communication needs. This will enable the person to be fully involved in processes and meetings at which decisions are made. The committee noted that providing person-centred services that adapt to each person's needs and circumstances is essential to effective advocacy. The committee agreed on specific suggestions for ensuring this, based on the advocacy QPM and their knowledge and experience. These included taking account of the person's views, values, culture and other experiences. The committee agreed that this individualised approach is vital to ensure that the person is comfortable and to help establish trust. The committee acknowledged that although it is an important part of making people comfortable and building relationships, offering people a choice of advocate might be difficult for some organisations, particularly smaller ones. Based on their experience, the committee agreed that the person-centred approach would have benefits beyond the effectiveness of the service. It would it also show other professionals and people using services what effective advocacy looks like, and what to expect from the service. The committee agreed that a fundamental element of advocacy support is a shared understanding about what the person's optimal result would be. This allows the success of the advocacy to be assessed. But the committee were aware of variation in practice and the need to standardise good practice. They discussed the importance of advocates continually discussing and assessing goals and desired outcomes with the person, and agreed that everyone involved with advocacy needs to work together. They discussed that goals are recorded in initial meetings, but it is also important to discuss them each time and record any changes. Based on their experience, the committee acknowledged the challenges of such ongoing discussions if people lack capacity. But they agreed it is vital to make all possible efforts to establish the person's wishes and preferred outcomes. To ensure that the service is in the person's best interests, the committee agreed that it is important to involve other people who have an understanding of what the person would want (for example, family members or carers). The committee discussed the benefits of actively involving people with lived experience of health inequalities or using health and social care or advocacy in designing and developing advocacy services. Having had the experience of using services could give them an understanding of what works and what the person needs from an advocate. This can ensure that services are more relevant and that they address needs sensitively and comprehensively. The committee agreed on the need to encourage services to get people with lived experience involved or to help them become advocates themselves. The committee agreed it is essential to promote equality, equity of access, social inclusion and justice, and culturally relevant advocacy for all. Despite this being a legal requirement covered by the Equality Act 2010, the committee were aware of variations in service provision. Based on knowledge of the Care Act 2014, the committee discussed the importance of providers supporting advocates to identify and raise safeguarding concerns. They stated that not carrying out advocacy effectively and in line with safeguarding policies would potentially expose the person to discrimination, abuse or neglect, but the role of advocacy in safeguarding is often not well understood. Based on the committee's expertise and experience of safeguarding, they agreed on suggested ways in which providers can achieve effective advocacy that meets their legal safeguarding duties. Despite the Care Act 2014 specifying that local authorities must appoint an independent advocate to support someone through a Safeguarding Adults Review, the committee were aware this does not always happen. The committee discussed that people value continuity and consistency in their advocacy services. Effective advocacy depends on developing trust and a mutual understanding of the issues that are important to the person. The committee agreed that this takes time to develop. So, to help this, the committee decided that the advocate ought to remain constant for as long as the person needs advocacy (unless the person using the advocate wishes to change). The committee agreed on the importance of people being confident that their advocate is independent, so they know they have their advocate's full support and that there are no conflicts of interest. So, they agreed on the need for clear protocols to ensure the independence of advocacy. They agreed specific examples of ways in which advocacy services can demonstrate their independence from other services. Advocates with mixed skillsets, such as experience in different types of advocacy, are valuable when supporting a diverse range of clients. Some people may have needs in many areas and need support in multiple issues. Having a single advocate able to provide several types of advocacy can be more effective and promote continuity of care. This could help with consistency and improving the overall quality of their advocacy. The committee conceded that sometimes specialist advocates are needed for more specific support (for example, a specialist in supporting people who lack capacity). The committee also acknowledged that it may not always be possible for all advocacy providers to provide advocates with mixed skillsets. Advocacy services need to address inequalities in access to services and in service provision. This includes issues such as language (for example, use of interpreters) as well as consideration of any specific groups that may be disadvantaged or experience inequalities, such as taking into account a person's cultural needs and preferences. Effective and accessible communication and language is essential for an advocate to gain an in-depth understanding of a person's wishes and preferences. Interpreters are important if the advocate does not share the person's same first language. A lack of interpreting and translation services often poses as a barrier when using advocacy services. The committee also noted expert testimony on the importance of culturally appropriate advocacy, which extends beyond language. They discussed that culturally appropriate advocacy is critical to achieve equity and social justice, and to reach people who are already disadvantaged and underserved by services. But there is a lack of provision for people from minority cultural backgrounds. Advocates should already be knowledgeable about existing health inequalities and would use this knowledge to influence and improve their work. The testimony highlighted that if people perceive that services are culturally relevant, in terms of their own ethnic identity, this can create a sense of shared understanding and encourage access to that service. The possible gain from providing culturally sensitive advocacy therefore should be larger than for standard advocacy. The committee were aware from their knowledge and experience that many of a person's wishes, needs and preferences will be influenced by their cultural or ethnic identity. Advocates need to be sensitive to this, and this is integral to good practice. The committee agreed this could be facilitated by supporting staff to develop cultural competence through training, supervision and reflective practice so that they are confident in speaking to people about preferences related to culture. Based on the committee's knowledge of the UK General Data Protection Regulation of the Data Protection Act 2018 as well as legal requirements related to safeguarding, they highlighted the importance of confidentiality and privacy in person-centred advocacy. These are requirements of advocacy and fundamental to building trusting relationships. From their knowledge and experience, the committee were aware that in practice, there are some complications, particularly with confidentiality. For example, an advocate must breach a person's confidence if there are safeguarding concerns or if it appears a law has been broken. The committee agreed the key was for advocates to be open about this, maintaining confidentiality and assuring people but also explaining the circumstances or conditions under which they may need to breach confidentiality in line with legal requirements. In the committee's experience, important aspects of professional relationships are sharing learning, insights and tools; and developing joint publications, guidance and resources. They agreed this improves collective effectiveness in the advocacy sector and helps to improve standards, provide consistency and sustain a drive towards best practice. It also encourages innovation and helps services develop new tools and techniques. Based on their experience, the committee agreed that smaller providers may have less capacity for this work, and competition for funding could act as a disincentive to share best practice. But they agreed it was still important to promote this joint learning and sharing. ## How the recommendations might affect practice or services The largest change in practice is likely to be in translation services and culturally appropriate advocacy. There may need to be investment in translation services, co‑location of services and culturally appropriate advocacy. This will increase access for people who have been less likely to access advocacy or had poorer service because of communication difficulties or lack of sensitivity to cultural needs. This will reduce inequality and unfairness in accessing advocacy services and will increase their overall uptake. Producing best practice and shared learning materials may have a resource impact in terms of the time needed to develop, quality assure and promote such tools. This may also need time from advocates to share their experiences and knowledge with others in writing or in other ways. This may be particularly difficult for smaller providers who may not have the advocate levels or facilities to produce such tools. But sharing best practice and promoting joint learning would lead to better advocacy with less repetition, challenges to decisions or need to repeat meetings. Such tools could also be used to promote cost-effective or cost-saving practices, leading to more efficient use of limited resources. Providing a greater range of venues for in-person meetings may mean that advocates need to travel further and may increase hosting costs. Using digital platforms for remote meetings has become common practice since COVID‑19. Organisations may need to build extra capacity in services so that advocates have flexibility to work with different people according to a person's choice of advocate. The recommendations will lead to changes in the number and range of people involved in designing advocacy services, and to changes in the information given to people about availability of and access to services. The way that goals are recorded and updated will also be a change in practice in some areas. All of these can be achieved by reallocating existing resources and are not expected to need additional investment. Having the same advocate throughout the process will need multi-skilled advocates to be available at the start of a person's contact with advocacy. This may mean moving or employing multi-skilled workers, resulting in upfront costs. There may be less need for multi-skilled advocates later in the process if duplication of meetings and the need for handovers are reduced. Return to recommendations # Partnership working and relationships with families, friends and carers, commissioners and providers Recommendations 1.7.1 to 1.7.11 ## Why the committee made the recommendations For more information about how these recommendations were developed, see the section on developing the recommendations. In the committee's experience, families, friends and carers commonly report that advocacy services do not work collaboratively with them. Such cooperation could be beneficial to the person and their care when the person wants them to or when the person cannot express a view about this but it is in their best interests, for example to gain an understanding of the persons' views, preferences, and desired outcomes. This is particularly important when people may not be able to communicate this effectively themselves, for example people with learning disabilities and communication challenges or when people lack capacity. The committee discussed the importance of advocates being aware of support services that are available in their area. This will ensure they can provide people with information about other local support that may be available to them. The committee agreed that advocates are not always up to date with this information. They highlighted that it would usually be on council websites because the Care Act 2014 requires local authorities to make information about care and support services, including advocacy services, publicly available. In the committee's experience, advocates could help raise awareness of issues, such as problems with referrals and difficulties people may have in accessing services, and the extent of such issues. They noted that Safeguarding Adults Boards might be unaware of all issues on the front line of services, and that raising awareness could improve services and safeguarding. Safeguarding Adults Boards engaging with advocacy providers could also raise the profile of advocacy, lead to less variation and support effective advocacy. The committee acknowledged that people in need of advocacy services would not always know how to go about finding such services. They agreed on the need for commissioners to support advocacy providers giving this information. This could include allowing time in contracts for advocates to give information about which services are available, and how, where and when to access them, as well as for delivering advocacy. From their knowledge and experience, the committee were aware that sometimes there can be tension between advocacy providers, commissioners and service providers when balancing the need to advocate for a person with providing safe and effective services. They discussed that procedures or protocols could provide clarity, including for service referrals and dispute resolution. They particularly noted the need for jointly developed protocols to facilitate positive and consistent working relationships between services. The committee were aware that this is consistent with the advocacy QPM, which also highlights the need for protocols for promoting services. The committee discussed the benefits of commissioners collaborating with other commissioners and commissioning bodies, locally and in other areas. In their experience, working together is important for effective commissioning. It also encourages a long-term view that considers the future commissioning and provision of services. Working together could improve the consistency and quality of advocacy services across different areas, and reduce the likelihood of gaps between geographical areas or between different parts of the health and social care system. This would also help address geographical inequalities in access to services. The committee agreed that advocates need to be protected if there is risk, because there is the potential for ineffective advocacy if the advocate or the person they support does not feel safe. But in their experience, risks are not always clearly communicated and shared between advocacy services and care providers. In the committee's experience, advocates do not always know whether they are allowed to access a person's notes and what the legislation is in relation to information sharing. Health and social care providers may not routinely share information, so there is inconsistency in what is made available. The committee noted that the legislation on sharing information, such as the Data Protection Act 2018 is complex, and agreed on the need for health, social care and advocacy providers to ensure that their staff understand when and how advocates may access a person's records in line with legislation. The committee discussed that commissioners of IMHA services and mental health services working in partnership would help coordinate services and provide a good interface between them. They agreed, based on their experience, that this would also help to identify gaps in services. And it would give commissioners of one service, input into commissioning decisions made by another, which could help to improve the quality of both. The committee discussed the importance of all organisations working together to provide culturally appropriate advocacy that meets local needs. From their knowledge and experience, and based on the expert testimony, the committee noted that mainstream advocacy provision has a narrow focus. It often fails to take account of broader issues relevant to minority communities, leading to disadvantage. The committee noted that these issues include social disadvantage, lack of equality and diversity within the workforce, and inequalities in access to services and service provision. The expert testimony specifically highlighted support for integrating or co‑locating advocacy in other Black community and voluntary sector services. The committee agreed that these organisations could play a critical role in building relationships and partnerships and addressing social disadvantage. The testimony also supported increasing the diversity of staff in advocacy services if people express a preference for advocates who share their gender, language and culture. The committee agreed that this is important to break down barriers to accessing services and building trusting relationships, which would improve the effectiveness of advocacy. The committee were aware that regulators may need the input of advocates in order to monitor the Mental Health Act in England. Access to advocacy is an area that could be looked at as part of the monitoring. Monitoring involves visits to institutions and interviews with staff, including IMHA. The committee agreed that advocacy providers should liaise with and facilitate the regulator in carrying out their role, including in inspecting regulated services. ## How the recommendations might affect practice or services The level of partnership working and relationships with families, friends and carers, commissioners and providers is variable. But many of the recommendations reinforce legal requirements, so services in almost all areas already comply. More effective partnership working would lead to cost savings from improving services, reducing repetition and complaints, and making services more efficient. There would be some initial costs to establish collaborative services where these are not already set up. Many advocacy providers already work with local support services to ensure they are familiar with what these services can offer, but this does not happen consistently. This may need a reorganisation of resources in some areas but it is not expected to increase costs. Making sure that advocacy providers have the time and resources to make patient information available, including information in a variety of formats, should reduce costs even if initial upfront investment is needed. Having correct and up-to-date information on advocacy services that is accessible will speed up access to advocacy, avoid duplication, and avoid people losing contact with advocacy services if their needs escalate. Any decrease in the efficient use of resources would be more than compensated for by the reduction in inequality and increase in the fairness of society. The suggested actions may not be cost effective in all areas, so it would be up to individual service providers to decide how best to achieve the overall objectives. There is currently a lack of continuity of advocacy providers liaising with and facilitating the regulator in carrying out their role, so the recommendation for closer working would lead to a change in practice. However, the Care Quality Commission has existing duties to assess the quality of care provided and need to assess if people have access to advocacy, which is not expected to result in further cost. Furthermore, this would ensure an improved feedback system, which in turn would lead to an improved quality of services and reduce costs in the long term. Return to recommendations # Planning and commissioning services for advocacy Recommendations 1.8.1 to 1.8.15 ## Why the committee made the recommendations For more information about how these recommendations were developed, see the section on developing the recommendations. The evidence highlighted the need to improve the commissioning of advocacy services and suggested ways that this could be done. In the committee's experience, understanding the needs of the local population is essential when commissioning services to ensure that they are responsive to local needs and targeted at the people who need them. This approach to commissioning is considered best practice. But the committee highlighted that it is not mandated, so they wanted to place a greater emphasis on this approach to standardise effective, evidence-informed commissioning. Furthermore, this approach would help to ensure that advocacy services are commissioned in a way that would avoid the effects of structural, systemic and health inequalities, which result in unequal status, treatment and opportunities among population groups. The committee agreed that there is currently a lack of evidence of long-term proactive planning for the development of advocacy, making it less likely that people will get the support they need in future. Having long-term plans based on assessment of need would ensure that service commissioning had clear long-term intentions and would be based on future local need. The evidence highlighted that advocacy services tend to be commissioned only to meet legislative requirements. This means that people who have a genuine need for advocacy but fall outside the statutory requirements may have difficulty accessing it. In the committee's experience, commissioning advocacy services that can be used by people who do not meet the criteria for statutory advocacy would help to close the gap in provision, ensuring that more people benefit. The committee also agreed that this would facilitate earlier intervention at a lower level of need, which could prevent an escalation to situations in which statutory advocacy might be needed. Based on their experience, the committee agreed that commissioners need to be aware of policies, legislation and guidance beyond those that explicitly address statutory requirement for advocacy (for example, the Equality Act 2010). Advocacy services may need to change so that services are compliant with these wider requirements. The committee agreed that this would ensure that commissioning decisions create advocacy services that are as comprehensive as possible, compliant with all legislation, meet a diverse range of needs and promote equality. The Care Act 2014 and statutory guidance require local authorities to ensure adequate high-quality care and support is provided that meets the needs of the local population. The Care Act 2014 also includes the concept of market development, which means the local authority has a responsibility to ensure there are sufficient, good quality services available in their area. In the committee's experience, closer collaboration between local authorities, commissioners, health and social care service providers and community stakeholders would help to establish a clear picture of whether or not existing services are meeting local population needs, to ensure these requirements are fulfilled. The evidence highlighted the need to involve people who use or are likely to use advocacy services in planning, designing and monitoring services. In the committee's experience, service user involvement happens in some areas but not consistently. The committee agreed that involving service users in planning, designing and monitoring helps ensure services are relevant and suited to people's needs and preferences. They were aware of guidance on this in the NICE guideline on community engagement so they agreed to make a cross reference to support implementation of this practice. Based on their experience, the committee agreed that the provision of advocacy services for people who are detained or deprived of their liberty in independent hospitals is inconsistent. This is despite the fact that it is a legal requirement for local authority commissioners to provide advocacy to people in these circumstances. For example, there is currently very poor commissioning for people in private mental health settings. In the committee's experience, people have different needs and therefore need different amounts of advocacy. Having overly restrictive contracts that specify what advocates can and cannot do and limit the amount of time advocates can spend with a person compromises the independence of the advocate, makes it difficult for them to work in line with the principles of advocacy and reduces the quality and effectiveness of the advocacy they provide. The committee agreed that advocates need to undertake training and continuing professional development to be able to provide high-quality, effective advocacy. Contracts and specifications for advocacy providers need to include time allowances to make this possible but not all of them currently do so. In the committee's experience, quality standards provide an important benchmark to measure performance against. This helps to promote a consistent, high-quality service and identify any improvements needed. The committee were aware that the advocacy QPM is a widely used quality assurance assessment. The QPM is given to organisations demonstrating excellent service provision in line with QPM standards, the Advocacy Charter and the Advocacy Code of Practice. The effectiveness of the QPM was not reviewed as part of this guideline so the committee did not recommend its use. But they agreed with the benefits of external quality accreditation. In the committee's view, taking a person-centred approach is a key principle of advocacy. Embedding this in contracts and service specifications is essential in enabling advocacy services to be truly person centred. Based on the expert testimony and a report from the Care Quality Commission (recommending a level of personalised care that equated to intensive and long-term support), the committee gave examples of steps commissioners could take to ensure that services are person centred. In the committee's experience, it is not possible to specify a particular way of developing service specifications and contracts that would ensure that services meet the needs of everyone. When planning and providing support, it is important to allow for reasonable adjustments that promote equality and avoid disadvantaging particular people. Doing this alongside the recommendations on training (see section 1.9 and section 1.10), will ensure advocates have the dedicated time and space to deliver a person-centred service and to continuously enhance their skills, all of which is essential for maintaining quality and standards. In the committee's experience, people are most comfortable with advocates they can relate to and trust, and this tends to lead to more effective advocacy. The expert testimony highlighted that a lack of diversity and understanding of equality and issues relevant to minority communities can form a barrier to people accessing, or taking up, advocacy services. The evidence highlighted that local organisations could be better placed to support access for potentially disadvantaged groups. The committee agreed that working with local organisations would help commissioners provide services tailored to the local population. This could help remove barriers to access for underserved groups, such as those with refugee status and people from Gypsy, Roma and Traveller communities. The evidence highlighted the lack of suitable advocacy for people with complex needs, such as learning disabilities. The committee agreed that people's different advocacy needs can be best met by offering a variety of advocacy models and commissioning services tailored to the local population. This includes commissioning services with advocates specialising in different types of advocacy and multi-skilled advocates. The evidence highlighted the need to establish consistent good practice in safeguarding as part of the advocacy role. Advocacy is important in safeguarding because it supports people's involvement and decision making when there are safeguarding concerns, safeguarding enquiries or safeguarding adult's reviews. Involving someone independent from other services, who is representing the person's best interests and is aware of their circumstances and living conditions, can help to identify the potential for abuse or neglect, enabling concerns about service quality to be raised before they become a safeguarding issue. But in the committee's experience, advocates are not consistently involved in safeguarding processes. ## How the recommendations might affect practice or services There is already a statutory duty to make information about advocacy services available. This will remind services to comply if they do not already. The Joint Strategic Needs Assessment already involves an element of forward planning. However, this does not include agreeing and publishing long-term plans for advocacy. Therefore, some change in practice will be needed to extend the timeframe over which planning takes place. There may be some upfront costs associated with commissioning bodies working in partnership to agree and publish long-term plans, but these plans would ensure that future resources are better allocated. Once the advocacy providers have longer contracts, the initial investment made would be retained as it would result in improved retention and a long-term workforce that would not need new training. Active analysis of public policies, legislation and guidance may initially have a resource impact but will lead to more effective, efficient practice and will potentially save costs in the longer term. Changes in practice may also occur as a result of commissioning different or modified services in line with statutory requirements and lessons from shared learning. There may be some upfront costs associated with involving people who use independent advocacy services in planning and designing the services, especially as some groups may be challenging to recruit from and may need interventions to help them actively participate. But this should lead to services being more responsive and efficient, and avoid wastage. This would lead to cost savings. It is also in line with the general move towards shared decision making in health and social care. Although it is a legal requirement for commissioners to ensure there are sufficient advocacy services available for people who are detained in independent hospitals, this is not happening consistently. Where it is not currently happening, there will be some costs associated with it because more people would receive advocacy. But this is expected to lead to more efficient services, with better decisions being made, leading to cost savings in the long term. Supporting advocacy providers to maintain their independence will lead to better quality service, reducing complaints and needs for judicial reviews, therefore saving costs in the long term. There may be some resource impact associated with engaging with the community and carrying out local needs assessments on which to base commissioning of advocacy services. But in most areas, this is already happening. Not all contracts and specification for advocacy include time allowances for training and continuing professional development so some change in practice may be needed. But having advocates who are suitably trained and competent should result in fewer complaints, improved services and the ability to identify needs before they escalate. Ensuring that advocacy services are person centred is not expected to have a resource impact. All health and social care services should already personalise care or treatment specifically for each person who uses the service. Return to recommendations # Training, skills and support for advocates Recommendations 1.9.1 to 1.9.8 ## Why the committee made the recommendations For more information about how these recommendations were developed, see the section on developing the recommendations. In the committee's view, advocacy is still establishing itself in the consciousness of both the people who would benefit from using it and the practitioners who can make referrals to it. If it is to be effective, it is crucial that advocacy is recognised and valued. Advocates need to be able to support people from a variety of backgrounds and with different needs. So, they need to develop the appropriate skills, knowledge and behaviours to do this effectively. In the committee's experience, comprehensive and consistent training is the most effective way to achieve this. But there is variation in the current content and availability of training. The committee agreed with evidence from NICE's guideline on decision making and mental capacity that an increase in investment in training for advocates would improve the availability and quality of advocacy. The evidence highlighted several areas that advocates need to be trained in. In the committee's experience, advocates need knowledge and skills in these processes and areas to undertake their role effectively. In their experience, training for advocates is inconsistent, and the committee agreed that all training needs to be brought up to an agreed standard. Statutory guidance to the Care Act (section 7.43) states that 'Once appointed, all independent advocates should be expected to work towards the National Qualification in Independent Advocacy within a year of being appointed, and to achieve it in a reasonable amount of time'. The committee noted that the statutory guidance is vague about the timeframe for achieving this qualification and in their experience, 'a reasonable amount of time' is interpreted very differently. The committee agreed that the quality of advocacy services would improve if all advocates achieved this qualification, although they could not recommend a specific timeframe because the statutory guidance does not stipulate one. The committee agreed that supervision of advocates is crucial. It ensures consistency across services and that advocates are meeting the necessary standards. It also provides an opportunity for all advocates to develop skills and learn from others. In the committee's experience, people who cannot instruct an advocate are less likely to have one. Therefore, providing non-instructed advocacy helps to ensure that people's rights to advocacy are protected. In the committee's experience, the skill and confidence of advocates in using non-instructed advocacy varies across the sector. Because non-instructed advocacy is used when someone needs an advocate but cannot tell the advocate what they want, the advocate's role is more challenging. Extra steps may be needed to determine the person's likely wishes, feelings and desired outcomes in the absence of instruction. The committee agreed that providing extra training and support for non-instructed advocates would improve practice in this area. The committee agreed it is essential that volunteer advocates receive the same support and supervision as paid advocates. This will ensure that the services provided by volunteer advocates meet the necessary standard. ## How the recommendations might affect practice or services There are currently variations in the training that advocates are given on health and social care, justice, legal processes and skills needed for effective advocacy. The bespoke economic model for the guideline estimated that there would be an initial resource impact from improving training, especially when training takes advocates away from core duties for a long time. But there would be cost savings in the future from advocates working more efficiently and a reduction in complaints and repeated meetings. Better training for advocates would also lead to a higher quality of service. This would improve people's outcomes and quality of life, while reducing the number of expensive interventions such as unplanned admissions to hospital. The economic model gave an upper estimate for costs involving a qualification needing a long period of training and study. Not all advocates will need training in all the processes and areas. The amount of training needed will depend on the role and responsibility of individual advocates and the needs of the population in their local area. Because there is already a requirement for all independent advocates to work towards the National Qualification in Independent Advocacy, this should not need additional resources. Training in non-instructed advocacy is in line with the Care Act 2014 requirement for advocates to have appropriate training, so this should not have additional resource requirements. Currently there are inconsistencies in the amount of training provided for volunteer advocates so there may be additional costs associated with this. The amount of training needed will depend on the role and responsibility of individual advocates and the needs of the population in their local area. It is not anticipated that all volunteer advocates will need training in all the processes and areas. Training volunteer advocates will ensure that the required service standard is met, and there might also be improvements from reduced complaints. Return to recommendations # Training and skills for health and social care practitioners who work with advocates Recommendations 1.10.1 to 1.10.5 ## Why the committee made the recommendations For more information about how these recommendations were developed, see the section on developing the recommendations. It is a legal duty for an advocacy referral to be made when people are entitled to advocacy support, and people who cannot self-refer to advocacy rely on these referrals. In the committee's experience, the different statutory duties and eligibility criteria for advocacy are complex and difficult to understand, making it hard for practitioners to know who is entitled to an advocate. In the committee's view, training would be the most effective way of improving practitioners' knowledge about entitlement to advocacy support, so that they could comply with the legal requirements on referral. To retain organisational and individual knowledge and prevent issues associated with staff turnover, the committee agreed that training about entitlement to advocacy should form part of induction training and be regularly refreshed. This would lead to consistent practice and referrals and increase effective practice. Refresher training every 2 to 3 years achieves a balance between the need to keep knowledge current and the time needed to attend training. The committee used the evidence to decide on the most important elements of training. The committee agreed that staff who may be the first point of contact in health and social care services need to understand who is entitled to advocacy and when and how to request it so that people do not fall through the gaps at this early stage. In their experience, this understanding is not consistent across staff. Staff in organisations working with advocacy services should receive training on the role and function of advocacy as part of their training. In the committee's experience, this is not consistent, which can lead to misunderstandings about advocacy, poor practice and negative working relationships. Having better knowledge would enable staff in organisations working with advocacy services to facilitate advocacy more effectively and improve working relationships. The committee used their experience of common misunderstandings about the role of advocacy to decide on what this training should cover. Different health and social care practitioners will need different levels of training in advocacy, depending on their role. In the committee's experience, tailored training is more cost effective than providing the same training for everyone. The committee also agreed that delivering training in different formats should maximise its effectiveness. For example, it may be easier and more cost effective for people to access training remotely, at a time of their choosing, rather than attending fixed, face-to-face training sessions. In the committee's experience, it is important to include people with lived experience of advocacy services in developing and delivering training for practitioners. Having real-life input can make the training more impactful and memorable, and increase the likelihood it will be implemented. People with lived experience are likely to have different priorities for what practitioners need to know and the gaps that exist in practice. From their knowledge and experience, the committee were aware that the knowledge gained during training is not always implemented or used effectively in practice, and so this needs to be checked. ## How the recommendations might affect practice or services Some changes in practice or services may be needed. Health and social care practitioners should already be receiving training in legislation and the role of advocates, but this is delivered inconsistently. Refresher training is not routine and there is variation across regions in how much training is tailored. Although there may be some changes in practice needed to deliver training, there are existing materials that can be used which would minimise cost. This is especially true for refresher training where previous training materials can be reused and costs should be minimal. Not everyone will need the same depth of knowledge and amount of training, so the training can also be tailored to individuals for efficiency. Training does not consistently include people with lived experience. For organisations that are not currently doing this, there is likely to be a change in practice. And there will be some costs from providing support to enable people with lived experience to take part in the training and share their experiences. This would improve the overall quality of training, making it more relevant and meaningful and help to improve practitioners' understanding of advocacy. This can help the right people access advocacy at the right time, and in the long term, could improve services. Delivering training in a variety of formats may have some costs. But costs will be minimal if training is by self-directed learning or is delivered remotely. Improved training for practitioners should help identify people who have a right to advocacy under current legislation. This will increase the total number of people accessing advocacy services, leading to a greater resource impact than the training itself, at least in the short term. But the increased access will be from people who have a legal right to advocacy services, so resources should already be in place to meet this statutory requirement. Better access to advocacy should also lead to better outcomes and less risk of needs escalating, leading to lower downstream costs and higher quality of life. There may be some costs associated with ensuring that knowledge gained through training is applied in practice, for example from changing approaches to enable effective supervision, although these should be small and short term. But increased use of knowledge in practice should lead to improvements in the quality of service and a reduction in complaints and adverse outcomes, resulting in cost savings. Return to recommendations # Monitoring services and collecting data for quality improvement Recommendations 1.11.1 to 1.11.18 ## Why the committee made the recommendations For more information about how these recommendations were developed, see the section on developing the recommendations. In the committee's experience, advocacy providers need to have defined, service-level outcomes that can be measured to ensure that they are delivering an effective, high-quality service. Many providers currently report key performance indicators as part of contracts and commissioning arrangements. But in the committee's view, these service-level outcomes should include more person-centred metrics (for example, whether people's voices are heard and the effect on empowerment). Input from people who use advocacy services and other stakeholders would help to achieve this. The committee also noted that collaboration between commissioners and advocacy providers when agreeing outcomes would reduce the likelihood of gaps occurring between geographical areas or people falling between different parts of the health and social care system. The committee agreed it was important to be clear about how outcomes will be reported. This enables data to be analysed for protected characteristics or other disadvantaged groups, such as those experiencing health inequalities. Currently, advocacy services tend to collect data on the impact of advocacy at an individual level. In the committee's experience, collecting data that also enables an understanding of population-level needs would assist the commissioning of more effective services and would align with developments in Health and Social Care services such as the move to Integrated Care Systems. Based on the evidence, they agreed areas for data collection that would help this. The committee were aware that advocates sometimes face pressure from other services or commissioners to prioritise certain outcomes or not to raise concerns. Advocates are also sometimes asked for unnecessary information that could identify individual people, potentially breaching the Data Protection Act 2018 and damaging relationships between the advocate and the person they support. The committee agreed that commissioners need to be alert to these issues when collecting data. In the committee's experience, there is variation in what information is collected about people using advocacy services, and information about the impact of advocacy services is not routinely collected in a standardised format. Collecting data in a standardised format makes it easier to evaluate, so that gaps in service provision can be identified and it can be seen whether services are meeting local needs. It also makes it easier to share key information with other organisations. Based on the evidence, the committee agreed some important standard types of data to collect and suggested formats for doing so. The committee agreed that including protected characteristics would help identify whether there are particular groups that are not receiving services they would benefit from and help to reduce health and other inequalities. In the committee's experience, information about advocacy services is not provided consistently. Monitoring whether health and social care providers are doing this should help drive improvements in access to advocacy for those who need it. The committee were aware of wide discrepancies in how advocacy is commissioned in different areas, with some areas only commissioning statutory services rather than being responsive to local needs. Monitoring access to advocacy and take up of it would help to identify any groups who would benefit from advocacy services but are not currently using them. This could help address inequalities in access. Because advocacy is an emerging field relative to other areas of health and social care, there are no evidence-based quality standards mandated for use. In the committee's experience, quality standards provide an important benchmark with which to measure performance. Having a robust method of quality assurance would help to promote a consistent, high-quality service and identify any improvements needed. The information and data used by commissioners is diverse, and varies according to area and local need. The committee agreed that standardised data recording and collection methods, with the same type of information collected by different commissioners and in different areas, would produce data that is consistent and transparent. This would allow data to be compared across services, which may in turn help improve the quality of services. In the committee's experience, getting feedback from the full range of people using advocacy services is necessary to ensure that services are responsive to the needs of the local population. They agreed that it may be necessary to support individual preferences and communication needs to get this feedback, but that doing so should give a better view of whether services are meeting needs and any necessary improvements. The committee also noted that the provider of the service is typically the point of contact for feedback and were keen to facilitate anonymous feedback to prevent any barriers to receiving feedback. In the committee's view, the monitoring data collected needs to be evaluated and used to generate continuous improvement in services. From their knowledge and experience, the committee were aware that commissioners do not always use information gathered from advocacy services to inform improvements in practice. The committee also agreed that sharing this information with other organisations would help highlight gaps in provision, areas for improvement, trends and themes for service change. All of these would help to improve the quality of advocacy services. There is a statutory requirement to involve an independent advocate to support people who are subject to a safeguarding enquiry or safeguarding adult review, as outlined in the statutory guidance to the Care Act 2014. In the committee's experience, advocates are not always informed about safeguarding concerns in a timely manner. The committee agreed that it is important to monitor the involvement of advocates to ensure that the legal duty is being upheld, and that processes are in place to do this. They also agreed that advocates are in a good position to recognise and report when this is not being done so that steps can be taken to address problems. From their knowledge and experience, the committee were aware that there is a longstanding issue of referrals for advocacy not being made when needed. They discussed that complying with statutory duties is essential to ensure that a person's rights are upheld. The committee agreed that commissioners have the power to help enforce this compliance, given that they are the ones responsible for funding and contracts. Based on the evidence, and their knowledge about gaps in evidence and about the factors that make an advocacy service effective, the committee agreed that more information is needed about the effectiveness of advocacy delivered through different approaches. For example, advocacy delivered by an advocate with lived experience, or by an advocate with the same ethnicity as the person being supported (see the recommendation for research on ways of providing advocacy services). ## How the recommendations might affect practice or services Collecting data is not expected to lead to any long-term increase in resource use. Most centres already have data collection and monitoring processes in place. There will be some short-term costs for services whose monitoring, data collection or quality assurance systems are not in line with the recommendations. There will also be some upfront costs from initial meetings between advocacy services and commissioners to develop protocols or operating procedures. Better and standardised monitoring, data collection and quality assurance should lead to more effective and efficient advocacy services with potentially large cost savings. Return to recommendations	{'Context': "Advocacy helps to ensure that people's voices, wishes and preferences are heard, their rights are upheld and their needs are met, particularly when they have difficulty in speaking up for themselves or are concerned that they are not being heard.\n\nAn advocate helps someone with health and social care needs to express their needs and wishes, and to weigh up and take decisions about options available to them. Advocates can help people find services, make sure correct procedures are followed and challenge decisions made by councils, health services and other relevant health-based organisations. Advocacy helps protect human rights and plays a critical part in safeguarding. The advocate is there to represent the person's interests, which they can do by supporting them to speak, or by speaking on their behalf, including when the person is unable to instruct the advocate. (Adapted from the Think Local, Act Personal Care and Support Jargon Buster.)\n\nThis guideline covers advocacy delivered by a trained person whose sole engagement is to support the person and help ensure that their voice, needs and preferences are heard (referred to in law as 'independent advocacy'). Family members and friends play a vital role in the lives of people who draw on support, for example ensuring that the person's voice and concerns are heard. However, the focus of this guidance is on a trained person whose sole involvement is as an advocate.\n\nSeveral Acts of Parliament specify the local authority's responsibility to ensure the provision of independent advocates and the situations in which they must make an advocate available. But many more people at certain points in their lives could benefit from access to the services of a trained advocate.\n\nLittle information is available about how many people access independent advocacy or how many independent advocates are currently operating. There is a widely held view that there is a shortage of advocates. The commissioning of advocacy services, their availability and the ongoing training and support of advocates varies significantly across the country, although the National Qualification in Independent Advocacy is widely recognised.\n\nThis guideline aims to help advocates and those who train and manage them, as well as those who commission their services and health and social care practitioners who interact with them, by setting out key aspects of service quality. It will also be of interest to people who use advocacy services and their families and carers.\n\nThis guideline is relevant to people who need advocacy regardless of their condition or life circumstance. For more specific guidance about conditions or circumstances where advocacy is likely to be helpful, see the NICE guidelines on decision making and mental capacity, people growing older with learning disabilities, people experiencing homelessness and safeguarding adults in care homes.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe recommendations in this guideline apply to both instructed and non-instructed advocacy. When providing non-instructed advocacy, advocates will need to take additional steps to determine as far as possible what the person's wishes, feelings and desired outcomes are likely to be, to best represent the person.\n\nIf the person lacks the capacity to instruct an advocate, advocates will need to act based on the person's likely wishes, feelings and desired outcomes.\n\n# Legal right to advocacy\n\nAdvocacy must be offered according to the relevant legislation. The criteria for when and to whom to offer it are described in the:\n\nCare Act 2014 and the Care and Support statutory guidance for independent advocates for people using social care services\n\nMental Capacity Act 2005 and its Code of Practice for independent mental capacity advocates\n\nMental Health Act 1983 and its Code of Practice for independent mental health advocates.\n\nLocal authorities must make appropriate arrangements for independent advocacy services to provide assistance to people making or intending to make complaints as described in the Health and Social Care Act 2012. For a summary, see box\xa01 on the legal entitlement to advocacy, as well as supporting information and resources on the Social Care Institute for Excellence's information on advocacy. For more guidance on helping people to make complaints, see the NICE guidelines on patient experience in adult NHS services and service user experience in adult mental health.\n\nAdapted from the Care Act 2014 statutory guidance, the Mental Capacity Act Code of Practice, the Mental Health Act 1983: Code of Practice and the Health and Social Care Act\xa02012.\n\nCare Act 2014\n\nFrom the point of first contact, the local authority must appoint an independent advocate if an adult would experience substantial difficulty in any of these 4\xa0areas:\n\nunderstanding the information provided\n\nretaining the information\n\nusing or weighing up the information as part of the process of being involved\n\ncommunicating the person's views, wishes or feelings.\n\nAnd\n\nThere is thought to be no one appropriate and independent to support and represent the person, for the purpose of facilitating their involvement.\n\nThis applies to adults taking part in:\n\na needs assessment\n\na carer's assessment\n\npreparing a care and support or support plan\n\nrevising a care and support or support plan\n\na child's needs assessment\n\na child's carer's assessment\n\na young carer's assessment\n\na safeguarding enquiry\n\na safeguarding adult review\n\nan appeal against a local authority decision under Part\xa01 of the Care Act (subject to further consultation).\n\nCare and Support (Independent Advocacy Support) (No. 2) Regulations 2014\n\nThe Care and Support (Independent Advocacy Support) (No.\xa02) Regulations is a Statutory Instrument, which adds to the Care Act 2014 section\xa067(2). It extends the circumstances in which a person is entitled to an independent advocate to where an assessment or plan is likely to result in a hospital stay of more than 28\xa0days or a stay in a care home for more than 8\xa0weeks (although there are some exceptions).\n\nMental Capacity Act 2005\n\nAn independent mental capacity advocate (IMCA) must be instructed, and then consulted, for people lacking capacity who have no one else to support them (other than paid staff), whenever:\n\nan NHS body is proposing to provide serious medical treatment or\n\nan NHS body or local authority is proposing to arrange accommodation (or a change of accommodation) in hospital or a care home.\n\nAnd\n\nthe person will stay in hospital longer than 28\xa0days or\n\nthey will stay in the care home for more than 8\xa0weeks.\n\nAn IMCA may be instructed to support someone who lacks capacity to make decisions concerning:\n\ncare reviews, if no one else is available to be consulted\n\nadult protection cases, whether or not family, friends or others are involved.\n\nMental Health Act\xa01983\n\nPeople are eligible for support from an independent mental health advocate, irrespective of their age, if they are:\n\ndetained under the Mental Health Act 1983 (excluding certain short-term sections)\n\nliable to be detained even if not actually detained, including those who are currently on leave of absence from hospital or absent without leave, or those for whom an application or court order for admission has been completed\n\nconditionally discharged restricted patients\n\nsubject to guardianship\n\nsubject to a community treatment order\n\nbeing considered for treatment under section\xa057 of the Act or, for under‑18s, any treatment under section\xa058A.\n\nHealth and Social Care Act\xa02012\n\nThe 2012 Health and Social Care Act amendment to the 2007 Local Government and Public Involvement in Health Act.\n\nThe local authority must make arrangements for independent advocacy services to provide assistance to people making or intending to make a complaint:\n\nunder a procedure operated by a health service body or independent provider\n\nsection\xa0113(1) or (2) of the Health and Social Care (Community Health and Standards) Act\xa02003\n\nto the Health Service Commissioner for England\n\nto the Public Services Ombudsman for Wales, which relates to a Welsh health body\n\nunder section\xa073C(1) of the National Health Service Act\xa02006\n\nto a Local Commissioner under Part\xa03 of the Local Government Act 1974 about a matter which could be the subject of a complaint under section\xa073C(1) of the National Health Service Act\xa02006\n\nof such description as the Secretary of State may by regulations prescribe which relates to the provision of services as part of the health service and is made under a procedure of a description prescribed in the regulations, or gives rise, or may give rise, to proceedings of a description prescribed in the regulations.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on legal right to advocacy\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: who has a legal right to advocacy?\n\nevidence review E: enabling and supporting effective advocacy.\n\nLoading. Please wait.\n\n# Who else may benefit from advocacy\n\nOffer advocacy to people who are not covered by the legal entitlement but who would otherwise not be able to express their views or sufficiently influence decisions that are likely to have a substantial impact on their wellbeing or the wellbeing of someone they have caring or parental responsibility for.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice or services, see the rationale and impact section on who else may benefit from advocacy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: who else would benefit from advocacy and how do we identify them?\n\nLoading. Please wait.\n\n# Information about effective advocacy and signposting to services\n\nLocal authorities must meet the requirement of the Care Act 2014 to make information and advice publicly available about care and support services for adults in their area. This should include advocacy services.\n\nLocal authorities, health authorities, NHS trusts, health and social care providers and advocacy services should provide everyone legally entitled to advocacy (including young people who are using adult services) with information about their entitlement to advocacy and what this means. There should be proactive signposting to the information using accessible formats.\n\nLocal authorities, health authorities, NHS trusts, health and social care providers and advocacy services should provide everyone who would benefit from advocacy (whether or not they are legally entitled to it) with information about:\n\nwhat advocacy services are available to them\n\nhow an advocate could help them\n\nhow to access and contact advocacy services.\n\nLocal authorities, health authorities, NHS trusts, health and social care providers and advocacy services should ensure that all information about advocacy is provided in a variety of ways to suit people's needs (including for family, friends and carers), using accessible formats where relevant. Examples include using interpreters, sign language and versions such as Easy Read, large print, braille and audio. For more guidance on communicating and providing information, see the NICE guideline on patient experience in adult NHS services and the NHS Accessible Information Standard.\n\nLocal authorities, health authorities, NHS trusts, health and social care providers and advocacy services should repeat information about advocacy and how to access it at each key point in the person's interaction with health and social care.\n\nIf a person is offered healthcare, care or support out of their home area, the organisation arranging the placement should give them (and their family, friends or carers, as appropriate) information about the advocacy support available and help them to access it.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on information about effective advocacy and signposting to services\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review C: information about effective advocacy and signposting to services\n\nevidence review F: what does effective advocacy look like?\n\nLoading. Please wait.\n\n# Improving access to advocacy\n\nThis section should be read alongside the section on training and skills for health and social care practitioners who work with advocates.\n\nHealth and social care providers should ensure that advocates can meet people in person to support them to make initial contact with advocacy services.\n\nHealth and social care providers in all settings, including hospitals, care homes and prisons, should ensure that policies and procedures do not act as an obstacle to people accessing advocacy. This includes finding alternative methods to mitigate any risks, for example from infection.\n\nIf a person has been detained under the Mental Health Act 1983 and has legal representation, they still have a legal right to advocacy and therefore mental health services must continue to facilitate access to independent mental health advocacy (IMHA) support. See the section on legal right to advocacy.\n\nCommissioners and advocacy providers should make it easy for people to access advocacy by having:\n\nflexible ways to make contact, including by self-referral\n\na simple process that directs people to the right advocacy support without them needing to know what type of advocacy they need (for example, a universal point of access).\n\nAdvocacy providers should aim to support continuity by offering people the same advocate for different types of advocacy (for example, statutory advocacy in line with the Care Act 2014, IMHA, independent mental capacity advocate [IMCA] and non-statutory advocacy). If this is not possible, they should ensure that systems for handover are in place that are not reliant on a new referral.\n\nIndependent mental health advocates should make regular visits to inpatient settings to identify people who would benefit from advocacy and help them to access it. This includes taking all necessary steps to ensure that people who would otherwise be unable to instruct an advocate, or who would find it particularly difficult, do not miss out on statutory advocacy services. Particular efforts should also be made to facilitate access to advocacy for people in isolation, seclusion or segregation.\n\nAdvocacy providers, hospital and health trusts and commissioners should offer IMHA on an opt-out basis so that everyone who is eligible meets an advocate and is offered the service.\n\nAdvocacy organisations should ensure that IMHA is offered at the earliest opportunity and then regularly afterwards to people who are eligible. This includes people who have initially declined support. For these people, advocacy organisations should explore, where appropriate, the reasons why the support was declined and what could be done to help them access advocacy.\n\nIMHA services should raise awareness of disabled people's organisations and user-led organisations, self-advocacy groups or patient participation forums and promote peer advocacy and self-advocacy options.\n\nAdvocacy organisations should have a plan for how to ensure that their services are taken up by the people with the greatest need, who may not be able to ask for them.\n\nLocal authorities and advocacy providers should collaborate to make it clear how people can access advocacy and how they can provide support to help them to do so if they:\n\nare supported outside of their home area or\n\nare carers who care for someone outside their area.\n\nHealth and social care practitioners should ensure that people who are unable to ask for an advocate get advocacy when they are entitled to it.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on improving access to advocacy\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D: improving access to advocacy\n\nevidence review E: enabling and supporting effective advocacy\n\nevidence review G: partnership working and relationships with families and carers, commissioners and providers\n\nevidence review H: planning and commissioning services for advocacy.\n\nLoading. Please wait.\n\n# Enabling and supporting effective advocacy\n\nHealth and social care practitioners and other referrers should:\n\nidentify the need for advocacy as early as possible and\n\nmake a referral to an advocacy service without delay.\n\nWhen the need for advocacy is identified, allow enough time:\n\nto appoint an advocate if the person does not have one\n\nto make any other arrangements, for example if the person needs an interpreter\n\nfor the advocate to help the person prepare before any meetings or discussions, and to ensure they understand the outcome afterwards.\n\nService providers should accommodate the availability of the advocate when planning and scheduling meetings, ward rounds or other situations where decisions are being made, including rearranging meetings where needed and practicable.\n\nIf people have not had enough time to prepare with their advocate before a meeting, their advocate should support them in requesting to rearrange the meeting.\n\nAdvocacy organisations should ensure that there is adequate time for the advocate and person to build relationships and trust according to their individual needs.\n\nService providers should ensure that people can have discussions with their advocates in a private area where they can talk in confidence without being overheard.\n\nHealth and social care practitioners should involve a person's advocate in all discussions with the person until a decision has been made and explained to the person, and they have had a chance to challenge the decision if they want to.\n\nHealth and social care practitioners should facilitate advocacy, for example by:\n\nrespecting the advocate's independence\n\nsharing information appropriately with advocates\n\nsupporting the person and building good working relationships with them\n\nencouraging and supporting ongoing contact between the person and their advocate\n\ngiving the person privacy to talk to their advocate\n\nsupporting people to understand about advocacy and to ask for the advocacy that they would want, or ask for it on their behalf if appropriate\n\nresponding to advocates in a timely manner\n\nsupporting any communication needs, such as arranging for an interpreter.\n\nHealth and social care providers should offer practical support to help people to communicate with their advocate remotely. This may include providing:\n\naccess to computers, the internet and phones\n\nsupport to use technology\n\nhelp to schedule and remember meeting times.\n\nAdvocacy providers should use digital platforms to communicate with the person when necessary or the person prefers it, and only when it is safe, effective and appropriate to do so.\n\nHealth and social care practitioners responsible for decisions should ensure that all formal and informal concerns that are raised, by either the person or the advocate on their behalf, are understood, responded to and recorded.\n\nHealth and social care providers should periodically audit cases to assess whether referrals have been made to advocacy services in line with statutory duties.\n\nIf gaps in compliance (for example, people not being informed of their right to an advocate) are identified by audits, or otherwise, health and social care providers should develop action plans to improve compliance.\n\nLocal authorities and health and social care providers should consider including the numbers of referrals they make to advocacy services as a part of their corporate performance information.\n\nAdvocacy services should ensure that advocacy staff know when and how to report and act on safeguarding concerns.\n\nAdvocacy services should ensure that their advocacy staff are delivering effective safeguarding by:\n\nhaving robust internal guidance\n\nkeeping detailed, accurate records that are written at the time of the discussion or event\n\nappointing a safeguarding lead\n\ndeveloping systems for tracking and monitoring concerns\n\ntraining, supervision and reflective practice\n\nproviding input to local Safeguarding Adults Boards\n\nlearning from adverse events\n\ncontinuing to advocate for the person throughout the process.For more guidance on communicating and discussing complex information, see the NICE guidelines on people's experience in adult social care services, patient experience in adult NHS services and shared decision making.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on enabling and supporting effective advocacy\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D: improving access to advocacy\n\nevidence review E: enabling and supporting effective advocacy\n\nevidence review F: what does effective advocacy look like?\n\nLoading. Please wait.\n\n# Effective advocacy\n\nAdvocacy providers should ensure that their advocacy service is accessible, for example by:\n\nmaking face-to-face advocacy available unless this is not possible\n\nusing remote advocacy if the person prefers this and it is effective\n\noperating outside normal working hours if possible as well as during them\n\nmaking referral processes simple, flexible and clear\n\nmaking referral forms easily available online\n\nensuring that meeting places are accessible in all aspects\n\nclearly describing available services\n\nproducing policies, procedures and publicity materials in accessible formats, including Easy Read\n\nmeeting people's communication needs\n\nproviding advocacy free of charge for people who are eligible\n\nmaking efforts (directly and indirectly through other organisations) to reach under-represented and underserved communities\n\nproviding non-instructed advocacy.\n\nAdvocacy providers should ensure that their advocacy service is person centred, for example by:\n\nensuring that advocates are directed by the wishes and interests of the person they are advocating for\n\nbeing non-judgemental and respectful of the person's needs, views, values, culture and experiences\n\navoiding and challenging stereotyping\n\nsupporting and helping the person to self-advocate as much as possible\n\nsupporting the person to choose their own level of involvement and the way they and their advocate work together to progress matters\n\nenabling the person to lead and be involved in addressing the advocacy issue or decision-making processes\n\nclearly agreeing with the person their advocacy needs, their impact and desired outcomes\n\nonly consulting, meeting or accepting information and documentation from third parties with the consent of the person, or if the person is unable to consent and it is in their best interests\n\noffering a choice of advocate (for example, gender and culture) for people seeking support.\n\nAdvocates should work with the person they are supporting to develop a shared understanding of what the person wants to achieve. They should discuss and agree with the person whether they have achieved the outcome they wanted and what to do if this does not happen, and review regularly.\n\nWhen people lack capacity to instruct their advocate, advocacy providers should ensure that the advocacy remains person led and involves people with an interest in the person's welfare.\n\nAdvocacy providers should include people with lived experience of health inequalities or using health and social care or advocacy services in their organisation, for example, as paid advocates or as part of management committees or boards.\n\nAdvocacy providers must promote equality throughout their services for everyone with protected characteristics under the Equality Act\xa02010.\n\nAdvocacy providers should deliver effective advocacy in relation to safeguarding by supporting their advocates to:\n\nbe sensitive and alert to what the person is telling them and to observe the person's communications and circumstances to identify any safeguarding concerns\n\nrespond to concerns about poor practice that fall below the threshold for safeguarding\n\nchallenge decisions if safeguarding concerns have been raised but the local authority has decided they do not meet the threshold for action\n\ncontinue to advocate for a person throughout any safeguarding processes\n\ntake action if they observe other safeguarding issues while they are advocating for a person\n\nprovide non-instructed advocacy.\n\nAdvocacy providers should ensure that the same advocate works with a person throughout the advocacy process, if possible and the person prefers it.\n\nAdvocacy providers should maintain independence from any other organisations the person is in contact with, to avoid any conflict of interest. Ways to do this include:\n\nestablishing themselves as a free-standing organisation with governance documents that promote and protect their independence\n\nensuring that their independence is clearly reflected in all publicity material, including on their website\n\nensuring that their service is structurally independent of any other services offered\n\ndeveloping an organisational culture that encourages advocates to challenge freely and as directed by the people they are working with\n\nhaving a conflict of interests policy, keeping a register of conflicts that might influence board members, staff and volunteers, and ensuring that advocates are free from any conflicts of interest\n\nactively seeking funding from more than 1\xa0source\n\nensuring that funders, commissioners and external health and social care practitioners are not involved in organisational decisions such as how or by whom advocacy is delivered\n\nputting in place engagement protocols that govern the organisation's interaction with other organisations.\n\nAdvocacy providers should, wherever possible, have advocates specialising in different types of advocacy and multi-skilled advocates who can provide different types of advocacy to the same person.\n\nAdvocacy services should ensure that they can provide access to interpretation and translation services when the person needs them.\n\nAdvocacy services should ensure that advocacy is culturally appropriate by respecting and taking into account the person's cultural needs, preferences, customs or religious beliefs and experience of health inequalities.\n\nAdvocacy services should support their staff to develop cultural competence to meet the needs of the populations in their local areas, for example by training, supervision and reflective practice.\n\nAdvocates should maintain confidentiality, and explain the principles and the limitations of confidentiality in advance to people they are supporting. This should include:\n\nwhat information will be shared, who with, and when and\n\nwhen confidentiality may need to be breached, for example, to make a child or adult safeguarding alert or when required by law.\n\nAdvocacy providers should work together to promote best practice and consistency. This could be done, for example, by sharing learning, insight and tools, and developing joint publications, guidance and resources.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on effective advocacy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: what does effective advocacy look like?\n\nLoading. Please wait.\n\n# Partnership working and relationships with families, friends and carers, commissioners and providers\n\nAdvocates should liaise with family members, friends and carers when the person wants them to or when the person cannot express a view about this but it is in their best interests. This includes, for example, and where appropriate:\n\nseeking information from family members, friends and carers to help understand the person's circumstances, communication preferences, views and wishes\n\nsharing information with family members, friends and carers about the work that they are doing on the person's behalf.\n\nAdvocacy providers should be familiar with local support services, such as health, social care, education, employment support and community action, and what these services offer so that they can give up-to-date and accurate information to people accessing advocacy.\n\nSafeguarding Adults Boards should ensure that they have input from advocacy providers, for example by having them as board members and giving them the opportunity to give feedback about services.\n\nCommissioners should support advocacy providers to ensure that information is available to people who may use advocacy services, for example ensuring there is enough time in contracts to develop and provide the information in accessible formats.\n\nAdvocacy providers should work with commissioners and service providers to develop protocols that facilitate effective advocacy (for example, referrals, engagement and dispute resolution).\n\nCommissioners of advocacy services should work with other local commissioners and commissioning bodies, and those in other geographical areas, to:\n\nidentify and address any current gaps in services\n\ndevelop a long-term view of what advocacy services are needed and plan how to achieve this.\n\nPractitioners should share relevant elements of individual risk assessments and safety plans with advocates to ensure their safety, and the safety of the people they support.\n\nHealth and social care providers and advocacy providers should ensure that their staff understand when and how advocates can access a person's records, in line with legislation.\n\nCommissioners of IMHA services should work in partnership with commissioners of mental health services to understand and maximise the impact of IMHA provision on mental health service development.\n\nAdvocacy providers and commissioners should work in partnership with other organisations to ensure culturally appropriate advocacy that meets local needs. For example, by:\n\nproviding advocacy as an integral part of wider Black community and voluntary sector mental health service\n\nworking closely with a south Asian community group to share insights and improve access to advocacy\n\nproviding mental health advocacy as a discrete casework advocacy service managed by a Black community and voluntary sector service\n\nincreasing the diversity of staff within advocacy services to reflect the local population\n\nco-locating different types of advocacy services, for example, an African and Caribbean advocacy service located in the same community centre as a mental health advocacy service.\n\nAdvocacy providers should liaise with and facilitate the regulator in carrying out their role, including in inspecting regulated services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on partnership working and relationships with families, friends and carers, commissioners and providers\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: partnership working and relationships with families and carers, commissioners and providers.\n\nLoading. Please wait.\n\n# Planning and commissioning services for advocacy\n\nCommission advocacy services based on an assessment of local need, building on the Joint Strategic Needs Assessment and taking into account the effects of structural, systemic and health inequalities on the population, in co-production with people who use health and social care services.\n\nCommissioning bodies in a locality should work together to agree and publish a long-term plan for advocacy based on the assessment of need. Commissioners should take into account the broad range of advocacy needs when planning and commissioning advocacy. This includes the need for statutory and non-statutory advocacy, peer advocacy and self-advocacy.\n\nConsider commissioning advocacy services that can also be used by people who do not meet the criteria for statutory advocacy but could benefit from using them (see the section on who else may benefit from advocacy).\n\nConsider taking into account wider public policies, strategy, legislation and guidance to inform advocacy commissioning decisions.\n\nLocal authorities and commissioners should engage with health and social care service providers and community stakeholders to help them understand and address gaps in advocacy provision, including their duty to develop the market under the Care Act\xa02014.\n\nCommissioners and local authorities should involve people who use advocacy services in planning and designing advocacy services, including in monitoring contracts. For more guidance on involving people who use services, see the NICE guideline on community engagement.\n\nCommissioners must ensure that sufficient advocacy services are available to meet statutory duties for people who are detained or deprived of their liberty in independent hospitals.\n\nCommissioners should ensure that contracts support advocacy providers to maintain their independence and operate in line with advocacy principles, for example by avoiding caps on the number of hours an advocate can spend supporting someone.\n\nWhen drafting contracts and specifications for advocacy services, commissioners should take account of the overall resources needed, so that providers have enough time and funding for advocates to undertake continuing professional development and training.\n\nConsider the benefits of advocacy providers having an external quality accreditation, such as the Quality Performance Mark.\n\nCommissioners should ensure that service specifications, service costs and contracts with advocacy service providers specify that the service should be person centred and based on the relationship between the person and their advocate. For example, specify that advocacy services:\n\nallow the person to receive advocacy on issues that have a major impact on their health and social care needs\n\nensure adequate and long-term support for people in situations that place them at high risk (for example, risk of exclusion or abuse).\n\nWhen planning and providing support, commissioners and advocacy providers should consider whether reasonable adjustments can be made to protect against or help the person deal with discrimination or inequalities arising from a person's protected characteristics as defined by the Equality Act 2010, or from other life circumstances and experiences such as health inequalities (see box\xa02).\n\nProtected characteristics of the Equality Act 2010\n\nage\n\ndisability\n\ngender reassignment\n\nmarriage and civil partnership\n\npregnancy and maternity\n\nrace\n\nreligion or belief\n\nsex\n\nsexual orientation.\n\nExamples of life circumstances and experiences that could lead to discrimination or inequalities\n\ntransitioning from children's to adult care services\n\ncommunication impairment\n\nlearning difficulties\n\nlearning disability\n\npoor literacy\n\nrefugee status\n\nEnglish not being a first language\n\nbeing an offender\n\nhomelessness\n\nbeing from a Gypsy, Roma or Traveller community\n\ncoercive control\n\nhealth inequalities.\n\nNote: Some people could have multiple protected characteristics or life circumstances and experiences listed here and intersectionality may occur.\n\nCommissioners and advocacy providers should consider working with local organisations that have the skills, knowledge and networks to help promote access to advocacy for underserved groups (for example, people with refugee status and people from Gypsy, Roma and Traveller communities).\n\nWhen commissioning advocacy services, consider commissioning flexibility in services and a range of services so that:\n\nproviders can have multidisciplinary advocates or specific ones, depending on the needs of clients\n\nservices tailored to the local population are made available, for example, peer advocacy, family advocacy, group advocacy, statutory advocacy and non-statutory advocacy.\n\nCommissioners should ensure that the role of advocates in safeguarding is included in specifications when commissioning, developing policy and practice, and by promoting the value of advocacy in safeguarding people.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on planning and commissioning services for advocacy\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D: improving access to advocacy\n\nevidence review F: what does effective advocacy look like?\n\nevidence review H: planning and commissioning services for advocacy\n\nevidence review I: training, skills and support for advocates\n\nevidence review K: monitoring services and collecting data for quality improvement.\n\nLoading. Please wait.\n\n# Training, skills and support for advocates\n\nCommissioners and advocacy providers should work with public bodies and providers to increase investment in training for advocates so that they are trained and competent to support people from a variety of backgrounds and with a variety of needs.\n\nAdvocacy providers should ensure that training, skills development and support for advocates covers the health, social care, housing, welfare and justice processes that are relevant to their role, so they can support people to navigate these services. These could include:\n\nNHS continuing healthcare and other health-funded support\n\nadult social care\n\npersonal budgets, personal health budgets and integrated personal budgets\n\npersonal independence payments\n\nmental health services\n\nsection\xa0117 aftercare under the Mental Health Act\xa01983\n\nsafeguarding procedures.\n\nAdvocacy services should provide training, skills development and support including induction, to their advocacy staff. Training could include:\n\ncore advocacy principles, for example those laid out in the Advocacy Charter\n\nanti-oppressive practice and culturally appropriate advocacy training\n\ncommunication, including specialised communication skills, for example communicating with people with a learning disability\n\nidentifying abuse or neglect\n\nunderstanding human rights and how to promote them\n\nhealth inequalities\n\nmaking information available to people about how to make complaints, for example about health and social care services or local authorities\n\nsocial skills, for example being approachable and building rapport\n\nperseverance and tenacity\n\ntime management\n\nmanaging expectations\n\nconfidence to challenge decisions\n\nconsistency\n\nmaintaining General Data Protection Regulation (GDPR) compliance, report writing and record keeping\n\nunderstanding structural inequalities and intersectionality\n\nequity, diversity and inclusion.\n\nAdvocates should complete the National Qualification in Independent Advocacy.\n\nAdvocacy organisations should ensure arrangements are in place for the regular support and supervision of all advocates.\n\nTraining for advocacy staff should include when and how to use non-instructed advocacy.\n\nConsider giving advocates who deliver non-instructed advocacy increased access to support, supervision and reflective practice to ensure their advocacy remains person led, independent and outcome focused.\n\nAdvocacy services should ensure any volunteer advocates are trained and given adequate support and supervision.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on training, skills and support for advocates\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review I: training, skills and support for advocates\n\nevidence review J: training and skills for practitioners who work with advocates\n\nevidence review K: monitoring services and collecting data for quality improvement.\n\nLoading. Please wait.\n\n# Training and skills for health and social care practitioners who work with advocates\n\nProviders and commissioners should ensure that information about advocacy is included in training for all health and social care practitioners at induction, with refresher training every 2\xa0to 3\xa0years or as needed, so that they understand:\n\nwhat advocacy is\n\nwho is entitled to advocacy support under current legislation\n\nwhat advocacy support services are available locally in addition to those required by law\n\nwhen and how to request advocacy\n\nhow to facilitate advocacy\n\nthe role of the advocate in different settings and situations.\n\nProviders and commissioners should ensure that staff who may be the first point of contact for people using health and social care services that regularly work with advocacy services (for example receptionists) understand:\n\nwho is entitled to advocacy support under current legislation\n\nwhat additional advocacy is available locally\n\nwhen and how to request advocacy.\n\nProviders and commissioners should ensure that staff in organisations working with advocacy services (including social workers, members of Safeguarding Adults Board members and commissioners of advocacy) have training in the role and function of advocates. This includes understanding that advocates:\n\nhelp people to get the support they need from services, for example by offering to attend meetings, writing letters and emails, and making phone calls\n\nsupport the person to make decisions, for example by providing information about available support services, making sure people understand their options and exploring the potential outcomes of the possible options\n\nrepresent only the views of the person they are supporting\n\nensure the person's voice is heard and their rights are respected in all discussions\n\naim to empower the person to develop personal agency, self-advocacy and confidence\n\nare independent of any provider service\n\nshare information they receive with the person they are supporting\n\nchallenge decisions and poor practice\n\nknow what to do about safeguarding\n\nhave a role in protecting a person's rights and promoting wellbeing\n\nare involved in non-instructed advocacy and know what this is.\n\nProviders of training on advocacy should:\n\ntailor training to practitioners' roles and responsibilities\n\ninclude people with lived experience of using advocacy services when designing and delivering training\n\nbe able to deliver training in different formats, including face-to-face, digitally (for example, as e‑modules) and self-paced.\n\nHealth and social care providers should check that practitioners are using the knowledge and understanding of advocacy obtained through training, in their day-to-day practice, for example through supervision and reflective practice.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on training and skills for health and social care practitioners who work with advocates\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D: improving access to advocacy\n\nevidence review F: what does effective advocacy look like?\n\nevidence review J: training and skills for practitioners who work with advocates.\n\nLoading. Please wait.\n\n# Monitoring services and collecting data for quality improvement\n\n## Agreeing outcomes\n\nAdvocacy service providers, commissioners, people who use advocacy services and other stakeholders should work together to agree:\n\nwhat service-level outcomes should be achieved (for example, making sure people's voices are heard, improving people's experience of safeguarding, empowerment and reducing health inequalities)\n\nhow these outcomes will be reported (for example, information on outcomes could be separated out based on protected characteristics or other disadvantaged groups, such as those experiencing health inequalities).\n\nAdvocacy service providers and commissioners should work together to agree how they will record their progress against the service-level outcomes.\n\nWhen monitoring advocacy services, advocacy providers and commissioners should measure outcomes that show the impact of advocacy on:\n\npeople using an advocate (for example, to what extent they feel, or are, protected from harm, and the effects on their voice being heard, personal control and independence, their opportunities, challenging injustice and having their rights upheld)\n\nthe health and care system (for example, the effects on the quality-of-service response and experience of people using it, person-led decision making and health inequalities)\n\ncommunities (for example, the effects on social inclusion; access to community services; and opportunities for people to contribute positively to society and get involved in their local community and engage with local forums, such as partnership boards and Safeguarding Adults Boards)\n\nthe way advocacy services are run (for example, the effects on access to advocacy, governance and best practice; co‑production; and how advocacy is delivered).\n\n## What data to collect\n\nCommissioners should ensure that measuring outcomes or monitoring activity does not compromise the independence or integrity of the advocacy provider, or individual privacy.\n\nAdvocacy providers, in partnership with commissioners, should record anonymised information on people who use advocacy services, including:\n\nprotected characteristics in the Equality Act\xa02010\n\nthe main subject of advocacy support\n\nidentified health inequalities\n\ncommunication need and preferences\n\nreasons for referral\n\ntype of location or residence (such as urban, rural, care home or independent accommodation)\n\nwhether the advocacy provided is instructed or non-instructed.\n\nAdvocacy providers should collect information about the impact of their services. Types of information include:\n\nsurvey data (such as satisfaction with the service provided)\n\nexamples or short case studies describing how outcomes have changed as a result of advocacy\n\nthe number of people reporting a particular outcome or the proportion of people who achieved a particular outcome\n\ndetailed feedback on the experiences and views of people using advocacy services.\n\nLocal authorities and commissioners should monitor:\n\nwhether health and social care providers are telling people about advocacy and the criteria for accessing it and take steps where there are gaps in this\n\naccess to advocacy and take up of it by different populations in the local community.\n\nCommissioners should check that advocacy providers have a robust method of quality assurance that monitors and reports on their quality of service.\n\n## How to collect data\n\nAdvocacy providers, in partnership with commissioners, should develop shared, consistent, practical and robust methods to record and collect information and data.\n\nAdvocacy providers, in partnership with commissioners, should tailor the formats and methods of seeking feedback about advocacy support to the person's communication needs and preferences.\n\nAdvocacy providers should find ways of gathering feedback that maximise the person's ability to provide that feedback anonymously and without the input of the advocacy provider.\n\n## Evaluating and sharing data\n\nCommissioners should use the outcomes, data and information on user demographics and the impact of advocacy services to evaluate the effectiveness and quality of current advocacy services and to plan future services.\n\nCommissioners, advocacy providers and health and social care providers should work together to evaluate data they have collected on advocacy services. They should use this to make any changes that are needed to health, social care or advocacy services so that they meet the needs of all communities within the local population, including under-represented groups, those with protected characteristics or those experiencing health or other inequalities.\n\nCommissioners and advocacy providers should share insights and key information on common trends and themes from data they have collected on advocacy services and issues affecting people using advocacy services with relevant stakeholders. For example, health and social care providers, voluntary and community sector organisations, the Care Quality Commission, Safeguarding Adults Boards, integrated care partnerships and boards and local Healthwatch.\n\n## Monitoring advocacy in safeguarding\n\nLocal authorities and commissioners should monitor how advocates are involved in supporting people experiencing safeguarding concerns.\n\nSafeguarding Adults Boards should be assured that local authorities have auditing processes in place to monitor how people and their advocates are included in safeguarding processes.\n\nAdvocacy providers should report to Safeguarding Adults Boards on the extent to which partner organisations fulfil statutory duties for advocacy and safeguarding.\n\n## Adhering to statutory duties\n\nCommissioners and health and social care providers should ensure that they:\n\nconsistently adhere to and monitor the statutory duties to refer to and involve advocacy\n\naddress failures in the duty to refer to statutory advocacy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on monitoring services and collecting data for quality improvement\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review F: what does effective advocacy look like?\n\nevidence review G: partnership working and relationships with families and carers, commissioners and providers\n\nevidence review K: monitoring services and collecting data for quality improvement.\n\nLoading. Please wait.", 'Terms used in this guideline': "This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.\n\n# Anti-oppressive practice\n\nThe phrase describes a critical examination of the impact of power, inequality and oppression on people. This could include examining an organisational structure while taking into account the wider social, cultural and political context. Anti-oppressive practice seeks to lessen the exclusion of certain social groups from social equality, rights and social justice.\n\nAnti-oppressive practice may include:\n\nrecognising the barriers that people might face, such as personal, cultural or structural barriers\n\nrecognising a person's place in a structure or culture and how this might affect other people\n\nworking to understand people's experience of oppression\n\nrecognising people's attributes and contribution\n\nempowering people to realise their rights.\n\n# Cultural competence\n\nCultural competence is the ability to understand and respond to a person's particular religious, cultural or language needs and experiences.\n\n# Digital platforms\n\nThis describes digital spaces where communication can occur, or information can be exchanged, securely. This could include some social media.\n\n# Health inequalities\n\nSystematic, unfair and avoidable differences in health across the population and between different groups within society. They arise because of the conditions in which we are born, grow, live, work and age. These conditions influence our opportunities for good mental and physical health.\n\n# Intersectionality\n\nThe interconnection of social categorisations such as age, disability, gender reassignment, pregnancy and maternity, marriage or civil partnership, race, religion or belief, sex and sexual orientation and other characteristics or experiences listed in box\xa02, creating unique overlapping and interdependent systems of discrimination or disadvantage.\n\n# Non-instructed advocacy\n\nWhen a person cannot communicate their views or wishes in a way that can be understood by other people, then advocates may use recognised approaches to ensure that what may matter most to the person is represented. Advocates will need to take additional steps to determine as far as possible what the person's likely wishes, feelings and desired outcomes are likely to be, to best represent the person. The advocate's role in non-instructed advocacy may include: upholding the person's rights; making sure that their likely concerns are recognised and responded to; ensuring access to support; and encouraging decisions to be taken based on what is important for the person, and challenging any that appear not to be. A person's ability to communicate what is important to them might fluctuate and advocates may move between using non-instructed advocacy and using instructed advocacy.\n\n# Opt-out\n\nOpt-out is when a person is automatically referred to the advocacy service unless they opt out of the referral. The opt-out system is designed to ensure that people who are eligible for advocacy are made aware of independent mental health advocacy services and have the opportunity to access them. An opt-out measure may overcome barriers to access.\n\n# Peer advocacy\n\nPeer advocates have lived experience and can support others with a similar disability or experience.\n\n# Reflective practice\n\nA process for staff to:\n\nreflect on previous practice\n\ntalk about why they made the decisions they made, and why they acted or behaved in particular ways\n\ntalk about their emotional responses to their actions and the actions of others\n\nengage in continuous learning.\n\nReflective practice may also provide insight into personal values and beliefs, and help staff understand how these influence action and decision making.\n\n# Self-advocacy\n\nThe action of representing oneself or one's views or interests. This may be with respect to the care and support that people receive or the way that services are organised locally.\n\n# Structural inequalities\n\nThe phrase refers to the inequalities that are systemically rooted in the normal operations of social institutions, in which different categories of people may not be seen as having equal status. This can result in the marginalisation of, or discrimination against, certain categories of people and manifest itself in areas such as unequal access to healthcare, housing or education.\n\n# Wellbeing\n\nThe Care Act 2014 defines 'wellbeing' as a broad concept, relating to the following areas in particular:\n\npersonal dignity (including treatment of the individual with respect)\n\nphysical and mental health and emotional wellbeing\n\nprotection from abuse and neglect\n\ncontrol by the individual over day-to-day life (including over care and support provided and the way it is provided)\n\nparticipation in work, education, training or recreation\n\nsocial and economic wellbeing\n\ndomestic, family and personal\n\nsuitability of living accommodation\n\nthe individual's contribution to society.", 'Recommendations for research': "The guideline committee has made the following recommendation for research.\n\n# Ways of providing advocacy services\n\nWhat is the effectiveness and acceptability of providing advocacy through different approaches?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on monitoring services and collecting data for quality improvement\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: monitoring services and collecting data for quality improvement.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect services.\n\n# Legal right to advocacy\n\nRecommendations 1.1.1 and 1.1.2\n\n## Why the committee made the recommendations\n\nFor more information about how these recommendations were developed, see the section on developing the recommendations.\n\nThe committee agreed that the legislation covering statutory entitlement to advocacy is complex and can be difficult to understand. Referring to guidance in legislation would make it easier for advocacy providers, health and social care practitioners and other referrers to find the information they need and help them to understand when they are legally required to offer advocacy.\n\n## How the recommendations might affect practice\n\nThe recommendations bring together statutory guidance. Any change in practice would be a result of becoming compliant with current legal requirements.\n\nReturn to recommendations\n\n# Who else may benefit from advocacy\n\nRecommendation 1.2.1\n\n## Why the committee made the recommendation\n\nFor more information about how this recommendation was developed, see the section on developing the recommendations.\n\nThe committee noted that advocacy was often mentioned in NICE guidance.\n\nIn their experience, the reasons that a person may benefit from advocacy are related to their circumstances or situation rather than their personal characteristics. Therefore, the committee focused on defining these circumstances.\n\n## How the recommendation might affect practice or services\n\nThe provision of non-statutory advocacy services varies widely across areas and service providers. Many areas have little or no provision beyond what is legally required. Therefore, investment is needed to expand the scope and range of services.\n\nAlthough there was no economic evidence included in the evidence review for this topic, several published NICE guidelines recommended the use of non-statutory advocacy as it was considered both effective and cost effective in the populations they covered, because it reduced or prevented the need for medical or other interventions. The populations considered in those guidelines had a substantial overlap with the population covered here, so the results are likely to be generalisable to this guideline.\n\nIf people who would benefit from non-statutory advocacy do not receive it, their needs often eventually escalate to a point at which they meet the threshold for statutory provision. So, providing non-statutory advocacy often does not represent new costs, but rather costs incurred sooner. Given the lower level of need for this group, the time needed for advocacy is likely to be substantially lower than for statutory advocacy. It is likely to reduce unplanned hospital admissions and the need for residential care. This should also lead to a higher quality of life by addressing needs earlier and preventing escalation. This reduction in time needed should also free up capacity in the statutory advocacy system, although this may take a few years. This will reduce or remove the need for longer-term investment in services, especially in employing new advocates.\n\nReturn to recommendation\n\n# Information about effective advocacy and signposting to services\n\nRecommendations 1.3.1 to 1.3.6\n\n## Why the committee made the recommendations\n\nFor more information about how these recommendations were developed, see the section on developing the recommendations.\n\nLocal authorities have a legal duty to make information available about the care and support services in their area, but the committee were aware that this does not always happen.\n\nIn the committee's experience, advocacy services are not widely known about and people are often unaware of their entitlement to advocacy. So, they do not access services. The committee agreed that providing this information should help to ensure that those with a legal entitlement to advocacy know about these services and can access them.\n\nThey also agreed that awareness of non-statutory advocacy services is particularly low. So, giving information to people who are not legally entitled to advocacy, but could benefit from it, is equally important. In their experience, if a publicly funded service is provided, there is also a duty to give people information to help them access it. The committee agreed that providing information about non-statutory advocacy would increase knowledge and uptake.\n\nThe Accessible Information Standard requires information to be given in accessible formats. The committee's experience is that this often does not happen for information about advocacy services. So, there is a risk of inequalities in access to both statutory and non-statutory advocacy. For example, people with communication difficulties might be less able to access services.\n\nIn the committee's experience, some people who initially decline an advocate later change their minds. Repeating information at different times means that the person has the knowledge and opportunity to use an advocate when they want to.\n\nIn the committee's experience, there is often confusion about who should provide information about advocacy services if someone is offered an out-of-area placement. They agreed that this responsibility needs to be clear.\n\n## How the recommendations might affect practice or services\n\nThere is a legal requirement for all advocacy services to provide information and signposting. But there are inconsistencies in how well this is met in different areas. There may be some change in practice for those not fully compliant with statutory requirements. For example, information is not always given in a range of formats, so there will be a cost for areas not currently adhering to this requirement.\n\nProviding information and signposting to people using out-of-area services will be a change in practice, because there is currently variation and confusion about who should do this. But implementing this recommendation is not expected to need extra resources.\n\nProviding information about non-statutory advocacy services is currently not a legal requirement. But it will not need any additional resource use because it can be included on existing information sources, such as printed leaflets or online. There may be an increase in resource use from more people using non-statutory advocacy services.\n\nReturn to recommendations\n\n# Improving access to advocacy\n\nRecommendations 1.4.1 to 1.4.12\n\n## Why the committee made the recommendations\n\nFor more information about how these recommendations were developed, see the section on developing the recommendations.\n\nIn the committee's experience, meeting in person was routine practice before the COVID‑19 pandemic. But to reduce costs, many services have continued with remote meetings after restrictions have lifted. The committee discussed the benefits of advocates meeting with people in person to help them start using advocacy services. These include being able to see each other's body language, which is an important way of getting to know and understand each other, and it can speed up the process of developing trust. This is particularly important when people are accessing advocacy services for the first time. Furthermore, advocates physically being in the same space with the person can help them to raise issues that are usually unspoken or non-verbalised, for example safeguarding issues. They agreed that in-person meetings for the first contact would improve access for people who would otherwise be unwilling to use advocacy services. But they also noted that although in-person meetings were optimal, there are situations for which remote meetings using digital platforms could still be effective and some people may prefer them.\n\nThe committee were aware that advocates experienced difficulties accessing certain settings due to blanket restrictions. These increased during the COVID‑19 pandemic (for example, limits on hospital and care home visiting). The committee agreed that access to an advocate was an essential part of upholding people's rights.\n\nHaving legal representation does not fulfil, or negate, the legal entitlement to advocacy. But in the committee's experience, there are often misconceptions that people do not need an independent mental health advocate if they have legal representation.\n\nFrom their knowledge and experience, the committee were aware of difficulties with referrals, which are often sent back when the right information is not included. This delays access to services and may reduce service engagement. Based on the evidence and their experience, the committee agreed that making access easier may help hard-to-reach groups and improve empowerment and self-advocacy.\n\nThe evidence indicated that there can be problems with continuity and access when people transition between different types of advocacy. Effective advocacy depends on developing trust and mutual understanding between the advocate and the person receiving support, so keeping the same advocate (for example, by having multi-skilled advocates) is important. But when this is not possible, ensuring that systems are in place for handover will make it less likely that people are lost to services.\n\nHealthcare practitioners should refer people for non-instructed advocacy if they need it, but in the committee's experience, this does not routinely happen. If independent mental health advocates are regularly present in inpatient settings, people are less likely to miss out on their statutory right to advocacy. The committee agreed that this could also have an important safeguarding effect, because it will give the advocates a comprehensive view of people's circumstances and environment.\n\nThe expert testimony highlighted barriers to access, such as lack of awareness or understanding and negative attitudes, and stated that an opt-out system for independent mental health advocacy (IMHA) could help to overcome these barriers. Based on their experience, the committee agreed that referrals are not always made when they should be and that offering advocacy on an opt-out basis is an effective way of ensuring access to statutory advocacy.\n\nIn the committee's experience, late referrals to IMHA services do not give people enough time to arrange advocacy support or meet their advocates before key meetings or events. This means that they cannot participate fully and effectively in decision making. Ensuring that people are offered IMHA early will help to avoid this. The committee agreed that repeating the offer of an advocate would give people more opportunities to take up advocacy support if they need it, especially if they had declined the original offer. For example, people who were too unwell when advocacy was first offered or people whose circumstances changed.\n\nBased on their own experience and evidence from the expert testimony, the committee agreed that raising awareness of service user groups and supporting peer and self-advocacy is important, because some people may prefer to seek advocacy from a peer rather than from a professional. People may feel better understood by, or more trusting of, people who have had similar experiences. Self-advocacy can also help the person to develop skills such as communication or decision making. This is in line with the advocacy ethos of supporting independence.\n\nIn the committee's experience, people with the greatest need for advocacy services may not be able to ask for them, and so they do not get the support they are entitled to. Based on the evidence, the committee agreed it was therefore important for advocacy organisations to have a plan to proactively offer support to people who may want to use the service.\n\nBased on the evidence and the committee's experience, it is often unclear who is responsible for providing advocacy services when someone is supported out of their home area. This can form a barrier to accessing services and cause delays, potentially leading to ineffective advocacy. Under the Care Act 2014, local authorities have a duty to make information available about the care and support services in their area. This includes advocacy services. The committee agreed that, as part of this, it would be sensible to provide information about access to advocacy for people supported out of their home area. This would need collaboration with advocacy providers.\n\nIn the committee's experience, people who are unable to ask for an advocate often are not offered advocacy services, despite being entitled to them. They agreed that it was the responsibility of healthcare and social care practitioners to ensure that advocacy is provided for everyone who needs it, even if they are not able to ask.\n\n## How the recommendations might affect practice or services\n\nDuring the COVID‑19 pandemic, most meetings with advocates were by phone or videoconference. Increasing the number of in-person meetings, especially initial meetings, is likely to increase the average time of a meeting. It will also increase the need for advocate travel to levels at or near to those before the pandemic. In‑person meetings may also increase the uptake of advocacy, again increasing costs. But there would be likely cost savings in the long term because greater uptake, and improvement in the quality of interactions, would result in identifying problems earlier. This would avoid costly medical interventions, such as unplanned admissions to hospital, and prevent duplicate or inappropriate referrals.\n\nRemote meetings are likely to be less expensive, but if the added convenience increases uptake those cost savings will be reduced.\n\nThe removal of blanket restrictions should not increase resource use, apart from the effect of in-person meetings restarting. Most new places that advocates would visit would not need substantially more travel or time than existing venues. Although extra time may be needed for visiting prisons, to clear security protocols, this will only be relevant to a small percentage of visits.\n\nProviding a simple process to access advocacy services will need some resources. But this is likely to mean shifting existing resources to fewer access points, rather than providing new ones. Cost savings should also occur from the economies of scale of having fewer access points, and a reduction in repeated or inappropriate referrals. Regular visits to inpatient settings by independent mental health advocates will be a change in practice in most places.\n\nThe committee agreed that providing continuity of access could have some upfront costs to employ multi-skilled advocates where these are not currently used, but this should be offset in part through more effective use of resources.\n\nThere is likely to be an increase in resource use from IMHA services making regular visits to hospital wards, both from the visits and from an increase in people using the service. Healthcare practitioners should already be making referrals for non-instructed advocacy, but in many places, this does not happen. Although it is likely to increase costs, savings are also likely to be made through improved safeguarding practices and through advocates obtaining a better understanding of peoples' needs. This should allow for better management of needs, improving quality of life and preventing costly unplanned hospitalisations.\n\nProviding an IMHA to people who are eligible for one is a legal requirement. But making access to IMHA opt-out rather than opt-in will mean that more people are aware of their right to access independent mental health advocates, and barriers to access (whether from process, lack of understanding or negative attitudes) will be substantially reduced. This is likely to increase access to those most in need of IMHA services, who may have had difficulty opting in, and to increase the number of meetings between advocates and people using their service. Although there is likely to be a significant resource impact in the short term, it will lead to improved access to advocacy services, and the benefits of these could offset costs in the longer term.\n\nReturn to recommendations\n\n# Enabling and supporting effective advocacy\n\nRecommendations 1.5.1 to 1.5.16\n\n## Why the committee made the recommendations\n\nFor more information about how these recommendations were developed, see the section on developing the recommendations.\n\nThe committee noted that the Care Act 2014 sets out who is legally entitled to have an advocate but that there is variation in how quickly this is currently determined. In the committee's experience, referrals to advocacy services are often made too late. This can mean the service does not have time to tailor meetings to the person's needs, for example communication needs. The committee also agreed that timely appointments mean the advocate can help the person prepare for meetings. They noted that delays to this would have a detrimental effect on the outcomes because advocacy helps people to take part effectively in decision making. From their knowledge and experience, the committee were aware that the inconsistency is partly because it is difficult to specify how much time is needed. This depends on the person's individual circumstances and needs, for example if they need an interpreter.\n\nMany people who use an advocate have a statutory right to be represented at meetings. This is also crucial for non-statutory advocacy, so that people have their voices heard when decisions are being made. But in the committee's experience, the availability of the advocate is often not taken into account when arranging meetings. This may be because of other urgent commitments, competing demands and service pressures. The committee noted that checking advocate availability will make planning more efficient by reducing the need to reschedule meetings.\n\nFrom their knowledge and experience, the committee were aware that delays in appointing advocates or not checking the availability of the advocate also put the person under time pressure. Lack of preparation time has a negative impact on the outcomes of meetings. So, the committee agreed it was important to give people the chance to rearrange meetings if they think that the time with their advocate was insufficient.\n\nThe committee agreed that building relationships and trust is a fundamental aspect of advocacy services. In their experience, effective advocacy is only possible when advocates have adequate time to build this relationship, so people feel comfortable sharing personal information and what is important to them. The committee were aware that the time it can take to build a trusting relationship could vary greatly based on individual needs, communication styles and personalities. Their experience was that this is often not factored in sufficiently when advocacy services are arranged.\n\nThe committee agreed on the importance of privacy and ensuring that people can talk to their advocate in private spaces, without being overheard. This promotes a trusting relationship and allows people to talk frankly about their goals, wishes and needs.\n\nThe committee discussed involving advocates in all discussions with the person. This promotes continuity of care, allowing the person using advocacy services to feel supported throughout the process. In the committee's experience, advocates are often only used during the decision-making process and less so after decisions have been made. But they noted that the discussions in meetings may sometimes be hard for the person to take in. This means that they may misinterpret what they have agreed to. The committee therefore decided that an advocate should be involved in all discussions (before and after meetings) to ensure that the person has understood fully what decisions have been made and the impact they may have, so that they have opportunities to challenge decisions and to raise any concerns.\n\nThe committee agreed that health and social care practitioners need to work collaboratively with advocacy services. This could facilitate decision making with the person in many ways. In the committee's experience, health and social care practitioners are often busy and sometimes assume that once they have made a referral, that their job is completed. But their ongoing support is necessary to enable effective advocacy to take place. Based on their experience, the committee provided examples of how to facilitate advocacy effectively. They agreed that it is important to encourage practitioners and advocates to build good relationships from the start so that they can work together effectively and in the best interests of the person.\n\nThe committee agreed that for advocacy services to be effective, advocates need to be able to meet the person and resources need to be used efficiently. They also noted that virtual meetings have become common and that people may need support with the software to access such meetings. From their knowledge and experience, they were aware that more practical support is needed to help people communicate remotely with their advocate or help them access virtual meetings that may otherwise not go ahead or be postponed. The committee discussed that this could include access to the internet, support to use technology, and help when scheduling meetings. The committee were aware of a person's need for privacy while communicating remotely with their advocates. The committee discussed that digital platforms could help advocacy services to engage with people and therefore ensure they are regularly contacted, get timely updates and are informed and empowered.\n\nThe committee agreed on the vital role of advocates in supporting a person to have their voice heard. This includes ensuring that concerns raised by the person (or on their behalf) are not only listened to but are also interpreted in the way they are intended, are acted on and are noted in records. This can then be referred to in any future meetings and followed up for a response if necessary.\n\nIn the committee's experience, there is wide variation in referrals for statutory advocacy, and non-compliance with legal duties is common. They highlighted the need to audit and monitor advocacy services to identify gaps in service delivery. The committee recognised that if health and social care practitioners developed action plans, this would help to improve compliance, by having clear steps that need to be taken to bring advocacy services up to the standard required by the legislation. The committee also agreed that including the numbers of referrals in corporate performance information would help to highlight discrepancies between the amount of advocacy commissioned and the number of people supported.\n\nThe committee noted that advocacy services commonly deal with vulnerable people who may experience discrimination or abuse. If an advocate has reasonable cause to suspect a person has experienced, is experiencing or is at risk of abuse or neglect, they must follow local safeguarding policies as set out in the Care Act (2014). But in the committee's experience, there is variation in advocates' knowledge of the actions required in these situations. Not acting in accordance with statutory safeguarding processes could have serious consequences.\n\nThe committee agreed that in their experience, the quality of safeguarding from advocacy providers varies and guidance is needed to ensure that safeguarding is effective, consistent and in line with legislation. They agreed that robust internal guidance would ensure providers consistently work to the required standard. Having effective governance, leadership, lines of communication and responsibilities also ensures that these processes are followed. The committee were aware that a safeguarding lead is already part of many local safeguarding policies but emphasised the need for this role to maintain good practice. The committee agreed on other examples that would ensure that staff know the relevant actions to take, so that they can prove that concerns have been raised and that actions have been taken. The committee also noted that safeguarding situations and related legislation are complex, and that training and supervision can help advocates feel confident in what to do if issues arise.\n\nThe committee noted that guidance on communicating and discussing complex information is covered by the NICE guidelines on people's experience in adult social care services, patient experience in adult NHS services and service user experience in adult mental health.\n\n## How the recommendations might affect practice or services\n\nThere is variation in how effectively advocacy is enabled and supported in different areas, so the impact on practice will vary. More advocacy hours will be needed to allow time and availability to help a person prepare before any meeting and ensure adequate arrangements are made, such as providing an interpreter if needed. Services may need to employ additional advocates. It may be possible to reallocate staff from other roles as services are streamlined and fewer meetings are repeated or decisions challenged.\n\nEnsuring that service providers consider the availability of the advocate when planning and scheduling meetings is expected to lead to more productive meetings with less revisiting of decisions. This could lead to cost savings or free up resources.\n\nInvolving advocates until decisions have been communicated will need a reorganisation of resources but is not expected to lead to additional cost or need for advocacy hours. There might also be some resources associated with rearranging meetings. But this might mean that meeting time is used more effectively, resulting in fewer decisions being challenged and resources being used more efficiently.\n\nThe type of information that gets audited may change, but this is not expected to need additional time or costs and will make data collection compliant with statutory requirements.\n\nThe guideline will reinforce best practice for health and social care workers facilitating advocacy and ensuring that advocates know how and when to act on safeguarding concerns.\n\nDigital platforms are already in almost universal use since COVID‑19. It is unlikely that further changes would be needed to this part of the service.\n\nReturn to recommendations\n\n# Effective advocacy\n\nRecommendations 1.6.1 to 1.6.15\n\n## Why the committee made the recommendations\n\nFor more information about how these recommendations were developed, see the section on developing the recommendations.\n\nThe committee agreed that people were more likely to access advocacy if organisations provided accessible services. Based on their knowledge and experience, they agreed on ways that advocacy providers could make their services more accessible, for example by making efforts to reach underserved communities. The committee agreed that access needs are not just physical but also involve the environment and location and the person's sensory needs. They also drew on their knowledge of the Advocacy Charter and Quality Performance Mark (QPM), to agree on ways to improve accessibility and tailor advocacy to the person's individual needs, for example physical or communication needs. This will enable the person to be fully involved in processes and meetings at which decisions are made.\n\nThe committee noted that providing person-centred services that adapt to each person's needs and circumstances is essential to effective advocacy. The committee agreed on specific suggestions for ensuring this, based on the advocacy QPM and their knowledge and experience. These included taking account of the person's views, values, culture and other experiences. The committee agreed that this individualised approach is vital to ensure that the person is comfortable and to help establish trust. The committee acknowledged that although it is an important part of making people comfortable and building relationships, offering people a choice of advocate might be difficult for some organisations, particularly smaller ones. Based on their experience, the committee agreed that the person-centred approach would have benefits beyond the effectiveness of the service. It would it also show other professionals and people using services what effective advocacy looks like, and what to expect from the service.\n\nThe committee agreed that a fundamental element of advocacy support is a shared understanding about what the person's optimal result would be. This allows the success of the advocacy to be assessed. But the committee were aware of variation in practice and the need to standardise good practice. They discussed the importance of advocates continually discussing and assessing goals and desired outcomes with the person, and agreed that everyone involved with advocacy needs to work together. They discussed that goals are recorded in initial meetings, but it is also important to discuss them each time and record any changes. Based on their experience, the committee acknowledged the challenges of such ongoing discussions if people lack capacity. But they agreed it is vital to make all possible efforts to establish the person's wishes and preferred outcomes. To ensure that the service is in the person's best interests, the committee agreed that it is important to involve other people who have an understanding of what the person would want (for example, family members or carers).\n\nThe committee discussed the benefits of actively involving people with lived experience of health inequalities or using health and social care or advocacy in designing and developing advocacy services. Having had the experience of using services could give them an understanding of what works and what the person needs from an advocate. This can ensure that services are more relevant and that they address needs sensitively and comprehensively. The committee agreed on the need to encourage services to get people with lived experience involved or to help them become advocates themselves.\n\nThe committee agreed it is essential to promote equality, equity of access, social inclusion and justice, and culturally relevant advocacy for all. Despite this being a legal requirement covered by the Equality Act 2010, the committee were aware of variations in service provision.\n\nBased on knowledge of the Care Act 2014, the committee discussed the importance of providers supporting advocates to identify and raise safeguarding concerns. They stated that not carrying out advocacy effectively and in line with safeguarding policies would potentially expose the person to discrimination, abuse or neglect, but the role of advocacy in safeguarding is often not well understood. Based on the committee's expertise and experience of safeguarding, they agreed on suggested ways in which providers can achieve effective advocacy that meets their legal safeguarding duties. Despite the Care Act 2014 specifying that local authorities must appoint an independent advocate to support someone through a Safeguarding Adults Review, the committee were aware this does not always happen.\n\nThe committee discussed that people value continuity and consistency in their advocacy services. Effective advocacy depends on developing trust and a mutual understanding of the issues that are important to the person. The committee agreed that this takes time to develop. So, to help this, the committee decided that the advocate ought to remain constant for as long as the person needs advocacy (unless the person using the advocate wishes to change).\n\nThe committee agreed on the importance of people being confident that their advocate is independent, so they know they have their advocate's full support and that there are no conflicts of interest. So, they agreed on the need for clear protocols to ensure the independence of advocacy. They agreed specific examples of ways in which advocacy services can demonstrate their independence from other services.\n\nAdvocates with mixed skillsets, such as experience in different types of advocacy, are valuable when supporting a diverse range of clients. Some people may have needs in many areas and need support in multiple issues. Having a single advocate able to provide several types of advocacy can be more effective and promote continuity of care. This could help with consistency and improving the overall quality of their advocacy. The committee conceded that sometimes specialist advocates are needed for more specific support (for example, a specialist in supporting people who lack capacity). The committee also acknowledged that it may not always be possible for all advocacy providers to provide advocates with mixed skillsets.\n\nAdvocacy services need to address inequalities in access to services and in service provision. This includes issues such as language (for example, use of interpreters) as well as consideration of any specific groups that may be disadvantaged or experience inequalities, such as taking into account a person's cultural needs and preferences.\n\nEffective and accessible communication and language is essential for an advocate to gain an in-depth understanding of a person's wishes and preferences. Interpreters are important if the advocate does not share the person's same first language. A lack of interpreting and translation services often poses as a barrier when using advocacy services.\n\nThe committee also noted expert testimony on the importance of culturally appropriate advocacy, which extends beyond language. They discussed that culturally appropriate advocacy is critical to achieve equity and social justice, and to reach people who are already disadvantaged and underserved by services. But there is a lack of provision for people from minority cultural backgrounds. Advocates should already be knowledgeable about existing health inequalities and would use this knowledge to influence and improve their work. The testimony highlighted that if people perceive that services are culturally relevant, in terms of their own ethnic identity, this can create a sense of shared understanding and encourage access to that service. The possible gain from providing culturally sensitive advocacy therefore should be larger than for standard advocacy.\n\nThe committee were aware from their knowledge and experience that many of a person's wishes, needs and preferences will be influenced by their cultural or ethnic identity. Advocates need to be sensitive to this, and this is integral to good practice. The committee agreed this could be facilitated by supporting staff to develop cultural competence through training, supervision and reflective practice so that they are confident in speaking to people about preferences related to culture.\n\nBased on the committee's knowledge of the UK General Data Protection Regulation of the Data Protection Act 2018 as well as legal requirements related to safeguarding, they highlighted the importance of confidentiality and privacy in person-centred advocacy. These are requirements of advocacy and fundamental to building trusting relationships. From their knowledge and experience, the committee were aware that in practice, there are some complications, particularly with confidentiality. For example, an advocate must breach a person's confidence if there are safeguarding concerns or if it appears a law has been broken. The committee agreed the key was for advocates to be open about this, maintaining confidentiality and assuring people but also explaining the circumstances or conditions under which they may need to breach confidentiality in line with legal requirements.\n\nIn the committee's experience, important aspects of professional relationships are sharing learning, insights and tools; and developing joint publications, guidance and resources. They agreed this improves collective effectiveness in the advocacy sector and helps to improve standards, provide consistency and sustain a drive towards best practice. It also encourages innovation and helps services develop new tools and techniques. Based on their experience, the committee agreed that smaller providers may have less capacity for this work, and competition for funding could act as a disincentive to share best practice. But they agreed it was still important to promote this joint learning and sharing.\n\n## How the recommendations might affect practice or services\n\nThe largest change in practice is likely to be in translation services and culturally appropriate advocacy. There may need to be investment in translation services, co‑location of services and culturally appropriate advocacy. This will increase access for people who have been less likely to access advocacy or had poorer service because of communication difficulties or lack of sensitivity to cultural needs. This will reduce inequality and unfairness in accessing advocacy services and will increase their overall uptake.\n\nProducing best practice and shared learning materials may have a resource impact in terms of the time needed to develop, quality assure and promote such tools. This may also need time from advocates to share their experiences and knowledge with others in writing or in other ways. This may be particularly difficult for smaller providers who may not have the advocate levels or facilities to produce such tools. But sharing best practice and promoting joint learning would lead to better advocacy with less repetition, challenges to decisions or need to repeat meetings. Such tools could also be used to promote cost-effective or cost-saving practices, leading to more efficient use of limited resources.\n\nProviding a greater range of venues for in-person meetings may mean that advocates need to travel further and may increase hosting costs. Using digital platforms for remote meetings has become common practice since COVID‑19.\n\nOrganisations may need to build extra capacity in services so that advocates have flexibility to work with different people according to a person's choice of advocate.\n\nThe recommendations will lead to changes in the number and range of people involved in designing advocacy services, and to changes in the information given to people about availability of and access to services. The way that goals are recorded and updated will also be a change in practice in some areas. All of these can be achieved by reallocating existing resources and are not expected to need additional investment.\n\nHaving the same advocate throughout the process will need multi-skilled advocates to be available at the start of a person's contact with advocacy. This may mean moving or employing multi-skilled workers, resulting in upfront costs. There may be less need for multi-skilled advocates later in the process if duplication of meetings and the need for handovers are reduced.\n\nReturn to recommendations\n\n# Partnership working and relationships with families, friends and carers, commissioners and providers\n\nRecommendations 1.7.1 to 1.7.11\n\n## Why the committee made the recommendations\n\nFor more information about how these recommendations were developed, see the section on developing the recommendations.\n\nIn the committee's experience, families, friends and carers commonly report that advocacy services do not work collaboratively with them. Such cooperation could be beneficial to the person and their care when the person wants them to or when the person cannot express a view about this but it is in their best interests, for example to gain an understanding of the persons' views, preferences, and desired outcomes. This is particularly important when people may not be able to communicate this effectively themselves, for example people with learning disabilities and communication challenges or when people lack capacity.\n\nThe committee discussed the importance of advocates being aware of support services that are available in their area. This will ensure they can provide people with information about other local support that may be available to them. The committee agreed that advocates are not always up to date with this information. They highlighted that it would usually be on council websites because the Care Act 2014 requires local authorities to make information about care and support services, including advocacy services, publicly available.\n\nIn the committee's experience, advocates could help raise awareness of issues, such as problems with referrals and difficulties people may have in accessing services, and the extent of such issues. They noted that Safeguarding Adults Boards might be unaware of all issues on the front line of services, and that raising awareness could improve services and safeguarding. Safeguarding Adults Boards engaging with advocacy providers could also raise the profile of advocacy, lead to less variation and support effective advocacy.\n\nThe committee acknowledged that people in need of advocacy services would not always know how to go about finding such services. They agreed on the need for commissioners to support advocacy providers giving this information. This could include allowing time in contracts for advocates to give information about which services are available, and how, where and when to access them, as well as for delivering advocacy.\n\nFrom their knowledge and experience, the committee were aware that sometimes there can be tension between advocacy providers, commissioners and service providers when balancing the need to advocate for a person with providing safe and effective services. They discussed that procedures or protocols could provide clarity, including for service referrals and dispute resolution. They particularly noted the need for jointly developed protocols to facilitate positive and consistent working relationships between services. The committee were aware that this is consistent with the advocacy QPM, which also highlights the need for protocols for promoting services.\n\nThe committee discussed the benefits of commissioners collaborating with other commissioners and commissioning bodies, locally and in other areas. In their experience, working together is important for effective commissioning. It also encourages a long-term view that considers the future commissioning and provision of services. Working together could improve the consistency and quality of advocacy services across different areas, and reduce the likelihood of gaps between geographical areas or between different parts of the health and social care system. This would also help address geographical inequalities in access to services.\n\nThe committee agreed that advocates need to be protected if there is risk, because there is the potential for ineffective advocacy if the advocate or the person they support does not feel safe. But in their experience, risks are not always clearly communicated and shared between advocacy services and care providers.\n\nIn the committee's experience, advocates do not always know whether they are allowed to access a person's notes and what the legislation is in relation to information sharing. Health and social care providers may not routinely share information, so there is inconsistency in what is made available. The committee noted that the legislation on sharing information, such as the Data Protection Act 2018 is complex, and agreed on the need for health, social care and advocacy providers to ensure that their staff understand when and how advocates may access a person's records in line with legislation.\n\nThe committee discussed that commissioners of IMHA services and mental health services working in partnership would help coordinate services and provide a good interface between them. They agreed, based on their experience, that this would also help to identify gaps in services. And it would give commissioners of one service, input into commissioning decisions made by another, which could help to improve the quality of both.\n\nThe committee discussed the importance of all organisations working together to provide culturally appropriate advocacy that meets local needs. From their knowledge and experience, and based on the expert testimony, the committee noted that mainstream advocacy provision has a narrow focus. It often fails to take account of broader issues relevant to minority communities, leading to disadvantage. The committee noted that these issues include social disadvantage, lack of equality and diversity within the workforce, and inequalities in access to services and service provision.\n\nThe expert testimony specifically highlighted support for integrating or co‑locating advocacy in other Black community and voluntary sector services. The committee agreed that these organisations could play a critical role in building relationships and partnerships and addressing social disadvantage. The testimony also supported increasing the diversity of staff in advocacy services if people express a preference for advocates who share their gender, language and culture. The committee agreed that this is important to break down barriers to accessing services and building trusting relationships, which would improve the effectiveness of advocacy.\n\nThe committee were aware that regulators may need the input of advocates in order to monitor the Mental Health Act in England. Access to advocacy is an area that could be looked at as part of the monitoring. Monitoring involves visits to institutions and interviews with staff, including IMHA. The committee agreed that advocacy providers should liaise with and facilitate the regulator in carrying out their role, including in inspecting regulated services.\n\n## How the recommendations might affect practice or services\n\nThe level of partnership working and relationships with families, friends and carers, commissioners and providers is variable. But many of the recommendations reinforce legal requirements, so services in almost all areas already comply.\n\nMore effective partnership working would lead to cost savings from improving services, reducing repetition and complaints, and making services more efficient.\n\nThere would be some initial costs to establish collaborative services where these are not already set up. Many advocacy providers already work with local support services to ensure they are familiar with what these services can offer, but this does not happen consistently. This may need a reorganisation of resources in some areas but it is not expected to increase costs.\n\nMaking sure that advocacy providers have the time and resources to make patient information available, including information in a variety of formats, should reduce costs even if initial upfront investment is needed. Having correct and up-to-date information on advocacy services that is accessible will speed up access to advocacy, avoid duplication, and avoid people losing contact with advocacy services if their needs escalate.\n\nAny decrease in the efficient use of resources would be more than compensated for by the reduction in inequality and increase in the fairness of society. The suggested actions may not be cost effective in all areas, so it would be up to individual service providers to decide how best to achieve the overall objectives.\n\nThere is currently a lack of continuity of advocacy providers liaising with and facilitating the regulator in carrying out their role, so the recommendation for closer working would lead to a change in practice. However, the Care Quality Commission has existing duties to assess the quality of care provided and need to assess if people have access to advocacy, which is not expected to result in further cost. Furthermore, this would ensure an improved feedback system, which in turn would lead to an improved quality of services and reduce costs in the long term.\n\nReturn to recommendations\n\n# Planning and commissioning services for advocacy\n\nRecommendations 1.8.1 to 1.8.15\n\n## Why the committee made the recommendations\n\nFor more information about how these recommendations were developed, see the section on developing the recommendations.\n\nThe evidence highlighted the need to improve the commissioning of advocacy services and suggested ways that this could be done. In the committee's experience, understanding the needs of the local population is essential when commissioning services to ensure that they are responsive to local needs and targeted at the people who need them. This approach to commissioning is considered best practice. But the committee highlighted that it is not mandated, so they wanted to place a greater emphasis on this approach to standardise effective, evidence-informed commissioning. Furthermore, this approach would help to ensure that advocacy services are commissioned in a way that would avoid the effects of structural, systemic and health inequalities, which result in unequal status, treatment and opportunities among population groups.\n\nThe committee agreed that there is currently a lack of evidence of long-term proactive planning for the development of advocacy, making it less likely that people will get the support they need in future. Having long-term plans based on assessment of need would ensure that service commissioning had clear long-term intentions and would be based on future local need.\n\nThe evidence highlighted that advocacy services tend to be commissioned only to meet legislative requirements. This means that people who have a genuine need for advocacy but fall outside the statutory requirements may have difficulty accessing it. In the committee's experience, commissioning advocacy services that can be used by people who do not meet the criteria for statutory advocacy would help to close the gap in provision, ensuring that more people benefit. The committee also agreed that this would facilitate earlier intervention at a lower level of need, which could prevent an escalation to situations in which statutory advocacy might be needed. Based on their experience, the committee agreed that commissioners need to be aware of policies, legislation and guidance beyond those that explicitly address statutory requirement for advocacy (for example, the Equality Act 2010). Advocacy services may need to change so that services are compliant with these wider requirements. The committee agreed that this would ensure that commissioning decisions create advocacy services that are as comprehensive as possible, compliant with all legislation, meet a diverse range of needs and promote equality.\n\nThe Care Act 2014 and statutory guidance require local authorities to ensure adequate high-quality care and support is provided that meets the needs of the local population. The Care Act 2014 also includes the concept of market development, which means the local authority has a responsibility to ensure there are sufficient, good quality services available in their area. In the committee's experience, closer collaboration between local authorities, commissioners, health and social care service providers and community stakeholders would help to establish a clear picture of whether or not existing services are meeting local population needs, to ensure these requirements are fulfilled.\n\nThe evidence highlighted the need to involve people who use or are likely to use advocacy services in planning, designing and monitoring services. In the committee's experience, service user involvement happens in some areas but not consistently. The committee agreed that involving service users in planning, designing and monitoring helps ensure services are relevant and suited to people's needs and preferences. They were aware of guidance on this in the NICE guideline on community engagement so they agreed to make a cross reference to support implementation of this practice.\n\nBased on their experience, the committee agreed that the provision of advocacy services for people who are detained or deprived of their liberty in independent hospitals is inconsistent. This is despite the fact that it is a legal requirement for local authority commissioners to provide advocacy to people in these circumstances. For example, there is currently very poor commissioning for people in private mental health settings.\n\nIn the committee's experience, people have different needs and therefore need different amounts of advocacy. Having overly restrictive contracts that specify what advocates can and cannot do and limit the amount of time advocates can spend with a person compromises the independence of the advocate, makes it difficult for them to work in line with the principles of advocacy and reduces the quality and effectiveness of the advocacy they provide.\n\nThe committee agreed that advocates need to undertake training and continuing professional development to be able to provide high-quality, effective advocacy. Contracts and specifications for advocacy providers need to include time allowances to make this possible but not all of them currently do so.\n\nIn the committee's experience, quality standards provide an important benchmark to measure performance against. This helps to promote a consistent, high-quality service and identify any improvements needed. The committee were aware that the advocacy QPM is a widely used quality assurance assessment. The QPM is given to organisations demonstrating excellent service provision in line with QPM standards, the Advocacy Charter and the Advocacy Code of Practice. The effectiveness of the QPM was not reviewed as part of this guideline so the committee did not recommend its use. But they agreed with the benefits of external quality accreditation.\n\nIn the committee's view, taking a person-centred approach is a key principle of advocacy. Embedding this in contracts and service specifications is essential in enabling advocacy services to be truly person centred. Based on the expert testimony and a report from the Care Quality Commission (recommending a level of personalised care that equated to intensive and long-term support), the committee gave examples of steps commissioners could take to ensure that services are person centred.\n\nIn the committee's experience, it is not possible to specify a particular way of developing service specifications and contracts that would ensure that services meet the needs of everyone. When planning and providing support, it is important to allow for reasonable adjustments that promote equality and avoid disadvantaging particular people. Doing this alongside the recommendations on training (see section\xa01.9 and section\xa01.10), will ensure advocates have the dedicated time and space to deliver a person-centred service and to continuously enhance their skills, all of which is essential for maintaining quality and standards.\n\nIn the committee's experience, people are most comfortable with advocates they can relate to and trust, and this tends to lead to more effective advocacy. The expert testimony highlighted that a lack of diversity and understanding of equality and issues relevant to minority communities can form a barrier to people accessing, or taking up, advocacy services. The evidence highlighted that local organisations could be better placed to support access for potentially disadvantaged groups. The committee agreed that working with local organisations would help commissioners provide services tailored to the local population. This could help remove barriers to access for underserved groups, such as those with refugee status and people from Gypsy, Roma and Traveller communities.\n\nThe evidence highlighted the lack of suitable advocacy for people with complex needs, such as learning disabilities. The committee agreed that people's different advocacy needs can be best met by offering a variety of advocacy models and commissioning services tailored to the local population. This includes commissioning services with advocates specialising in different types of advocacy and multi-skilled advocates.\n\nThe evidence highlighted the need to establish consistent good practice in safeguarding as part of the advocacy role. Advocacy is important in safeguarding because it supports people's involvement and decision making when there are safeguarding concerns, safeguarding enquiries or safeguarding adult's reviews. Involving someone independent from other services, who is representing the person's best interests and is aware of their circumstances and living conditions, can help to identify the potential for abuse or neglect, enabling concerns about service quality to be raised before they become a safeguarding issue. But in the committee's experience, advocates are not consistently involved in safeguarding processes.\n\n## How the recommendations might affect practice or services\n\nThere is already a statutory duty to make information about advocacy services available. This will remind services to comply if they do not already.\n\nThe Joint Strategic Needs Assessment already involves an element of forward planning. However, this does not include agreeing and publishing long-term plans for advocacy. Therefore, some change in practice will be needed to extend the timeframe over which planning takes place. There may be some upfront costs associated with commissioning bodies working in partnership to agree and publish long-term plans, but these plans would ensure that future resources are better allocated. Once the advocacy providers have longer contracts, the initial investment made would be retained as it would result in improved retention and a long-term workforce that would not need new training.\n\nActive analysis of public policies, legislation and guidance may initially have a resource impact but will lead to more effective, efficient practice and will potentially save costs in the longer term. Changes in practice may also occur as a result of commissioning different or modified services in line with statutory requirements and lessons from shared learning.\n\nThere may be some upfront costs associated with involving people who use independent advocacy services in planning and designing the services, especially as some groups may be challenging to recruit from and may need interventions to help them actively participate. But this should lead to services being more responsive and efficient, and avoid wastage. This would lead to cost savings. It is also in line with the general move towards shared decision making in health and social care.\n\nAlthough it is a legal requirement for commissioners to ensure there are sufficient advocacy services available for people who are detained in independent hospitals, this is not happening consistently. Where it is not currently happening, there will be some costs associated with it because more people would receive advocacy. But this is expected to lead to more efficient services, with better decisions being made, leading to cost savings in the long term.\n\nSupporting advocacy providers to maintain their independence will lead to better quality service, reducing complaints and needs for judicial reviews, therefore saving costs in the long term. There may be some resource impact associated with engaging with the community and carrying out local needs assessments on which to base commissioning of advocacy services. But in most areas, this is already happening.\n\nNot all contracts and specification for advocacy include time allowances for training and continuing professional development so some change in practice may be needed. But having advocates who are suitably trained and competent should result in fewer complaints, improved services and the ability to identify needs before they escalate.\n\nEnsuring that advocacy services are person centred is not expected to have a resource impact. All health and social care services should already personalise care or treatment specifically for each person who uses the service.\n\nReturn to recommendations\n\n# Training, skills and support for advocates\n\nRecommendations 1.9.1 to 1.9.8\n\n## Why the committee made the recommendations\n\nFor more information about how these recommendations were developed, see the section on developing the recommendations.\n\nIn the committee's view, advocacy is still establishing itself in the consciousness of both the people who would benefit from using it and the practitioners who can make referrals to it. If it is to be effective, it is crucial that advocacy is recognised and valued. Advocates need to be able to support people from a variety of backgrounds and with different needs. So, they need to develop the appropriate skills, knowledge and behaviours to do this effectively. In the committee's experience, comprehensive and consistent training is the most effective way to achieve this. But there is variation in the current content and availability of training.\n\nThe committee agreed with evidence from NICE's guideline on decision making and mental capacity that an increase in investment in training for advocates would improve the availability and quality of advocacy.\n\nThe evidence highlighted several areas that advocates need to be trained in. In the committee's experience, advocates need knowledge and skills in these processes and areas to undertake their role effectively. In their experience, training for advocates is inconsistent, and the committee agreed that all training needs to be brought up to an agreed standard.\n\nStatutory guidance to the Care Act (section\xa07.43) states that 'Once appointed, all independent advocates should be expected to work towards the National Qualification in Independent Advocacy within a year of being appointed, and to achieve it in a reasonable amount of time'. The committee noted that the statutory guidance is vague about the timeframe for achieving this qualification and in their experience, 'a reasonable amount of time' is interpreted very differently. The committee agreed that the quality of advocacy services would improve if all advocates achieved this qualification, although they could not recommend a specific timeframe because the statutory guidance does not stipulate one.\n\nThe committee agreed that supervision of advocates is crucial. It ensures consistency across services and that advocates are meeting the necessary standards. It also provides an opportunity for all advocates to develop skills and learn from others.\n\nIn the committee's experience, people who cannot instruct an advocate are less likely to have one. Therefore, providing non-instructed advocacy helps to ensure that people's rights to advocacy are protected. In the committee's experience, the skill and confidence of advocates in using non-instructed advocacy varies across the sector. Because non-instructed advocacy is used when someone needs an advocate but cannot tell the advocate what they want, the advocate's role is more challenging. Extra steps may be needed to determine the person's likely wishes, feelings and desired outcomes in the absence of instruction. The committee agreed that providing extra training and support for non-instructed advocates would improve practice in this area.\n\nThe committee agreed it is essential that volunteer advocates receive the same support and supervision as paid advocates. This will ensure that the services provided by volunteer advocates meet the necessary standard.\n\n## How the recommendations might affect practice or services\n\nThere are currently variations in the training that advocates are given on health and social care, justice, legal processes and skills needed for effective advocacy. The bespoke economic model for the guideline estimated that there would be an initial resource impact from improving training, especially when training takes advocates away from core duties for a long time. But there would be cost savings in the future from advocates working more efficiently and a reduction in complaints and repeated meetings. Better training for advocates would also lead to a higher quality of service. This would improve people's outcomes and quality of life, while reducing the number of expensive interventions such as unplanned admissions to hospital.\n\nThe economic model gave an upper estimate for costs involving a qualification needing a long period of training and study. Not all advocates will need training in all the processes and areas. The amount of training needed will depend on the role and responsibility of individual advocates and the needs of the population in their local area. Because there is already a requirement for all independent advocates to work towards the National Qualification in Independent Advocacy, this should not need additional resources.\n\nTraining in non-instructed advocacy is in line with the Care Act 2014 requirement for advocates to have appropriate training, so this should not have additional resource requirements.\n\nCurrently there are inconsistencies in the amount of training provided for volunteer advocates so there may be additional costs associated with this. The amount of training needed will depend on the role and responsibility of individual advocates and the needs of the population in their local area. It is not anticipated that all volunteer advocates will need training in all the processes and areas. Training volunteer advocates will ensure that the required service standard is met, and there might also be improvements from reduced complaints.\n\nReturn to recommendations\n\n# Training and skills for health and social care practitioners who work with advocates\n\nRecommendations 1.10.1 to 1.10.5\n\n## Why the committee made the recommendations\n\nFor more information about how these recommendations were developed, see the section on developing the recommendations.\n\nIt is a legal duty for an advocacy referral to be made when people are entitled to advocacy support, and people who cannot self-refer to advocacy rely on these referrals. In the committee's experience, the different statutory duties and eligibility criteria for advocacy are complex and difficult to understand, making it hard for practitioners to know who is entitled to an advocate. In the committee's view, training would be the most effective way of improving practitioners' knowledge about entitlement to advocacy support, so that they could comply with the legal requirements on referral.\n\nTo retain organisational and individual knowledge and prevent issues associated with staff turnover, the committee agreed that training about entitlement to advocacy should form part of induction training and be regularly refreshed. This would lead to consistent practice and referrals and increase effective practice. Refresher training every 2\xa0to 3\xa0years achieves a balance between the need to keep knowledge current and the time needed to attend training. The committee used the evidence to decide on the most important elements of training.\n\nThe committee agreed that staff who may be the first point of contact in health and social care services need to understand who is entitled to advocacy and when and how to request it so that people do not fall through the gaps at this early stage. In their experience, this understanding is not consistent across staff.\n\nStaff in organisations working with advocacy services should receive training on the role and function of advocacy as part of their training. In the committee's experience, this is not consistent, which can lead to misunderstandings about advocacy, poor practice and negative working relationships. Having better knowledge would enable staff in organisations working with advocacy services to facilitate advocacy more effectively and improve working relationships. The committee used their experience of common misunderstandings about the role of advocacy to decide on what this training should cover.\n\nDifferent health and social care practitioners will need different levels of training in advocacy, depending on their role. In the committee's experience, tailored training is more cost effective than providing the same training for everyone. The committee also agreed that delivering training in different formats should maximise its effectiveness. For example, it may be easier and more cost effective for people to access training remotely, at a time of their choosing, rather than attending fixed, face-to-face training sessions.\n\nIn the committee's experience, it is important to include people with lived experience of advocacy services in developing and delivering training for practitioners. Having real-life input can make the training more impactful and memorable, and increase the likelihood it will be implemented. People with lived experience are likely to have different priorities for what practitioners need to know and the gaps that exist in practice.\n\nFrom their knowledge and experience, the committee were aware that the knowledge gained during training is not always implemented or used effectively in practice, and so this needs to be checked.\n\n## How the recommendations might affect practice or services\n\nSome changes in practice or services may be needed. Health and social care practitioners should already be receiving training in legislation and the role of advocates, but this is delivered inconsistently. Refresher training is not routine and there is variation across regions in how much training is tailored. Although there may be some changes in practice needed to deliver training, there are existing materials that can be used which would minimise cost. This is especially true for refresher training where previous training materials can be reused and costs should be minimal. Not everyone will need the same depth of knowledge and amount of training, so the training can also be tailored to individuals for efficiency.\n\nTraining does not consistently include people with lived experience. For organisations that are not currently doing this, there is likely to be a change in practice. And there will be some costs from providing support to enable people with lived experience to take part in the training and share their experiences. This would improve the overall quality of training, making it more relevant and meaningful and help to improve practitioners' understanding of advocacy. This can help the right people access advocacy at the right time, and in the long term, could improve services.\n\nDelivering training in a variety of formats may have some costs. But costs will be minimal if training is by self-directed learning or is delivered remotely.\n\nImproved training for practitioners should help identify people who have a right to advocacy under current legislation. This will increase the total number of people accessing advocacy services, leading to a greater resource impact than the training itself, at least in the short term. But the increased access will be from people who have a legal right to advocacy services, so resources should already be in place to meet this statutory requirement. Better access to advocacy should also lead to better outcomes and less risk of needs escalating, leading to lower downstream costs and higher quality of life.\n\nThere may be some costs associated with ensuring that knowledge gained through training is applied in practice, for example from changing approaches to enable effective supervision, although these should be small and short term. But increased use of knowledge in practice should lead to improvements in the quality of service and a reduction in complaints and adverse outcomes, resulting in cost savings.\n\nReturn to recommendations\n\n# Monitoring services and collecting data for quality improvement\n\nRecommendations 1.11.1 to 1.11.18\n\n## Why the committee made the recommendations\n\nFor more information about how these recommendations were developed, see the section on developing the recommendations.\n\nIn the committee's experience, advocacy providers need to have defined, service-level outcomes that can be measured to ensure that they are delivering an effective, high-quality service. Many providers currently report key performance indicators as part of contracts and commissioning arrangements. But in the committee's view, these service-level outcomes should include more person-centred metrics (for example, whether people's voices are heard and the effect on empowerment). Input from people who use advocacy services and other stakeholders would help to achieve this. The committee also noted that collaboration between commissioners and advocacy providers when agreeing outcomes would reduce the likelihood of gaps occurring between geographical areas or people falling between different parts of the health and social care system.\n\nThe committee agreed it was important to be clear about how outcomes will be reported. This enables data to be analysed for protected characteristics or other disadvantaged groups, such as those experiencing health inequalities.\n\nCurrently, advocacy services tend to collect data on the impact of advocacy at an individual level. In the committee's experience, collecting data that also enables an understanding of population-level needs would assist the commissioning of more effective services and would align with developments in Health and Social Care services such as the move to Integrated Care Systems. Based on the evidence, they agreed areas for data collection that would help this.\n\nThe committee were aware that advocates sometimes face pressure from other services or commissioners to prioritise certain outcomes or not to raise concerns. Advocates are also sometimes asked for unnecessary information that could identify individual people, potentially breaching the Data Protection Act 2018 and damaging relationships between the advocate and the person they support. The committee agreed that commissioners need to be alert to these issues when collecting data.\n\nIn the committee's experience, there is variation in what information is collected about people using advocacy services, and information about the impact of advocacy services is not routinely collected in a standardised format. Collecting data in a standardised format makes it easier to evaluate, so that gaps in service provision can be identified and it can be seen whether services are meeting local needs. It also makes it easier to share key information with other organisations.\n\nBased on the evidence, the committee agreed some important standard types of data to collect and suggested formats for doing so. The committee agreed that including protected characteristics would help identify whether there are particular groups that are not receiving services they would benefit from and help to reduce health and other inequalities.\n\nIn the committee's experience, information about advocacy services is not provided consistently. Monitoring whether health and social care providers are doing this should help drive improvements in access to advocacy for those who need it. The committee were aware of wide discrepancies in how advocacy is commissioned in different areas, with some areas only commissioning statutory services rather than being responsive to local needs. Monitoring access to advocacy and take up of it would help to identify any groups who would benefit from advocacy services but are not currently using them. This could help address inequalities in access.\n\nBecause advocacy is an emerging field relative to other areas of health and social care, there are no evidence-based quality standards mandated for use. In the committee's experience, quality standards provide an important benchmark with which to measure performance. Having a robust method of quality assurance would help to promote a consistent, high-quality service and identify any improvements needed.\n\nThe information and data used by commissioners is diverse, and varies according to area and local need. The committee agreed that standardised data recording and collection methods, with the same type of information collected by different commissioners and in different areas, would produce data that is consistent and transparent. This would allow data to be compared across services, which may in turn help improve the quality of services.\n\nIn the committee's experience, getting feedback from the full range of people using advocacy services is necessary to ensure that services are responsive to the needs of the local population. They agreed that it may be necessary to support individual preferences and communication needs to get this feedback, but that doing so should give a better view of whether services are meeting needs and any necessary improvements. The committee also noted that the provider of the service is typically the point of contact for feedback and were keen to facilitate anonymous feedback to prevent any barriers to receiving feedback.\n\nIn the committee's view, the monitoring data collected needs to be evaluated and used to generate continuous improvement in services. From their knowledge and experience, the committee were aware that commissioners do not always use information gathered from advocacy services to inform improvements in practice. The committee also agreed that sharing this information with other organisations would help highlight gaps in provision, areas for improvement, trends and themes for service change. All of these would help to improve the quality of advocacy services.\n\nThere is a statutory requirement to involve an independent advocate to support people who are subject to a safeguarding enquiry or safeguarding adult review, as outlined in the statutory guidance to the Care Act 2014. In the committee's experience, advocates are not always informed about safeguarding concerns in a timely manner. The committee agreed that it is important to monitor the involvement of advocates to ensure that the legal duty is being upheld, and that processes are in place to do this. They also agreed that advocates are in a good position to recognise and report when this is not being done so that steps can be taken to address problems.\n\nFrom their knowledge and experience, the committee were aware that there is a longstanding issue of referrals for advocacy not being made when needed. They discussed that complying with statutory duties is essential to ensure that a person's rights are upheld. The committee agreed that commissioners have the power to help enforce this compliance, given that they are the ones responsible for funding and contracts.\n\nBased on the evidence, and their knowledge about gaps in evidence and about the factors that make an advocacy service effective, the committee agreed that more information is needed about the effectiveness of advocacy delivered through different approaches. For example, advocacy delivered by an advocate with lived experience, or by an advocate with the same ethnicity as the person being supported (see the recommendation for research on ways of providing advocacy services).\n\n## How the recommendations might affect practice or services\n\nCollecting data is not expected to lead to any long-term increase in resource use. Most centres already have data collection and monitoring processes in place. There will be some short-term costs for services whose monitoring, data collection or quality assurance systems are not in line with the recommendations.\n\nThere will also be some upfront costs from initial meetings between advocacy services and commissioners to develop protocols or operating procedures.\n\nBetter and standardised monitoring, data collection and quality assurance should lead to more effective and efficient advocacy services with potentially large cost savings.\n\nReturn to recommendations"}	https://www.nice.org.uk/guidance/ng227	This guideline covers advocacy for people using health and social care services in all adult settings (including young people under 18 using adult services). It describes how to commission and deliver effective advocacy, as well as identifying who should be offered advocacy (including who is legally entitled to it). It also covers monitoring and improving advocacy services, and training and skills for advocates and practitioners.
afb3806cd4ae6253cbb5dd69ccb830f96567bde0	nice	Palbociclib with fulvestrant for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy	Palbociclib with fulvestrant for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy Evidence-based recommendations on palbociclib (Ibrance) with fulvestrant for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy. # Recommendations Palbociclib plus fulvestrant is recommended as an option for treating hormone receptor‑positive, HER2‑negative locally advanced or metastatic breast cancer in adults who have had endocrine therapy only if: exemestane plus everolimus is the most appropriate alternative to a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor and the company provides it according to the commercial arrangement. If patients and their clinicians consider palbociclib plus fulvestrant and abemaciclib plus fulvestrant or ribociclib plus fulvestrant to be suitable options, use the least expensive treatment. Take account of the monitoring and adverse event costs, dosage, price per dose and commercial arrangements. Why the committee made these recommendations This appraisal reviews the evidence for palbociclib plus fulvestrant for hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer after endocrine therapy (NICE technology appraisal guidance TA619). It also reviews new evidence from a clinical trial and data collected from people having treatment through the Cancer Drugs Fund managed access agreement. Treatment for hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer after endocrine therapy includes exemestane plus everolimus, and the CDK4/6 inhibitors abemaciclib (plus fulvestrant) and ribociclib (plus fulvestrant) if exemestane plus everolimus is the most appropriate alternative. Palbociclib plus fulvestrant is another option that works in a similar way to abemaciclib and ribociclib. The new evidence collected from people having treatment through the Cancer Drugs Fund shows that palbociclib plus fulvestrant is clinically effective. Additional clinical trial evidence shows that it increases how long people live compared with placebo plus fulvestrant. Indirect comparisons suggest that it has similar clinical effectiveness to abemaciclib plus fulvestrant and ribociclib plus fulvestrant. A cost comparison suggests palbociclib plus fulvestrant has similar costs to abemaciclib plus fulvestrant and ribociclib plus fulvestrant. So, palbociclib plus fulvestrant is recommended if it is used in the same population as abemaciclib and ribociclib.# Information about palbociclib # Marketing authorisation indication Palbociclib (Ibrance, Pfizer) is indicated 'for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer: in combination with an aromatase inhibitor; in combination with fulvestrant in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for palbociclib. # Price The company's list price is £2,950 per 21-pack of 75 mg, 100 mg or 125 mg capsules (excluding VAT; BNF online, accessed July 2022). The average cost of a course of combination treatment at list price is £6,170.70 for the loading dose and £5,126.42 for the following cycles. The company has a commercial arrangement. This makes palbociclib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Pfizer, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # Treatment pathway ## People with advanced breast cancer value a choice of treatment options People with advanced breast cancer who have had endocrine therapy are eligible for the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors abemaciclib or ribociclib, in combination with fulvestrant, if exemestane plus everolimus is the most appropriate alternative (see NICE's technology appraisal guidance on abemaciclib and ribociclib). Patient experts said that these treatments can delay disease progression and delay or avoid the need for chemotherapy. Patient experts noted that they value a choice of treatment options because CDK4/6 inhibitors have different side effect profiles. Choice would give people the option to change to a different treatment if needed. Patient experts noted that the side effect profile of palbociclib is more similar to ribociclib than abemaciclib, but unlike ribociclib, palbociclib does not need any ECG monitoring. The committee concluded that having a choice of treatments is valued by people with advanced breast cancer. # Clinical evidence ## PALOMA-3 is relevant to the NHS and has a long follow-up period PALOMA-3 is a multicentre double-blind randomised placebo-controlled trial comparing palbociclib plus fulvestrant (n=347) with placebo plus fulvestrant (n=174) in adults with hormone receptor-positive, HER2-negative advanced breast cancer. An additional 28 months of overall survival data were collected in the ongoing trial while palbociclib was also available to people through the Cancer Drugs Fund. After a median follow-up of 73.3 months in the trial, median overall survival was 6.8 months longer in people who had palbociclib plus fulvestrant compared with those who had placebo plus fulvestrant (median 34.8 months for palbociclib plus fulvestrant compared with 28.0 months for placebo plus fulvestrant ). The committee noted that there was a relatively long follow-up period in PALOMA-3. The EAG noted that people in the trial may have had more previous treatments than people seen in NHS clinical practice, but considered that the results are generalisable to the NHS. The committee concluded that the results from PALOMA-3 are relevant to the NHS and the trial has a long follow-up period. ## A large Systemic Anticancer Therapy (SACT) dataset supports the clinical effectiveness of palbociclib plus fulvestrant Public Health England provided observational data from the SACT dataset for 1,140 people who had palbociclib plus fulvestrant through the Cancer Drugs Fund. Median follow-up was 10 months. Median treatment duration with palbociclib plus fulvestrant was 9.4 months and median overall survival was not yet reached. At 6 months, 88% of people taking palbociclib plus fulvestrant were alive; at 12 months, 75% were alive; and at 18 months, 63% were alive. The committee noted that equivalent overall survival rates were seen with abemaciclib plus fulvestrant at 6 and 12 months in SACT. It noted that the SACT dataset did not directly compare palbociclib plus fulvestrant with abemaciclib plus fulvestrant but the findings showing similar efficacy of the 2 treatments in NHS clinical practice were reassuring. The committee concluded that a large SACT dataset supports the clinical effectiveness of palbociclib plus fulvestrant. ## Abemaciclib plus fulvestrant and ribociclib plus fulvestrant are appropriate comparators Abemaciclib and ribociclib are CDK4/6 inhibitors recommended by NICE for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy. Palbociclib is another CDK4/6 inhibitor that works in a similar way to abemaciclib and ribociclib. The EAG's clinical advisers noted that the 3 drugs have the same primary mechanism although with some differences in individual inhibition of CDK4 and CDK6 in laboratory studies. They also noted differences in dosing schedules, serum concentration and toxicity. All 3 CDK4/6 inhibitors are administered orally. Palbociclib and ribociclib are given once daily for 21 days of a 28‑day cycle. Abemaciclib is given twice daily for the whole cycle. All are combined with fulvestrant, which is given by intramuscular injection, twice in the first month, followed by once monthly. The committee concluded that abemaciclib plus fulvestrant and ribociclib plus fulvestrant are appropriate comparators for palbociclib plus fulvestrant. ## MONARCH 2 and MONALEESA-3 can be compared with PALOMA-3, although there are some differences between the 3 trial populations The pivotal clinical trials of abemaciclib plus fulvestrant and ribociclib plus fulvestrant are MONARCH 2 (n=669) and MONALEESA-3 (n=726). As in PALOMA-3 (see section 3.2), these trials compared a CDK4/6 inhibitor plus fulvestrant with placebo plus fulvestrant. All 3 trials had investigator-assessed progression-free survival as the primary endpoint. The committee considered that MONARCH 2 and MONALEESA-3 provided suitable clinical evidence for a comparison with PALOMA-3. People in PALOMA-3 and MONARCH 2 could be in any stage of menopause, while those in MONALEESA-3 were in postmenopause. However, in PALOMA‑3 and MONARCH 2, people who were in premenopause or perimenopause had a luteinising hormone-releasing hormone agonist to make them functionally in postmenopause. The EAG noted that people in PALOMA-3 had more previous chemotherapy in the metastatic setting than the other 2 trials. The committee also noted that people in PALOMA‑3 were younger (75% aged under 65 years) than those in MONARCH 2 (63% aged under 65 years) or MONALEESA-3 (53% aged under 65 years). The committee concluded that MONARCH 2 and MONALEESA-3 can be compared with PALOMA-3, although there are some differences between the 3 trial populations. ## Clinical trials evidence suggests that palbociclib, abemaciclib and ribociclib are likely to provide similar health benefits The results of PALOMA-3, MONARCH 2 and MONALEESA-3 show that palbociclib plus fulvestrant, abemaciclib plus fulvestrant and ribociclib plus fulvestrant improve progression‑free survival and overall survival compared with placebo plus fulvestrant. The EAG stated that the hazard ratios for these outcomes were similar for the 3 treatments and the committee was aware that follow up was longer in the palbociclib trial than the others. Only PALOMA-3 and MONALEESA-3 collected data on subsequent therapy. This showed that most people had a follow-on therapy. The EAG stated that some people had a subsequent CDK4/6 inhibitor which is not standard NHS practice. However, the committee noted that this was more common in people who had placebo plus fulvestrant in the trial and had not had a CDK4/6 inhibitor before. The committee concluded that evidence from the 3 clinical trials suggests that palbociclib, abemaciclib and ribociclib, all in combination with fulvestrant, are likely to provide similar health benefits in terms of progression-free and overall survival. ## There are some differences in low grade adverse events between palbociclib, abemaciclib and ribociclib that may impact treatment choice The company noted that the 3 CDK4/6 inhibitors have a broadly similar profile of grade 3 or higher adverse events. But there are important differences in some low grade adverse events. Neutropenia is less common and lower grade with abemaciclib plus fulvestrant than with palbociclib plus fulvestrant or ribociclib plus fulvestrant. Any grade diarrhoea is more common with abemaciclib plus fulvestrant (87%) than with palbociclib plus fulvestrant or ribociclib plus fulvestrant (both less than 30%). The EAG noted that the lower rates of diarrhoea seen with palbociclib plus fulvestrant than with abemaciclib plus fulvestrant have the potential to improve health-related quality of life. The Cancer Drugs Fund clinical lead noted that diarrhoea has a direct impact on people having treatment. Neutropenia is a toxicity detected through regular blood testing but it may not affect the person having treatment or cause symptoms. The committee recalled that people with advanced breast cancer value choice in treatments and the option to change to a different treatment if needed (see section 3.1). The committee concluded that there are some differences in low grade adverse events between palbociclib, abemaciclib and ribociclib that may impact treatment choice. # Indirect treatment comparisons ## Well-designed indirect comparisons suggest that the clinical efficacy of palbociclib plus fulvestrant is similar to or better than the comparators The company presented matching-adjusted indirect treatment comparisons (MAICs) of palbociclib plus fulvestrant compared with abemaciclib plus fulvestrant and ribociclib plus fulvestrant. These used latest survival data from the 3 pivotal trials (see section 3.6). In the MAICs, the PALOMA-3 population was statistically adjusted to resemble the MONARCH 2 and MONALEESA-3 populations. This was to predict the treatment effect if palbociclib plus fulvestrant had been evaluated in these populations. The EAG agreed with the company's approach to account for differences between the 3 trial populations (see section 3.5). It considered that the MAICs were well designed. The MAICs of palbociclib plus fulvestrant and abemaciclib plus fulvestrant included up to 12 potential treatment effect modifiers. The results suggested no statistically significant difference in progression-free survival or overall survival with palbociclib plus fulvestrant compared with abemaciclib plus fulvestrant. The committee noted that the MAICs suggest that the clinical efficacy of palbociclib plus fulvestrant is similar to abemaciclib plus fulvestrant. The MAICs of palbociclib plus fulvestrant and ribociclib plus fulvestrant included up to 13 potential treatment effect modifiers. The results suggested no statistically significant difference in overall survival with palbociclib plus fulvestrant compared with abemaciclib plus fulvestrant. However, some of the MAICs for progression-free survival, including when all effect modifiers were considered, suggested a statistically significant difference in favour of palbociclib plus fulvestrant. The committee noted that the MAICs suggest that the clinical efficacy of palbociclib plus fulvestrant is similar to or better than that of ribociclib plus fulvestrant. The committee concluded that the well-designed MAICs suggest that palbociclib plus fulvestrant is similar to or better than the comparators. # Cost comparison ## Palbociclib plus fulvestrant is likely to have similar costs to abemaciclib plus fulvestrant and ribociclib plus fulvestrant The company presented a cost-comparison analysis that included the costs of drug acquisition, administration, monitoring and adverse events. The company base case assumed a 40‑year time horizon. Adverse event rates were assumed to vary by treatment and were based on publicly available data. Monitoring differed by treatment, with: palbociclib needing a full blood count abemaciclib needing a full blood count and liver enzyme tests ribociclib needing a full blood count, ECG, serum electrolytes and a liver function test.The EAG agreed the company's approach was reasonable. When taking account of the commercial arrangements for all treatments, the committee was satisfied that the total costs associated with palbociclib plus fulvestrant were likely to be similar to abemaciclib plus fulvestrant and ribociclib plus fulvestrant (the exact results are confidential and cannot be reported here). The committee therefore recommended palbociclib plus fulvestrant as an option for treating hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer in adults who have had endocrine therapy, only if exemestane plus everolimus is the most appropriate alternative to a CDK4/6 inhibitor. # Other factors ## There are no equality issues relevant to the recommendations The committee did not identify any equality issues.	{'Recommendations': 'Palbociclib plus fulvestrant is recommended as an option for treating hormone receptor‑positive, HER2‑negative locally advanced or metastatic breast cancer in adults who have had endocrine therapy only if:\n\nexemestane plus everolimus is the most appropriate alternative to a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor and\n\nthe company provides it according to the commercial arrangement.\n\nIf patients and their clinicians consider palbociclib plus fulvestrant and abemaciclib plus fulvestrant or ribociclib plus fulvestrant to be suitable options, use the least expensive treatment. Take account of the monitoring and adverse event costs, dosage, price per dose and commercial arrangements.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the evidence for palbociclib plus fulvestrant for hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer after endocrine therapy (NICE technology appraisal guidance TA619). It also reviews new evidence from a clinical trial and data collected from people having treatment through the Cancer Drugs Fund managed access agreement.\n\nTreatment for hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer after endocrine therapy includes exemestane plus everolimus, and the CDK4/6 inhibitors abemaciclib (plus fulvestrant) and ribociclib (plus fulvestrant) if exemestane plus everolimus is the most appropriate alternative. Palbociclib plus fulvestrant is another option that works in a similar way to abemaciclib and ribociclib.\n\nThe new evidence collected from people having treatment through the Cancer Drugs Fund shows that palbociclib plus fulvestrant is clinically effective. Additional clinical trial evidence shows that it increases how long people live compared with placebo plus fulvestrant. Indirect comparisons suggest that it has similar clinical effectiveness to abemaciclib plus fulvestrant and ribociclib plus fulvestrant.\n\nA cost comparison suggests palbociclib plus fulvestrant has similar costs to abemaciclib plus fulvestrant and ribociclib plus fulvestrant. So, palbociclib plus fulvestrant is recommended if it is used in the same population as abemaciclib and ribociclib.', 'Information about palbociclib': "# Marketing authorisation indication\n\nPalbociclib (Ibrance, Pfizer) is indicated 'for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer:\n\nin combination with an aromatase inhibitor;\n\nin combination with fulvestrant in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for palbociclib.\n\n# Price\n\nThe company's list price is £2,950 per 21-pack of 75\xa0mg, 100\xa0mg or 125\xa0mg capsules (excluding VAT; BNF online, accessed July 2022). The average cost of a course of combination treatment at list price is £6,170.70 for the loading dose and £5,126.42 for the following cycles. The company has a commercial arrangement. This makes palbociclib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Pfizer, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## People with advanced breast cancer value a choice of treatment options\n\nPeople with advanced breast cancer who have had endocrine therapy are eligible for the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors abemaciclib or ribociclib, in combination with fulvestrant, if exemestane plus everolimus is the most appropriate alternative (see NICE's technology appraisal guidance on abemaciclib and ribociclib). Patient experts said that these treatments can delay disease progression and delay or avoid the need for chemotherapy. Patient experts noted that they value a choice of treatment options because CDK4/6 inhibitors have different side effect profiles. Choice would give people the option to change to a different treatment if needed. Patient experts noted that the side effect profile of palbociclib is more similar to ribociclib than abemaciclib, but unlike ribociclib, palbociclib does not need any ECG monitoring. The committee concluded that having a choice of treatments is valued by people with advanced breast cancer.\n\n# Clinical evidence\n\n## PALOMA-3 is relevant to the NHS and has a long follow-up period\n\nPALOMA-3 is a multicentre double-blind randomised placebo-controlled trial comparing palbociclib plus fulvestrant (n=347) with placebo plus fulvestrant (n=174) in adults with hormone receptor-positive, HER2-negative advanced breast cancer. An additional 28\xa0months of overall survival data were collected in the ongoing trial while palbociclib was also available to people through the Cancer Drugs Fund. After a median follow-up of 73.3\xa0months in the trial, median overall survival was 6.8\xa0months longer in people who had palbociclib plus fulvestrant compared with those who had placebo plus fulvestrant (median 34.8\xa0months for palbociclib plus fulvestrant compared with 28.0\xa0months for placebo plus fulvestrant [HR 0.81; 95% CI 0.65 to 0.99, p=0.02]). The committee noted that there was a relatively long follow-up period in PALOMA-3. The EAG noted that people in the trial may have had more previous treatments than people seen in NHS clinical practice, but considered that the results are generalisable to the NHS. The committee concluded that the results from PALOMA-3 are relevant to the NHS and the trial has a long follow-up period.\n\n## A large Systemic Anticancer Therapy (SACT) dataset supports the clinical effectiveness of palbociclib plus fulvestrant\n\nPublic Health England provided observational data from the SACT dataset for 1,140 people who had palbociclib plus fulvestrant through the Cancer Drugs Fund. Median follow-up was 10\xa0months. Median treatment duration with palbociclib plus fulvestrant was 9.4\xa0months and median overall survival was not yet reached. At 6\xa0months, 88% of people taking palbociclib plus fulvestrant were alive; at 12\xa0months, 75% were alive; and at 18\xa0months, 63% were alive. The committee noted that equivalent overall survival rates were seen with abemaciclib plus fulvestrant at 6 and 12\xa0months in SACT. It noted that the SACT dataset did not directly compare palbociclib plus fulvestrant with abemaciclib plus fulvestrant but the findings showing similar efficacy of the 2 treatments in NHS clinical practice were reassuring. The committee concluded that a large SACT dataset supports the clinical effectiveness of palbociclib plus fulvestrant.\n\n## Abemaciclib plus fulvestrant and ribociclib plus fulvestrant are appropriate comparators\n\nAbemaciclib and ribociclib are CDK4/6 inhibitors recommended by NICE for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy. Palbociclib is another CDK4/6 inhibitor that works in a similar way to abemaciclib and ribociclib. The EAG's clinical advisers noted that the 3 drugs have the same primary mechanism although with some differences in individual inhibition of CDK4 and CDK6 in laboratory studies. They also noted differences in dosing schedules, serum concentration and toxicity. All 3 CDK4/6 inhibitors are administered orally. Palbociclib and ribociclib are given once daily for 21\xa0days of a 28‑day cycle. Abemaciclib is given twice daily for the whole cycle. All are combined with fulvestrant, which is given by intramuscular injection, twice in the first month, followed by once monthly. The committee concluded that abemaciclib plus fulvestrant and ribociclib plus fulvestrant are appropriate comparators for palbociclib plus fulvestrant.\n\n## MONARCH 2 and MONALEESA-3 can be compared with PALOMA-3, although there are some differences between the 3 trial populations\n\nThe pivotal clinical trials of abemaciclib plus fulvestrant and ribociclib plus fulvestrant are MONARCH\xa02 (n=669) and MONALEESA-3 (n=726). As in PALOMA-3 (see section\xa03.2), these trials compared a CDK4/6 inhibitor plus fulvestrant with placebo plus fulvestrant. All 3 trials had investigator-assessed progression-free survival as the primary endpoint. The committee considered that MONARCH\xa02 and MONALEESA-3 provided suitable clinical evidence for a comparison with PALOMA-3. People in PALOMA-3 and MONARCH\xa02 could be in any stage of menopause, while those in MONALEESA-3 were in postmenopause. However, in PALOMA‑3 and MONARCH\xa02, people who were in premenopause or perimenopause had a luteinising hormone-releasing hormone agonist to make them functionally in postmenopause. The EAG noted that people in PALOMA-3 had more previous chemotherapy in the metastatic setting than the other 2 trials. The committee also noted that people in PALOMA‑3 were younger (75% aged under 65\xa0years) than those in MONARCH\xa02 (63% aged under\xa065\xa0years) or MONALEESA-3 (53% aged under 65\xa0years). The committee concluded that MONARCH\xa02 and MONALEESA-3 can be compared with PALOMA-3, although there are some differences between the 3 trial populations.\n\n## Clinical trials evidence suggests that palbociclib, abemaciclib and ribociclib are likely to provide similar health benefits\n\nThe results of PALOMA-3, MONARCH\xa02 and MONALEESA-3 show that palbociclib plus fulvestrant, abemaciclib plus fulvestrant and ribociclib plus fulvestrant improve progression‑free survival and overall survival compared with placebo plus fulvestrant. The EAG stated that the hazard ratios for these outcomes were similar for the 3\xa0treatments and the committee was aware that follow up was longer in the palbociclib trial than the others. Only PALOMA-3 and MONALEESA-3 collected data on subsequent therapy. This showed that most people had a follow-on therapy. The EAG stated that some people had a subsequent CDK4/6 inhibitor which is not standard NHS practice. However, the committee noted that this was more common in people who had placebo plus fulvestrant in the trial and had not had a CDK4/6 inhibitor before. The committee concluded that evidence from the 3\xa0clinical trials suggests that palbociclib, abemaciclib and ribociclib, all in combination with fulvestrant, are likely to provide similar health benefits in terms of progression-free and overall survival.\n\n## There are some differences in low grade adverse events between palbociclib, abemaciclib and ribociclib that may impact treatment choice\n\nThe company noted that the 3\xa0CDK4/6 inhibitors have a broadly similar profile of grade\xa03 or higher adverse events. But there are important differences in some low grade adverse events. Neutropenia is less common and lower grade with abemaciclib plus fulvestrant than with palbociclib plus fulvestrant or ribociclib plus fulvestrant. Any grade diarrhoea is more common with abemaciclib plus fulvestrant (87%) than with palbociclib plus fulvestrant or ribociclib plus fulvestrant (both less than 30%). The EAG noted that the lower rates of diarrhoea seen with palbociclib plus fulvestrant than with abemaciclib plus fulvestrant have the potential to improve health-related quality of life. The Cancer Drugs Fund clinical lead noted that diarrhoea has a direct impact on people having treatment. Neutropenia is a toxicity detected through regular blood testing but it may not affect the person having treatment or cause symptoms. The committee recalled that people with advanced breast cancer value choice in treatments and the option to change to a different treatment if needed (see section\xa03.1). The committee concluded that there are some differences in low grade adverse events between palbociclib, abemaciclib and ribociclib that may impact treatment choice.\n\n# Indirect treatment comparisons\n\n## Well-designed indirect comparisons suggest that the clinical efficacy of palbociclib plus fulvestrant is similar to or better than the comparators\n\nThe company presented matching-adjusted indirect treatment comparisons (MAICs) of palbociclib plus fulvestrant compared with abemaciclib plus fulvestrant and ribociclib plus fulvestrant. These used latest survival data from the 3\xa0pivotal trials (see section\xa03.6). In the MAICs, the PALOMA-3 population was statistically adjusted to resemble the MONARCH\xa02 and MONALEESA-3 populations. This was to predict the treatment effect if palbociclib plus fulvestrant had been evaluated in these populations. The EAG agreed with the company's approach to account for differences between the 3\xa0trial populations (see section\xa03.5). It considered that the MAICs were well designed. The MAICs of palbociclib plus fulvestrant and abemaciclib plus fulvestrant included up to 12\xa0potential treatment effect modifiers. The results suggested no statistically significant difference in progression-free survival or overall survival with palbociclib plus fulvestrant compared with abemaciclib plus fulvestrant. The committee noted that the MAICs suggest that the clinical efficacy of palbociclib plus fulvestrant is similar to abemaciclib plus fulvestrant. The MAICs of palbociclib plus fulvestrant and ribociclib plus fulvestrant included up to 13\xa0potential treatment effect modifiers. The results suggested no statistically significant difference in overall survival with palbociclib plus fulvestrant compared with abemaciclib plus fulvestrant. However, some of the MAICs for progression-free survival, including when all effect modifiers were considered, suggested a statistically significant difference in favour of palbociclib plus fulvestrant. The committee noted that the MAICs suggest that the clinical efficacy of palbociclib plus fulvestrant is similar to or better than that of ribociclib plus fulvestrant. The committee concluded that the well-designed MAICs suggest that palbociclib plus fulvestrant is similar to or better than the comparators.\n\n# Cost comparison\n\n## Palbociclib plus fulvestrant is likely to have similar costs to abemaciclib plus fulvestrant and ribociclib plus fulvestrant\n\nThe company presented a cost-comparison analysis that included the costs of drug acquisition, administration, monitoring and adverse events. The company base case assumed a 40‑year time horizon. Adverse event rates were assumed to vary by treatment and were based on publicly available data. Monitoring differed by treatment, with:\n\npalbociclib needing a full blood count\n\nabemaciclib needing a full blood count and liver enzyme tests\n\nribociclib needing a full blood count, ECG, serum electrolytes and a liver function test.The EAG agreed the company's approach was reasonable. When taking account of the commercial arrangements for all treatments, the committee was satisfied that the total costs associated with palbociclib plus fulvestrant were likely to be similar to abemaciclib plus fulvestrant and ribociclib plus fulvestrant (the exact results are confidential and cannot be reported here). The committee therefore recommended palbociclib plus fulvestrant as an option for treating hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer in adults who have had endocrine therapy, only if exemestane plus everolimus is the most appropriate alternative to a CDK4/6 inhibitor.\n\n# Other factors\n\n## There are no equality issues relevant to the recommendations\n\nThe committee did not identify any equality issues."}	https://www.nice.org.uk/guidance/ta836	Evidence-based recommendations on palbociclib (Ibrance) with fulvestrant for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy.
3c7dbe7abbf639c14b31f5b052bb817262c3f774	nice	Pembrolizumab for adjuvant treatment of resected stage 2B or 2C melanoma	Pembrolizumab for adjuvant treatment of resected stage 2B or 2C melanoma Evidence-based recommendations on pembrolizumab (Keytruda) for the adjuvant treatment of resected stage 2B and 2C melanoma in people 12 years and over. # Recommendations Pembrolizumab is recommended, within its marketing authorisation, as an option for the adjuvant treatment of completely resected stage 2B or 2C melanoma in people 12 years and over. It is recommended only if the company provides pembrolizumab according to the commercial arrangement. Why the committee made these recommendations Standard care for people with stage 2B or 2C melanoma that has been removed with surgery (resected) is routine follow-up. There is an unmet need for treatments after surgery (adjuvant treatment). Clinical evidence shows that adjuvant pembrolizumab increases how long people live without the cancer coming back and getting worse compared with placebo. There is still not enough evidence to know how much pembrolizumab increases how long people live. Because of this, and because introducing pembrolizumab for stage 2B or 2C melanoma is likely to change the treatment pathway, there is some uncertainty in the cost-effectiveness estimates. But despite the uncertainty, they are within what NICE considers an acceptable use of NHS resources. So, pembrolizumab is recommended.# Information about pembrolizumab # Marketing authorisation indication Pembrolizumab (Keytruda, MSD) is indicated 'for the adjuvant treatment of adults and adolescents aged 12 years and older with Stage 2B, 2C or 3 melanoma and who have undergone complete resection'. Pembrolizumab is also recommended for the adjuvant treatment of resected stage 3 melanoma (NICE technology appraisal guidance 766). # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for pembrolizumab. # Price The list price is £2,630.00 per 100 mg/4 ml concentrate for solution for infusion vial (excluding VAT; BNF online, accessed August 2022). The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by MSD, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need ## People with resected stage 2B or 2C melanoma would welcome an adjuvant treatment option Melanoma is a cancer that develops from melanocytes in the skin. There are multiple risk factors that increase the likelihood of developing melanoma, including a family history of melanoma, fair skin and hair colour, and intense or chronic exposure to ultraviolet (UV) light. Melanomas are classified by the size and depth of the melanoma and whether it has spread. Stage 2 melanoma is defined as having no evidence of spread to lymph nodes or distant metastases. Stage 2B and 2C tumours are deeply penetrating tumours, with or without ulceration, and are at high risk of recurrence. Standard care for people with stage 2B or stage 2C melanoma is complete surgical excision with wide margins. After surgery, people then have routine follow-up for 5 years, which is tailored according to individual risk. The clinical experts explained that the risk of disease recurrence is greatest in the first 3 years after surgery. There are currently no adjuvant treatment options available for stage 2 melanoma. The aim of adjuvant treatment is to remove any residual microscopic disease after surgery to reduce the risk of local recurrence or progression to metastatic disease, which is currently considered incurable. The patient expert described how people with resected stage 2B or 2C melanoma experience a substantial physical, mental and emotional burden. This is because of the fear of recurrence and uncertainty about outcomes if the cancer were to recur. The clinical experts explained that stage 2B and 2C melanoma has a similar risk of recurrence to stage 3A and stage 3B melanoma, for which adjuvant treatments are available. So, there is a similar need for adjuvant treatment for stage 2B or stage 2C melanoma. The patient experts acknowledged that pembrolizumab may have adverse effects which can occasionally be severe and long lasting. However, they agreed the benefit in reducing the risk of recurrence outweighs the potential risk of adverse effects. The clinical experts stated that, generally, pembrolizumab is well tolerated across all ages, although about 10% of people can have permanent adverse effects. Clinicians are familiar with monitoring for adverse events in people having pembrolizumab because it is already used to treat melanoma at later disease stages. The committee concluded that there is an unmet need in this area, and that people with resected stage 2B or 2C melanoma would welcome an adjuvant treatment that reduces the risk of recurrence. # Current treatment pathway ## Adjuvant pembrolizumab is a step change in managing stage 2B or 2C melanoma and may change the treatment pathway People with stage 2B or 2C melanoma can have a locoregional recurrence after surgery. This means they can have a recurrence at the same site (stage 2B or 2C recurrence), or in the local lymph nodes (stage 3 melanoma). Currently, stage 3 melanoma is treated with complete surgical excision with wide margins, followed by adjuvant treatment with pembrolizumab, nivolumab or dabrafenib plus trametinib (see NICE's technology appraisal guidance on pembrolizumab, nivolumab and dabrafenib plus trametinib). The committee considered whether people would have adjuvant treatment again for stage 3 melanoma if they had had it for stage 2B or 2C. The clinical experts explained that people whose cancer recurs when having adjuvant pembrolizumab are likely to have immunotherapy-resistant cancer, so are unlikely to benefit from further adjuvant immunotherapies (such as pembrolizumab or nivolumab). But people who have a BRAF gene mutation could still benefit from BRAF-targeted adjuvant treatment with dabrafenib plus trametinib. The committee noted that all people with melanoma at high risk of recurrence (including stage 2B or 2C) will have testing to see if they have a BRAF mutation. The committee heard that about 45% of people will have a BRAF mutation. The clinical experts noted that restrictions from NHS England may affect access to further adjuvant immunotherapies after adjuvant pembrolizumab for stage 2B or 2C melanoma. In other indications, NHS England only permits the use of adjuvant immunotherapies at one point in the treatment pathway. The Cancer Drugs Fund clinical lead noted that this is an area of uncertainty and there is no evidence of the efficacy of further adjuvant immunotherapy for people who have already had it. The committee then discussed the treatment pathway for stage 2B or 2C melanoma with distant metastasis (advanced melanoma). For advanced melanoma, NICE recommends immunotherapies in combination (see NICE's technology appraisal guidance on nivolumab plus ipilimumab) or as monotherapy (see NICE's technology appraisal guidance on pembrolizumab, pembrolizumab after ipilimumab, nivolumab and ipilimumab). It also recommends targeted treatments for BRAF V600 mutation-positive advanced melanoma (see NICE's technology appraisal guidance on dabrafenib plus trametinib, trametinib plus dabrafenib, encorafenib plus binimetinib, vemurafenib and dabrafenib). NICE's guideline on melanoma also states that chemotherapy (dacarbazine) or best supportive care should be considered if immunotherapies or targeted therapies for BRAF V600 mutation-positive advanced melanoma are not appropriate. The Cancer Drugs Fund clinical lead noted that the objective of treatment for advanced melanoma is different to that of adjuvant treatment. Adjuvant treatment is used to prevent recurrence or metastases, but once there is metastatic spread the aim is to extend overall survival. The clinical experts noted that most people with advanced melanoma would have immunotherapies in combination. Or, if they had a BRAF V600 mutation, they would have targeted treatment. They further noted that if BRAF V600 mutation-positive melanoma had not responded to adjuvant immunotherapy monotherapy, it may respond to combination immunotherapy. The committee concluded that adjuvant pembrolizumab is an important step change in managing stage 2B or 2C melanoma but may change whether adjuvant treatment options are used later in the pathway. # Clinical evidence ## The population in KEYNOTE-716 adequately reflects the population in NHS practice KEYNOTE‑716 is an ongoing multinational 2-part phase 3 study. Part 1 is a double-blind placebo-controlled study that randomised 976 adults and young people with resected stage 2B or 2C melanoma to adjuvant pembrolizumab or placebo. Baseline characteristics were well balanced between the 2 treatment arms. Most people included in KEYNOTE‑716 were white, which is expected because fair skin is a risk factor for melanoma. Across both arms of the trial, 64.0% of people had stage 2B melanoma and 34.8% had stage 2C melanoma. The ERG noted that a larger proportion of people in KEYNOTE‑716 had stage 2B melanoma than is expected in England (using data from Public Health England in which 57% of people had stage 2B melanoma and 43% had stage 2C melanoma). Stage 2B melanoma has a better prognosis than stage 2C melanoma. Subgroup analyses from KEYNOTE‑716 appear to show a better outcome with pembrolizumab for stage 2B melanoma compared with stage 2C melanoma. The clinical experts stated that they did not consider that there was much difference between the trial and the Public Health England data, and that melanoma is increasingly being diagnosed earlier. So they considered the population in KEYNOTE‑716 to be generalisable to the eligible population in the NHS. The clinical experts also stated that they would expect pembrolizumab to work relatively similarly in stage 2B and 2C melanoma. One clinical expert highlighted that stage 2C melanoma without ulceration had similar outcomes to stage 2B melanoma, but stage 2C melanoma with ulceration tended to have a worse prognosis. The clinical experts noted that subgroup analyses in KEYNOTE‑716 were not statistically powered to detect differences between stage 2B and 2C melanoma and a larger trial would be needed to assess this. The committee agreed that it was more appropriate to consider the whole population rather than focusing on retrospective subgroup analyses. The committee concluded that the population included in KEYNOTE‑716 adequately reflects the population who would have treatment in NHS clinical practice. ## The results of KEYNOTE-716 are likely to be generalisable to young people aged 12 to 17 The median age of people in the KEYNOTE‑716 trial was 60.0 years in the pembrolizumab group and 61.0 years in the placebo group. Both groups included 1 young person (aged between 12 to 17). Because of this, the ERG noted that it is uncertain whether the trial results would be generalisable to young people. The company stated that melanoma incidence in young people is low, so there is low recruitment of young people to all melanoma trials. The European Medicines Agency has accepted that the results from KEYNOTE‑716 are generalisable to young people. This is because melanoma disease biology is similar between adults and young people. Also, disease response to pembrolizumab is similar between adults and young people in other disease areas. The clinical experts stated that they would expect the efficacy and safety outcomes with pembrolizumab in young people to be similar to outcomes in adults. The committee concluded that the results of KEYNOTE‑716 are likely to be generalisable to young people. ## Efficacy and safety data from KEYNOTE-716 for the 3-weekly dose of pembrolizumab is likely to be generalisable to the 6-weekly dose Pembrolizumab is licensed for treating melanoma in adults at doses of 200 mg every 3 weeks and 400 mg every 6 weeks. However, the KEYNOTE‑716 trial only assessed the efficacy and safety of the 200 mg every 3 weeks dose. The company explained that the European Medicines Agency has approved the 6‑weekly dosing schedule for adjuvant treatment of stage 2 melanoma because modelling of dose–exposure relationships found no significant differences in efficacy or safety between doses. Also, the 3‑weekly and 6‑weekly dosing schedule of pembrolizumab as monotherapy and in combination has been shown to be similar in other indications, including unresectable advanced melanoma. The clinical experts explained that the 6‑weekly dosing schedule of pembrolizumab is used for other lines of treatment for melanoma. They had no concerns about the generalisability of the data from KEYNOTE‑716 to NHS practice. The committee noted that the 6‑weekly dosing schedule is important to manage resource use in clinics, oncology day units and pharmacies, and is the dose that would be used most frequently in clinical practice. The committee concluded that the efficacy and safety data for the 3‑weekly dosing schedule of pembrolizumab from KEYNOTE‑716 is likely to be generalisable to the 6‑weekly dosing schedule. ## Pembrolizumab improves recurrence-free and distant metastasis-free survival compared with placebo, but overall survival data is immature The primary outcome of KEYNOTE‑716 was recurrence-free survival. At the first interim analysis (December 2020 data cut-off), a statistically significant improvement in recurrence-free survival was seen with pembrolizumab compared with placebo (hazard ratio 0.65, 95% confidence interval 0.46 to 0.92). At technical engagement, the company shared the results of the third interim analysis of the trial data, which had a January 2022 data cut-off. The additional follow-up data from the further data cuts supports the first interim analysis for recurrence-free survival. The January 2022 data cut-off also provided data for distant metastasis-free survival. This showed that adjuvant pembrolizumab statistically significantly improved distant metastasis-free survival compared with placebo (HR 0.64, 95% CI 0.47 to 0.88; p=0.00292). At the January 2022 data cut-off most people were still alive, which meant there was not enough data to analyse overall survival. The committee concluded that pembrolizumab improves recurrence-free survival and distant metastasis-free survival compared with placebo, but overall survival data is still immature. ## Improved recurrence-free and distant metastasis-free survival is likely to be associated with an overall survival benefit, but this is uncertain The committee was aware that there are challenges in gathering and interpreting overall survival data for adjuvant treatments, such as pembrolizumab for stage 2B or 2C melanoma. This is because people have no detectable disease at the time of treatment and some people may have no remaining disease at all. A large proportion of people with resected stage 2B or 2C disease will not have a recurrence. This means that people may live for a long time, so a long follow-up would be needed to collect sufficient survival data. In the absence of overall survival data, the committee considered whether recurrence-free or distant metastasis-free survival could be used as a surrogate for overall survival. The clinical experts explained that if a treatment makes a clinically meaningful difference to distant metastasis-free survival then it is likely that this would be reflected in an overall survival benefit. The committee concluded that, based on its earlier conclusion that pembrolizumab improves recurrence-free survival and distant metastasis-free survival compared with placebo (see section 3.6), it was likely that pembrolizumab also improved overall survival. However, given the immaturity of overall survival data, the extent of this benefit is uncertain. # Economic model ## The company's model structure is acceptable for decision making The company developed a Markov cohort state-transition model to assess the cost effectiveness of pembrolizumab for treating stage 2B or 2C melanoma. The model included 4 health states: recurrence-free, locoregional recurrence, distant metastasis and death. The distant metastasis state included 2 sub-states (pre-progression and post-progression) to include the costs and outcomes of subsequent treatments after the development of distant metastasis. The model used a lifetime time horizon (40.7 years) and a 1‑week cycle length, with a half-cycle correction. Transitions from the recurrence-free and locoregional recurrence health states were modelled using recurrence-free survival and distant metastasis-free survival data from the most recent data cut of KEYNOTE‑716. Transitions from the distant metastasis health states were dependent on the previous treatment for advanced melanoma, data from KEYNOTE‑006 (a randomised controlled trial comparing pembrolizumab with ipilimumab in advanced melanoma) and the results of a network meta-analysis. The ERG considered the model structure reasonable. The committee noted that the structure was similar to the model used in NICE's technology appraisal guidance on adjuvant pembrolizumab for stage 3 melanoma and concluded that it was suitable for decision making. ## People who have adjuvant pembrolizumab for stage 2B or 2C melanoma would probably not have further adjuvant treatment, unless they have a BRAF mutation The company's base assumed that people who have adjuvant pembrolizumab for resected stage 2B or 2C melanoma would not have any further adjuvant treatment for locoregional recurrence at stage 3. The company's clinical experts said that people are likely to have 'one shot' at adjuvant treatment. This is because of a lack of data and uncertainty about possible restrictions on multiple lines of adjuvant immunotherapies from NHS England (see section 3.2). The ERG stated that these assumptions were not aligned with KEYNOTE‑716 data, and in its base case assumed that equal proportions of people would have subsequent treatment after locoregional recurrence in both arms. The company noted that KEYNOTE‑716 is a global clinical trial and several of the treatments used after locoregional recurrence in the trial are not approved for use in the UK, so the trial may not reflect UK clinical practice. The committee recalled previous comments from the clinical experts and Cancer Drugs Fund clinical lead (see section 3.2). It agreed that there is uncertainty about the treatment pathway for stage 3 melanoma if adjuvant pembrolizumab were recommended for stage 2B or 2C melanoma. The committee agreed that it is likely that people who have adjuvant pembrolizumab at stage 2 would not have further adjuvant immunotherapy. However, it noted that people who have a BRAF V600 mutation would be able to have dabrafenib plus trametinib for the adjuvant treatment of stage 3 melanoma. So the committee considered that its preferred assumption for adjuvant treatment for locoregional recurrence would be between the ERG's and company's assumptions used in the base-case analyses. The committee concluded that the most likely assumption would align with a scenario analysis done by the company. In this scenario, people with a BRAF mutation are eligible for adjuvant treatment at stage 3 with dabrafenib plus trametinib after they have had adjuvant treatment at stage 2B or 2C, adjusted for the percentage of the overall cohort who will have no adjuvant treatment. ## The proportions of subsequent treatments for metastatic disease and how long people will have these for is uncertain In the company's base case, the proportions of people having each subsequent treatment for distant metastasis was informed by Systemic Anti-Cancer Therapy data collected for NICE's technology appraisal guidance on adjuvant pembrolizumab for stage 3 melanoma and market share data. These proportions were adjusted to assume that 2 years after starting a 1‑year course of adjuvant treatment, some people who develop metastasis may have pembrolizumab again. The ERG used the same assumptions as the company in its base-case analyses. But it noted that there is uncertainty about these inputs and did a scenario analysis assuming equal proportions of subsequent treatments after distant metastasis in both arms. This reduced the incremental cost-effectiveness ratio (ICER) by about £15,000 per quality-adjusted life year (QALY) gained. In the company's base case, the duration of first-line distant metastasis treatment was based on modelled progression-free survival for each regimen. The duration of second-line treatment was assumed to be 21 weeks for all regimens except ipilimumab, for which the duration was assumed to be 12 weeks. The ERG also used these assumptions in its base case but noted that it is unclear whether these assumptions are clinically plausible. The ERG explored this uncertainty by doing an extreme scenario analysis in which subsequent treatment acquisition costs in the distant metastasis state for both arms were excluded. This led to a substantial increase in the ICER, although the committee noted this was still below the range NICE considers a cost-effective use of NHS resources. The committee concluded that there is uncertainty about the market shares and duration of subsequent treatments in the distant metastasis health state. ## Distributions used to model transition probabilities from the recurrence-free health state are uncertain but reasonable The company's base case used a lognormal distribution to model transitions from the recurrence-free health state to the locoregional recurrence state and distant metastasis state for both arms. The company explained that the lognormal-lognormal combination was selected for the base case because it has a high ranking in terms of statistical fit. It explained that the incremental recurrence-free and distant metastasis-free survival benefit for pembrolizumab compared with observation was aligned with, or slightly below, the average incremental benefit across the other potential combinations. The ERG also used these distributions in its base case but did a scenario analysis using the generalised gamma-lognormal distribution, which led to an increase in the ICER above £30,000 per QALY gained. The ERG explained that this scenario was done to reflect the uncertainty in transitions from the recurrence-free health state. But it noted that the distributions selected by the company are also plausible and it is difficult to determine which distribution is most appropriate. The committee asked why the statistical fit of the transition curves was based on mean squared errors, rather than using Akaike information criterion (AIC) and Bayesian information criterion (BIC) statistics. The company explained that AIC and BIC fit statistics are not suitable measures of fit when modelling competing risks, so mean squared errors were used to assess statistical fit. The ERG agreed that this approach is appropriate. The company noted that it had used the same methodology as in NICE's technology appraisal guidance on adjuvant pembrolizumab for stage 3 melanoma, and that the observed cumulative incidence function was aligned with predicted curves for the observed period. The ERG noted that a substantial proportion of the recurrence-free survival benefit was accrued beyond the observed data period. The committee concluded that there is uncertainty about the appropriate distributions to model transition probabilities from the recurrence-free health state but noted that the company's approach appears to be reasonable. ## The data inputs for end of life care costs and post-progression utility values in the distant metastasis health state are uncertain The economic model included intervention costs, health state costs, costs of managing adverse events and end of life care costs. These were based on NHS reference prices and prices from the BNF, Personal Social Services Research Unit and Medical Information Management System. In the company's base case, end of life care costs were applied to deaths from the distant metastasis health state only. But in the ERG's base-case end of life care costs were applied regardless of the cause of death. In the recurrence-free, locoregional recurrence and pre-progression distant metastasis states, utility values in the company's model were sourced from a regression model developed using EQ-5D data from KEYNOTE‑716. In the post-progression distant metastasis health state, the company's base-case utility value was derived from Beusterien et al. 2009, which used a standard gamble approach to elicit values from the UK general population. The ERG used a value from KEYNOTE-006, based on EQ-5D. The committee noted that the company's assumptions aligned with NICE's technology appraisal guidance on adjuvant pembrolizumab for stage 3 melanoma. But, it was aware that the different assumptions used by the company and the ERG had a limited effect on the ICER. The committee concluded that end of life care costs and post-progression utility values in the distant metastasis health state are uncertain but unlikely to significantly affect the cost-effectiveness results. # Cost-effectiveness estimates ## Because of the uncertainty an acceptable ICER should be around £20,000 per QALY gained NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the uncertainties in the modelling assumptions, specifically that: The overall survival data for pembrolizumab is immature (see section 3.6), and that this uncertainty would not have been reflected in the cost-effectiveness results. Because the results are dependent on a surrogate relationship to estimate overall survival, the committee agreed it would have preferred to see some analyses assessing the relationship between recurrence-free survival, distant metastases-free survival and overall survival, to check the robustness of this approach. There is uncertainty about some of the inputs in the economic model, including the use of subsequent adjuvant treatments after adjuvant treatment with pembrolizumab for stage 2B or 2C melanoma (see section 3.9).So it agreed that an acceptable ICER would be towards the lower end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). ## The cost-effectiveness estimates are uncertain but are likely within what NICE considers to be an acceptable use of NHS resources The committee noted that when the confidential patient access schemes for pembrolizumab and subsequent treatments were applied, most of the ICERs were around £20,000 per QALY gained. The committee considered the uncertainty about subsequent adjuvant treatments after adjuvant pembrolizumab at stage 2 (see section 3.9). It noted that in the scenario analysis in which people who had adjuvant pembrolizumab for stage 2 disease, had a BRAF V600 mutation, and could have dabrafenib plus trametinib for adjuvant stage 3 treatment, the ICER was also around £20,000 per QALY gained. Taking all of this into account, the committee concluded that pembrolizumab was an acceptable use of NHS resources. # Other factors ## Equalities The committee did not identify any equality issues associated with using pembrolizumab in this indication. ## Innovation There are currently no adjuvant treatment options for people with stage 2 melanoma in the UK. Standard care is routine follow-up. So the committee concluded that introducing pembrolizumab as adjuvant treatment for people with stage 2B and stage 2C melanoma would be a step change in clinical management. ## End of life criteria NICE's advice about life-extending treatments for people with a short life expectancy did not apply. # Conclusion ## Pembrolizumab is recommended for routine use The committee concluded that the most plausible cost-effectiveness estimates are within what NICE considers to be an acceptable use of NHS resources. So pembrolizumab is recommended for the adjuvant treatment of resected stage 2B or 2C melanoma in people aged 12 or over.	{'Recommendations': 'Pembrolizumab is recommended, within its marketing authorisation, as an option for the adjuvant treatment of completely resected stage 2B or 2C melanoma in people 12\xa0years and over. It is recommended only if the company provides pembrolizumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nStandard care for people with stage 2B or 2C melanoma that has been removed with surgery (resected) is routine follow-up. There is an unmet need for treatments after surgery (adjuvant treatment).\n\nClinical evidence shows that adjuvant pembrolizumab increases how long people live without the cancer coming back and getting worse compared with placebo. There is still not enough evidence to know how much pembrolizumab increases how long people live.\n\nBecause of this, and because introducing pembrolizumab for stage 2B or 2C melanoma is likely to change the treatment pathway, there is some uncertainty in the cost-effectiveness estimates. But despite the uncertainty, they are within what NICE considers an acceptable use of NHS resources. So, pembrolizumab is recommended.', 'Information about pembrolizumab': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, MSD) is indicated 'for the adjuvant treatment of adults and adolescents aged 12 years and older with Stage 2B, 2C or 3 melanoma and who have undergone complete resection'.\n\nPembrolizumab is also recommended for the adjuvant treatment of resected stage 3 melanoma (NICE technology appraisal guidance 766).\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for pembrolizumab.\n\n# Price\n\nThe list price is £2,630.00 per 100\xa0mg/4\xa0ml concentrate for solution for infusion vial (excluding VAT; BNF online, accessed August 2022).\n\nThe company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by MSD, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## People with resected stage 2B or 2C melanoma would welcome an adjuvant treatment option\n\nMelanoma is a cancer that develops from melanocytes in the skin. There are multiple risk factors that increase the likelihood of developing melanoma, including a family history of melanoma, fair skin and hair colour, and intense or chronic exposure to ultraviolet (UV) light. Melanomas are classified by the size and depth of the melanoma and whether it has spread. Stage 2 melanoma is defined as having no evidence of spread to lymph nodes or distant metastases. Stage 2B and 2C tumours are deeply penetrating tumours, with or without ulceration, and are at high risk of recurrence. Standard care for people with stage 2B or stage 2C melanoma is complete surgical excision with wide margins. After surgery, people then have routine follow-up for 5\xa0years, which is tailored according to individual risk. The clinical experts explained that the risk of disease recurrence is greatest in the first 3\xa0years after surgery. There are currently no adjuvant treatment options available for stage 2 melanoma. The aim of adjuvant treatment is to remove any residual microscopic disease after surgery to reduce the risk of local recurrence or progression to metastatic disease, which is currently considered incurable. The patient expert described how people with resected stage 2B or 2C melanoma experience a substantial physical, mental and emotional burden. This is because of the fear of recurrence and uncertainty about outcomes if the cancer were to recur. The clinical experts explained that stage 2B and 2C melanoma has a similar risk of recurrence to stage 3A and stage 3B melanoma, for which adjuvant treatments are available. So, there is a similar need for adjuvant treatment for stage 2B or stage 2C melanoma. The patient experts acknowledged that pembrolizumab may have adverse effects which can occasionally be severe and long lasting. However, they agreed the benefit in reducing the risk of recurrence outweighs the potential risk of adverse effects. The clinical experts stated that, generally, pembrolizumab is well tolerated across all ages, although about 10% of people can have permanent adverse effects. Clinicians are familiar with monitoring for adverse events in people having pembrolizumab because it is already used to treat melanoma at later disease stages. The committee concluded that there is an unmet need in this area, and that people with resected stage 2B or 2C melanoma would welcome an adjuvant treatment that reduces the risk of recurrence.\n\n# Current treatment pathway\n\n## Adjuvant pembrolizumab is a step change in managing stage 2B or 2C melanoma and may change the treatment pathway\n\nPeople with stage 2B or 2C melanoma can have a locoregional recurrence after surgery. This means they can have a recurrence at the same site (stage 2B or 2C recurrence), or in the local lymph nodes (stage 3 melanoma). Currently, stage 3 melanoma is treated with complete surgical excision with wide margins, followed by adjuvant treatment with pembrolizumab, nivolumab or dabrafenib plus trametinib (see NICE's technology appraisal guidance on pembrolizumab, nivolumab and dabrafenib plus trametinib). The committee considered whether people would have adjuvant treatment again for stage 3 melanoma if they had had it for stage 2B or 2C. The clinical experts explained that people whose cancer recurs when having adjuvant pembrolizumab are likely to have immunotherapy-resistant cancer, so are unlikely to benefit from further adjuvant immunotherapies (such as pembrolizumab or nivolumab). But people who have a BRAF gene mutation could still benefit from BRAF-targeted adjuvant treatment with dabrafenib plus trametinib. The committee noted that all people with melanoma at high risk of recurrence (including stage 2B or 2C) will have testing to see if they have a BRAF mutation. The committee heard that about 45% of people will have a BRAF mutation. The clinical experts noted that restrictions from NHS England may affect access to further adjuvant immunotherapies after adjuvant pembrolizumab for stage 2B or 2C melanoma. In other indications, NHS England only permits the use of adjuvant immunotherapies at one point in the treatment pathway. The Cancer Drugs Fund clinical lead noted that this is an area of uncertainty and there is no evidence of the efficacy of further adjuvant immunotherapy for people who have already had it. The committee then discussed the treatment pathway for stage 2B or 2C melanoma with distant metastasis (advanced melanoma). For advanced melanoma, NICE recommends immunotherapies in combination (see NICE's technology appraisal guidance on nivolumab plus ipilimumab) or as monotherapy (see NICE's technology appraisal guidance on pembrolizumab, pembrolizumab after ipilimumab, nivolumab and ipilimumab). It also recommends targeted treatments for BRAF V600 mutation-positive advanced melanoma (see NICE's technology appraisal guidance on dabrafenib plus trametinib, trametinib plus dabrafenib, encorafenib plus binimetinib, vemurafenib and dabrafenib). NICE's guideline on melanoma also states that chemotherapy (dacarbazine) or best supportive care should be considered if immunotherapies or targeted therapies for BRAF V600 mutation-positive advanced melanoma are not appropriate. The Cancer Drugs Fund clinical lead noted that the objective of treatment for advanced melanoma is different to that of adjuvant treatment. Adjuvant treatment is used to prevent recurrence or metastases, but once there is metastatic spread the aim is to extend overall survival. The clinical experts noted that most people with advanced melanoma would have immunotherapies in combination. Or, if they had a BRAF V600 mutation, they would have targeted treatment. They further noted that if BRAF V600 mutation-positive melanoma had not responded to adjuvant immunotherapy monotherapy, it may respond to combination immunotherapy. The committee concluded that adjuvant pembrolizumab is an important step change in managing stage 2B or 2C melanoma but may change whether adjuvant treatment options are used later in the pathway.\n\n# Clinical evidence\n\n## The population in KEYNOTE-716 adequately reflects the population in NHS practice\n\nKEYNOTE‑716 is an ongoing multinational 2-part phase 3 study. Part 1 is a double-blind placebo-controlled study that randomised 976\xa0adults and young people with resected stage 2B or 2C melanoma to adjuvant pembrolizumab or placebo. Baseline characteristics were well balanced between the 2\xa0treatment arms. Most people included in KEYNOTE‑716 were white, which is expected because fair skin is a risk factor for melanoma. Across both arms of the trial, 64.0% of people had stage 2B melanoma and 34.8% had stage 2C melanoma. The ERG noted that a larger proportion of people in KEYNOTE‑716 had stage 2B melanoma than is expected in England (using data from Public Health England in which 57% of people had stage 2B melanoma and 43% had stage 2C melanoma). Stage 2B melanoma has a better prognosis than stage 2C melanoma. Subgroup analyses from KEYNOTE‑716 appear to show a better outcome with pembrolizumab for stage 2B melanoma compared with stage 2C melanoma. The clinical experts stated that they did not consider that there was much difference between the trial and the Public Health England data, and that melanoma is increasingly being diagnosed earlier. So they considered the population in KEYNOTE‑716 to be generalisable to the eligible population in the NHS. The clinical experts also stated that they would expect pembrolizumab to work relatively similarly in stage 2B and 2C melanoma. One clinical expert highlighted that stage 2C melanoma without ulceration had similar outcomes to stage 2B melanoma, but stage 2C melanoma with ulceration tended to have a worse prognosis. The clinical experts noted that subgroup analyses in KEYNOTE‑716 were not statistically powered to detect differences between stage 2B and 2C melanoma and a larger trial would be needed to assess this. The committee agreed that it was more appropriate to consider the whole population rather than focusing on retrospective subgroup analyses. The committee concluded that the population included in KEYNOTE‑716 adequately reflects the population who would have treatment in NHS clinical practice.\n\n## The results of KEYNOTE-716 are likely to be generalisable to young people aged 12 to 17\n\nThe median age of people in the KEYNOTE‑716 trial was 60.0\xa0years in the pembrolizumab group and 61.0\xa0years in the placebo group. Both groups included 1\xa0young person (aged between 12 to 17). Because of this, the ERG noted that it is uncertain whether the trial results would be generalisable to young people. The company stated that melanoma incidence in young people is low, so there is low recruitment of young people to all melanoma trials. The European Medicines Agency has accepted that the results from KEYNOTE‑716 are generalisable to young people. This is because melanoma disease biology is similar between adults and young people. Also, disease response to pembrolizumab is similar between adults and young people in other disease areas. The clinical experts stated that they would expect the efficacy and safety outcomes with pembrolizumab in young people to be similar to outcomes in adults. The committee concluded that the results of KEYNOTE‑716 are likely to be generalisable to young people.\n\n## Efficacy and safety data from KEYNOTE-716 for the 3-weekly dose of pembrolizumab is likely to be generalisable to the 6-weekly dose\n\nPembrolizumab is licensed for treating melanoma in adults at doses of 200\xa0mg every 3\xa0weeks and 400\xa0mg every 6\xa0weeks. However, the KEYNOTE‑716 trial only assessed the efficacy and safety of the 200\xa0mg every 3\xa0weeks dose. The company explained that the European Medicines Agency has approved the 6‑weekly dosing schedule for adjuvant treatment of stage 2 melanoma because modelling of dose–exposure relationships found no significant differences in efficacy or safety between doses. Also, the 3‑weekly and 6‑weekly dosing schedule of pembrolizumab as monotherapy and in combination has been shown to be similar in other indications, including unresectable advanced melanoma. The clinical experts explained that the 6‑weekly dosing schedule of pembrolizumab is used for other lines of treatment for melanoma. They had no concerns about the generalisability of the data from KEYNOTE‑716 to NHS practice. The committee noted that the 6‑weekly dosing schedule is important to manage resource use in clinics, oncology day units and pharmacies, and is the dose that would be used most frequently in clinical practice. The committee concluded that the efficacy and safety data for the 3‑weekly dosing schedule of pembrolizumab from KEYNOTE‑716 is likely to be generalisable to the 6‑weekly dosing schedule.\n\n## Pembrolizumab improves recurrence-free and distant metastasis-free survival compared with placebo, but overall survival data is immature\n\nThe primary outcome of KEYNOTE‑716 was recurrence-free survival. At the first interim analysis (December 2020 data cut-off), a statistically significant improvement in recurrence-free survival was seen with pembrolizumab compared with placebo (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.46 to 0.92). At technical engagement, the company shared the results of the third interim analysis of the trial data, which had a January 2022 data cut-off. The additional follow-up data from the further data cuts supports the first interim analysis for recurrence-free survival. The January 2022 data cut-off also provided data for distant metastasis-free survival. This showed that adjuvant pembrolizumab statistically significantly improved distant metastasis-free survival compared with placebo (HR 0.64, 95% CI 0.47 to 0.88; p=0.00292). At the January 2022 data cut-off most people were still alive, which meant there was not enough data to analyse overall survival. The committee concluded that pembrolizumab improves recurrence-free survival and distant metastasis-free survival compared with placebo, but overall survival data is still immature.\n\n## Improved recurrence-free and distant metastasis-free survival is likely to be associated with an overall survival benefit, but this is uncertain\n\nThe committee was aware that there are challenges in gathering and interpreting overall survival data for adjuvant treatments, such as pembrolizumab for stage 2B or 2C melanoma. This is because people have no detectable disease at the time of treatment and some people may have no remaining disease at all. A large proportion of people with resected stage 2B or 2C disease will not have a recurrence. This means that people may live for a long time, so a long follow-up would be needed to collect sufficient survival data. In the absence of overall survival data, the committee considered whether recurrence-free or distant metastasis-free survival could be used as a surrogate for overall survival. The clinical experts explained that if a treatment makes a clinically meaningful difference to distant metastasis-free survival then it is likely that this would be reflected in an overall survival benefit. The committee concluded that, based on its earlier conclusion that pembrolizumab improves recurrence-free survival and distant metastasis-free survival compared with placebo (see section 3.6), it was likely that pembrolizumab also improved overall survival. However, given the immaturity of overall survival data, the extent of this benefit is uncertain.\n\n# Economic model\n\n## The company's model structure is acceptable for decision making\n\nThe company developed a Markov cohort state-transition model to assess the cost effectiveness of pembrolizumab for treating stage 2B or 2C melanoma. The model included 4 health states: recurrence-free, locoregional recurrence, distant metastasis and death. The distant metastasis state included 2 sub-states (pre-progression and post-progression) to include the costs and outcomes of subsequent treatments after the development of distant metastasis. The model used a lifetime time horizon (40.7\xa0years) and a 1‑week cycle length, with a half-cycle correction. Transitions from the recurrence-free and locoregional recurrence health states were modelled using recurrence-free survival and distant metastasis-free survival data from the most recent data cut of KEYNOTE‑716. Transitions from the distant metastasis health states were dependent on the previous treatment for advanced melanoma, data from KEYNOTE‑006 (a randomised controlled trial comparing pembrolizumab with ipilimumab in advanced melanoma) and the results of a network meta-analysis. The ERG considered the model structure reasonable. The committee noted that the structure was similar to the model used in NICE's technology appraisal guidance on adjuvant pembrolizumab for stage 3 melanoma and concluded that it was suitable for decision making.\n\n## People who have adjuvant pembrolizumab for stage 2B or 2C melanoma would probably not have further adjuvant treatment, unless they have a BRAF mutation\n\nThe company's base assumed that people who have adjuvant pembrolizumab for resected stage 2B or 2C melanoma would not have any further adjuvant treatment for locoregional recurrence at stage 3. The company's clinical experts said that people are likely to have 'one shot' at adjuvant treatment. This is because of a lack of data and uncertainty about possible restrictions on multiple lines of adjuvant immunotherapies from NHS England (see section\xa03.2). The ERG stated that these assumptions were not aligned with KEYNOTE‑716 data, and in its base case assumed that equal proportions of people would have subsequent treatment after locoregional recurrence in both arms. The company noted that KEYNOTE‑716 is a global clinical trial and several of the treatments used after locoregional recurrence in the trial are not approved for use in the UK, so the trial may not reflect UK clinical practice. The committee recalled previous comments from the clinical experts and Cancer Drugs Fund clinical lead (see section\xa03.2). It agreed that there is uncertainty about the treatment pathway for stage 3 melanoma if adjuvant pembrolizumab were recommended for stage 2B or 2C melanoma. The committee agreed that it is likely that people who have adjuvant pembrolizumab at stage 2 would not have further adjuvant immunotherapy. However, it noted that people who have a BRAF V600 mutation would be able to have dabrafenib plus trametinib for the adjuvant treatment of stage 3 melanoma. So the committee considered that its preferred assumption for adjuvant treatment for locoregional recurrence would be between the ERG's and company's assumptions used in the base-case analyses. The committee concluded that the most likely assumption would align with a scenario analysis done by the company. In this scenario, people with a BRAF mutation are eligible for adjuvant treatment at stage 3 with dabrafenib plus trametinib after they have had adjuvant treatment at stage 2B or 2C, adjusted for the percentage of the overall cohort who will have no adjuvant treatment.\n\n## The proportions of subsequent treatments for metastatic disease and how long people will have these for is uncertain\n\nIn the company's base case, the proportions of people having each subsequent treatment for distant metastasis was informed by Systemic Anti-Cancer Therapy data collected for NICE's technology appraisal guidance on adjuvant pembrolizumab for stage 3 melanoma and market share data. These proportions were adjusted to assume that 2\xa0years after starting a 1‑year course of adjuvant treatment, some people who develop metastasis may have pembrolizumab again. The ERG used the same assumptions as the company in its base-case analyses. But it noted that there is uncertainty about these inputs and did a scenario analysis assuming equal proportions of subsequent treatments after distant metastasis in both arms. This reduced the incremental cost-effectiveness ratio (ICER) by about £15,000 per quality-adjusted life year (QALY) gained. In the company's base case, the duration of first-line distant metastasis treatment was based on modelled progression-free survival for each regimen. The duration of second-line treatment was assumed to be 21\xa0weeks for all regimens except ipilimumab, for which the duration was assumed to be 12\xa0weeks. The ERG also used these assumptions in its base case but noted that it is unclear whether these assumptions are clinically plausible. The ERG explored this uncertainty by doing an extreme scenario analysis in which subsequent treatment acquisition costs in the distant metastasis state for both arms were excluded. This led to a substantial increase in the ICER, although the committee noted this was still below the range NICE considers a cost-effective use of NHS resources. The committee concluded that there is uncertainty about the market shares and duration of subsequent treatments in the distant metastasis health state.\n\n## Distributions used to model transition probabilities from the recurrence-free health state are uncertain but reasonable\n\nThe company's base case used a lognormal distribution to model transitions from the recurrence-free health state to the locoregional recurrence state and distant metastasis state for both arms. The company explained that the lognormal-lognormal combination was selected for the base case because it has a high ranking in terms of statistical fit. It explained that the incremental recurrence-free and distant metastasis-free survival benefit for pembrolizumab compared with observation was aligned with, or slightly below, the average incremental benefit across the other potential combinations. The ERG also used these distributions in its base case but did a scenario analysis using the generalised gamma-lognormal distribution, which led to an increase in the ICER above £30,000 per QALY gained. The ERG explained that this scenario was done to reflect the uncertainty in transitions from the recurrence-free health state. But it noted that the distributions selected by the company are also plausible and it is difficult to determine which distribution is most appropriate. The committee asked why the statistical fit of the transition curves was based on mean squared errors, rather than using Akaike information criterion (AIC) and Bayesian information criterion (BIC) statistics. The company explained that AIC and BIC fit statistics are not suitable measures of fit when modelling competing risks, so mean squared errors were used to assess statistical fit. The ERG agreed that this approach is appropriate. The company noted that it had used the same methodology as in NICE's technology appraisal guidance on adjuvant pembrolizumab for stage 3 melanoma, and that the observed cumulative incidence function was aligned with predicted curves for the observed period. The ERG noted that a substantial proportion of the recurrence-free survival benefit was accrued beyond the observed data period. The committee concluded that there is uncertainty about the appropriate distributions to model transition probabilities from the recurrence-free health state but noted that the company's approach appears to be reasonable.\n\n## The data inputs for end of life care costs and post-progression utility values in the distant metastasis health state are uncertain\n\nThe economic model included intervention costs, health state costs, costs of managing adverse events and end of life care costs. These were based on NHS reference prices and prices from the BNF, Personal Social Services Research Unit and Medical Information Management System. In the company's base case, end of life care costs were applied to deaths from the distant metastasis health state only. But in the ERG's base-case end of life care costs were applied regardless of the cause of death. In the recurrence-free, locoregional recurrence and pre-progression distant metastasis states, utility values in the company's model were sourced from a regression model developed using EQ-5D data from KEYNOTE‑716. In the post-progression distant metastasis health state, the company's base-case utility value was derived from Beusterien et al. 2009, which used a standard gamble approach to elicit values from the UK general population. The ERG used a value from KEYNOTE-006, based on EQ-5D. The committee noted that the company's assumptions aligned with NICE's technology appraisal guidance on adjuvant pembrolizumab for stage 3 melanoma. But, it was aware that the different assumptions used by the company and the ERG had a limited effect on the ICER. The committee concluded that end of life care costs and post-progression utility values in the distant metastasis health state are uncertain but unlikely to significantly affect the cost-effectiveness results.\n\n# Cost-effectiveness estimates\n\n## Because of the uncertainty an acceptable ICER should be around £20,000 per QALY gained\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the uncertainties in the modelling assumptions, specifically that:\n\nThe overall survival data for pembrolizumab is immature (see section 3.6), and that this uncertainty would not have been reflected in the cost-effectiveness results. Because the results are dependent on a surrogate relationship to estimate overall survival, the committee agreed it would have preferred to see some analyses assessing the relationship between recurrence-free survival, distant metastases-free survival and overall survival, to check the robustness of this approach.\n\nThere is uncertainty about some of the inputs in the economic model, including the use of subsequent adjuvant treatments after adjuvant treatment with pembrolizumab for stage 2B or 2C melanoma (see section 3.9).So it agreed that an acceptable ICER would be towards the lower end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained).\n\n## The cost-effectiveness estimates are uncertain but are likely within what NICE considers to be an acceptable use of NHS resources\n\nThe committee noted that when the confidential patient access schemes for pembrolizumab and subsequent treatments were applied, most of the ICERs were around £20,000 per QALY gained. The committee considered the uncertainty about subsequent adjuvant treatments after adjuvant pembrolizumab at stage 2 (see section 3.9). It noted that in the scenario analysis in which people who had adjuvant pembrolizumab for stage 2 disease, had a BRAF V600 mutation, and could have dabrafenib plus trametinib for adjuvant stage 3 treatment, the ICER was also around £20,000 per QALY gained. Taking all of this into account, the committee concluded that pembrolizumab was an acceptable use of NHS resources.\n\n# Other factors\n\n## Equalities\n\nThe committee did not identify any equality issues associated with using pembrolizumab in this indication.\n\n## Innovation\n\nThere are currently no adjuvant treatment options for people with stage 2 melanoma in the UK. Standard care is routine follow-up. So the committee concluded that introducing pembrolizumab as adjuvant treatment for people with stage 2B and stage 2C melanoma would be a step change in clinical management.\n\n## End of life criteria\n\nNICE's advice about life-extending treatments for people with a short life expectancy did not apply.\n\n# Conclusion\n\n## Pembrolizumab is recommended for routine use\n\nThe committee concluded that the most plausible cost-effectiveness estimates are within what NICE considers to be an acceptable use of NHS resources. So pembrolizumab is recommended for the adjuvant treatment of resected stage 2B or 2C melanoma in people aged 12\xa0or over."}	https://www.nice.org.uk/guidance/ta837	Evidence-based recommendations on pembrolizumab (Keytruda) for the adjuvant treatment of resected stage 2B and 2C melanoma in people 12 years and over.
c1d8b48336eae4f35babe1ced72cce0a32e93642	nice	YAG laser vitreolysis for symptomatic vitreous floaters	YAG laser vitreolysis for symptomatic vitreous floaters Evidence-based recommendations on YAG laser vitreolysis for symptomatic vitreous floaters. This involves a special type of laser (YAG) firing short pulses of energy into the floaters, to break them up (vitreolysis) and reduce sight disturbances. # Recommendations Evidence on the safety and efficacy of YAG laser vitreolysis for symptomatic vitreous floaters is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. Further research should include suitably powered randomised controlled trials. Research should report details of patient selection (including type, size and location of floaters), degree of visual disturbance and details of the procedure. This procedure should only be done by retinal specialists experienced in laser surgery and with expertise in managing vitreoretinal disease.# The condition, current treatments and procedure # The condition Vitreous floaters are microscopic clumps of collagen fibres in the vitreous that cast shadows on the retina, appearing as floaters. The most common cause of vitreous floaters is posterior vitreous detachment, when the posterior hyaloid face separates from the retina. Vitreous floaters can be primary or secondary. Primary vitreous floaters originate from the vitreous body. Secondary vitreous floaters originate from outside the vitreous body, generally from proteins, amyloid or cells. # Current treatments Vitreous floaters do not usually threaten vision and can be managed conservatively. When they do affect vision, treatment options include vitrectomy and vitreolysis with YAG laser. # The procedure This procedure aims to improve vision and reduce symptoms by removing or reducing the size of floaters. The pupil is dilated and anaesthetic eye drops are administered. A specialised contact lens is placed on the cornea. Coaxial illumination is used. A laser microscope focuses on the front surface of the floater and creates short bursts of energy (nanosecond pulses). The laser energy usually starts at a low level, and is increased until it is high enough to break up the floater. The laser is stopped once all visually significant floaters are treated. YAG laser vitreolysis is done as an outpatient procedure. Depending on the characteristics and numbers of floaters, more than 1 session may be needed.	{'Recommendations': 'Evidence on the safety and efficacy of YAG laser vitreolysis for symptomatic vitreous floaters is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should include suitably powered randomised controlled trials. Research should report details of patient selection (including type, size and location of floaters), degree of visual disturbance and details of the procedure.\n\nThis procedure should only be done by retinal specialists experienced in laser surgery and with expertise in managing vitreoretinal disease.', 'The condition, current treatments and procedure': '# The condition\n\nVitreous floaters are microscopic clumps of collagen fibres in the vitreous that cast shadows on the retina, appearing as floaters. The most common cause of vitreous floaters is posterior vitreous detachment, when the posterior hyaloid face separates from the retina.\n\nVitreous floaters can be primary or secondary. Primary vitreous floaters originate from the vitreous body. Secondary vitreous floaters originate from outside the vitreous body, generally from proteins, amyloid or cells.\n\n# Current treatments\n\nVitreous floaters do not usually threaten vision and can be managed conservatively. When they do affect vision, treatment options include vitrectomy and vitreolysis with YAG laser.\n\n# The procedure\n\nThis procedure aims to improve vision and reduce symptoms by removing or reducing the size of floaters.\n\nThe pupil is dilated and anaesthetic eye drops are administered. A specialised contact lens is placed on the cornea. Coaxial illumination is used. A laser microscope focuses on the front surface of the floater and creates short bursts of energy (nanosecond pulses). The laser energy usually starts at a low level, and is increased until it is high enough to break up the floater. The laser is stopped once all visually significant floaters are treated.\n\nYAG laser vitreolysis is done as an outpatient procedure. Depending on the characteristics and numbers of floaters, more than 1 session may be needed.'}	https://www.nice.org.uk/guidance/ipg741	Evidence-based recommendations on YAG laser vitreolysis for symptomatic vitreous floaters. This involves a special type of laser (YAG) firing short pulses of energy into the floaters, to break them up (vitreolysis) and reduce sight disturbances.
282ed2b492839d98990b9629a4b5c56aa212a995	nice	Transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine	Transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine Evidence-based recommendations on transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine in adults. This involves attaching a small device on the forehead to send small electrical currents to the nerves that bring sensation to the upper eyelids, forehead and scalp. # Recommendations Evidence on the safety of transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine is adequate and raises no major safety concerns. For efficacy: The evidence for treating an acute migraine attack is adequate but, for treating subsequent attacks, is limited in quality and quantity. So, for treating acute migraine, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. The evidence for preventing migraine is inadequate in quality. So, for preventing migraine, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. Clinicians wanting to do transcutaneous electrical stimulation of the supraorbital nerve for acute treatment of migraine should: Inform the clinical governance leads in their healthcare organisation. Give people and their families and carers clear written information to support shared decision making, including NICE's information for the public. Ensure that people and their families and carers understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedures outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Patient selection should usually be done by clinicians (including clinical nurse specialists) with expertise in managing migraine. NICE encourages further research on transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine. Studies should describe clearly whether the procedure is used for treatment or prevention. They should include details of patient selection, and the intensity, duration and frequency of use. Outcome measures should include the number and severity of migraine episodes, quality of life in the short and long term, any changes in medication and management of subsequent attacks. The development of any complications after starting treatment should be documented.# The condition, current treatments and procedure # The condition Migraines are moderate to severe headaches that may last for hours, days or longer. They are often accompanied by nausea, photophobia, phonophobia and the perception of unpleasant odours. In some people, they may be accompanied by an aura, characterised by the focal neurological symptoms that usually precede or sometimes accompany the headache. The International Headache Society's international classification of headache disorders classifies migraine types. # Current treatments The usual treatment options for migraines are medical therapies, to either stop or prevent attacks (see NICE's guideline on headaches in over 12s). For acute migraine attacks, these include analgesics, triptans and antiemetics. Treatments to stop or reduce the frequency of migraine attacks include beta blockers, calcium-channel blockers, tricyclic antidepressants, antiepileptics and calcitonin gene-related peptide inhibitors. Invasive treatments are reserved for people with distressing symptoms that are refractory to medical therapy. These include nerve blocks, botulinum toxin (see NICE's technology appraisal guidance on botulinum toxin type A for the prevention of headaches in adults with chronic migraine), acupuncture, and interventional procedures (see NICE's interventional procedures guidance on occipital nerve stimulation, transcutaneous stimulation of the cervical branch of the vagus nerve and transcranial magnetic stimulation). # The procedure Transcutaneous electrical stimulation of the supraorbital nerve uses small electrical currents to stimulate the supraorbital nerves (branches of the ophthalmic nerve, the first division of the trigeminal nerve) through the skin overlying the nerves. It is also called external trigeminal nerve stimulation or eTNS. The aim is to relieve headache and, when used regularly, to reduce the severity and the frequency of migraine attacks. People with migraine administer the therapy themselves using a small battery-operated device. For example, 1 device consists of a headband with a central button connected to a self-adhesive electrode patch. This is applied to the forehead above the eyebrows. When the device is activated, small electrical impulses stimulate the supraorbital nerves (branches of the ophthalmic nerve, the first division of the trigeminal nerve). The intensity of the electrical pulses increases periodically and can be self-adjusted. Stimulation is applied daily for about 1 to 2 hours during an acute migraine attack, and for 20 minutes for prevention between attacks.	{'Recommendations': "Evidence on the safety of transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine is adequate and raises no major safety concerns. For efficacy:\n\nThe evidence for treating an acute migraine attack is adequate but, for treating subsequent attacks, is limited in quality and quantity. So, for treating acute migraine, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nThe evidence for preventing migraine is inadequate in quality. So, for preventing migraine, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nClinicians wanting to do transcutaneous electrical stimulation of the supraorbital nerve for acute treatment of migraine should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people and their families and carers clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that people and their families and carers understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedures outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should usually be done by clinicians (including clinical nurse specialists) with expertise in managing migraine.\n\nNICE encourages further research on transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine. Studies should describe clearly whether the procedure is used for treatment or prevention. They should include details of patient selection, and the intensity, duration and frequency of use. Outcome measures should include the number and severity of migraine episodes, quality of life in the short and long term, any changes in medication and management of subsequent attacks. The development of any complications after starting treatment should be documented.", 'The condition, current treatments and procedure': "# The condition\n\nMigraines are moderate to severe headaches that may last for hours, days or longer. They are often accompanied by nausea, photophobia, phonophobia and the perception of unpleasant odours. In some people, they may be accompanied by an aura, characterised by the focal neurological symptoms that usually precede or sometimes accompany the headache. The International Headache Society's international classification of headache disorders classifies migraine types.\n\n# Current treatments\n\nThe usual treatment options for migraines are medical therapies, to either stop or prevent attacks (see NICE's guideline on headaches in over 12s). For acute migraine attacks, these include analgesics, triptans and antiemetics. Treatments to stop or reduce the frequency of migraine attacks include beta blockers, calcium-channel blockers, tricyclic antidepressants, antiepileptics and calcitonin gene-related peptide inhibitors.\n\nInvasive treatments are reserved for people with distressing symptoms that are refractory to medical therapy. These include nerve blocks, botulinum toxin (see NICE's technology appraisal guidance on botulinum toxin type A for the prevention of headaches in adults with chronic migraine), acupuncture, and interventional procedures (see NICE's interventional procedures guidance on occipital nerve stimulation, transcutaneous stimulation of the cervical branch of the vagus nerve and transcranial magnetic stimulation).\n\n# The procedure\n\nTranscutaneous electrical stimulation of the supraorbital nerve uses small electrical currents to stimulate the supraorbital nerves (branches of the ophthalmic nerve, the first division of the trigeminal nerve) through the skin overlying the nerves. It is also called external trigeminal nerve stimulation or eTNS. The aim is to relieve headache and, when used regularly, to reduce the severity and the frequency of migraine attacks.\n\nPeople with migraine administer the therapy themselves using a small battery-operated device. For example, 1\xa0device consists of a headband with a central button connected to a self-adhesive electrode patch. This is applied to the forehead above the eyebrows. When the device is activated, small electrical impulses stimulate the supraorbital nerves (branches of the ophthalmic nerve, the first division of the trigeminal nerve). The intensity of the electrical pulses increases periodically and can be self-adjusted. Stimulation is applied daily for about 1\xa0to 2\xa0hours during an acute migraine attack, and for 20\xa0minutes for prevention between attacks."}	https://www.nice.org.uk/guidance/ipg740	Evidence-based recommendations on transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine in adults. This involves attaching a small device on the forehead to send small electrical currents to the nerves that bring sensation to the upper eyelids, forehead and scalp.
9bec10cb0737aa124c9d2634ef071555485da37c	nice	Pembrolizumab for adjuvant treatment of renal cell carcinoma	Pembrolizumab for adjuvant treatment of renal cell carcinoma Evidence-based recommendations on pembrolizumab (Keytruda) for adjuvant treatment of renal cell carcinoma in adults. # Recommendations Pembrolizumab is recommended, within its marketing authorisation, as an option for the adjuvant treatment of renal cell carcinoma at increased risk of recurrence after nephrectomy, with or without metastatic lesion resection, in adults. It is recommended only if the company provides it according to the commercial arrangement. Why the committee made these recommendations People who have had renal cell carcinoma that has been treated surgically with either a partial or radical nephrectomy, and that is at increased risk of recurrence, have routine surveillance (regular monitoring) as follow up. Pembrolizumab plus routine surveillance is a possible option as an adjuvant treatment (that is, after surgery). Evidence from a clinical trial suggests that, after surgery, pembrolizumab plus routine surveillance increases the time people have before their cancer comes back and how long they live compared with placebo plus routine surveillance. The cost-effectiveness estimates for pembrolizumab as adjuvant treatment are within the range that NICE normally considers an acceptable use of NHS resources. So, it is recommended.# Information about pembrolizumab # Marketing authorisation indication Pembrolizumab (Keytruda, Merck Sharp and Dohme) as 'monotherapy is indicated for the adjuvant treatment of adults with renal cell carcinoma at increased risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for pembrolizumab. # Price The cost of a 100 mg per 4 ml vial of pembrolizumab is £2,630 (excluding VAT; BNF online accessed April 2022). The cost of a 12‑month course (17 cycles) of treatment is £89,420. The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Merck Sharp and Dohme (MSD), a review of this submission by the external review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## There is an unmet need for adjuvant treatments for renal cell carcinoma and people with the condition would welcome new treatment options Renal cell carcinoma is the most common type of kidney cancer, accounting for more than 80% of cases. The highest rate is in people aged over 85 because the number of new cases increases with age. Initial treatment depends on whether, at the time of diagnosis, the cancer has spread to other parts of the body (advanced renal cell carcinoma) or is localised to the kidneys. The clinical experts explained that current treatments for advanced renal cell carcinoma cause a lot of side effects. These include extreme fatigue, night sweats, rashes, chronic diarrhoea, severe mouth ulcers, nausea, hypertension, and muscle and joint pain. These can severely affect quality of life. For people with localised cancer, surgery is the usual treatment. There are no adjuvant (after surgery) treatment options available for people who have nephrectomy (partial or radical) for renal cell carcinoma at increased risk of recurrence. The patient experts explained that, after surgery, people often feel abandoned, emotionally low and anxious about the cancer returning. The clinical experts explained that adjuvant treatment options would help prevent the cancer returning and spreading, especially more aggressive and rare types. The committee noted that people with renal cell carcinoma are anxious about the cancer returning. It concluded that there is an unmet need for adjuvant treatment options, and that the addition of pembrolizumab would be welcome. # Treatment pathway and dosing regimen ## The company's positioning of pembrolizumab in the treatment pathway is appropriate The company's proposed positioning of pembrolizumab was as an adjuvant treatment after partial or complete nephrectomy in people with renal cell carcinoma at increased risk of recurrence. The committee found this acceptable. There is currently no globally accepted standard care for adjuvant treatment of renal cell carcinoma. Also, NICE has not appraised a medical treatment to reduce the risk of recurrence after surgery for renal cell carcinoma before. Most renal cell carcinomas are treated by complete or partial nephrectomy. After tumour resection, the cancer can be graded. Risk of recurrence is greater in higher-grade cancers. After surgery, micrometastases and individual tumour cells may still be present or may reoccur. They can potentially develop into larger tumours and spread to distant sites around the body. This results in advanced, unresectable tumours. The aim of adjuvant treatment is to prevent recurrence and potential progression to advanced (unresectable or metastatic) disease. The committee concluded that the positioning of pembrolizumab was acceptable for decision making. ## The 400 mg dose once every 6 weeks pembrolizumab regimen is preferable Pembrolizumab can be administered as a 200 mg dose once every 3 weeks or a 400 mg dose once every 6 weeks. The clinical experts noted that the 400 mg dosage is easier for people and reduces NHS resource use, and they would prefer to use pembrolizumab every 6 weeks. The committee agreed that pembrolizumab is likely to be administered at a 400 mg dose once every 6 weeks, and that this would be preferable to a 3‑weekly dosage. # Clinical effectiveness ## The population is narrower than that in the scope, but is aligned with the marketing authorisation and KEYNOTE-564 The clinical-effectiveness evidence presented for adjuvant pembrolizumab was from KEYNOTE‑564. This was a phase 3, randomised, double-blind, placebo-controlled, multicentre clinical trial comparing pembrolizumab with placebo, both administered with routine surveillance. About 950 people were planned to be randomised 1:1 to have either placebo or pembrolizumab 200 mg, by intravenous infusion, every 3 weeks. They were adults with renal cell carcinoma that had a clear cell component. The study protocol defined increased risk as being carcinoma at intermediate-high or high risk of recurrence after nephrectomy, or metastasis stage M1 with no evidence of disease after nephrectomy and resection of metastatic lesions. Risk categories were based on pathological tumour node metastasis, Fuhrman grade and presence of sarcomatoid features. The intermediate high-risk category included: pathological tumour stage T2, or grade 4, sarcomatoid or both, with no nodal involvement and no metastases pathological tumour stage T3, any grade, with no nodal involvement and no metastases.The high-risk category included: pathological tumour stage T4, any grade, with no nodal involvement and no metastases any pathological tumour stage, any grade, with nodal involvement and no metastases.The M1 stage with no evidence of disease category included people with metastatic disease who had had complete resection of primary and metastatic lesions. The population in the scope included everyone with renal cell carcinoma who had had a nephrectomy. The marketing authorisation limits the population to people with renal cell carcinoma at increased risk of recurrence after nephrectomy, or after nephrectomy and resection of metastatic lesions. The increased risk was defined in the clinical trial as intermediate or high. The committee considered the population in the trial to be generalisable to the NHS. It queried whether a complete resection with clear margins and complete removal of metastases would be needed for the indication to use pembrolizumab. The clinical experts stated that resections are generally straightforward and that almost no one needs to have a repeat surgery. But resection of metastases will depend on factors such as the person's fitness and location of metastases. The committee concluded that the population in which the clinical-effectiveness estimates were based was narrower than that in the scope. But it agreed that it was aligned with the marketing authorisation and clinical trial. ## Pembrolizumab improves DFS but the data is immature In KEYNOTE‑564, the rate of disease recurrence was lower with pembrolizumab than with placebo. The investigator-assessed (IA) hazard ratio was 0.63 (95% confidence interval 0.50 to 0.80). Median disease-free survival (DFS) and overall survival (OS) has not been reached in either treatment group of KEYNOTE‑564. The immaturity of the data introduced uncertainty that may have affected the cost effectiveness. The clinical experts noted that the goal of adjuvant treatment is to help people live longer. The results from KEYNOTE‑564 suggested a lower risk of relapse for people who had pembrolizumab. The clinical experts noted that, in the adjuvant setting, DFS is important. This is because OS in isolation can be affected by subsequent treatments. The company agreed that the data was immature but considered that data collection beyond the planned final analysis in 2024 may not be more informative. The committee concluded that, although the data was immature, people who had pembrolizumab had a lower risk of relapse than people who did not. ## Grade 3 to 5 adverse events are more common with pembrolizumab than with placebo The company stated that adverse events were similar between the pembrolizumab and placebo treatment groups in KEYNOTE‑564. The committee queried this. It highlighted that the results showed that people who had pembrolizumab had more grade 3 to 5 adverse events than people who had placebo. The clinical experts explained that adverse events profiles are very unpredictable and that people have differing experiences in the severity, frequency and duration of side effects. The patient experts stated that side effects can come on very quickly after pembrolizumab treatment, but agreed that people are likely to experience side effects differently. The committee recognised that active treatment will usually result in more adverse events than placebo. It noted that there were more grade 3 to 5 adverse events in the pembrolizumab than placebo group. But it concluded that this would be expected with an active immunotherapy. # Cost effectiveness ## The company's model is structurally appropriate for decision making The company presented a cohort-level, state-transition Markov model to estimate the cost effectiveness of pembrolizumab. The model consisted of 4 mutually exclusive health states: disease free, locoregional recurrence, distant metastases and death. The model estimated the disease pathway after nephrectomy, in that people remained disease free, had disease recurrence or died. The model's time horizon was set to 41.1 years (lifetime), pembrolizumab treatment duration was a maximum of 17 cycles (about 1 year). The ERG considered the company's model structure to be appropriate. Also, the model structure had been accepted in a previous NICE technology appraisal guidance on pembrolizumab for adjuvant treatment of completely resected stage 3 melanoma. The committee concluded that the company's model was structurally appropriate for decision making. ## Transitions from the disease-free health state are extrapolated and modelled appropriately For transitions out of the disease-free health state the parametric models selected by the company were: Approach 1: standard parametric models fitted independently to pembrolizumab and placebo data from KEYNOTE‑564. Approach 2: standard proportional hazards (PH) parametric models (exponential, Weibull and Gompertz) jointly fitted to pembrolizumab and placebo data from KEYNOTE‑564, with a time-constant hazard ratio applied for pembrolizumab compared with placebo (PH model). Approach 3: standard PH parametric models (exponential, Weibull and Gompertz) jointly fitted to pembrolizumab and placebo data from KEYNOTE‑564, with a hazard ratio for pembrolizumab compared with placebo applied to year 1 and another hazard ratio applied for year 2 onwards (time-varying PH model).The company preferred approach 3. The ERG considered that, when patient level data is available from a trial, using PH modelling is not necessary. It considered that independent models for each treatment group were preferred, as in NICE's Decision Support Unit Technical Support Document 14. So, the ERG considered approach 1 to be a more robust method for extrapolating the cause-specific time-to-event data used in the model. The committee concluded that either extrapolation approach could be justified but preferred approach 1. ## Choice of extrapolation approach affects the ICERs in all cost-effectiveness scenarios Incremental cost-effectiveness ratios (ICERs) were calculated using the ERG's preferred approach 1 (see section 3.8) with treatment waning scenarios (see section 3.10) and scenarios comparing investigator assessment or blinded central independent review (BICR; see section 3.11). This resulted in ICERs that included some which were higher than what NICE usually considers an acceptable use of NHS resources. The committee concluded that the ERG's approach was preferred for extrapolation, noting that it aligned with NICE's Decision Support Unit Technical Support Document 14. ## Whether the pattern of renal cell carcinoma relapse is the same with pembrolizumab as with routine surveillance is uncertain Pembrolizumab is given for a maximum of 17 cycles (1 year) but, in the model, the long-term DFS was extrapolated over a lifetime horizon. The aim of treatment is to remove any residual microscopic cancer after resection, and reduce the risk of relapse and progression to metastatic disease (see section 3.2). There is substantial uncertainty around the duration of the treatment effect, the waning of the treatment effect and the long-term risk of relapse. The clinical experts agreed that the pattern of relapse is unknown but the longer someone remains cancer free, the lower the risk of recurrence. The ERG considered that the risk of relapse may increase over time to match routine surveillance. It did 3 scenario analyses exploring risk of relapse for the pembrolizumab group. It modelled the transitions from 'disease free to locoregional recurrence' and from 'disease free to distant metastases' to become equal to routine surveillance at 4, 7 and 10 years. It also applied treatment waning effects to 100%, 50% and 20% of people. The company considered treatment waning to be implausible in the adjuvant setting. The company presented scenarios exploring the assumptions that at 7 or 10 years, either 15% or 20% of people in the pembrolizumab treatment group would experience risk of relapse equal to routine surveillance. The clinical experts agreed that most relapses occur within 5 years and the risk at 10 years is much smaller. The committee understood that the long-term treatment effect of pembrolizumab was uncertain even with the scenarios presented. It concluded that a treatment waning effect should have been considered, and took account of the scenarios explored by the ERG and the company in its decision making. ## Whether IA or BICR is a better estimate of DFS is uncertain The primary outcome in KEYNOTE‑564 was DFS assessed by an investigator. It was also assessed by BICR. The company considered that investigator assessment was more reflective of UK clinical practice and used the results of this analysis in its base case. But, as part of the response to consultation, the company submitted an analysis incorporating extrapolation of DFS based on BICR. The committee took into account ICERs based on DFS by BICR in their decision making. The ERG considered the BICR assessment more methodologically robust. The company explained that the IA and BICR results for DFS were consistent. The committee noted the difference between the IA and BICR-assessed hazard ratios. The ERG noted that it would have expected the results of the IA and BICR analyses to be similar. It could not tell from the data provided what gave rise to the difference in the hazard ratios. The ERG was unable to robustly include the BICR data in its base case, but provided an illustrative scenario of the likely effect of using BICR-assessed DFS. It applied an inflation factor to the 'disease free to locoregional' and 'disease free to distant metastases' transition probabilities using the ratio of the BICR and IA hazard ratios. This increased the ICER. The company considered investigator assessment to be reflective of clinical practice. It stated that the discrepancy between the IA and BICR-assessed results was not statistically meaningful, and could possibly have been explained by administrative processes and timings. The committee questioned why the difference in DFS estimates came about. It suggested that it could have been because the blinded independent reviewers noted fewer events with placebo and more events with pembrolizumab compared with local judgements. The reason behind this was unclear. But the clinical experts noted that blinding may have been an issue for investigator assessment because the adverse events profile (see section 3.6) could have indicated who was on active treatment. The committee was uncertain about why the IA and BICR-assessed results differed, but the clinical expert noted that they would expect to see differences in the IA and BICR results. The committee agreed that investigator assessment reflected what is done in UK clinical practice. It concluded that it would consider the cost-effectiveness estimates using both approaches. But it thought that the BICR data was more methodologically robust and provided a plausible estimate of DFS. # Cost-effectiveness estimates ## Pembrolizumab is recommended for routine use in the NHS The committee acknowledged the difference between survival extrapolations in the company's and ERG's base cases (see section 3.8). It also noted that, if BICR assessment was used, it resulted in increased ICERs (see section 3.11). NICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the uncertainty about whether investigator assessment or BICR gives a more robust estimate of DFS. But it expressed a preference for BICR analysis. It considered both the company's and ERG's preferred assumptions and concluded that its preferred assumptions were: approach 1, that is, the standard parametric models fitted independently to pembrolizumab and placebo data from KEYNOTE‑564 to extrapolate the cause-specific time-to-event data used in the model cost-effectiveness estimates using both the IA DFS and the BICR-assessed DFS including treatment waning in the pembrolizumab treatment group.The committee considered what effect the uncertainty around the approach used to extrapolate DFS data had on the cost-effectiveness estimates. It recognised that pembrolizumab is promising in that it increased DFS. It also noted that the range of plausible ICERs using its preferred assumptions and with the confidential discount applied were in the range usually considered a cost-effective use of NHS resources. The committee concluded that pembrolizumab could be recommended for routine use in the NHS for the adjuvant treatment of renal cell carcinoma at increased risk of recurrence. # Other factors ## There are no equality issues and pembrolizumab is not innovative No equality or social value judgement issues were identified by the committee. The committee noted that there is no NICE recommended active adjuvant treatment for renal cell carcinoma post-nephrectomy at increased risk of recurrence. But, when focusing specifically on relevant benefits associated with innovation, the committee considered that there were no additional benefits that had not been captured in the QALY.	{'Recommendations': 'Pembrolizumab is recommended, within its marketing authorisation, as an option for the adjuvant treatment of renal cell carcinoma at increased risk of recurrence after nephrectomy, with or without metastatic lesion resection, in adults. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nPeople who have had renal cell carcinoma that has been treated surgically with either a partial or radical nephrectomy, and that is at increased risk of recurrence, have routine surveillance (regular monitoring) as follow up. Pembrolizumab plus routine surveillance is a possible option as an adjuvant treatment (that is, after surgery).\n\nEvidence from a clinical trial suggests that, after surgery, pembrolizumab plus routine surveillance increases the time people have before their cancer comes back and how long they live compared with placebo plus routine surveillance.\n\nThe cost-effectiveness estimates for pembrolizumab as adjuvant treatment are within the range that NICE normally considers an acceptable use of NHS resources. So, it is recommended.', 'Information about pembrolizumab': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, Merck Sharp and Dohme) as 'monotherapy is indicated for the adjuvant treatment of adults with renal cell carcinoma at increased risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for pembrolizumab.\n\n# Price\n\nThe cost of a 100\xa0mg per 4\xa0ml vial of pembrolizumab is £2,630 (excluding VAT; BNF online accessed April 2022). The cost of a 12‑month course (17\xa0cycles) of treatment is £89,420.\n\nThe company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Merck Sharp and Dohme (MSD), a review of this submission by the external review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## There is an unmet need for adjuvant treatments for renal cell carcinoma and people with the condition would welcome new treatment options\n\nRenal cell carcinoma is the most common type of kidney cancer, accounting for more than 80% of cases. The highest rate is in people aged over\xa085 because the number of new cases increases with age. Initial treatment depends on whether, at the time of diagnosis, the cancer has spread to other parts of the body (advanced renal cell carcinoma) or is localised to the kidneys. The clinical experts explained that current treatments for advanced renal cell carcinoma cause a lot of side effects. These include extreme fatigue, night sweats, rashes, chronic diarrhoea, severe mouth ulcers, nausea, hypertension, and muscle and joint pain. These can severely affect quality of life. For people with localised cancer, surgery is the usual treatment. There are no adjuvant (after surgery) treatment options available for people who have nephrectomy (partial or radical) for renal cell carcinoma at increased risk of recurrence. The patient experts explained that, after surgery, people often feel abandoned, emotionally low and anxious about the cancer returning. The clinical experts explained that adjuvant treatment options would help prevent the cancer returning and spreading, especially more aggressive and rare types. The committee noted that people with renal cell carcinoma are anxious about the cancer returning. It concluded that there is an unmet need for adjuvant treatment options, and that the addition of pembrolizumab would be welcome.\n\n# Treatment pathway and dosing regimen\n\n## The company's positioning of pembrolizumab in the treatment pathway is appropriate\n\nThe company's proposed positioning of pembrolizumab was as an adjuvant treatment after partial or complete nephrectomy in people with renal cell carcinoma at increased risk of recurrence. The committee found this acceptable. There is currently no globally accepted standard care for adjuvant treatment of renal cell carcinoma. Also, NICE has not appraised a medical treatment to reduce the risk of recurrence after surgery for renal cell carcinoma before. Most renal cell carcinomas are treated by complete or partial nephrectomy. After tumour resection, the cancer can be graded. Risk of recurrence is greater in higher-grade cancers. After surgery, micrometastases and individual tumour cells may still be present or may reoccur. They can potentially develop into larger tumours and spread to distant sites around the body. This results in advanced, unresectable tumours. The aim of adjuvant treatment is to prevent recurrence and potential progression to advanced (unresectable or metastatic) disease. The committee concluded that the positioning of pembrolizumab was acceptable for decision making.\n\n## The 400\xa0mg dose once every 6\xa0weeks pembrolizumab regimen is preferable\n\nPembrolizumab can be administered as a 200\xa0mg dose once every 3\xa0weeks or a 400\xa0mg dose once every 6\xa0weeks. The clinical experts noted that the 400\xa0mg dosage is easier for people and reduces NHS resource use, and they would prefer to use pembrolizumab every 6\xa0weeks. The committee agreed that pembrolizumab is likely to be administered at a 400\xa0mg dose once every 6\xa0weeks, and that this would be preferable to a 3‑weekly dosage.\n\n# Clinical effectiveness\n\n## The population is narrower than that in the scope, but is aligned with the marketing authorisation and KEYNOTE-564\n\nThe clinical-effectiveness evidence presented for adjuvant pembrolizumab was from KEYNOTE‑564. This was a phase\xa03, randomised, double-blind, placebo-controlled, multicentre clinical trial comparing pembrolizumab with placebo, both administered with routine surveillance. About 950\xa0people were planned to be randomised 1:1 to have either placebo or pembrolizumab 200\xa0mg, by intravenous infusion, every 3\xa0weeks. They were adults with renal cell carcinoma that had a clear cell component. The study protocol defined increased risk as being carcinoma at intermediate-high or high risk of recurrence after nephrectomy, or metastasis stage\xa0M1 with no evidence of disease after nephrectomy and resection of metastatic lesions. Risk categories were based on pathological tumour node metastasis, Fuhrman grade and presence of sarcomatoid features. The intermediate high-risk category included:\n\npathological tumour stage\xa0T2, or grade\xa04, sarcomatoid or both, with no nodal involvement and no metastases\n\npathological tumour stage\xa0T3, any grade, with no nodal involvement and no metastases.The high-risk category included:\n\npathological tumour stage\xa0T4, any grade, with no nodal involvement and no metastases\n\nany pathological tumour stage, any grade, with nodal involvement and no metastases.The M1\xa0stage with no evidence of disease category included people with metastatic disease who had had complete resection of primary and metastatic lesions. The population in the scope included everyone with renal cell carcinoma who had had a nephrectomy. The marketing authorisation limits the population to people with renal cell carcinoma at increased risk of recurrence after nephrectomy, or after nephrectomy and resection of metastatic lesions. The increased risk was defined in the clinical trial as intermediate or high. The committee considered the population in the trial to be generalisable to the NHS. It queried whether a complete resection with clear margins and complete removal of metastases would be needed for the indication to use pembrolizumab. The clinical experts stated that resections are generally straightforward and that almost no one needs to have a repeat surgery. But resection of metastases will depend on factors such as the person's fitness and location of metastases. The committee concluded that the population in which the clinical-effectiveness estimates were based was narrower than that in the scope. But it agreed that it was aligned with the marketing authorisation and clinical trial.\n\n## Pembrolizumab improves DFS but the data is immature\n\nIn KEYNOTE‑564, the rate of disease recurrence was lower with pembrolizumab than with placebo. The investigator-assessed (IA) hazard ratio was\xa00.63 (95% confidence interval [CI] 0.50\xa0to\xa00.80). Median disease-free survival (DFS) and overall survival (OS) has not been reached in either treatment group of KEYNOTE‑564. The immaturity of the data introduced uncertainty that may have affected the cost effectiveness. The clinical experts noted that the goal of adjuvant treatment is to help people live longer. The results from KEYNOTE‑564 suggested a lower risk of relapse for people who had pembrolizumab. The clinical experts noted that, in the adjuvant setting, DFS is important. This is because OS in isolation can be affected by subsequent treatments. The company agreed that the data was immature but considered that data collection beyond the planned final analysis in 2024 may not be more informative. The committee concluded that, although the data was immature, people who had pembrolizumab had a lower risk of relapse than people who did not.\n\n## Grade\xa03 to\xa05 adverse events are more common with pembrolizumab than with placebo\n\nThe company stated that adverse events were similar between the pembrolizumab and placebo treatment groups in KEYNOTE‑564. The committee queried this. It highlighted that the results showed that people who had pembrolizumab had more grade 3\xa0to\xa05 adverse events than people who had placebo. The clinical experts explained that adverse events profiles are very unpredictable and that people have differing experiences in the severity, frequency and duration of side effects. The patient experts stated that side effects can come on very quickly after pembrolizumab treatment, but agreed that people are likely to experience side effects differently. The committee recognised that active treatment will usually result in more adverse events than placebo. It noted that there were more grade\xa03 to\xa05 adverse events in the pembrolizumab than placebo group. But it concluded that this would be expected with an active immunotherapy.\n\n# Cost effectiveness\n\n## The company's model is structurally appropriate for decision making\n\nThe company presented a cohort-level, state-transition Markov model to estimate the cost effectiveness of pembrolizumab. The model consisted of 4\xa0mutually exclusive health states: disease free, locoregional recurrence, distant metastases and death. The model estimated the disease pathway after nephrectomy, in that people remained disease free, had disease recurrence or died. The model's time horizon was set to 41.1\xa0years (lifetime), pembrolizumab treatment duration was a maximum of 17\xa0cycles (about 1\xa0year). The ERG considered the company's model structure to be appropriate. Also, the model structure had been accepted in a previous NICE technology appraisal guidance on pembrolizumab for adjuvant treatment of completely resected stage\xa03 melanoma. The committee concluded that the company's model was structurally appropriate for decision making.\n\n## Transitions from the disease-free health state are extrapolated and modelled appropriately\n\nFor transitions out of the disease-free health state the parametric models selected by the company were:\n\nApproach\xa01: standard parametric models fitted independently to pembrolizumab and placebo data from KEYNOTE‑564.\n\nApproach\xa02: standard proportional hazards (PH) parametric models (exponential, Weibull and Gompertz) jointly fitted to pembrolizumab and placebo data from KEYNOTE‑564, with a time-constant hazard ratio applied for pembrolizumab compared with placebo (PH model).\n\nApproach\xa03: standard PH parametric models (exponential, Weibull and Gompertz) jointly fitted to pembrolizumab and placebo data from KEYNOTE‑564, with a hazard ratio for pembrolizumab compared with placebo applied to year\xa01 and another hazard ratio applied for year\xa02 onwards (time-varying PH model).The company preferred approach\xa03. The ERG considered that, when patient level data is available from a trial, using PH modelling is not necessary. It considered that independent models for each treatment group were preferred, as in NICE's Decision Support Unit Technical Support Document\xa014. So, the ERG considered approach\xa01 to be a more robust method for extrapolating the cause-specific time-to-event data used in the model. The committee concluded that either extrapolation approach could be justified but preferred approach\xa01.\n\n## Choice of extrapolation approach affects the ICERs in all cost-effectiveness scenarios\n\nIncremental cost-effectiveness ratios (ICERs) were calculated using the ERG's preferred approach\xa01 (see section\xa03.8) with treatment waning scenarios (see section\xa03.10) and scenarios comparing investigator assessment or blinded central independent review (BICR; see section\xa03.11). This resulted in ICERs that included some which were higher than what NICE usually considers an acceptable use of NHS resources. The committee concluded that the ERG's approach was preferred for extrapolation, noting that it aligned with NICE's Decision Support Unit Technical Support Document\xa014.\n\n## Whether the pattern of renal cell carcinoma relapse is the same with pembrolizumab as with routine surveillance is uncertain\n\nPembrolizumab is given for a maximum of 17\xa0cycles (1\xa0year) but, in the model, the long-term DFS was extrapolated over a lifetime horizon. The aim of treatment is to remove any residual microscopic cancer after resection, and reduce the risk of relapse and progression to metastatic disease (see section\xa03.2). There is substantial uncertainty around the duration of the treatment effect, the waning of the treatment effect and the long-term risk of relapse. The clinical experts agreed that the pattern of relapse is unknown but the longer someone remains cancer free, the lower the risk of recurrence. The ERG considered that the risk of relapse may increase over time to match routine surveillance. It did 3\xa0scenario analyses exploring risk of relapse for the pembrolizumab group. It modelled the transitions from 'disease free to locoregional recurrence' and from 'disease free to distant metastases' to become equal to routine surveillance at\xa04, 7\xa0and 10\xa0years. It also applied treatment waning effects to 100%, 50% and 20% of people. The company considered treatment waning to be implausible in the adjuvant setting. The company presented scenarios exploring the assumptions that at 7\xa0or 10\xa0years, either 15% or 20% of people in the pembrolizumab treatment group would experience risk of relapse equal to routine surveillance. The clinical experts agreed that most relapses occur within\xa05 years and the risk at 10\xa0years is much smaller. The committee understood that the long-term treatment effect of pembrolizumab was uncertain even with the scenarios presented. It concluded that a treatment waning effect should have been considered, and took account of the scenarios explored by the ERG and the company in its decision making.\n\n## Whether IA or BICR is a better estimate of DFS is uncertain\n\nThe primary outcome in KEYNOTE‑564 was DFS assessed by an investigator. It was also assessed by BICR. The company considered that investigator assessment was more reflective of UK clinical practice and used the results of this analysis in its base case. But, as part of the response to consultation, the company submitted an analysis incorporating extrapolation of DFS based on BICR. The committee took into account ICERs based on DFS by BICR in their decision making. The ERG considered the BICR assessment more methodologically robust. The company explained that the IA and BICR results for DFS were consistent. The committee noted the difference between the IA and BICR-assessed hazard ratios. The ERG noted that it would have expected the results of the IA and BICR analyses to be similar. It could not tell from the data provided what gave rise to the difference in the hazard ratios. The ERG was unable to robustly include the BICR data in its base case, but provided an illustrative scenario of the likely effect of using BICR-assessed DFS. It applied an inflation factor to the 'disease free to locoregional' and 'disease free to distant metastases' transition probabilities using the ratio of the BICR and IA hazard ratios. This increased the ICER. The company considered investigator assessment to be reflective of clinical practice. It stated that the discrepancy between the IA and BICR-assessed results was not statistically meaningful, and could possibly have been explained by administrative processes and timings. The committee questioned why the difference in DFS estimates came about. It suggested that it could have been because the blinded independent reviewers noted fewer events with placebo and more events with pembrolizumab compared with local judgements. The reason behind this was unclear. But the clinical experts noted that blinding may have been an issue for investigator assessment because the adverse events profile (see section\xa03.6) could have indicated who was on active treatment. The committee was uncertain about why the IA and BICR-assessed results differed, but the clinical expert noted that they would expect to see differences in the IA and BICR results. The committee agreed that investigator assessment reflected what is done in UK clinical practice. It concluded that it would consider the cost-effectiveness estimates using both approaches. But it thought that the BICR data was more methodologically robust and provided a plausible estimate of DFS.\n\n# Cost-effectiveness estimates\n\n## Pembrolizumab is recommended for routine use in the NHS\n\nThe committee acknowledged the difference between survival extrapolations in the company's and ERG's base cases (see section\xa03.8). It also noted that, if BICR assessment was used, it resulted in increased ICERs (see section\xa03.11). NICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the uncertainty about whether investigator assessment or BICR gives a more robust estimate of DFS. But it expressed a preference for BICR analysis. It considered both the company's and ERG's preferred assumptions and concluded that its preferred assumptions were:\n\napproach\xa01, that is, the standard parametric models fitted independently to pembrolizumab and placebo data from KEYNOTE‑564 to extrapolate the cause-specific time-to-event data used in the model\n\ncost-effectiveness estimates using both the IA DFS and the BICR-assessed DFS\n\nincluding treatment waning in the pembrolizumab treatment group.The committee considered what effect the uncertainty around the approach used to extrapolate DFS data had on the cost-effectiveness estimates. It recognised that pembrolizumab is promising in that it increased DFS. It also noted that the range of plausible ICERs using its preferred assumptions and with the confidential discount applied were in the range usually considered a cost-effective use of NHS resources. The committee concluded that pembrolizumab could be recommended for routine use in the NHS for the adjuvant treatment of renal cell carcinoma at increased risk of recurrence.\n\n# Other factors\n\n## There are no equality issues and pembrolizumab is not innovative\n\nNo equality or social value judgement issues were identified by the committee. The committee noted that there is no NICE recommended active adjuvant treatment for renal cell carcinoma post-nephrectomy at increased risk of recurrence. But, when focusing specifically on relevant benefits associated with innovation, the committee considered that there were no additional benefits that had not been captured in the QALY."}	https://www.nice.org.uk/guidance/ta830	Evidence-based recommendations on pembrolizumab (Keytruda) for adjuvant treatment of renal cell carcinoma in adults.
a713a29bdd65f5f30ca2f37ef064037d9a32ed04	nice	Relugolix–estradiol–norethisterone acetate for treating moderate to severe symptoms of uterine fibroids	Relugolix–estradiol–norethisterone acetate for treating moderate to severe symptoms of uterine fibroids Evidence-based recommendations on relugolix–estradiol–norethisterone acetate (Ryeqo) for treating moderate to severe symptoms of uterine fibroids in adults of reproductive age. # Recommendations Relugolix–estradiol–norethisterone acetate is recommended, within its marketing authorisation, as an option for treating moderate to severe symptoms of uterine fibroids in adults of reproductive age. Why the committee made these recommendations Treatment options for symptoms of uterine fibroids include a levonorgestrel-releasing intrauterine system or combined hormonal contraception. For moderate to severe symptoms, injectable gonadotrophin-releasing hormone (GnRH) agonists are often used before surgical options. Relugolix–estradiol–norethisterone acetate, taken orally, is another treatment option for moderate to severe symptoms. Clinical trial evidence shows that relugolix–estradiol–norethisterone acetate is more effective than placebo for reducing heavy menstrual bleeding. It has only been indirectly compared with GnRH agonists and this suggests it is similarly effective to them, but the results are uncertain. The cost-effectiveness estimates for relugolix–estradiol–norethisterone acetate are mostly within the range normally considered by NICE to represent an acceptable use of NHS resources. There are also likely additional benefits of the treatment not captured in the economic model, including that: it is an effective non-surgical treatment it is taken orally there is no restriction on treatment duration in the marketing authorisation (in contrast to GnRH agonists) it is well tolerated it preserves the uterus (in contrast to surgical options). So, despite the uncertainty in the clinical evidence, taking these benefits into account, all the cost-effectiveness estimates for relugolix–estradiol–norethisterone acetate are likely within what NICE normally considers an acceptable use of NHS resources. It is therefore recommended.# Information about relugolix–estradiol–norethisterone acetate # Marketing authorisation indication Relugolix–estradiol–norethisterone acetate (Ryeqo, Gedeon Richter UK) is indicated for the 'treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for relugolix–estradiol–norethisterone acetate. # Price The list price of relugolix–estradiol–norethisterone acetate is £72.00 for a 28‑pack of 40 mg/1 mg/0.5 mg tablets (excluding VAT; BNF online, accessed April 2022). The annual treatment cost is £939.21. Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion The appraisal committee considered evidence submitted by Gedeon Richter UK, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Uterine fibroids can have substantial effects on quality of life Uterine fibroids are non-cancerous growths (myomas or leiomyomas) that develop in or around the uterus. The exact cause is not known, but they have been linked to oestrogen, occur in people of reproductive age and can become smaller after menopause. Around 1 in 3 women develop uterine fibroids, and incidence increases with age until the menopause, with a peak in the 40s. Symptoms are broadly classed into prolonged and heavy menstrual bleeding, pelvic pain and pressure, and reproductive dysfunction. A patient organisation submission noted that the symptoms can significantly affect the careers and family lives of people with uterine fibroids, who typically manage them without any support. This is because there are limited long-term treatment options, recovery times after surgical interventions are prolonged, and some treatment options affect fertility and sexual function. The clinical experts explained that heavy menstrual bleeding from uterine fibroids can have a significant effect on the social and professional lives of people affected, and on finances. This can affect mental health and quality of life. The committee concluded that uterine fibroids represent a significant burden for people with them, affecting both physical and psychological aspects of quality of life. # Treatment pathway and comparator ## There is an unmet need for effective treatments to manage symptoms of uterine fibroids and a new treatment option would be welcomed A clinical expert submission at the technical engagement stage highlighted that the aim of treatment for uterine fibroids can vary. It can be to prevent disability due to anaemia or pressure, or for effect on fertility. Therefore, in clinical practice, treatment is determined based on clinical presentation, effect on quality of life, fertility desires and preferred treatment choice. The clinical experts highlighted that treatment for symptomatic uterine fibroids is generally aligned with NICE's guideline on heavy menstrual bleeding: assessment and management. This recommends that, when there is no identified cause and fibroids are less than 3 cm in diameter, pharmacological treatments include non-hormonal (tranexamic acid, non-steroidal anti-inflammatories) and hormonal medicines (levonorgestrel intrauterine system, combined hormonal contraception, cyclical oral progestogens). If pharmacological treatment is unsuccessful or declined, or symptoms are severe, then surgical options (endometrial ablation, hysterectomy) are offered. When fibroids are 3 cm or more in diameter, uterine artery embolisation is another option before surgery. Ulipristal acetate (a hormonal medicine) and myomectomy (a surgical option) are only considered if other surgical options and uterine artery embolisation are unsuitable, declined or unsuccessful. Pretreatment with injectable gonadotropin-releasing hormone (GnRH) agonists before hysterectomy and myomectomy is considered if uterine fibroids are causing an enlarged or distorted uterus. The clinical experts explained that control of menstrual blood loss volume is a clinically important outcome because it reduces the risk of anaemia and improves quality of life. Both the patient organisation submission and the clinical experts explained the limitations of current treatments. These included short-term management before hospital treatment, unpleasant side effects with hormonal therapies, and the effect on fertility from some surgical procedures, such as hysterectomies and endometrial ablation. The clinical experts further highlighted the logistical challenges, resourcing needs and associated costs, and the inconvenience of having to attend clinics to have injectable GnRH agonists. Also, GnRH agonists are only licensed to be used for up to 6 months. The committee concluded that there is an unmet need for a licensed, long-term, non-invasive, safe and effective treatment to manage symptoms of uterine fibroids. It added that people with the condition and clinicians would welcome a new treatment option. ## GnRH agonists are the most relevant comparators for relugolix–estradiol–norethisterone acetate In its submission, the company compared relugolix–estradiol–norethisterone acetate with GnRH agonists. It considered that options such as a levonorgestrel-releasing intrauterine system or combined hormonal contraception were not relevant for treating moderate to severe symptoms of uterine fibroids. It stated that GnRH agonists would be the most relevant comparators expected to be displaced by relugolix–estradiol–norethisterone acetate for managing heavy menstrual bleeding. It highlighted that 3 of the GnRH antagonists identified in its systematic literature review (elagolix, linzagolix and cetrorelix) are not licensed for use in people with uterine fibroids. Therefore, they were not considered relevant comparators for this appraisal. It further explained that, because of safety concerns about liver injuries, ulipristal acetate is only indicated for intermittent treatment when uterine fibroid embolisation or surgery are unsuitable or unsuccessful. The company also asserted that the low usage of ulipristal acetate in clinical practice showed that GnRH agonists are the most relevant comparators for this appraisal. The ERG agreed that it was justifiable to exclude GnRH antagonists as comparators. It considered it unlikely that many people with uterine fibroids needing treatment would agree to have ulipristal acetate, given the level of monitoring needed and potential risks of liver damage. The company's submission assumed that all GnRH agonists are equally effective, and the evidence for GnRH agonists as a comparator was represented by clinical evidence for leuprorelin acetate. The clinical experts explained that the choice of GnRH agonists in clinical practice varies between NHS trusts. Some clinicians prefer leuprorelin because of the smaller needle size while others prefer goserelin. The committee considered that the company's positioning of relugolix–estradiol–norethisterone acetate reflected the place in therapy anticipated by the European Medicines Agency in the European Public Assessment Report. It therefore concluded that GnRH agonists were the most appropriate comparators for relugolix–estradiol–norethisterone acetate. # Clinical-effectiveness evidence ## Trial evidence from LIBERTY 1 and LIBERTY 2 suggests that relugolix–estradiol–norethisterone acetate is more effective than placebo The clinical evidence for relugolix–estradiol–norethisterone acetate came from 2 identical phase 3 randomised controlled trials, LIBERTY 1 and LIBERTY 2. The trials compared relugolix–estradiol–norethisterone acetate (n=128 and n=126 respectively), relugolix with delayed oestradiol and norethisterone acetate (n=132 and n=127 respectively) and placebo (n=128 and n=129 respectively) for heavy menstrual bleeding associated with uterine fibroids. The key inclusion criteria in the trials were: being premenopausal age 18 to 50 years regular menstrual periods lasting less than 14 days a cycle of 21 to 38 days a diagnosis of fibroids confirmed with ultrasonography heavy menstrual bleeding (160 ml or more during 1 cycle or 80 ml or more per cycle for 2 menstrual cycles) assessed by the alkaline haematin (AH) technique of measuring menstrual blood loss volume.Planned surgery within 6 months of enrolment was an exclusion criterion in both trials. None of the data from the relugolix with delayed oestradiol and norethisterone acetate arms from the trials are considered in this appraisal. The primary outcome measure was a menstrual blood loss volume of less than 80 ml and at least a 50% reduction from baseline in menstrual blood loss volume over the previous 35 days of treatment. The results from LIBERTY 1 and 2 showed that the primary outcome measure was reached by 73% and 71% of people respectively in the relugolix–estradiol–norethisterone acetate arms compared with 19% and 15% respectively in the placebo arms. Also, LIBERTY 3 (n=477), an open-label single-arm extension study of LIBERTY 1 and 2, provided long-term clinical evidence for relugolix–estradiol–norethisterone acetate. Evidence from all 3 trials was used to inform the economic model. However, only evidence from LIBERTY 1 and 2 was used to inform the indirect treatment comparison. The committee concluded that the results from LIBERTY 1 and 2 showed that relugolix–estradiol–norethisterone acetate is more effective than placebo for treating heavy menstrual bleeding associated with uterine fibroids. ## The indirect treatment comparison is appropriate in the absence of head-to-head trials with GnRH agonists There was no evidence directly comparing relugolix–estradiol–norethisterone acetate with GnRH agonists. Therefore, the company presented a separate indirect treatment comparison of relugolix–estradiol–norethisterone acetate (LIBERTY 1 and 2) compared with ulipristal acetate (PEARL 1) and a direct comparison of ulipristal acetate compared with leuprorelin, a GnRH agonist (PEARL 2). Menstrual blood loss volume was the only outcome reported in the results of the indirect and direct treatment comparisons. The ERG considered that a network meta-analysis would have been a more appropriate form of analysis. This was because it would better represent the uncertainty because of the number of comparisons needed and the imbalances in the baseline characteristics between PEARL 1 and the LIBERTY and PEARL 2 trials. At technical engagement, the company highlighted that a network meta-analysis would not have been more informative, and that its method was more transparent. It explained that the model used menstrual blood loss volume at 14 different timepoints and converted the values to utility. Therefore, a network meta-analysis of these timepoints would have been needed to provide inputs for the economic model. The committee questioned whether the company could have done an anchored matching adjusted indirect comparison using patient-level data from the LIBERTY and PEARL trials to better characterise this uncertainty. The company highlighted that it did not have access to the patient-level data needed to do this. It explained that it considered the differences in baseline characteristics were not treatment-effect modifiers. This was because the subgroup analysis at the clarification stage showed no differences in menstrual blood loss volume. The committee was concerned that the most robust methods to characterise uncertainty in the comparative effectiveness of relugolix–estradiol–norethisterone acetate compared with GnRH agonists may not have been used. However, it concluded that an indirect comparison was appropriate in the absence of head-to-head trials with GnRH agonists. ## Menstrual blood loss volume is a relevant outcome measure of treatment effectiveness for uterine fibroids Heavy menstrual bleeding is defined as greater than 80 ml or more menstrual blood loss volume. Assessing menstrual blood loss volume using the AH technique by chemically measuring the blood content of used sanitary products is considered the 'gold standard'. Other validated tools include Pictorial Blood Loss Assessment Charts (PBACs), which offers a semi-objective method for evaluating heavy menstrual bleeding. A PBAC score of more than 100 points correlates with a menstrual blood loss volume of 80 ml or more. The committee was concerned that 2 different methods for measuring menstrual blood loss volume were used in the LIBERTY and PEARL trials (AH technique and PBAC, respectively). This may have meant that the treatment effect was not comparable across trials. One clinical expert highlighted that the AH technique is a more accurate measurement of menstrual blood loss volume. Another clinical expert highlighted that the perception of improvement in symptoms and quality of life associated with reduced menstrual blood loss is also important. However, this is subjective. That is, 1 person may have a higher menstrual blood loss volume but be able to cope with their condition better than another who has lower menstrual blood loss volume, depending on how it affects their lives. Although the AH technique is the more accurate of the 2 methods, the PBAC score may more accurately reflect the subjective experience associated with menstrual bleeding. The clinical expert further explained that because the LIBERTY and PEARL trials both measured menstrual blood loss volume, the trials should be considered comparable. Menstrual blood loss volume was the only outcome used to assess the comparative efficacy of relugolix–estradiol–norethisterone acetate compared with GnRH agonists. The ERG report noted concerns with using menstrual blood loss volume as the only outcome for which the company did an indirect treatment comparison. Uterine fibroid volume, haemoglobin levels and health-related quality of life were reported in the LIBERTY and PEARL trials. Also, time to menstrual blood loss response and pain were listed in both the NICE final scope and the company's decision problem. Any of these outcomes could have been assessed using an indirect treatment comparison. However, the company's technical engagement response highlighted that doing indirect treatment comparisons of other outcomes was not feasible. The clinical experts explained that amenorrhoea is the principal aim when treating heavy menstrual bleeding associated with uterine fibroids, and reducing menstrual blood loss volume is an important outcome. They explained that menorrhagia has a significant effect on quality of life. Although reducing fibroid size may be an important clinical outcome, it is the reduction in menstrual blood loss volume that people with uterine fibroids value more. The committee was aware that other relevant outcomes could have been assessed in the indirect treatment comparison to determine the comparative effectiveness of relugolix–estradiol–norethisterone acetate and GnRH agonists more robustly. However, it concluded that menstrual blood loss volume was a relevant outcome to measure the effectiveness of treatments for uterine fibroids. ## Relugolix–estradiol–norethisterone acetate is likely to be as equally effective as GnRH agonists The results of the company's indirect treatment comparison suggested that relugolix–estradiol–norethisterone acetate is at least as equally effective as GnRH agonists. The mean differences in percentage change from baseline in menstrual blood loss volume between relugolix–estradiol–norethisterone acetate and leuprorelin were: at week 4, -50.6 ml (95% confidence interval -141.6 ml to 40.4 ml) at week 8, 8.3 ml (95% CI -96.5 ml to 113.1 ml) at week 12, -9.2 ml (95% CI -84.5 ml to 66.0 ml).The ERG agreed that the results suggested relugolix–estradiol–norethisterone acetate and GnRH agonists were equally effective in reducing menstrual blood loss volume from heavy menstrual bleeding associated with uterine fibroids. However, it highlighted that the wide confidence intervals suggested substantial uncertainty, which should have been represented in the probabilistic sensitivity analysis. The committee noted the large differences in baseline menstrual blood loss volume between the pooled data from LIBERTY 1 and 2 and PEARL 1 and 2. It questioned the increase in menstrual blood loss volume from baseline to week 4 for leuprorelin and from week 8 to week 12 for both ulipristal acetate and leuprorelin in PEARL 2. The clinical experts explained that, because of the mechanism of action of GnRH agonists, an initial increase in menstrual blood loss volume would be expected in the first couple of months. They added that this is often discussed with patients before starting treatment. They further highlighted that, in PEARL 2, add-back therapies were not included and noted that such therapies may reduce the efficacy of GnRH agonists. The committee remained concerned that the results of the indirect treatment comparison were highly uncertain. It considered that the evidence presented did not clearly show a difference in treatment effect. However, it cautiously accepted that the treatment effect for relugolix–estradiol–norethisterone acetate was not any worse than for GnRH agonists. The committee concluded that, despite the uncertainty in the indirect treatment comparisons, relugolix–estradiol–norethisterone acetate is likely to be as equally effective as GnRH agonists. ## Relugolix–estradiol–norethisterone acetate is likely to be used in NHS clinical practice whether the surgery is planned or not The ERG report noted that the population assessed in the LIBERTY trials did not match that assessed in the PEARL trials. In the PEARL trials, everyone had surgery planned after 13 weeks. For the LIBERTY trials, planned surgery within 6 months of enrolment was an exclusion criterion. The ERG also considered that relugolix–estradiol–norethisterone acetate may be used in clinical practice as a 'presurgery' treatment. This would be more consistent with the population in PEARL 2 than with the population in the LIBERTY trials. Surgery rates were not collected in the LIBERTY trials. As such, in the economic model, monthly probabilities of transition to surgery for people having relugolix–estradiol–norethisterone acetate were based on data from PEARL 2 for GnRH agonists. The ERG suggested that analysis in the 2 populations (that is, no planned surgery or planned surgery including people planning to have surgery) may have been more appropriate. At technical engagement, the company highlighted that relugolix–estradiol–norethisterone acetate is not restricted to presurgical use. Rather, it is a longer-term treatment option for people wishing to delay or avoid surgery. It also highlighted that GnRH agonists are not used solely as a preoperative treatment. In PEARL 2, 54.9% of people did not have surgery and transferred to best supportive care. The clinical experts noted that surgery was an exclusion criterion in the LIBERTY trials. However, they highlighted that relugolix–estradiol–norethisterone acetate is expected to be used longer term for people who cannot or choose not to have surgery, and also in the presurgical setting. This is because surgery is the main option for most people with heavy menstrual bleeding associated with uterine fibroids. The committee noted the paucity of clinical evidence for short-term use of relugolix–estradiol–norethisterone acetate in the presurgical setting. However, it concluded that relugolix–estradiol–norethisterone acetate is likely to be used in NHS clinical practice whether the surgery is planned or not. # Adverse events ## Relugolix–estradiol–norethisterone acetate is generally well tolerated The adverse event profile of relugolix–estradiol–norethisterone acetate for treating uterine fibroids in the company submission was informed by evidence from the LIBERTY trials. In LIBERTY 1, 62% of people who had relugolix–estradiol–norethisterone acetate had adverse events compared with 66% who had placebo. In LIBERTY 2, 60% of people who had relugolix–estradiol–norethisterone acetate had adverse events compared with 59% who had placebo. The most frequently reported adverse events in any treatment group included headache and hot flushes. Compared with placebo, vasomotor symptoms (most frequently hot flushes) were more common with relugolix–estradiol–norethisterone acetate (14 compared with 10 in LIBERTY 1, and 7 compared with 5 in LIBERTY 2). The hot flush events were reported mostly to be grade 1 or 2 in severity. No deaths were reported across both trials. Least-squares mean percent changes from baseline in bone mineral density in the relugolix–estradiol–norethisterone acetate arm compared with placebo at week 24 were -0.356% compared with 0.052% respectively in LIBERTY 1 and -0.126% compared with 0.315% respectively in LIBERTY 2. There were no statistically significant differences seen between the groups. Serious adverse events in LIBERTY 1 were reported for 7 people (5.5%) in the relugolix–estradiol–norethisterone acetate arm and for 2 people (1.6%) in the placebo arm. In the relugolix–estradiol–norethisterone acetate arm, 2 serious adverse events were related to expulsion or prolapse of uterine fibroid. One of these events was assessed as being related to study drugs. In LIBERTY 2, serious adverse events were reported for 1 person (0.8%) in the relugolix–estradiol–norethisterone acetate arm and for 4 people (3.1%) in the placebo arm. None of them were considered to be related to the study drug. The incidence and distribution of adverse events between LIBERTY 1 and 2 and the open-label extension study, LIBERTY 3, were generally similar, with no unexpected safety issues. The ERG did not highlight any concerns with any differences in serious adverse events or rates of adverse events. The committee concluded that relugolix–estradiol–norethisterone acetate is generally well tolerated. # Economic model ## The model structure using treatment states rather than health states may not adequately capture all health outcomes The company presented a Markov model with mutually exclusive 'treatment' states informed by treatment-discontinuation assumptions to capture cost and quality-adjusted life year (QALY) implications. It used a lifetime horizon and a cycle length of 1 month. The ERG highlighted that modelling 'treatment' states rather than states defined by 'health' outcomes was unconventional and that this approach was not fully justified by the company. It considered that health states (for example, mild, moderate and severe bleeding) or symptom control (controlled, uncontrolled) would have been more appropriate to capture health and quality-of-life benefits. This approach would have allowed menstrual blood loss volume data from the LIBERTY and PEARL 2 trials to be linked directly to treatment used. Also, in clinical practice, management of uterine fibroids is likely to be based on clinical need, determined by symptom control, and not necessarily treatment status (on or off). At technical engagement, the company highlighted that the use of treatment states was based on the approach reported in a peer-reviewed publication by Geale et al. (2017) for ulipristal acetate. It explained that consistent response criteria were not available in the LIBERTY and PEARL trials to allocate people to health states. It further highlighted that the treatment-state approach allowed best use of the limited available data, comparisons with other treatments and modelling of treatment discontinuation based on trial data. The committee considered that the company's use of treatment states rather than health states in the economic model may not have adequately captured all health outcomes associated with different treatment options. However, it concluded that the model was broadly appropriate for decision making. ## The discontinuation rates used in the economic model are highly uncertain In its economic model, the company used discontinuation rates for relugolix–estradiol–norethisterone acetate from the LIBERTY trials, which were modified based on clinical expert opinion. For GnRH agonists, these were from PEARL 2. The ERG highlighted that modifying discontinuation rates from the LIBERTY trials' data based on clinical expert opinion was subjective. It thought that using data directly from the trials would have been more reliable, ensuring consistency between modelled costs and treatment benefits for relugolix–estradiol–norethisterone acetate. The ERG acknowledged that PEARL 2 only provided discontinuation data for 3 months compared with 24 months of data from the LIBERTY trials. However, in the absence of data for discontinuation rates for GnRH agonists over the longer term, the ERG considered it was appropriate to use the PEARL 2 data to get discontinuation rates for GnRH agonists for a longer period. The company's technical engagement response highlighted that the discontinuation rates showed good face validity. This was because the proportion of discontinuations in LIBERTY 1 and 2 (45%) were derived from patient choice. Also, they were potentially associated with the inconvenience of the AH collection method for measuring menstrual blood loss volume. However, the ERG considered that this implied that stopping treatment because of patient choice was excluded. Therefore, the discontinuation rates for relugolix–estradiol–norethisterone acetate may be substantially higher than those included in the company's economic model. The clinical experts explained that, before the COVID‑19 pandemic, people prescribed GnRH agonists before surgery were happy to continue treatment for the licensed 6 months. This was particularly so if they did not have to wait too long for surgery. But the clinical experts estimated that about 40% of people having GnRH agonists would stop treatment, for example, because of side effects. They explained that this has changed during the COVID‑19 pandemic because of waiting lists and delays for surgical procedures. It has meant that people have had no choice but to continue GnRH agonists for longer than the licensed 6 months. Trade-offs have had to be made between the side effects and benefits associated with GnRH agonists and the effect of heavy menstrual bleeding associated with uterine fibroids on quality of life if not treated. The committee heard that people having GnRH agonists need to attend a clinic regularly for injections. This can become onerous, and people are more likely to stop treatment than if they were taking oral tablets. However, the committee questioned whether adherence would also be an issue with oral medication, for example, as seen in psychiatry and with oral contraception. One clinical expert explained that lifestyle can affect adherence with oral medicines. However, another noted that many people would prefer to take an effective oral medicine regularly than visit a hospital for clinics for an injection. The committee remained concerned that the discontinuation rates were not accurately captured in the company's economic analysis, concluding that the rates used in the economic model were highly uncertain. ## The model likely underestimates the utility values informing the QALY gains with relugolix–estradiol–norethisterone acetate The company's economic model included treatment-specific utility values. These were informed by menstrual blood loss from the relugolix–estradiol–norethisterone acetate and best supportive care arms of the LIBERTY studies and, for GnRH agonists, using an indirect treatment comparison with PEARL 2. Three measures of quality of life were included in the LIBERTY studies: EQ‑5D‑5L, uterine fibroid symptom and quality of life (UFS‑QoL) and patient global assessment. In both LIBERTY studies, the improvement in the UFS‑QoL score was statistically significantly greater with relugolix–estradiol–norethisterone acetate than with placebo. Because EQ‑5D‑5L data was insufficiently captured in the trials, an unpublished mapping algorithm was used to transform disease-specific data from UFS‑QoL to EQ‑5D-based utilities. This used an ordinary least-squares function including age and menstrual blood loss volume as covariates. However, the ERG noted that the company did not provide sufficient justification for the choice of regression model. Therefore, the ERG considered the repeated-measures model provided by the company in response to clarification more appropriate for estimating appropriate standard errors to include in the probabilistic analysis. The committee considered that there may be additional treatment benefits with relugolix–estradiol–norethisterone acetate that were not captured in the utility estimates used in the economic model to inform the QALY gains. These would likely have a positive effect on the quality of life of people with uterine fibroids, and included that: it is an effective non-surgical treatment it is administered orally there is no restriction on treatment duration in the marketing authorisation (in contrast to GnRH agonists) it has good tolerability it preserves the uterus (in contrast to surgical options).The committee concluded that the model likely underestimated the utility values used to inform the QALY gains with relugolix–estradiol–norethisterone acetate. # Cost-effectiveness estimates ## Relugolix–estradiol–norethisterone acetate is recommended for treating moderate to severe symptoms of uterine fibroids The company's base-case deterministic incremental cost-effectiveness ratio (ICER) for relugolix–estradiol–norethisterone acetate was less than £20,000 per QALY gained (using the confidential price discounts for the comparators). Because of the uncertainties in the clinical evidence, the committee considered the scenario analysis in which the effectiveness of relugolix–estradiol–norethisterone acetate was equalised with GnRH agonists. Taking into account the confidential prices for GnRH agonists, this resulted in a higher incremental cost for relugolix–estradiol–norethisterone acetate. There was a small QALY gain because of different discontinuation and adverse event rates, but an ICER compared with GnRH agonists above NICE's usual cost-effectiveness range. However, the committee considered that there were uncaptured QALY benefits for relugolix–estradiol–norethisterone acetate (see section 3.12). It was aware that it would only need a small increase in the QALYs for relugolix–estradiol–norethisterone acetate for the resulting ICER to represent a cost-effective use of NHS resources, even assuming equal effectiveness. Therefore, the committee concluded that relugolix–estradiol–norethisterone acetate is recommended for treating moderate to severe symptoms of uterine fibroids in adults of reproductive age. # Innovation ## Relugolix–estradiol–norethisterone acetate is innovative The company considered relugolix–estradiol–norethisterone acetate to be innovative. This was because it addresses a significant unmet need for an effective non-surgical treatment that can be taken orally and long term, is well tolerated and preserves the uterus and fertility, compared with GnRH agonists. Uterine fibroids are associated with a substantial health and economic burden, and current treatment options are often inadequate. The company highlighted that clinical trial evidence showed a reduction in symptoms and incidence of adverse events, with evidence of sustained treatment effectiveness for 2 years. The clinical experts highlighted that the treatment would be a step change for managing heavy menstrual bleeding associated with uterine fibroids. It could save a substantial amount of time for people having treatment and for their clinicians compared with injectable GnRH agonists. This could reduce financial consequences, particularly for people from lower socioeconomic groups. The clinical experts explained that there are several benefits with an oral treatment compared with current treatment options. These include convenience, potentially leading to improved adherence, maintaining fertility and providing long-term control of symptoms. The committee recalled that some of these benefits were not adequately captured in the economic analysis by the company (see section 3.12). But it acknowledged the benefits offered by relugolix–estradiol–norethisterone acetate as an additional treatment option for managing moderate to severe symptoms of uterine fibroids. The committee concluded that relugolix–estradiol–norethisterone acetate is an innovative treatment for moderate to severe symptoms of uterine fibroids. # Equalities considerations ## Recommending relugolix–estradiol–norethisterone acetate would adequately address equalities concerns During the scoping stage, it was highlighted that relugolix–estradiol–norethisterone acetate should be available to everyone with uterine fibroids who is eligible. This may include people who are trans or non-binary. The company submission highlighted that women with an African or Caribbean family background are 2 or 3 times more likely to develop uterine fibroids than White women. It also noted that they may be more opposed to surgery because of cultural beliefs. Some people may also decline surgery because of professional and family commitments. The clinical experts highlighted that clinic visits for treatment with GnRH agonists can result in significant financial and time costs. This could be a particular problem for people from lower socioeconomic groups and may increase the 'did not attend' rate at clinics. During the committee meeting, 1 clinical expert highlighted the need for a more effective non-surgical treatment option for people not wanting to have a hysterectomy. The patient organisation submission noted the need for 'equality of esteem' with 'men's' conditions. For example, prostatectomies are rare unless there is progressive cancer. But removal of the uterus and other reproductive organs is common and often the only option because of a lack of other treatment choices. The committee acknowledged the equality concerns raised. It recognised that non-surgical interventions, such as relugolix–estradiol–norethisterone acetate, may provide a more suitable treatment option than surgery for uterine fibroids. In particular, it considered that the recommendations will provide the benefit of another treatment option when surgery has been declined. No other potential equalities issues were raised.	{'Recommendations': 'Relugolix–estradiol–norethisterone acetate is recommended, within its marketing authorisation, as an option for treating moderate to severe symptoms of uterine fibroids in adults of reproductive age.\n\nWhy the committee made these recommendations\n\nTreatment options for symptoms of uterine fibroids include a levonorgestrel-releasing intrauterine system or combined hormonal contraception. For moderate to severe symptoms, injectable gonadotrophin-releasing hormone (GnRH) agonists are often used before surgical options. Relugolix–estradiol–norethisterone acetate, taken orally, is another treatment option for moderate to severe symptoms.\n\nClinical trial evidence shows that relugolix–estradiol–norethisterone acetate is more effective than placebo for reducing heavy menstrual bleeding. It has only been indirectly compared with GnRH agonists and this suggests it is similarly effective to them, but the results are uncertain.\n\nThe cost-effectiveness estimates for relugolix–estradiol–norethisterone acetate are mostly within the range normally considered by NICE to represent an acceptable use of NHS resources. There are also likely additional benefits of the treatment not captured in the economic model, including that:\n\nit is an effective non-surgical treatment\n\nit is taken orally\n\nthere is no restriction on treatment duration in the marketing authorisation (in contrast to GnRH agonists)\n\nit is well tolerated\n\nit preserves the uterus (in contrast to surgical options).\n\nSo, despite the uncertainty in the clinical evidence, taking these benefits into account, all the cost-effectiveness estimates for relugolix–estradiol–norethisterone acetate are likely within what NICE normally considers an acceptable use of NHS resources. It is therefore recommended.', 'Information about relugolix–estradiol–norethisterone acetate': "# Marketing authorisation indication\n\nRelugolix–estradiol–norethisterone acetate (Ryeqo, Gedeon Richter UK) is indicated for the 'treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for relugolix–estradiol–norethisterone acetate.\n\n# Price\n\nThe list price of relugolix–estradiol–norethisterone acetate is £72.00 for a 28‑pack of 40\xa0mg/1\xa0mg/0.5\xa0mg tablets (excluding VAT; BNF online, accessed April\xa02022). The annual treatment cost is £939.21. Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by Gedeon Richter UK, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Uterine fibroids can have substantial effects on quality of life\n\nUterine fibroids are non-cancerous growths (myomas or leiomyomas) that develop in or around the uterus. The exact cause is not known, but they have been linked to oestrogen, occur in people of reproductive age and can become smaller after menopause. Around 1\xa0in\xa03 women develop uterine fibroids, and incidence increases with age until the menopause, with a peak in the\xa040s. Symptoms are broadly classed into prolonged and heavy menstrual bleeding, pelvic pain and pressure, and reproductive dysfunction. A patient organisation submission noted that the symptoms can significantly affect the careers and family lives of people with uterine fibroids, who typically manage them without any support. This is because there are limited long-term treatment options, recovery times after surgical interventions are prolonged, and some treatment options affect fertility and sexual function. The clinical experts explained that heavy menstrual bleeding from uterine fibroids can have a significant effect on the social and professional lives of people affected, and on finances. This can affect mental health and quality of life. The committee concluded that uterine fibroids represent a significant burden for people with them, affecting both physical and psychological aspects of quality of life.\n\n# Treatment pathway and comparator\n\n## There is an unmet need for effective treatments to manage symptoms of uterine fibroids and a new treatment option would be welcomed\n\nA clinical expert submission at the technical engagement stage highlighted that the aim of treatment for uterine fibroids can vary. It can be to prevent disability due to anaemia or pressure, or for effect on fertility. Therefore, in clinical practice, treatment is determined based on clinical presentation, effect on quality of life, fertility desires and preferred treatment choice. The clinical experts highlighted that treatment for symptomatic uterine fibroids is generally aligned with NICE's guideline on heavy menstrual bleeding: assessment and management. This recommends that, when there is no identified cause and fibroids are less than 3\xa0cm in diameter, pharmacological treatments include non-hormonal (tranexamic acid, non-steroidal anti-inflammatories) and hormonal medicines (levonorgestrel intrauterine system, combined hormonal contraception, cyclical oral progestogens). If pharmacological treatment is unsuccessful or declined, or symptoms are severe, then surgical options (endometrial ablation, hysterectomy) are offered. When fibroids are 3\xa0cm or more in diameter, uterine artery embolisation is another option before surgery. Ulipristal acetate (a hormonal medicine) and myomectomy (a surgical option) are only considered if other surgical options and uterine artery embolisation are unsuitable, declined or unsuccessful. Pretreatment with injectable gonadotropin-releasing hormone (GnRH) agonists before hysterectomy and myomectomy is considered if uterine fibroids are causing an enlarged or distorted uterus. The clinical experts explained that control of menstrual blood loss volume is a clinically important outcome because it reduces the risk of anaemia and improves quality of life. Both the patient organisation submission and the clinical experts explained the limitations of current treatments. These included short-term management before hospital treatment, unpleasant side effects with hormonal therapies, and the effect on fertility from some surgical procedures, such as hysterectomies and endometrial ablation. The clinical experts further highlighted the logistical challenges, resourcing needs and associated costs, and the inconvenience of having to attend clinics to have injectable GnRH agonists. Also, GnRH agonists are only licensed to be used for up to 6\xa0months. The committee concluded that there is an unmet need for a licensed, long-term, non-invasive, safe and effective treatment to manage symptoms of uterine fibroids. It added that people with the condition and clinicians would welcome a new treatment option.\n\n## GnRH agonists are the most relevant comparators for relugolix–estradiol–norethisterone acetate\n\nIn its submission, the company compared relugolix–estradiol–norethisterone acetate with GnRH agonists. It considered that options such as a levonorgestrel-releasing intrauterine system or combined hormonal contraception were not relevant for treating moderate to severe symptoms of uterine fibroids. It stated that GnRH agonists would be the most relevant comparators expected to be displaced by relugolix–estradiol–norethisterone acetate for managing heavy menstrual bleeding. It highlighted that 3\xa0of the GnRH antagonists identified in its systematic literature review (elagolix, linzagolix and cetrorelix) are not licensed for use in people with uterine fibroids. Therefore, they were not considered relevant comparators for this appraisal. It further explained that, because of safety concerns about liver injuries, ulipristal acetate is only indicated for intermittent treatment when uterine fibroid embolisation or surgery are unsuitable or unsuccessful. The company also asserted that the low usage of ulipristal acetate in clinical practice showed that GnRH agonists are the most relevant comparators for this appraisal. The ERG agreed that it was justifiable to exclude GnRH antagonists as comparators. It considered it unlikely that many people with uterine fibroids needing treatment would agree to have ulipristal acetate, given the level of monitoring needed and potential risks of liver damage. The company's submission assumed that all GnRH agonists are equally effective, and the evidence for GnRH agonists as a comparator was represented by clinical evidence for leuprorelin acetate. The clinical experts explained that the choice of GnRH agonists in clinical practice varies between NHS trusts. Some clinicians prefer leuprorelin because of the smaller needle size while others prefer goserelin. The committee considered that the company's positioning of relugolix–estradiol–norethisterone acetate reflected the place in therapy anticipated by the European Medicines Agency in the European Public Assessment Report. It therefore concluded that GnRH agonists were the most appropriate comparators for relugolix–estradiol–norethisterone acetate.\n\n# Clinical-effectiveness evidence\n\n## Trial evidence from LIBERTY\xa01 and LIBERTY\xa02 suggests that relugolix–estradiol–norethisterone acetate is more effective than placebo\n\nThe clinical evidence for relugolix–estradiol–norethisterone acetate came from 2\xa0identical phase\xa03 randomised controlled trials, LIBERTY\xa01 and LIBERTY\xa02. The trials compared relugolix–estradiol–norethisterone acetate (n=128 and n=126 respectively), relugolix with delayed oestradiol and norethisterone acetate (n=132 and n=127 respectively) and placebo (n=128 and n=129 respectively) for heavy menstrual bleeding associated with uterine fibroids. The key inclusion criteria in the trials were:\n\nbeing premenopausal\n\nage 18\xa0to 50\xa0years\n\nregular menstrual periods lasting less than 14\xa0days\n\na cycle of 21\xa0to 38\xa0days\n\na diagnosis of fibroids confirmed with ultrasonography\n\nheavy menstrual bleeding (160\xa0ml or more during 1\xa0cycle or 80\xa0ml or more per cycle for 2\xa0menstrual cycles) assessed by the alkaline haematin (AH) technique of measuring menstrual blood loss volume.Planned surgery within 6\xa0months of enrolment was an exclusion criterion in both trials. None of the data from the relugolix with delayed oestradiol and norethisterone acetate arms from the trials are considered in this appraisal. The primary outcome measure was a menstrual blood loss volume of less than 80\xa0ml and at least a 50% reduction from baseline in menstrual blood loss volume over the previous 35\xa0days of treatment. The results from LIBERTY\xa01 and\xa02 showed that the primary outcome measure was reached by 73% and 71% of people respectively in the relugolix–estradiol–norethisterone acetate arms compared with 19% and 15% respectively in the placebo arms. Also, LIBERTY\xa03 (n=477), an open-label single-arm extension study of LIBERTY\xa01 and\xa02, provided long-term clinical evidence for relugolix–estradiol–norethisterone acetate. Evidence from all 3\xa0trials was used to inform the economic model. However, only evidence from LIBERTY\xa01 and\xa02 was used to inform the indirect treatment comparison. The committee concluded that the results from LIBERTY\xa01 and\xa02 showed that relugolix–estradiol–norethisterone acetate is more effective than placebo for treating heavy menstrual bleeding associated with uterine fibroids.\n\n## The indirect treatment comparison is appropriate in the absence of head-to-head trials with GnRH agonists\n\nThere was no evidence directly comparing relugolix–estradiol–norethisterone acetate with GnRH agonists. Therefore, the company presented a separate indirect treatment comparison of relugolix–estradiol–norethisterone acetate (LIBERTY\xa01 and\xa02) compared with ulipristal acetate (PEARL\xa01) and a direct comparison of ulipristal acetate compared with leuprorelin, a GnRH agonist (PEARL\xa02). Menstrual blood loss volume was the only outcome reported in the results of the indirect and direct treatment comparisons. The ERG considered that a network meta-analysis would have been a more appropriate form of analysis. This was because it would better represent the uncertainty because of the number of comparisons needed and the imbalances in the baseline characteristics between PEARL\xa01 and the LIBERTY and PEARL\xa02 trials. At technical engagement, the company highlighted that a network meta-analysis would not have been more informative, and that its method was more transparent. It explained that the model used menstrual blood loss volume at 14\xa0different timepoints and converted the values to utility. Therefore, a network meta-analysis of these timepoints would have been needed to provide inputs for the economic model. The committee questioned whether the company could have done an anchored matching adjusted indirect comparison using patient-level data from the LIBERTY and PEARL trials to better characterise this uncertainty. The company highlighted that it did not have access to the patient-level data needed to do this. It explained that it considered the differences in baseline characteristics were not treatment-effect modifiers. This was because the subgroup analysis at the clarification stage showed no differences in menstrual blood loss volume. The committee was concerned that the most robust methods to characterise uncertainty in the comparative effectiveness of relugolix–estradiol–norethisterone acetate compared with GnRH agonists may not have been used. However, it concluded that an indirect comparison was appropriate in the absence of head-to-head trials with GnRH agonists.\n\n## Menstrual blood loss volume is a relevant outcome measure of treatment effectiveness for uterine fibroids\n\nHeavy menstrual bleeding is defined as greater than 80\xa0ml or more menstrual blood loss volume. Assessing menstrual blood loss volume using the AH\xa0technique by chemically measuring the blood content of used sanitary products is considered the 'gold standard'. Other validated tools include Pictorial Blood Loss Assessment Charts (PBACs), which offers a semi-objective method for evaluating heavy menstrual bleeding. A PBAC score of more than 100\xa0points correlates with a menstrual blood loss volume of 80\xa0ml or more. The committee was concerned that 2\xa0different methods for measuring menstrual blood loss volume were used in the LIBERTY and PEARL trials (AH\xa0technique and PBAC, respectively). This may have meant that the treatment effect was not comparable across trials. One clinical expert highlighted that the AH\xa0technique is a more accurate measurement of menstrual blood loss volume. Another clinical expert highlighted that the perception of improvement in symptoms and quality of life associated with reduced menstrual blood loss is also important. However, this is subjective. That is, 1\xa0person may have a higher menstrual blood loss volume but be able to cope with their condition better than another who has lower menstrual blood loss volume, depending on how it affects their lives. Although the AH\xa0technique is the more accurate of the 2\xa0methods, the PBAC score may more accurately reflect the subjective experience associated with menstrual bleeding. The clinical expert further explained that because the LIBERTY and PEARL trials both measured menstrual blood loss volume, the trials should be considered comparable. Menstrual blood loss volume was the only outcome used to assess the comparative efficacy of relugolix–estradiol–norethisterone acetate compared with GnRH agonists. The ERG report noted concerns with using menstrual blood loss volume as the only outcome for which the company did an indirect treatment comparison. Uterine fibroid volume, haemoglobin levels and health-related quality of life were reported in the LIBERTY and PEARL trials. Also, time to menstrual blood loss response and pain were listed in both the NICE final scope and the company's decision problem. Any of these outcomes could have been assessed using an indirect treatment comparison. However, the company's technical engagement response highlighted that doing indirect treatment comparisons of other outcomes was not feasible. The clinical experts explained that amenorrhoea is the principal aim when treating heavy menstrual bleeding associated with uterine fibroids, and reducing menstrual blood loss volume is an important outcome. They explained that menorrhagia has a significant effect on quality of life. Although reducing fibroid size may be an important clinical outcome, it is the reduction in menstrual blood loss volume that people with uterine fibroids value more. The committee was aware that other relevant outcomes could have been assessed in the indirect treatment comparison to determine the comparative effectiveness of relugolix–estradiol–norethisterone acetate and GnRH agonists more robustly. However, it concluded that menstrual blood loss volume was a relevant outcome to measure the effectiveness of treatments for uterine fibroids.\n\n## Relugolix–estradiol–norethisterone acetate is likely to be as equally effective as GnRH agonists\n\nThe results of the company's indirect treatment comparison suggested that relugolix–estradiol–norethisterone acetate is at least as equally effective as GnRH agonists. The mean differences in percentage change from baseline in menstrual blood loss volume between relugolix–estradiol–norethisterone acetate and leuprorelin were:\n\nat week\xa04, -50.6\xa0ml (95% confidence interval [CI] -141.6\xa0ml to 40.4\xa0ml)\n\nat week\xa08, 8.3\xa0ml (95%\xa0CI -96.5\xa0ml to 113.1\xa0ml)\n\nat week\xa012, -9.2\xa0ml (95%\xa0CI -84.5\xa0ml to 66.0\xa0ml).The ERG agreed that the results suggested relugolix–estradiol–norethisterone acetate and GnRH agonists were equally effective in reducing menstrual blood loss volume from heavy menstrual bleeding associated with uterine fibroids. However, it highlighted that the wide confidence intervals suggested substantial uncertainty, which should have been represented in the probabilistic sensitivity analysis. The committee noted the large differences in baseline menstrual blood loss volume between the pooled data from LIBERTY\xa01 and\xa02 and PEARL\xa01 and\xa02. It questioned the increase in menstrual blood loss volume from baseline to week\xa04 for leuprorelin and from week\xa08 to week\xa012 for both ulipristal acetate and leuprorelin in PEARL\xa02. The clinical experts explained that, because of the mechanism of action of GnRH agonists, an initial increase in menstrual blood loss volume would be expected in the first couple of months. They added that this is often discussed with patients before starting treatment. They further highlighted that, in PEARL\xa02, add-back therapies were not included and noted that such therapies may reduce the efficacy of GnRH agonists. The committee remained concerned that the results of the indirect treatment comparison were highly uncertain. It considered that the evidence presented did not clearly show a difference in treatment effect. However, it cautiously accepted that the treatment effect for relugolix–estradiol–norethisterone acetate was not any worse than for GnRH agonists. The committee concluded that, despite the uncertainty in the indirect treatment comparisons, relugolix–estradiol–norethisterone acetate is likely to be as equally effective as GnRH agonists.\n\n## Relugolix–estradiol–norethisterone acetate is likely to be used in NHS clinical practice whether the surgery is planned or not\n\nThe ERG report noted that the population assessed in the LIBERTY trials did not match that assessed in the PEARL trials. In the PEARL trials, everyone had surgery planned after 13\xa0weeks. For the LIBERTY trials, planned surgery within 6\xa0months of enrolment was an exclusion criterion. The ERG also considered that relugolix–estradiol–norethisterone acetate may be used in clinical practice as a 'presurgery' treatment. This would be more consistent with the population in PEARL\xa02 than with the population in the LIBERTY trials. Surgery rates were not collected in the LIBERTY trials. As such, in the economic model, monthly probabilities of transition to surgery for people having relugolix–estradiol–norethisterone acetate were based on data from PEARL\xa02 for GnRH agonists. The ERG suggested that analysis in the 2\xa0populations (that is, no planned surgery or planned surgery including people planning to have surgery) may have been more appropriate. At technical engagement, the company highlighted that relugolix–estradiol–norethisterone acetate is not restricted to presurgical use. Rather, it is a longer-term treatment option for people wishing to delay or avoid surgery. It also highlighted that GnRH agonists are not used solely as a preoperative treatment. In PEARL\xa02, 54.9% of people did not have surgery and transferred to best supportive care. The clinical experts noted that surgery was an exclusion criterion in the LIBERTY trials. However, they highlighted that relugolix–estradiol–norethisterone acetate is expected to be used longer term for people who cannot or choose not to have surgery, and also in the presurgical setting. This is because surgery is the main option for most people with heavy menstrual bleeding associated with uterine fibroids. The committee noted the paucity of clinical evidence for short-term use of relugolix–estradiol–norethisterone acetate in the presurgical setting. However, it concluded that relugolix–estradiol–norethisterone acetate is likely to be used in NHS clinical practice whether the surgery is planned or not.\n\n# Adverse events\n\n## Relugolix–estradiol–norethisterone acetate is generally well tolerated\n\nThe adverse event profile of relugolix–estradiol–norethisterone acetate for treating uterine fibroids in the company submission was informed by evidence from the LIBERTY trials. In LIBERTY\xa01, 62% of people who had relugolix–estradiol–norethisterone acetate had adverse events compared with 66% who had placebo. In LIBERTY\xa02, 60% of people who had relugolix–estradiol–norethisterone acetate had adverse events compared with 59% who had placebo. The most frequently reported adverse events in any treatment group included headache and hot flushes. Compared with placebo, vasomotor symptoms (most frequently hot flushes) were more common with relugolix–estradiol–norethisterone acetate (14\xa0[11%] compared with 10\xa0[8%] in LIBERTY\xa01, and 7 [6%] compared with 5\xa0[4%] in LIBERTY\xa02). The hot flush events were reported mostly to be grade\xa01 or\xa02 in severity. No deaths were reported across both trials. Least-squares mean percent changes from baseline in bone mineral density in the relugolix–estradiol–norethisterone acetate arm compared with placebo at week\xa024 were -0.356% compared with 0.052% respectively in LIBERTY\xa01 and -0.126% compared with 0.315% respectively in LIBERTY\xa02. There were no statistically significant differences seen between the groups. Serious adverse events in LIBERTY\xa01 were reported for 7\xa0people (5.5%) in the relugolix–estradiol–norethisterone acetate arm and for 2\xa0people (1.6%) in the placebo arm. In the relugolix–estradiol–norethisterone acetate arm, 2\xa0serious adverse events were related to expulsion or prolapse of uterine fibroid. One of these events was assessed as being related to study drugs. In LIBERTY\xa02, serious adverse events were reported for 1\xa0person (0.8%) in the relugolix–estradiol–norethisterone acetate arm and for 4\xa0people (3.1%) in the placebo arm. None of them were considered to be related to the study drug. The incidence and distribution of adverse events between LIBERTY\xa01 and\xa02 and the open-label extension study, LIBERTY\xa03, were generally similar, with no unexpected safety issues. The ERG did not highlight any concerns with any differences in serious adverse events or rates of adverse events. The committee concluded that relugolix–estradiol–norethisterone acetate is generally well tolerated.\n\n# Economic model\n\n## The model structure using treatment states rather than health states may not adequately capture all health outcomes\n\nThe company presented a Markov model with mutually exclusive 'treatment' states informed by treatment-discontinuation assumptions to capture cost and quality-adjusted life year (QALY) implications. It used a lifetime horizon and a cycle length of 1\xa0month. The ERG highlighted that modelling 'treatment' states rather than states defined by 'health' outcomes was unconventional and that this approach was not fully justified by the company. It considered that health states (for example, mild, moderate and severe bleeding) or symptom control (controlled, uncontrolled) would have been more appropriate to capture health and quality-of-life benefits. This approach would have allowed menstrual blood loss volume data from the LIBERTY and PEARL\xa02 trials to be linked directly to treatment used. Also, in clinical practice, management of uterine fibroids is likely to be based on clinical need, determined by symptom control, and not necessarily treatment status (on or off). At technical engagement, the company highlighted that the use of treatment states was based on the approach reported in a peer-reviewed publication by Geale et al. (2017) for ulipristal acetate. It explained that consistent response criteria were not available in the LIBERTY and PEARL trials to allocate people to health states. It further highlighted that the treatment-state approach allowed best use of the limited available data, comparisons with other treatments and modelling of treatment discontinuation based on trial data. The committee considered that the company's use of treatment states rather than health states in the economic model may not have adequately captured all health outcomes associated with different treatment options. However, it concluded that the model was broadly appropriate for decision making.\n\n## The discontinuation rates used in the economic model are highly uncertain\n\nIn its economic model, the company used discontinuation rates for relugolix–estradiol–norethisterone acetate from the LIBERTY trials, which were modified based on clinical expert opinion. For GnRH agonists, these were from PEARL\xa02. The ERG highlighted that modifying discontinuation rates from the LIBERTY trials' data based on clinical expert opinion was subjective. It thought that using data directly from the trials would have been more reliable, ensuring consistency between modelled costs and treatment benefits for relugolix–estradiol–norethisterone acetate. The ERG acknowledged that PEARL\xa02 only provided discontinuation data for 3\xa0months compared with 24\xa0months of data from the LIBERTY trials. However, in the absence of data for discontinuation rates for GnRH agonists over the longer term, the ERG considered it was appropriate to use the PEARL\xa02 data to get discontinuation rates for GnRH agonists for a longer period. The company's technical engagement response highlighted that the discontinuation rates showed good face validity. This was because the proportion of discontinuations in LIBERTY\xa01 and\xa02 (45%) were derived from patient choice. Also, they were potentially associated with the inconvenience of the AH\xa0collection method for measuring menstrual blood loss volume. However, the ERG considered that this implied that stopping treatment because of patient choice was excluded. Therefore, the discontinuation rates for relugolix–estradiol–norethisterone acetate may be substantially higher than those included in the company's economic model. The clinical experts explained that, before the COVID‑19 pandemic, people prescribed GnRH agonists before surgery were happy to continue treatment for the licensed 6\xa0months. This was particularly so if they did not have to wait too long for surgery. But the clinical experts estimated that about 40% of people having GnRH agonists would stop treatment, for example, because of side effects. They explained that this has changed during the COVID‑19 pandemic because of waiting lists and delays for surgical procedures. It has meant that people have had no choice but to continue GnRH agonists for longer than the licensed 6\xa0months. Trade-offs have had to be made between the side effects and benefits associated with GnRH agonists and the effect of heavy menstrual bleeding associated with uterine fibroids on quality of life if not treated. The committee heard that people having GnRH agonists need to attend a clinic regularly for injections. This can become onerous, and people are more likely to stop treatment than if they were taking oral tablets. However, the committee questioned whether adherence would also be an issue with oral medication, for example, as seen in psychiatry and with oral contraception. One clinical expert explained that lifestyle can affect adherence with oral medicines. However, another noted that many people would prefer to take an effective oral medicine regularly than visit a hospital for clinics for an injection. The committee remained concerned that the discontinuation rates were not accurately captured in the company's economic analysis, concluding that the rates used in the economic model were highly uncertain.\n\n## The model likely underestimates the utility values informing the QALY gains with relugolix–estradiol–norethisterone acetate\n\nThe company's economic model included treatment-specific utility values. These were informed by menstrual blood loss from the relugolix–estradiol–norethisterone acetate and best supportive care arms of the LIBERTY studies and, for GnRH agonists, using an indirect treatment comparison with PEARL\xa02. Three measures of quality of life were included in the LIBERTY studies: EQ‑5D‑5L, uterine fibroid symptom and quality of life (UFS‑QoL) and patient global assessment. In both LIBERTY studies, the improvement in the UFS‑QoL score was statistically significantly greater with relugolix–estradiol–norethisterone acetate than with placebo. Because EQ‑5D‑5L data was insufficiently captured in the trials, an unpublished mapping algorithm was used to transform disease-specific data from UFS‑QoL to EQ‑5D-based utilities. This used an ordinary least-squares function including age and menstrual blood loss volume as covariates. However, the ERG noted that the company did not provide sufficient justification for the choice of regression model. Therefore, the ERG considered the repeated-measures model provided by the company in response to clarification more appropriate for estimating appropriate standard errors to include in the probabilistic analysis. The committee considered that there may be additional treatment benefits with relugolix–estradiol–norethisterone acetate that were not captured in the utility estimates used in the economic model to inform the QALY gains. These would likely have a positive effect on the quality of life of people with uterine fibroids, and included that:\n\nit is an effective non-surgical treatment\n\nit is administered orally\n\nthere is no restriction on treatment duration in the marketing authorisation (in contrast to GnRH agonists)\n\nit has good tolerability\n\nit preserves the uterus (in contrast to surgical options).The committee concluded that the model likely underestimated the utility values used to inform the QALY gains with relugolix–estradiol–norethisterone acetate.\n\n# Cost-effectiveness estimates\n\n## Relugolix–estradiol–norethisterone acetate is recommended for treating moderate to severe symptoms of uterine fibroids\n\nThe company's base-case deterministic incremental cost-effectiveness ratio (ICER) for relugolix–estradiol–norethisterone acetate was less than £20,000 per QALY gained (using the confidential price discounts for the comparators). Because of the uncertainties in the clinical evidence, the committee considered the scenario analysis in which the effectiveness of relugolix–estradiol–norethisterone acetate was equalised with GnRH agonists. Taking into account the confidential prices for GnRH agonists, this resulted in a higher incremental cost for relugolix–estradiol–norethisterone acetate. There was a small QALY gain because of different discontinuation and adverse event rates, but an ICER compared with GnRH agonists above NICE's usual cost-effectiveness range. However, the committee considered that there were uncaptured QALY benefits for relugolix–estradiol–norethisterone acetate (see section\xa03.12). It was aware that it would only need a small increase in the QALYs for relugolix–estradiol–norethisterone acetate for the resulting ICER to represent a cost-effective use of NHS resources, even assuming equal effectiveness. Therefore, the committee concluded that relugolix–estradiol–norethisterone acetate is recommended for treating moderate to severe symptoms of uterine fibroids in adults of reproductive age.\n\n# Innovation\n\n## Relugolix–estradiol–norethisterone acetate is innovative\n\nThe company considered relugolix–estradiol–norethisterone acetate to be innovative. This was because it addresses a significant unmet need for an effective non-surgical treatment that can be taken orally and long term, is well tolerated and preserves the uterus and fertility, compared with GnRH agonists. Uterine fibroids are associated with a substantial health and economic burden, and current treatment options are often inadequate. The company highlighted that clinical trial evidence showed a reduction in symptoms and incidence of adverse events, with evidence of sustained treatment effectiveness for 2\xa0years. The clinical experts highlighted that the treatment would be a step change for managing heavy menstrual bleeding associated with uterine fibroids. It could save a substantial amount of time for people having treatment and for their clinicians compared with injectable GnRH agonists. This could reduce financial consequences, particularly for people from lower socioeconomic groups. The clinical experts explained that there are several benefits with an oral treatment compared with current treatment options. These include convenience, potentially leading to improved adherence, maintaining fertility and providing long-term control of symptoms. The committee recalled that some of these benefits were not adequately captured in the economic analysis by the company (see section\xa03.12). But it acknowledged the benefits offered by relugolix–estradiol–norethisterone acetate as an additional treatment option for managing moderate to severe symptoms of uterine fibroids. The committee concluded that relugolix–estradiol–norethisterone acetate is an innovative treatment for moderate to severe symptoms of uterine fibroids.\n\n# Equalities considerations\n\n## Recommending relugolix–estradiol–norethisterone acetate would adequately address equalities concerns\n\nDuring the scoping stage, it was highlighted that relugolix–estradiol–norethisterone acetate should be available to everyone with uterine fibroids who is eligible. This may include people who are trans or non-binary. The company submission highlighted that women with an African or Caribbean family background are 2\xa0or 3\xa0times more likely to develop uterine fibroids than White women. It also noted that they may be more opposed to surgery because of cultural beliefs. Some people may also decline surgery because of professional and family commitments. The clinical experts highlighted that clinic visits for treatment with GnRH agonists can result in significant financial and time costs. This could be a particular problem for people from lower socioeconomic groups and may increase the 'did not attend' rate at clinics. During the committee meeting, 1\xa0clinical expert highlighted the need for a more effective non-surgical treatment option for people not wanting to have a hysterectomy. The patient organisation submission noted the need for 'equality of esteem' with 'men's' conditions. For example, prostatectomies are rare unless there is progressive cancer. But removal of the uterus and other reproductive organs is common and often the only option because of a lack of other treatment choices. The committee acknowledged the equality concerns raised. It recognised that non-surgical interventions, such as relugolix–estradiol–norethisterone acetate, may provide a more suitable treatment option than surgery for uterine fibroids. In particular, it considered that the recommendations will provide the benefit of another treatment option when surgery has been declined. No other potential equalities issues were raised."}	https://www.nice.org.uk/guidance/ta832	Evidence-based recommendations on relugolix–estradiol–norethisterone acetate (Ryeqo) for treating moderate to severe symptoms of uterine fibroids in adults of reproductive age.
babeead2495dc78a31886129007aa1aba1e678f6	nice	Zanubrutinib for treating Waldenstrom's macroglobulinaemia	Zanubrutinib for treating Waldenstrom's macroglobulinaemia Evidence-based recommendations on zanubrutinib (Brukinsa) for treating Waldenstrom’s macroglobulinaemia in adults. # Recommendations Zanubrutinib is recommended as an option for treating Waldenstrom's macroglobulinaemia in adults who have had at least 1 treatment, only if: bendamustine plus rituximab is also suitable and the company provides it according to the commercial arrangement. This recommendation is not intended to affect treatment with zanubrutinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Standard care for Waldenstrom's macroglobulinaemia varies but typically includes chemoimmunotherapy combinations such as bendamustine plus rituximab, or dexamethasone plus rituximab and cyclophosphamide. When chemoimmunotherapy is unsuitable, rituximab or chlorambucil alone are typically offered. Clinical evidence from an indirect comparison suggests that people with Waldenstrom's macroglobulinaemia may live longer and have a better quality of life with zanubrutinib than with standard care. Long-term evidence on the effectiveness of zanubrutinib is not yet available. So, it is unclear how much longer people having zanubrutinib live. For people who have had previous treatment, the cost-effectiveness estimates for zanubrutinib are only within what NICE usually considers an acceptable use of NHS resources when bendamustine plus rituximab is also suitable. Zanubrutinib is recommended for this group. For people who have not had previous treatment and if chemoimmunotherapy is unsuitable, the cost-effective estimates for zanubrutinib are above what NICE usually considers an acceptable use of NHS resources. Zanubrutinib is not recommended for this group.# Information about zanubrutinib # Marketing authorisation indication Zanubrutinib (Brukinsa, BeiGene) has a marketing authorisation in the UK for 'the treatment of adult patients with Waldenström's macroglobulinaemia (WM) in adults who have received at least one prior therapy, or in first-line treatment for patients unsuitable for chemo-immunotherapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for zanubrutinib. # Price The list price of zanubrutinib 120x80 mg capsules is £4,928.65 (excluding VAT; company submission). The company has a commercial arrangement. This makes zanubrutinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by BeiGene, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Current management ## Comparators are bendamustine plus rituximab, dexamethasone plus rituximab and cyclophosphamide, and rituximab or chlorambucil alone Waldenstrom's macroglobulinaemia is an incurable form of non-Hodgkin's lymphoma. It typically affects older people and has a long trajectory, with a median overall survival of 16 years in people with symptoms. Because the condition progresses slowly, many people die from causes other than Waldenstrom's macroglobulinaemia. The clinical experts explained that although there is variation in the clinical pathway, the first-line treatment options are commonly bendamustine plus rituximab (BR) and dexamethasone plus rituximab and cyclophosphamide (DRC) if chemoimmunotherapy is suitable. The clinical experts further explained that patient- and disease-related factors can influence the choice of first-line treatment. They stated that BR tends to produce a more rapid and deeper response, so may be preferred if disease burden needs to be quickly reduced. But BR has a less favourable toxicity profile than DRC, so DRC may be preferred in people who are frail or have comorbidities. Although purine analogues such as fludarabine were included in the NICE scope, their use is no longer recommended because of toxicity concerns and the risk of secondary malignancies. This is reflected in the latest clinical guidelines on managing Waldenstrom's macroglobulinaemia from the British Society for Haematology. An autologous stem cell transplant is also an option for people who are fit enough. But, because Waldenstrom's macroglobulinaemia mainly affects older people, this is not suitable for most. Until recently, when the condition relapsed or became refractory to first-line treatment most people were offered ibrutinib (a Bruton's tyrosine kinase inhibitor), which was available through the Cancer Drugs Fund. But, during the time course of this appraisal, a separate NICE appraisal of ibrutinib for treating Waldenstrom's macroglobulinemia was done. This found that ibrutinib could not be recommended for routine use in the NHS for this indication. Other second-line treatment options include rituximab-containing regimens (such as BR or DRC, if not used as a first-line treatment). After these treatments, practice varies, but repeated rounds of chemotherapy are often used. When chemoimmunotherapy is unsuitable, treatment options include rituximab or chlorambucil monotherapy, or best supportive care. The company noted that rituximab and chlorambucil are not widely used, particularly chlorambucil because it may be more toxic than rituximab. But the committee noted both were used in clinical practice. The clinical experts explained that, if zanubrutinib were recommended, it would be used as early as possible in the treatment pathway. But the committee noted that, when chemoimmunotherapy is suitable, zanubrutinib's licence limited it to use after at least 1 treatment. The committee was aware that there is variation in the treatment pathway for people with Waldenstrom's macroglobulinaemia, particularly when it is relapsed or refractory. It concluded that BR and DRC were the 2 most relevant comparators when chemoimmunotherapy is suitable. It also concluded that rituximab or chlorambucil alone were relevant comparators when chemoimmunotherapy is unsuitable. This is when the marketing authorisation allows zanubrutinib as a first-line treatment option. ## The availability of an effective and well-tolerated oral treatment is highly valued and addresses a significant unmet need The patient expert explained that Waldenstrom's macroglobulinaemia and its treatment can have a profound effect on quality of life. The condition itself can cause severe pain, fatigue, reduced mobility and increased susceptibility to infections. Current chemoimmunotherapy treatments can cause severe adverse reactions and the need for frequent hospital visits. Even though Waldenstrom's macroglobulinaemia may respond well to first-line treatment, the constant threat of relapse can be a huge burden on people with the condition and their families. For people who cannot have chemoimmunotherapy, treatment options are very limited. The patient expert said that people with the condition are acutely aware of this. Also, there is a desire among the patient community to have additional options as their condition progresses. The committee noted that zanubrutinib is a Bruton's tyrosine kinase inhibitor and has a different mechanism of action to existing chemoimmunotherapy treatments. Both the patient and clinical experts emphasised that zanubrutinib is highly effective and better tolerated than existing chemoimmunotherapy options. It is also an oral treatment, which is greatly valued by people with the condition because it avoids the need for hospital visits and infusions. The patient expert said that zanubrutinib had rapidly and dramatically made him "feel better" and improved his quality of life. He explained that it had allowed him to participate in general day-to-day activities and return to the normal life he had enjoyed before diagnosis. He explained that this was in stark contrast to his experience with chemoimmunotherapy treatments, with which he had had significant intolerance issues and side effects, some of which were persistent. The committee concluded that the availability of an effective and well-tolerated oral treatment would be highly valued by people with Waldenstrom's macroglobulinaemia and would address a significant unmet need. # Clinical effectiveness ## The ASPEN study provides generalisable evidence for zanubrutinib but its comparator, ibrutinib, is not relevant for this appraisal The clinical evidence for zanubrutinib came from the ASPEN study, a randomised clinical trial that compared zanubrutinib with ibrutinib. The committee noted that ibrutinib was not a comparator in this appraisal (see section 3.1). The people in the trial were divided into 2 cohorts: Cohort 1 included 201 people with Waldenstrom's macroglobulinaemia who had a mutation in the myeloid differentiation primary response gene (mutated MYD88 type). The people in this cohort were randomised to either zanubrutinib or ibrutinib. Cohort 2 included 28 people with Waldenstrom's macroglobulinaemia (wild type MYD88 type) and they were all assigned to zanubrutinib.One clinical expert explained that the trial was designed this way because earlier studies had suggested that ibrutinib may work less well in people without the MYD88 mutation. The committee understood that about 90% of people with Waldenstrom's macroglobulinaemia have the MYD88 mutation. But, overall, it expected that zanubrutinib would work equally well in people who did and did not have the MYD88 mutation. The company stated that comparing the data for zanubrutinib from the 2 cohorts supported the assumption that there was no difference in outcomes. The committee considered that the trial data from cohort 1 (which the company used in its model) was generalisable to both people with and without the MYD88 gene mutation. Cohort 1 included: people (83 in the zanubrutinib arm) with relapsed or refractory Waldenstrom's macroglobulinaemia who had had at least 1 treatment people (19 in the zanubrutinib arm) who had not had any treatment and for whom chemoimmunotherapy was unsuitable.The median age of people in the trial was 70. Also, almost everyone had an Eastern Cooperative Oncology Group performance status of 0 or 1, and many had had multiple previous treatments. One clinical expert stated that the trial population reflected the patient population in the NHS. The committee concluded that ASPEN provided clinical evidence for zanubrutinib that is generalisable to UK clinical practice. But it concluded that it had not compared zanubrutinib with the relevant comparators for this appraisal. ## Zanubrutinib is clinically effective, but the data is immature for progression-free and overall survival The committee noted that, at a median follow up of 19.5 months in ASPEN, the very good partial response rate was 28.4% in the zanubrutinib arm and 19.2% in the ibrutinib arm. This response occurred at a median time of 4.8 months in the zanubrutinib arm. The committee also noted that there was not a complete response in anyone. But 1 clinical expert said that this was not unexpected because it is acknowledged that this class of drugs is not curative. The clinical expert also noted that it was important to consider the durability of that response, and not just its depth. Median progression-free and overall survival had not been reached at the point of data cut-off, so the survival data for zanubrutinib was immature. This is to be expected because Waldenstrom's macroglobulinaemia is a slowly progressing condition. At 12 months, 97.0% (95% confidence interval 90.9 to 99.0) of people in the zanubrutinib arm were alive, and the condition had not yet progressed in 89.7% (95% confidence interval 81.7 to 94.3). Although ibrutinib was not a comparator in this appraisal, the committee noted that overall (93.9%) and progression-free survival (87.2%) was similar to that with zanubrutinib at 12 months. The clinical experts explained that zanubrutinib would be expected to have similar clinical efficacy to ibrutinib in clinical practice because they are in the same drug class. The committee concluded that zanubrutinib was clinically effective, but that data on progression-free and overall survival was immature. ## Zanubrutinib is more clinically effective than chemoimmunotherapy, but the size of the benefit compared with BR and DRC is uncertain Clinical evidence for the chemoimmunotherapy comparators (BR and DRC) in people who had had previous treatment came from 2 main studies: The clinical evidence for BR came from a single-arm study of 71 people with relapsed or refractory Waldenstrom's macroglobulinaemia (Tedeschi et al. 2015). The clinical evidence for DRC came from a single-arm trial of 72 people with Waldenstrom's macroglobulinaemia who had not had previous treatment but for whom chemoimmunotherapy was considered suitable (Dimopoulos et al. 2007; Kastritis et al. 2015).The committee noted that the DRC data came from a population having this type of chemoimmunotherapy as a first-line treatment, which does not correspond with the marketing authorisation for zanubrutinib (see section 2.1). Also, it is different from the population in ASPEN. About 81% of people in ASPEN had zanubrutinib after previous treatment. The remainder, for whom chemoimmunotherapy was unsuitable, had zanubrutinib as a first-line treatment (see section 3.3). The company attempted to match the populations used in the indirect treatment comparisons and make adjustments to minimise bias in the results. It presented results for zanubrutinib compared with BR in people whose condition was relapsed or refractory and compared it with DRC in people who had not had previous treatment. The company's original submission used a matching-adjusted indirect comparison (MAIC). The ERG noted the limited patient data available for the comparator studies. It thought that this may have led to differences in clinically relevant risk factors between the comparator groups that could not be adjusted for. In response to technical engagement, the company used another method for indirect comparison, a simulated treatment comparison (STC). The company explained that the STC was its preferred approach because it meant that a larger sample size could be maintained, more data used and covariates adjusted for more effectively. Both the STC and MAIC approaches for the indirect comparison suggested that there was improved overall and progression-free survival with zanubrutinib compared with both BR and DRC. While the hazard ratio point estimates generated by the MAIC and the STC were different, the confidence intervals had substantial overlap. The committee agreed that this showed some consistency in the results generated by the 2 methods. The clinical experts confirmed that the hazard ratios generated in the analyses to compare zanubrutinib with BR and DRC seemed plausible. The committee considered that there were uncertainties and limitations with both the MAIC and the STC. But it noted that MAIC methods are more transparent and that there was insufficient justification given by the company to switch from its original MAIC to the STC. So, the committee concluded that its preferred approach was the original MAIC analysis. But it acknowledged that this was an area of uncertainty. The committee noted that, for the BR and DRC comparisons, the hazard ratios in the company's indirect comparisons for progression-free survival were low compared with those typically seen with other cancer treatments. But it concluded that there was a high degree of uncertainty in the size of the treatment effect of zanubrutinib compared with both comparators. This was because of the limitations of the indirect comparisons. ## It is unclear whether overall survival is better with DRC than with BR but the committee accepted the company's estimates as the best available The overall-survival hazard ratios for BR compared with zanubrutinib were lower than the hazard ratios for DRC compared with zanubrutinib. This was regardless of whether the STC or MAIC approach was used. The committee noted that these hazard ratios suggested DRC may be more effective than BR used second line. But it could not determine whether this reflected a real difference in the benefits of these comparators or resulted from a difference in the populations being compared in each indirect comparison. The specific results of the analysis are confidential and cannot be shared here. The clinical experts explained that real-world data comparisons have consistently shown a favourable progression-free survival outcome for BR compared with DRC. But they added that the data for overall survival is less conclusive. This is because people with Waldenstrom's macroglobulinaemia often do not die because of the condition itself. Also, DRC tends to be used in people who are frail or have comorbidities, which may affect their life expectancy. The committee was not aware of any direct comparative evidence to determine whether BR and DRC would be equally effective had they been studied at the same stage in the treatment pathway. So, the committee accepted the company's estimates for its decision making. ## Zanubrutinib is clinically effective compared with rituximab when chemoimmunotherapy is unsuitable The clinical evidence for the chemoimmunotherapy unsuitable comparators (rituximab monotherapy and chlorambucil monotherapy) came from 2 main studies: The clinical evidence for rituximab came from a single-arm study of 69 people, including 34 people with Waldenstrom's macroglobulinaemia who had not had previous treatment (unknown whether chemoimmunotherapy was considered suitable) and 35 people with relapsed or refractory Waldenstrom's macroglobulinaemia (Gertz et al. 2004; Gertz et al. 2009). The clinical evidence for chlorambucil came from a randomised controlled trial of 46 people with Waldenstrom's macroglobulinaemia who had not had previous treatment (unknown whether chemoimmunotherapy was considered suitable). The trial compared continuous chlorambucil therapy with intermittent chlorambucil therapy (Kyle et al. 2000).The committee noted that, in ASPEN, there were 19 people (about 19%) in the zanubrutinib arm who had not had previous treatment and for whom chemoimmunotherapy was not considered suitable. There was a very good partial response in 26% of this subgroup, compared with 29% in the relapsed or refractory population. The company considered that it was reasonable to consider that the clinical effectiveness of zanubrutinib taken as a first-line treatment by people for whom chemoimmunotherapy is unsuitable would be similar to its effectiveness in people whose condition is relapsed or refractory. The company based its cost-effectiveness estimates for this population on an indirect comparison of zanubrutinib compared with rituximab, which it considered to be a more relevant comparator than chlorambucil. This was based on data from the Rory Morrison Registry showing that rituximab is more widely used than chlorambucil as a first-line treatment for Waldenstrom's macroglobulinaemia. The company also stated that rituximab is better tolerated and more clinically effective than chlorambucil. The committee noted that trial evidence used by the company for the effectiveness of rituximab (Gertz et al. 2004; Gertz et al. 2009) comprised about 50% of people with relapsed or refractory Waldenstrom's macroglobulinaemia and about 50% of people who had not had treatment. It also noted that it was unknown whether chemoimmunotherapy was considered suitable or not for people having rituximab as a first-line treatment. The company agreed that suitability for chemoimmunotherapy was not stated. But it added that the baseline characteristics of people in the rituximab trial were similar to the definition for people who had not had treatment in the ASPEN trial. The committee still considered that there was uncertainty about the comparability of these groups. This was because the inclusion criteria for the rituximab trial did not specify the suitability of chemoimmunotherapy, which could imply that there were different baseline characteristics. The company attempted to match the populations used in the indirect treatment comparison and make adjustments to minimise bias in the results by using a MAIC. The specific results of the analysis are confidential and cannot be shared here. But the comparison of zanubrutinib with rituximab suggested that zanubrutinib improved progression-free survival and overall survival. Also, the hazard ratios were lower than those for the comparisons of zanubrutinib with BR or DRC. This suggested more benefit with zanubrutinib compared with rituximab than in the comparisons of zanubrutinib with BR or DRC. The committee noted that the proportion of people in ASPEN for whom chemoimmunotherapy was not suitable was small, and considered whether this would be the same in clinical practice. The clinical experts advised that it may depend on the alternative treatment options that are available. They estimated that the figure could be up to 15% if effective options were available that better suited that group (for example, oral treatment that avoided the need for hospital visits). The committee concluded that there was uncertainty about the MAIC results when chemoimmunotherapy was unsuitable. But it agreed that zanubrutinib was clinically effective compared with the company's preferred comparator rituximab. # The company's economic model ## The structure of the company's model is appropriate for decision making The company developed a cohort partitioned survival model to project the long-term clinical and economic consequences. This consisted of 3 mutually exclusive health states: preprogression, postprogression, and death. The committee noted the ERG's concerns that this type of model relies on estimating progression-free and overall survival over a long period. This can be uncertain if the trial data for these outcomes is immature, as was the case in ASPEN. But, overall, the committee concluded that it was acceptable for decision making. ## The extrapolations of overall survival for zanubrutinib in the relapsed or refractory population are plausible but uncertain The company used parametric models to extrapolate the data over a 30‑year time horizon to estimate overall survival beyond the data collection periods for zanubrutinib and its comparators in the relapsed or refractory population. This population comprised people who had had at least 1 treatment. The models generated 5- and 10‑year survival estimates, which are confidential and cannot be shared here. The clinical experts explained that long-term overall survival on zanubrutinib and ibrutinib was likely to be similar (see section 3.4). So, the committee compared the modelled 5‑year overall-survival estimates in the zanubrutinib arm with long-term trial data from study 118E for ibrutinib. The 5‑year overall-survival data for ibrutinib was broadly consistent with the 5‑year overall-survival data estimated for zanubrutinib. The committee accepted that the extrapolated survival estimates for zanubrutinib were appropriate for decision making, noting that there were uncertainties in the data that underpinned them. ## Some adjustment of overall survival for comparators may be reasonable but is very uncertain and has a large effect on cost effectiveness In the first committee meeting, the committee concluded that ibrutinib should not be included as a subsequent treatment option because it is not available through routine commissioning. The committee noted that, in its original submission, the company had included the costs of follow-on treatment with ibrutinib. But it had removed these costs in its updated base case after consultation. The company stated that the populations in the BR and DRC trials did not have follow-on ibrutinib. But it added that the extrapolated modelled overall survival beyond the end of the study period may have included some benefit from follow-on ibrutinib. The company explained it had sought clinical opinion on the expected long-term survival outcomes for BR and DRC. This was to select a modelled distribution that gave clinically plausible extrapolated long-term survival outcomes. The company further stated that this opinion was based on current practice at that time, when 72% of people had ibrutinib after BR or DRC through the Cancer Drugs Fund. The company suggested that its modelled estimates of overall survival with BR and DRC may have been overestimated. This was because ibrutinib is no longer available in the NHS, and people on BR or DRC are expected to have poorer outcomes without this effective follow-on treatment. The company stated that its original modelled estimate of the difference in survival at 6 years between zanubrutinib and BR or DRC was smaller than that presented by an ERG during the NICE technology appraisal of ibrutinib for treating Waldenstrom's macroglobulinaemia. This difference was based on clinical expert opinion. The company suggested that the curves for overall survival in the BR and DRC arms should be adjusted downwards, while keeping the zanubrutinib curves the same. This was so that the probability of survival was 50% lower than the survival in the zanubrutinib arm at 6 years. The company also included this adjustment in its base case for the population for whom chemoimmunotherapy is unsuitable. This used the BR or DRC curves for overall survival as surrogate estimates for rituximab monotherapy. The clinical experts considered that some adjustment may be warranted. They noted that zanubrutinib delivers benefit both as an improvement on chemoimmunotherapy and as an additional treatment line for people with relapsed or refractory disease. They also noted that people in the BR and DRC trials may have had other effective treatments that are not available in the NHS, such as bortezomib. The clinical experts stated that it was challenging to confirm the level of adjustment needed. This was because of the difficulty in considering hypothetical situations that do not reflect current or previous clinical practice in the NHS. The ERG noted that the company had already used the parametric distribution giving the second most pessimistic modelled overall survival in the BR arm. So, even if the most pessimistic modelled distribution had been selected to reflect the absence of ibrutinib as a subsequent treatment, the effect on the cost-effectiveness results was minor. The ERG further considered that the extent of adjustment was based on clinical opinion rather than data. It preferred not to include adjustment of overall survival in the comparator overall-survival arms. The committee noted that the level of adjustment had a large effect on the incremental cost-effectiveness ratios (ICERs). It added that any adjustment would mean, in effect, that the overall-survival hazard ratio from the company's MAIC was not directly used in the analysis. It concluded that the modelled overall survival of BR and DRC was highly uncertain. It agreed that some adjustment to postprogression survival in the BR- or DRC-modelled arms might have been justified to account for the potential effect of follow-on treatments not available in the NHS. But it concluded that the ERG's base case was more reflective of the relative difference in overall survival of zanubrutinib compared with BR and DRC. This was because it was based on estimates from the MAIC, while the company's downward adjustment of the effectiveness of BR and DRC was based on clinical opinion. The committee concluded that this meant the company's approach was highly uncertain. ## Using the DRC data to estimate long-term survival with rituximab when chemoimmunotherapy is unsuitable is highly uncertain but appropriate For the population for which chemoimmunotherapy is unsuitable, the company modelled the cost effectiveness of zanubrutinib compared with rituximab. To represent progression-free survival and overall survival in the rituximab population, it used the modelled progression-free survival and overall survival for BR or DRC from its model for the relapsed or refractory population. The hazard ratios derived from the company's MAIC analysis comparing zanubrutinib with rituximab were then applied to the BR and DRC curves to generate curves for progression-free and overall survival for zanubrutinib. To reflect the cost of rituximab monotherapy, the company removed the treatment acquisition and administration costs of bendamustine from the BR-modelled costs, and of dexamethasone and cyclophosphamide from the DRC-modelled costs. This left only the costs of rituximab monotherapy in the analysis. The company explained that it used BR- and DRC-modelled estimates as a surrogate for rituximab. This was because of a lack of data for rituximab monotherapy to include in its economic model. The clinical experts stated that rituximab is less clinically effective than BR or DRC. The company agreed, stating that it considered its modelling approach to be conservative. The committee recalled that the data for BR had been from people whose condition was relapsed or refractory and for DRC had been from people who had not had previous chemoimmunotherapy (see section 3.7). This meant that the analysis in which DRC data was used as a baseline control arm was potentially more applicable to how rituximab monotherapy would be used in clinical practice (that is in people who had not had previous chemoimmunotherapy). The committee concluded that it preferred using DRC rather than BR as a surrogate for rituximab. It also noted that the company had already reduced the estimated survival for DRC in its model (on the basis of no follow-on ibrutinib being available, see section 3.10). It did not consider any further reduction was justified on the basis that the modelling approach was considered conservative. The committee also concluded that, although highly uncertain, the company's approach was broadly appropriate for decision making for the population for which chemoimmunotherapy is unsuitable. ## Utility values in the economic model are appropriate given the available evidence The utility value for preprogression was obtained from EQ‑5D data collected during the ASPEN study. The committee noted that the value was higher than that for the general UK population, which it thought was unrealistic. But it noted that this is commonly seen when comparing trial populations with the general population. There was not enough data in ASPEN to estimate the postprogression utility value for progressed Waldenstrom's macroglobulinaemia. So, the company and ERG agreed a reduction of 0.18 on the preprogression value. This was based on previous NICE technology appraisal guidance on ibrutinib for treating relapsed or refractory mantle cell lymphoma and on ibrutinib for treating Waldenstrom's macroglobulinaemia. The committee acknowledged that this value was uncertain but was suitable for decision making. It also noted that adjusting this value did not have a big effect on the cost-effectiveness results. ## Assuming that zanubrutinib suddenly stops working at 5 years is clinically implausible The company's base case assumed lifelong treatment effectiveness. But the ERG thought that this was not realistic and implemented a 5‑year treatment effect cut-off. This was based on NICE's technology appraisal guidance on lenalidomide with rituximab for previously treated follicular lymphoma. Once people had been on zanubrutinib for 5 years, the hazard ratio for progression-free and overall survival was assumed to become equal to that in the comparator arms. The people in the model continued to take zanubrutinib until their condition progressed rather than a stopping rule being applied. The NHS England Cancer Drugs Fund clinical lead stated that the risk of people's condition progressing while they were on treatment was already accounted for in the model. So, it was overly pessimistic to apply a sudden treatment effect cut-off. The clinical experts agreed with this view. They explained they have experience in other indications in which people have been taking the same type of drug, ibrutinib, for many years and are still deriving benefit. The committee concluded that there was insufficient evidence to justify this treatment effect cut-off. It noted that 'treatment waning effects' (meaning a reduced treatment effect over time) are typically applied after treatment has stopped, not while people are still on treatment. The committee concluded that a treatment effect cut-off was implausible and should not have been applied in the absence of any evidence to support this assumption. ## Cost-effectiveness results for the blended comparator are more uncertain than for the separate comparisons The company provided cost-effectiveness results for the comparison of zanubrutinib with BR and with DRC separately, and for a blended comparator. The blended comparator was produced using a weighted average of the results of the BR and DRC comparisons. The weighted average was calculated using the estimated proportions of who would have each treatment in clinical practice. The company used data from the Rory Morrison Registry to estimate that, in the absence of ibrutinib, 49% of people would have BR and 51% would have DRC. The clinical experts agreed that it was reasonable to estimate that about 50% of people would have each treatment. This was because, typically, people would initially have treatment with either BR or DRC, and their second-line treatment would be whichever they had not had first line (BR followed by DRC, or DRC followed by BR). The company also presented scenarios to account for variation in clinical practice across the UK, with use of BR and DRC varying between 40% and 60%. The committee recalled that the data for BR had been from people whose condition was relapsed or refractory and who had had previous treatment. It also recalled that the data for DRC had been from people who had not had previous chemoimmunotherapy. This meant that the comparison with BR was more applicable to how zanubrutinib would be used within its marketing authorisation (that is after 1 or more treatments). It also meant that it was more robust than the comparison with DRC. The committee noted that there was methodological difficulty with the blended comparator. This was because it relied on an assumption of the proportions of people who would have BR or DRC in clinical practice. It also included the comparison with DRC, which was the more uncertain. The committee concluded that it would take into account the cost-effectiveness results for both the blended and the pairwise comparisons. But it also took into account the greater uncertainty around the estimates compared with DRC, and from the blended comparator. # Cost-effectiveness results ## The ICER is under £30,000 per QALY gained only if zanubrutinib is used after at least 1 treatment and when compared with BR The committee noted that the company had agreed a patient access scheme for zanubrutinib. There are confidential prices for BR and DRC, so the exact ICERs cannot be reported here. The committee's preferred modelling assumptions after the first meeting were: using the MAIC rather than the STC method for indirect comparisons of the clinical data because, although both were uncertain, insufficient justification was given for using the STC, and the MAIC was a more transparent approach (see section 3.5) excluding the costs of ibrutinib as a subsequent treatment (see section 3.10) not to apply any treatment effect cut-off (see section 3.13).The committee noted that the company had updated its base case to reflect the committee's preferred modelling assumptions. It also noted the base case included an additional adjustment of overall survival in the BR- and DRC-modelled arms. The ERG's exploratory base case also included the committee's preferred assumptions but did not include the company's new adjustment of overall survival. The committee considered that it may have been reasonable to apply some adjustment to overall survival in the comparator arm, but not the full adjustment proposed by the company. For the population for whom chemoimmunotherapy is unsuitable, the committee considered that the comparison in which DRC data was used as a baseline control arm was the most appropriate (see section 3.11). Again, it thought that some adjustment of overall survival may have been reasonable. The only ICER that was under £30,000 per quality-adjusted life year (QALY) gained was from the comparison of zanubrutinib with BR in people for whom chemoimmunotherapy was suitable after 1 or more treatments. ## Because of the uncertainty an acceptable ICER is comfortably within the acceptable range of £20,000 to £30,000 per QALY gained NICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee considered that an acceptable ICER for zanubrutinib would need to be comfortably below £30,000 per QALY gained to be considered a cost-effective use of NHS resources. This decision took into account: the unmet need for a new treatment option the likelihood that it was an effective treatment the uncertainty around the indirect comparisons and long-term survival.The committee noted the uncertainty about the level of adjustment to the overall-survival estimates for BR and DRC. It also noted that the company's probabilistic ICER from the comparison of zanubrutinib with DRC in people for whom chemoimmunotherapy was suitable after 1 or more treatments was not under £30,000 per QALY gained. This was even when the company's full suggested reduction in DRC efficacy was included, which the committee considered to lack evidence. Similarly, it was over £30,000 per QALY gained in comparison with rituximab in people for whom chemoimmunotherapy is unsuitable. This was using the DRC curve as a baseline control arm, also with the full downward adjustment of that curve proposed by the company. The estimates from the ERG without any curve adjustment were substantially higher. The committee concluded that an acceptable ICER would need to be comfortably within the range of £20,000 to £30,000 per QALY gained. It concluded that the ICER for zanubrutinib was only likely to be comfortably within the £20,000 to £30,000 range compared with BR when chemoimmunotherapy was suitable after 1 or more treatments. But this was only if at least some downward adjustment was assumed to be reasonable. # Innovation ## Zanubrutinib is a step-change in managing Waldenstrom's macroglobulinaemia The committee accepted that zanubrutinib has several benefits over chemoimmunotherapy including oral administration, manageable adverse reactions, low toxicity and fewer hospital visits. The committee concluded that zanubrutinib could be considered a step-change in managing Waldenstrom's macroglobulinaemia compared with the treatment options available in UK clinical practice. # Conclusions ## Zanubrutinib is recommended after at least 1 treatment when BR is also suitable The committee concluded that it was not possible to recommend zanubrutinib for all people who had had previous treatment. This was because the ICER for zanubrutinib compared with the blended comparator was not below £30,000 per QALY gained. Also, the pairwise ICERs of zanubrutinib compared with DRC were consistently above £30,000 per QALY gained. The committee also concluded that it was only possible to recommend zanubrutinib in people who had had previous treatment and when BR is also suitable. This was because the ICER for this group was below £30,000 per QALY gained, so was an acceptable use of NHS resources. The committee also concluded that it was not possible to recommend zanubrutinib for the population for which chemoimmunotherapy is unsuitable. This was because the ICER for zanubrutinib compared with rituximab was not below £30,000 per QALY gained. ## The recommendations may affect the treatment pathway for Waldenstrom's macroglobulinaemia The committee recognised that its recommendation could affect the treatment pathway for Waldenstrom's macroglobulinaemia. This was because whether BR would be considered a second-line or later treatment would be related to the treatments people had already had. The committee considered opinions from the clinical and patient experts that: although DRC is generally better tolerated, there are certain clinical indications for choosing BR first -nly some people who have BR first line would be able to have retreatment with BR people for whom chemoimmunotherapy is not suitable have a particular unmet need for more treatment options.The committee was aware that the recommendation would exclude some people for whom the whole marketing authorisation for zanubrutinib applied. It recognised that they would be disappointed by the recommendation. But, based on the evidence available, zanubrutinib is not cost effective as a first-line treatment when chemotherapy is unsuitable, or for people who would have DRC after at least 1 treatment. For second-line use when chemoimmunotherapy is unsuitable, the company did not provide any information on the relevant comparators, or clinical or cost effectiveness. So, the committee was unable to make any recommendation for that population. The committee concluded that the treatment pathway may change for the treatment of Waldenstrom's macroglobulinaemia for people who are able to tolerate chemoimmunotherapy. It may mean that people would be more likely to have the generally better-tolerated DRC as their first-line treatment to preserve the option of zanubrutinib second line. But for some people, the benefits of first-line BR would outweigh the risk of being ineligible for zanubrutinib later. Unfortunately, the pathway when chemoimmunotherapy is unsuitable would be unchanged. Despite these disadvantages, the committee considered that it was not possible to make a different recommendation. It concluded that zanubrutinib could only be recommended for treating Waldenstrom's macroglobulinaemia in adults who have had at least 1 treatment, but only when BR is also suitable.	{'Recommendations': "Zanubrutinib is recommended as an option for treating Waldenstrom's macroglobulinaemia in adults who have had at least 1\xa0treatment, only if:\n\nbendamustine plus rituximab is also suitable and\n\nthe company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with zanubrutinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard care for Waldenstrom's macroglobulinaemia varies but typically includes chemoimmunotherapy combinations such as bendamustine plus rituximab, or dexamethasone plus rituximab and cyclophosphamide. When chemoimmunotherapy is unsuitable, rituximab or chlorambucil alone are typically offered.\n\nClinical evidence from an indirect comparison suggests that people with Waldenstrom's macroglobulinaemia may live longer and have a better quality of life with zanubrutinib than with standard care. Long-term evidence on the effectiveness of zanubrutinib is not yet available. So, it is unclear how much longer people having zanubrutinib live.\n\nFor people who have had previous treatment, the cost-effectiveness estimates for zanubrutinib are only within what NICE usually considers an acceptable use of NHS resources when bendamustine plus rituximab is also suitable. Zanubrutinib is recommended for this group. For people who have not had previous treatment and if chemoimmunotherapy is unsuitable, the cost-effective estimates for zanubrutinib are above what NICE usually considers an acceptable use of NHS resources. Zanubrutinib is not recommended for this group.", 'Information about zanubrutinib': "# Marketing authorisation indication\n\nZanubrutinib (Brukinsa, BeiGene) has a marketing authorisation in the UK for 'the treatment of adult patients with Waldenström's macroglobulinaemia (WM) in adults who have received at least one prior therapy, or in first-line treatment for patients unsuitable for chemo-immunotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for zanubrutinib.\n\n# Price\n\nThe list price of zanubrutinib 120x80\xa0mg capsules is £4,928.65 (excluding VAT; company submission). The company has a commercial arrangement. This makes zanubrutinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': 'The appraisal committee considered evidence submitted by BeiGene, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Current management\n\n## Comparators are bendamustine plus rituximab, dexamethasone plus rituximab and cyclophosphamide, and rituximab or chlorambucil alone\n\nWaldenstrom\'s macroglobulinaemia is an incurable form of non-Hodgkin\'s lymphoma. It typically affects older people and has a long trajectory, with a median overall survival of 16\xa0years in people with symptoms. Because the condition progresses slowly, many people die from causes other than Waldenstrom\'s macroglobulinaemia. The clinical experts explained that although there is variation in the clinical pathway, the first-line treatment options are commonly bendamustine plus rituximab (BR) and dexamethasone plus rituximab and cyclophosphamide (DRC) if chemoimmunotherapy is suitable. The clinical experts further explained that patient- and disease-related factors can influence the choice of first-line treatment. They stated that BR tends to produce a more rapid and deeper response, so may be preferred if disease burden needs to be quickly reduced. But BR has a less favourable toxicity profile than DRC, so DRC may be preferred in people who are frail or have comorbidities. Although purine analogues such as fludarabine were included in the NICE scope, their use is no longer recommended because of toxicity concerns and the risk of secondary malignancies. This is reflected in the latest clinical guidelines on managing Waldenstrom\'s macroglobulinaemia from the British Society for Haematology. An autologous stem cell transplant is also an option for people who are fit enough. But, because Waldenstrom\'s macroglobulinaemia mainly affects older people, this is not suitable for most. Until recently, when the condition relapsed or became refractory to first-line treatment most people were offered ibrutinib (a Bruton\'s tyrosine kinase inhibitor), which was available through the Cancer Drugs Fund. But, during the time course of this appraisal, a separate NICE appraisal of ibrutinib for treating Waldenstrom\'s macroglobulinemia was done. This found that ibrutinib could not be recommended for routine use in the NHS for this indication. Other second-line treatment options include rituximab-containing regimens (such as BR or DRC, if not used as a first-line treatment). After these treatments, practice varies, but repeated rounds of chemotherapy are often used. When chemoimmunotherapy is unsuitable, treatment options include rituximab or chlorambucil monotherapy, or best supportive care. The company noted that rituximab and chlorambucil are not widely used, particularly chlorambucil because it may be more toxic than rituximab. But the committee noted both were used in clinical practice. The clinical experts explained that, if zanubrutinib were recommended, it would be used as early as possible in the treatment pathway. But the committee noted that, when chemoimmunotherapy is suitable, zanubrutinib\'s licence limited it to use after at least 1\xa0treatment. The committee was aware that there is variation in the treatment pathway for people with Waldenstrom\'s macroglobulinaemia, particularly when it is relapsed or refractory. It concluded that BR and DRC were the 2\xa0most relevant comparators when chemoimmunotherapy is suitable. It also concluded that rituximab or chlorambucil alone were relevant comparators when chemoimmunotherapy is unsuitable. This is when the marketing authorisation allows zanubrutinib as a first-line treatment option.\n\n## The availability of an effective and well-tolerated oral treatment is highly valued and addresses a significant unmet need\n\nThe patient expert explained that Waldenstrom\'s macroglobulinaemia and its treatment can have a profound effect on quality of life. The condition itself can cause severe pain, fatigue, reduced mobility and increased susceptibility to infections. Current chemoimmunotherapy treatments can cause severe adverse reactions and the need for frequent hospital visits. Even though Waldenstrom\'s macroglobulinaemia may respond well to first-line treatment, the constant threat of relapse can be a huge burden on people with the condition and their families. For people who cannot have chemoimmunotherapy, treatment options are very limited. The patient expert said that people with the condition are acutely aware of this. Also, there is a desire among the patient community to have additional options as their condition progresses. The committee noted that zanubrutinib is a Bruton\'s tyrosine kinase inhibitor and has a different mechanism of action to existing chemoimmunotherapy treatments. Both the patient and clinical experts emphasised that zanubrutinib is highly effective and better tolerated than existing chemoimmunotherapy options. It is also an oral treatment, which is greatly valued by people with the condition because it avoids the need for hospital visits and infusions. The patient expert said that zanubrutinib had rapidly and dramatically made him "feel better" and improved his quality of life. He explained that it had allowed him to participate in general day-to-day activities and return to the normal life he had enjoyed before diagnosis. He explained that this was in stark contrast to his experience with chemoimmunotherapy treatments, with which he had had significant intolerance issues and side effects, some of which were persistent. The committee concluded that the availability of an effective and well-tolerated oral treatment would be highly valued by people with Waldenstrom\'s macroglobulinaemia and would address a significant unmet need.\n\n# Clinical effectiveness\n\n## The ASPEN study provides generalisable evidence for zanubrutinib but its comparator, ibrutinib, is not relevant for this appraisal\n\nThe clinical evidence for zanubrutinib came from the ASPEN study, a randomised clinical trial that compared zanubrutinib with ibrutinib. The committee noted that ibrutinib was not a comparator in this appraisal (see section\xa03.1). The people in the trial were divided into 2\xa0cohorts:\n\nCohort\xa01 included 201\xa0people with Waldenstrom\'s macroglobulinaemia who had a mutation in the myeloid differentiation primary response gene (mutated MYD88 type). The people in this cohort were randomised to either zanubrutinib or ibrutinib.\n\nCohort\xa02 included 28\xa0people with Waldenstrom\'s macroglobulinaemia (wild type MYD88 type) and they were all assigned to zanubrutinib.One clinical expert explained that the trial was designed this way because earlier studies had suggested that ibrutinib may work less well in people without the MYD88 mutation. The committee understood that about 90% of people with Waldenstrom\'s macroglobulinaemia have the MYD88 mutation. But, overall, it expected that zanubrutinib would work equally well in people who did and did not have the MYD88 mutation. The company stated that comparing the data for zanubrutinib from the 2\xa0cohorts supported the assumption that there was no difference in outcomes. The committee considered that the trial data from cohort\xa01 (which the company used in its model) was generalisable to both people with and without the MYD88 gene mutation. Cohort\xa01 included:\n\npeople (83\xa0in the zanubrutinib arm) with relapsed or refractory Waldenstrom\'s macroglobulinaemia who had had at least 1\xa0treatment\n\npeople (19\xa0in the zanubrutinib arm) who had not had any treatment and for whom chemoimmunotherapy was unsuitable.The median age of people in the trial was\xa070. Also, almost everyone had an Eastern Cooperative Oncology Group performance status of 0\xa0or\xa01, and many had had multiple previous treatments. One clinical expert stated that the trial population reflected the patient population in the NHS. The committee concluded that ASPEN provided clinical evidence for zanubrutinib that is generalisable to UK clinical practice. But it concluded that it had not compared zanubrutinib with the relevant comparators for this appraisal.\n\n## Zanubrutinib is clinically effective, but the data is immature for progression-free and overall survival\n\nThe committee noted that, at a median follow up of 19.5\xa0months in ASPEN, the very good partial response rate was 28.4% in the zanubrutinib arm and 19.2% in the ibrutinib arm. This response occurred at a median time of 4.8\xa0months in the zanubrutinib arm. The committee also noted that there was not a complete response in anyone. But 1\xa0clinical expert said that this was not unexpected because it is acknowledged that this class of drugs is not curative. The clinical expert also noted that it was important to consider the durability of that response, and not just its depth. Median progression-free and overall survival had not been reached at the point of data cut-off, so the survival data for zanubrutinib was immature. This is to be expected because Waldenstrom\'s macroglobulinaemia is a slowly progressing condition. At 12\xa0months, 97.0% (95% confidence interval 90.9\xa0to\xa099.0) of people in the zanubrutinib arm were alive, and the condition had not yet progressed in 89.7% (95% confidence interval 81.7\xa0to\xa094.3). Although ibrutinib was not a comparator in this appraisal, the committee noted that overall (93.9%) and progression-free survival (87.2%) was similar to that with zanubrutinib at 12\xa0months. The clinical experts explained that zanubrutinib would be expected to have similar clinical efficacy to ibrutinib in clinical practice because they are in the same drug class. The committee concluded that zanubrutinib was clinically effective, but that data on progression-free and overall survival was immature.\n\n## Zanubrutinib is more clinically effective than chemoimmunotherapy, but the size of the benefit compared with BR and DRC is uncertain\n\nClinical evidence for the chemoimmunotherapy comparators (BR and DRC) in people who had had previous treatment came from 2\xa0main studies:\n\nThe clinical evidence for BR came from a single-arm study of 71\xa0people with relapsed or refractory Waldenstrom\'s macroglobulinaemia (Tedeschi et al. 2015).\n\nThe clinical evidence for DRC came from a single-arm trial of 72\xa0people with Waldenstrom\'s macroglobulinaemia who had not had previous treatment but for whom chemoimmunotherapy was considered suitable (Dimopoulos et al. 2007; Kastritis et al. 2015).The committee noted that the DRC data came from a population having this type of chemoimmunotherapy as a first-line treatment, which does not correspond with the marketing authorisation for zanubrutinib (see section\xa02.1). Also, it is different from the population in ASPEN. About 81% of people in ASPEN had zanubrutinib after previous treatment. The remainder, for whom chemoimmunotherapy was unsuitable, had zanubrutinib as a first-line treatment (see section\xa03.3). The company attempted to match the populations used in the indirect treatment comparisons and make adjustments to minimise bias in the results. It presented results for zanubrutinib compared with BR in people whose condition was relapsed or refractory and compared it with DRC in people who had not had previous treatment. The company\'s original submission used a matching-adjusted indirect comparison (MAIC). The ERG noted the limited patient data available for the comparator studies. It thought that this may have led to differences in clinically relevant risk factors between the comparator groups that could not be adjusted for. In response to technical engagement, the company used another method for indirect comparison, a simulated treatment comparison (STC). The company explained that the STC was its preferred approach because it meant that a larger sample size could be maintained, more data used and covariates adjusted for more effectively. Both the STC and MAIC approaches for the indirect comparison suggested that there was improved overall and progression-free survival with zanubrutinib compared with both BR and DRC. While the hazard ratio point estimates generated by the MAIC and the STC were different, the confidence intervals had substantial overlap. The committee agreed that this showed some consistency in the results generated by the 2\xa0methods. The clinical experts confirmed that the hazard ratios generated in the analyses to compare zanubrutinib with BR and DRC seemed plausible. The committee considered that there were uncertainties and limitations with both the MAIC and the STC. But it noted that MAIC methods are more transparent and that there was insufficient justification given by the company to switch from its original MAIC to the STC. So, the committee concluded that its preferred approach was the original MAIC analysis. But it acknowledged that this was an area of uncertainty. The committee noted that, for the BR and DRC comparisons, the hazard ratios in the company\'s indirect comparisons for progression-free survival were low compared with those typically seen with other cancer treatments. But it concluded that there was a high degree of uncertainty in the size of the treatment effect of zanubrutinib compared with both comparators. This was because of the limitations of the indirect comparisons.\n\n## It is unclear whether overall survival is better with DRC than with BR but the committee accepted the company\'s estimates as the best available\n\nThe overall-survival hazard ratios for BR compared with zanubrutinib were lower than the hazard ratios for DRC compared with zanubrutinib. This was regardless of whether the STC or MAIC approach was used. The committee noted that these hazard ratios suggested DRC may be more effective than BR used second line. But it could not determine whether this reflected a real difference in the benefits of these comparators or resulted from a difference in the populations being compared in each indirect comparison. The specific results of the analysis are confidential and cannot be shared here. The clinical experts explained that real-world data comparisons have consistently shown a favourable progression-free survival outcome for BR compared with DRC. But they added that the data for overall survival is less conclusive. This is because people with Waldenstrom\'s macroglobulinaemia often do not die because of the condition itself. Also, DRC tends to be used in people who are frail or have comorbidities, which may affect their life expectancy. The committee was not aware of any direct comparative evidence to determine whether BR and DRC would be equally effective had they been studied at the same stage in the treatment pathway. So, the committee accepted the company\'s estimates for its decision making.\n\n## Zanubrutinib is clinically effective compared with rituximab when chemoimmunotherapy is unsuitable\n\nThe clinical evidence for the chemoimmunotherapy unsuitable comparators (rituximab monotherapy and chlorambucil monotherapy) came from 2\xa0main studies:\n\nThe clinical evidence for rituximab came from a single-arm study of 69\xa0people, including 34\xa0people with Waldenstrom\'s macroglobulinaemia who had not had previous treatment (unknown whether chemoimmunotherapy was considered suitable) and 35 people with relapsed or refractory Waldenstrom\'s macroglobulinaemia (Gertz et al. 2004; Gertz et al. 2009).\n\nThe clinical evidence for chlorambucil came from a randomised controlled trial of 46\xa0people with Waldenstrom\'s macroglobulinaemia who had not had previous treatment (unknown whether chemoimmunotherapy was considered suitable). The trial compared continuous chlorambucil therapy with intermittent chlorambucil therapy (Kyle et al. 2000).The committee noted that, in ASPEN, there were 19\xa0people (about 19%) in the zanubrutinib arm who had not had previous treatment and for whom chemoimmunotherapy was not considered suitable. There was a very good partial response in 26% of this subgroup, compared with 29% in the relapsed or refractory population. The company considered that it was reasonable to consider that the clinical effectiveness of zanubrutinib taken as a first-line treatment by people for whom chemoimmunotherapy is unsuitable would be similar to its effectiveness in people whose condition is relapsed or refractory. The company based its cost-effectiveness estimates for this population on an indirect comparison of zanubrutinib compared with rituximab, which it considered to be a more relevant comparator than chlorambucil. This was based on data from the Rory Morrison Registry showing that rituximab is more widely used than chlorambucil as a first-line treatment for Waldenstrom\'s macroglobulinaemia. The company also stated that rituximab is better tolerated and more clinically effective than chlorambucil. The committee noted that trial evidence used by the company for the effectiveness of rituximab (Gertz et al. 2004; Gertz et al. 2009) comprised about 50% of people with relapsed or refractory Waldenstrom\'s macroglobulinaemia and about 50% of people who had not had treatment. It also noted that it was unknown whether chemoimmunotherapy was considered suitable or not for people having rituximab as a first-line treatment. The company agreed that suitability for chemoimmunotherapy was not stated. But it added that the baseline characteristics of people in the rituximab trial were similar to the definition for people who had not had treatment in the ASPEN trial. The committee still considered that there was uncertainty about the comparability of these groups. This was because the inclusion criteria for the rituximab trial did not specify the suitability of chemoimmunotherapy, which could imply that there were different baseline characteristics. The company attempted to match the populations used in the indirect treatment comparison and make adjustments to minimise bias in the results by using a MAIC. The specific results of the analysis are confidential and cannot be shared here. But the comparison of zanubrutinib with rituximab suggested that zanubrutinib improved progression-free survival and overall survival. Also, the hazard ratios were lower than those for the comparisons of zanubrutinib with BR or DRC. This suggested more benefit with zanubrutinib compared with rituximab than in the comparisons of zanubrutinib with BR or DRC. The committee noted that the proportion of people in ASPEN for whom chemoimmunotherapy was not suitable was small, and considered whether this would be the same in clinical practice. The clinical experts advised that it may depend on the alternative treatment options that are available. They estimated that the figure could be up to 15% if effective options were available that better suited that group (for example, oral treatment that avoided the need for hospital visits). The committee concluded that there was uncertainty about the MAIC results when chemoimmunotherapy was unsuitable. But it agreed that zanubrutinib was clinically effective compared with the company\'s preferred comparator rituximab.\n\n# The company\'s economic model\n\n## The structure of the company\'s model is appropriate for decision making\n\nThe company developed a cohort partitioned survival model to project the long-term clinical and economic consequences. This consisted of 3\xa0mutually exclusive health states: preprogression, postprogression, and death. The committee noted the ERG\'s concerns that this type of model relies on estimating progression-free and overall survival over a long period. This can be uncertain if the trial data for these outcomes is immature, as was the case in ASPEN. But, overall, the committee concluded that it was acceptable for decision making.\n\n## The extrapolations of overall survival for zanubrutinib in the relapsed or refractory population are plausible but uncertain\n\nThe company used parametric models to extrapolate the data over a 30‑year time horizon to estimate overall survival beyond the data collection periods for zanubrutinib and its comparators in the relapsed or refractory population. This population comprised people who had had at least 1\xa0treatment. The models generated 5- and 10‑year survival estimates, which are confidential and cannot be shared here. The clinical experts explained that long-term overall survival on zanubrutinib and ibrutinib was likely to be similar (see section\xa03.4). So, the committee compared the modelled 5‑year overall-survival estimates in the zanubrutinib arm with long-term trial data from study\xa0118E for ibrutinib. The 5‑year overall-survival data for ibrutinib was broadly consistent with the 5‑year overall-survival data estimated for zanubrutinib. The committee accepted that the extrapolated survival estimates for zanubrutinib were appropriate for decision making, noting that there were uncertainties in the data that underpinned them.\n\n## Some adjustment of overall survival for comparators may be reasonable but is very uncertain and has a large effect on cost effectiveness\n\nIn the first committee meeting, the committee concluded that ibrutinib should not be included as a subsequent treatment option because it is not available through routine commissioning. The committee noted that, in its original submission, the company had included the costs of follow-on treatment with ibrutinib. But it had removed these costs in its updated base case after consultation. The company stated that the populations in the BR and DRC trials did not have follow-on ibrutinib. But it added that the extrapolated modelled overall survival beyond the end of the study period may have included some benefit from follow-on ibrutinib. The company explained it had sought clinical opinion on the expected long-term survival outcomes for BR and DRC. This was to select a modelled distribution that gave clinically plausible extrapolated long-term survival outcomes. The company further stated that this opinion was based on current practice at that time, when 72% of people had ibrutinib after BR or DRC through the Cancer Drugs Fund. The company suggested that its modelled estimates of overall survival with BR and DRC may have been overestimated. This was because ibrutinib is no longer available in the NHS, and people on BR or DRC are expected to have poorer outcomes without this effective follow-on treatment. The company stated that its original modelled estimate of the difference in survival at 6\xa0years between zanubrutinib and BR or DRC was smaller than that presented by an ERG during the NICE technology appraisal of ibrutinib for treating Waldenstrom\'s macroglobulinaemia. This difference was based on clinical expert opinion. The company suggested that the curves for overall survival in the BR and DRC arms should be adjusted downwards, while keeping the zanubrutinib curves the same. This was so that the probability of survival was 50% lower than the survival in the zanubrutinib arm at 6\xa0years. The company also included this adjustment in its base case for the population for whom chemoimmunotherapy is unsuitable. This used the BR or DRC curves for overall survival as surrogate estimates for rituximab monotherapy. The clinical experts considered that some adjustment may be warranted. They noted that zanubrutinib delivers benefit both as an improvement on chemoimmunotherapy and as an additional treatment line for people with relapsed or refractory disease. They also noted that people in the BR and DRC trials may have had other effective treatments that are not available in the NHS, such as bortezomib. The clinical experts stated that it was challenging to confirm the level of adjustment needed. This was because of the difficulty in considering hypothetical situations that do not reflect current or previous clinical practice in the NHS. The ERG noted that the company had already used the parametric distribution giving the second most pessimistic modelled overall survival in the BR arm. So, even if the most pessimistic modelled distribution had been selected to reflect the absence of ibrutinib as a subsequent treatment, the effect on the cost-effectiveness results was minor. The ERG further considered that the extent of adjustment was based on clinical opinion rather than data. It preferred not to include adjustment of overall survival in the comparator overall-survival arms. The committee noted that the level of adjustment had a large effect on the incremental cost-effectiveness ratios (ICERs). It added that any adjustment would mean, in effect, that the overall-survival hazard ratio from the company\'s MAIC was not directly used in the analysis. It concluded that the modelled overall survival of BR and DRC was highly uncertain. It agreed that some adjustment to postprogression survival in the BR- or DRC-modelled arms might have been justified to account for the potential effect of follow-on treatments not available in the NHS. But it concluded that the ERG\'s base case was more reflective of the relative difference in overall survival of zanubrutinib compared with BR and DRC. This was because it was based on estimates from the MAIC, while the company\'s downward adjustment of the effectiveness of BR and DRC was based on clinical opinion. The committee concluded that this meant the company\'s approach was highly uncertain.\n\n## Using the DRC data to estimate long-term survival with rituximab when chemoimmunotherapy is unsuitable is highly uncertain but appropriate\n\nFor the population for which chemoimmunotherapy is unsuitable, the company modelled the cost effectiveness of zanubrutinib compared with rituximab. To represent progression-free survival and overall survival in the rituximab population, it used the modelled progression-free survival and overall survival for BR or DRC from its model for the relapsed or refractory population. The hazard ratios derived from the company\'s MAIC analysis comparing zanubrutinib with rituximab were then applied to the BR and DRC curves to generate curves for progression-free and overall survival for zanubrutinib. To reflect the cost of rituximab monotherapy, the company removed the treatment acquisition and administration costs of bendamustine from the BR-modelled costs, and of dexamethasone and cyclophosphamide from the DRC-modelled costs. This left only the costs of rituximab monotherapy in the analysis. The company explained that it used BR- and DRC-modelled estimates as a surrogate for rituximab. This was because of a lack of data for rituximab monotherapy to include in its economic model. The clinical experts stated that rituximab is less clinically effective than BR or DRC. The company agreed, stating that it considered its modelling approach to be conservative. The committee recalled that the data for BR had been from people whose condition was relapsed or refractory and for DRC had been from people who had not had previous chemoimmunotherapy (see section\xa03.7). This meant that the analysis in which DRC data was used as a baseline control arm was potentially more applicable to how rituximab monotherapy would be used in clinical practice (that is in people who had not had previous chemoimmunotherapy). The committee concluded that it preferred using DRC rather than BR as a surrogate for rituximab. It also noted that the company had already reduced the estimated survival for DRC in its model (on the basis of no follow-on ibrutinib being available, see section\xa03.10). It did not consider any further reduction was justified on the basis that the modelling approach was considered conservative. The committee also concluded that, although highly uncertain, the company\'s approach was broadly appropriate for decision making for the population for which chemoimmunotherapy is unsuitable.\n\n## Utility values in the economic model are appropriate given the available evidence\n\nThe utility value for preprogression was obtained from EQ‑5D data collected during the ASPEN study. The committee noted that the value was higher than that for the general UK population, which it thought was unrealistic. But it noted that this is commonly seen when comparing trial populations with the general population. There was not enough data in ASPEN to estimate the postprogression utility value for progressed Waldenstrom\'s macroglobulinaemia. So, the company and ERG agreed a reduction of 0.18 on the preprogression value. This was based on previous NICE technology appraisal guidance on ibrutinib for treating relapsed or refractory mantle cell lymphoma and on ibrutinib for treating Waldenstrom\'s macroglobulinaemia. The committee acknowledged that this value was uncertain but was suitable for decision making. It also noted that adjusting this value did not have a big effect on the cost-effectiveness results.\n\n## Assuming that zanubrutinib suddenly stops working at 5\xa0years is clinically implausible\n\nThe company\'s base case assumed lifelong treatment effectiveness. But the ERG thought that this was not realistic and implemented a 5‑year treatment effect cut-off. This was based on NICE\'s technology appraisal guidance on lenalidomide with rituximab for previously treated follicular lymphoma. Once people had been on zanubrutinib for 5\xa0years, the hazard ratio for progression-free and overall survival was assumed to become equal to that in the comparator arms. The people in the model continued to take zanubrutinib until their condition progressed rather than a stopping rule being applied. The NHS England Cancer Drugs Fund clinical lead stated that the risk of people\'s condition progressing while they were on treatment was already accounted for in the model. So, it was overly pessimistic to apply a sudden treatment effect cut-off. The clinical experts agreed with this view. They explained they have experience in other indications in which people have been taking the same type of drug, ibrutinib, for many years and are still deriving benefit. The committee concluded that there was insufficient evidence to justify this treatment effect cut-off. It noted that \'treatment waning effects\' (meaning a reduced treatment effect over time) are typically applied after treatment has stopped, not while people are still on treatment. The committee concluded that a treatment effect cut-off was implausible and should not have been applied in the absence of any evidence to support this assumption.\n\n## Cost-effectiveness results for the blended comparator are more uncertain than for the separate comparisons\n\nThe company provided cost-effectiveness results for the comparison of zanubrutinib with BR and with DRC separately, and for a blended comparator. The blended comparator was produced using a weighted average of the results of the BR and DRC comparisons. The weighted average was calculated using the estimated proportions of who would have each treatment in clinical practice. The company used data from the Rory Morrison Registry to estimate that, in the absence of ibrutinib, 49% of people would have BR and 51% would have DRC. The clinical experts agreed that it was reasonable to estimate that about 50% of people would have each treatment. This was because, typically, people would initially have treatment with either BR or DRC, and their second-line treatment would be whichever they had not had first line (BR followed by DRC, or DRC followed by BR). The company also presented scenarios to account for variation in clinical practice across the UK, with use of BR and DRC varying between 40% and 60%. The committee recalled that the data for BR had been from people whose condition was relapsed or refractory and who had had previous treatment. It also recalled that the data for DRC had been from people who had not had previous chemoimmunotherapy. This meant that the comparison with BR was more applicable to how zanubrutinib would be used within its marketing authorisation (that is after 1\xa0or more treatments). It also meant that it was more robust than the comparison with DRC. The committee noted that there was methodological difficulty with the blended comparator. This was because it relied on an assumption of the proportions of people who would have BR or DRC in clinical practice. It also included the comparison with DRC, which was the more uncertain. The committee concluded that it would take into account the cost-effectiveness results for both the blended and the pairwise comparisons. But it also took into account the greater uncertainty around the estimates compared with DRC, and from the blended comparator.\n\n# Cost-effectiveness results\n\n## The ICER is under £30,000 per QALY gained only if zanubrutinib is used after at least 1\xa0treatment and when compared with BR\n\nThe committee noted that the company had agreed a patient access scheme for zanubrutinib. There are confidential prices for BR and DRC, so the exact ICERs cannot be reported here. The committee\'s preferred modelling assumptions after the first meeting were:\n\nusing the MAIC rather than the STC method for indirect comparisons of the clinical data because, although both were uncertain, insufficient justification was given for using the STC, and the MAIC was a more transparent approach (see section\xa03.5)\n\nexcluding the costs of ibrutinib as a subsequent treatment (see section\xa03.10)\n\nnot to apply any treatment effect cut-off (see section\xa03.13).The committee noted that the company had updated its base case to reflect the committee\'s preferred modelling assumptions. It also noted the base case included an additional adjustment of overall survival in the BR- and DRC-modelled arms. The ERG\'s exploratory base case also included the committee\'s preferred assumptions but did not include the company\'s new adjustment of overall survival. The committee considered that it may have been reasonable to apply some adjustment to overall survival in the comparator arm, but not the full adjustment proposed by the company. For the population for whom chemoimmunotherapy is unsuitable, the committee considered that the comparison in which DRC data was used as a baseline control arm was the most appropriate (see section\xa03.11). Again, it thought that some adjustment of overall survival may have been reasonable. The only ICER that was under £30,000 per quality-adjusted life year (QALY) gained was from the comparison of zanubrutinib with BR in people for whom chemoimmunotherapy was suitable after 1\xa0or more treatments.\n\n## Because of the uncertainty an acceptable ICER is comfortably within the acceptable range of £20,000 to £30,000 per QALY gained\n\nNICE\'s guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee considered that an acceptable ICER for zanubrutinib would need to be comfortably below £30,000 per QALY gained to be considered a cost-effective use of NHS resources. This decision took into account:\n\nthe unmet need for a new treatment option\n\nthe likelihood that it was an effective treatment\n\nthe uncertainty around the indirect comparisons and long-term survival.The committee noted the uncertainty about the level of adjustment to the overall-survival estimates for BR and DRC. It also noted that the company\'s probabilistic ICER from the comparison of zanubrutinib with DRC in people for whom chemoimmunotherapy was suitable after 1\xa0or more treatments was not under £30,000 per QALY gained. This was even when the company\'s full suggested reduction in DRC efficacy was included, which the committee considered to lack evidence. Similarly, it was over £30,000 per QALY gained in comparison with rituximab in people for whom chemoimmunotherapy is unsuitable. This was using the DRC curve as a baseline control arm, also with the full downward adjustment of that curve proposed by the company. The estimates from the ERG without any curve adjustment were substantially higher. The committee concluded that an acceptable ICER would need to be comfortably within the range of £20,000 to £30,000 per QALY gained. It concluded that the ICER for zanubrutinib was only likely to be comfortably within the £20,000 to £30,000 range compared with BR when chemoimmunotherapy was suitable after 1\xa0or more treatments. But this was only if at least some downward adjustment was assumed to be reasonable.\n\n# Innovation\n\n## Zanubrutinib is a step-change in managing Waldenstrom\'s macroglobulinaemia\n\nThe committee accepted that zanubrutinib has several benefits over chemoimmunotherapy including oral administration, manageable adverse reactions, low toxicity and fewer hospital visits. The committee concluded that zanubrutinib could be considered a step-change in managing Waldenstrom\'s macroglobulinaemia compared with the treatment options available in UK clinical practice.\n\n# Conclusions\n\n## Zanubrutinib is recommended after at least 1\xa0treatment when BR is also suitable\n\nThe committee concluded that it was not possible to recommend zanubrutinib for all people who had had previous treatment. This was because the ICER for zanubrutinib compared with the blended comparator was not below £30,000 per QALY gained. Also, the pairwise ICERs of zanubrutinib compared with DRC were consistently above £30,000 per QALY gained. The committee also concluded that it was only possible to recommend zanubrutinib in people who had had previous treatment and when BR is also suitable. This was because the ICER for this group was below £30,000 per QALY gained, so was an acceptable use of NHS resources. The committee also concluded that it was not possible to recommend zanubrutinib for the population for which chemoimmunotherapy is unsuitable. This was because the ICER for zanubrutinib compared with rituximab was not below £30,000 per QALY gained.\n\n## The recommendations may affect the treatment pathway for Waldenstrom\'s macroglobulinaemia\n\nThe committee recognised that its recommendation could affect the treatment pathway for Waldenstrom\'s macroglobulinaemia. This was because whether BR would be considered a second-line or later treatment would be related to the treatments people had already had. The committee considered opinions from the clinical and patient experts that:\n\nalthough DRC is generally better tolerated, there are certain clinical indications for choosing BR first\n\nonly some people who have BR first line would be able to have retreatment with BR\n\npeople for whom chemoimmunotherapy is not suitable have a particular unmet need for more treatment options.The committee was aware that the recommendation would exclude some people for whom the whole marketing authorisation for zanubrutinib applied. It recognised that they would be disappointed by the recommendation. But, based on the evidence available, zanubrutinib is not cost effective as a first-line treatment when chemotherapy is unsuitable, or for people who would have DRC after at least 1\xa0treatment. For second-line use when chemoimmunotherapy is unsuitable, the company did not provide any information on the relevant comparators, or clinical or cost effectiveness. So, the committee was unable to make any recommendation for that population. The committee concluded that the treatment pathway may change for the treatment of Waldenstrom\'s macroglobulinaemia for people who are able to tolerate chemoimmunotherapy. It may mean that people would be more likely to have the generally better-tolerated DRC as their first-line treatment to preserve the option of zanubrutinib second line. But for some people, the benefits of first-line BR would outweigh the risk of being ineligible for zanubrutinib later. Unfortunately, the pathway when chemoimmunotherapy is unsuitable would be unchanged. Despite these disadvantages, the committee considered that it was not possible to make a different recommendation. It concluded that zanubrutinib could only be recommended for treating Waldenstrom\'s macroglobulinaemia in adults who have had at least 1\xa0treatment, but only when BR is also suitable.'}	https://www.nice.org.uk/guidance/ta833	Evidence-based recommendations on zanubrutinib (Brukinsa) for treating Waldenstrom’s macroglobulinaemia in adults.
726c0bf91a6f8b86cc1025c0f9efd6389b43457d	nice	Fostamatinib for treating refractory chronic immune thrombocytopenia	Fostamatinib for treating refractory chronic immune thrombocytopenia Evidence-based recommendations on fostamatinib (Tavlesse) for chronic refractory chronic immune thrombocytopenia in adults. # Recommendations Fostamatinib is recommended as an option for treating refractory chronic immune thrombocytopenia (ITP) in adults, only if: they have previously had a thrombopoietin receptor agonist (TPO‑RA), or a TPO‑RA is unsuitable the company provides fostamatinib according to the commercial arrangement. This recommendation is not intended to affect treatment with fostamatinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Treatment options for refractory chronic ITP include TPO‑RAs, which are mostly followed by rituximab or mycophenolate. Fostamatinib is licensed for treating refractory chronic ITP, but the company has only provided evidence for using fostamatinib after a TPO‑RA, or when they are not suitable. Fostamatinib would be used at the same point in the treatment pathway as rituximab or mycophenolate. Clinical evidence shows that fostamatinib is effective compared with placebo. There is no clinical trial evidence directly comparing fostamatinib with rituximab or mycophenolate. An indirect comparison shows that fostamatinib works better than rituximab at increasing the number of platelets in the blood (cells that help the blood to clot). The cost-effectiveness estimates for fostamatinib compared with rituximab are within what NICE normally considers an acceptable use of NHS resources. So, fostamatinib is recommended.# Information about fostamatinib # Marketing authorisation indication Fostamatinib (Tavlesse, Grifols) is indicated 'for the treatment of chronic immune thrombocytopenia (ITP) in adult patients who are refractory to other treatments'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for fostamatinib. # Price The list prices of fostamatinib are: £3,090 per 60‑tablet pack, each tablet contains 100 mg of fostamatinib (excluding VAT; BNF online, accessed August 2022) £4,635 per 60‑tablet pack, each tablet contains 150 mg of fostamatinib (excluding VAT; BNF online, accessed August 2022).The company has a commercial arrangement. This makes fostamatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Grifols and another submission from Grifols for the rapid review, reviews of these submissions by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## People with chronic ITP and clinicians would welcome an additional treatment option Chronic immune thrombocytopenia (ITP) is an autoimmune condition characterised by platelet destruction, leading to a low number of platelets circulating in the blood. Platelets are a type of cell involved in blood clotting. Thrombocytopenia is usually defined as having a platelet count lower than 100x109 per litre. Signs and symptoms include bruising easily, the appearance of red spots under the skin (petechiae), fatigue and bleeding. Frequency and severity of bleeding may differ in people with similar platelet counts. Some have no bleeding, some bleed from the skin, nose, or urinary tract, and others have more serious intracranial and gastrointestinal bleeding. Because of the risk of bleeding, people may become stressed or depressed. A particular concern is a sudden drop in platelets, which can lead to life‑threatening bleeds. Although treatments called thrombopoietin receptor agonists (TPO‑RAs) are available, they do not work for everyone and some people cannot take them. The patient and clinical experts explained that some of the treatment options suppress the immune system, and increase the risk of infection. The committee concluded that people with chronic ITP and clinicians would welcome an additional treatment option. # Treatment pathway ## The treatment pathway includes TPO-RAs followed mostly by rituximab and mycophenolate Initial treatment for ITP involves high-dose oral corticosteroids or intravenous immunoglobulin G (IVIgG). Later treatments include: TPO‑RAs (see NICE's technology appraisal guidance on romiplostim and eltrombopag) rituximab surgical removal of the spleen (splenectomy) azathioprine, mycophenolate, cyclosporine, dapsone and danazol.The clinical experts explained that the choice of treatment after corticosteroids or IVIgG depends on time to relapse, but clinicians are most likely to offer TPO‑RAs. They noted that clinicians avoid offering splenectomy in the first year after diagnosis and are unlikely to offer it as a second line of treatment. After TPO‑RAs, rituximab and mycophenolate are the most common treatments, but azathioprine is offered to people who want to conceive. Cyclosporine is rarely used because of adverse effects, and dapsone is used as a last resort. The committee understood that danazol is no longer available in the UK. For people with platelet counts higher than 30x109 per litre and at low risk of bleeding, clinicians may adopt a 'watch and rescue' approach. A patient expert explained that once his platelet count had stabilised after treatment with IVIgG, he went onto a watch and rescue approach for 15 years. The committee concluded that the treatment pathway after TPO‑RAs includes many treatments, most commonly rituximab and mycophenolate. ## Treatment decisions are based on more than platelet count The clinical experts highlighted that they and people with ITP make treatment decisions based on platelet count and other risk factors for bleeding, such as age and use of anti‑platelet treatment. They explained that the objective of treatment is a platelet count higher than 30x109 per litre to reduce the risk of bleeding. Platelet counts higher than 50x109 per litre may be used as a target for maintenance treatment, to avoid fluctuating platelet levels and minimise the chance of counts dropping below 30x109 per litre. The committee appreciated that treatment aims to achieve platelet counts lower than those used to define thrombocytopenia. It concluded that treatment decisions were based on more than platelet count. ## The company's positioning of fostamatinib in the treatment pathway is broadly appropriate Fostamatinib has a marketing authorisation for treating chronic ITP after previous treatments. The company proposed that fostamatinib is used after a TPO‑RA (for example, romiplostim or eltrombopag) or when TPO‑RAs are not suitable. This is narrower than the marketing authorisation. The clinical experts considered the company's proposed positioning to be reasonable. They noted that other treatments such as rituximab and mycophenolate may be used after TPO‑RAs at the point where the company proposed using fostamatinib. The clinical experts noted that rituximab is considered more effective for young women and people with other autoimmune conditions. However, some people may be concerned about rituximab's immunosuppressive effects so would prefer an alternative treatment. The clinical experts also highlighted that for people at risk of blood clots, TPO‑RAs may not be suitable so fostamatinib could be considered instead. They also noted that other treatments such as rituximab and mycophenolate may be used after TPO‑RAs, but before fostamatinib. The committee acknowledged that treatment is individualised. They also noted that people may be cautious about using immunosuppressive drugs during the COVID‑19 pandemic. It concluded that the company's positioning of fostamatinib in the treatment pathway was narrower than the marketing authorisation but broadly appropriate. ## Rituximab and mycophenolate are relevant comparators for fostamatinib As relevant comparators, NICE's final scope included the TPO‑RAs romiplostim and eltrombopag, rituximab, splenectomy, cytotoxic agents, dapsone, danazol and 'watch and rescue'. However, the company excluded romiplostim and eltrombopag based on its positioning of fostamatinib after a TPO‑RA, or when TPO‑RAs are unsuitable. The company selected rituximab as the only comparator. For all other comparators, the company argued that there was little evidence to support comparisons with fostamatinib. The clinical experts agreed that many treatments used in practice do not have robust clinical trial data. They also noted that rituximab and mycophenolate are often used in clinical practice at the same point in the treatment pathway as the company proposed for fostamatinib (see section 3.4). The committee concluded that the relevant comparators for fostamatinib are rituximab and mycophenolate. # Clinical effectiveness ## Fostamatinib is effective at increasing platelet count compared with placebo, based on the FIT trials FIT1 and FIT2 are multinational, double-blind, randomised, phase 3 trials of the same design comparing fostamatinib with placebo. Both trials included adults with persistent or chronic ITP that had not responded to at least 1 treatment. Their average platelet count was less than 30x109 per litre. The primary endpoint in both trials was stable platelet response. This was defined as a platelet count of 50x109 per litre or more in at least 4 out of 6 assessments between week 14 and week 24. Secondary outcomes included: the percentage of people with a platelet count higher than 50x109 per litre at week 12 and week 24 the percentage of people with a platelet count higher than 30x109 per litre and an increase of at least 20x109 per litre from baseline at week 12 and week 24, after a platelet count of less than 15x109 per litre at baseline bleeding frequency and severity, measured by the Immune Thrombocytopenic Purpura Bleeding Scale and World Health Organization bleeding scores.People randomised to fostamatinib had 100 mg twice a day initially. This could be increased to 150 mg twice a day at week 4 if platelet count remained below 50x109 per litre and fostamatinib was well tolerated. Rescue treatments were allowed as needed in both treatment arms. People in FIT1 and FIT2 were invited to take part in FIT3, a 5‑year open-label extension study, if they: completed the full 24 weeks of treatment or stopped the trials after at least 12 weeks of double-blind treatment because of lack of efficacy (including at least 4 weeks at the 150 mg dose of fostamatinib or placebo).In FIT3, the initial fostamatinib dose was the dose that produced a platelet response in FIT1 and FIT2. If there was no platelet response in FIT1 and FIT2, the initial dose was 100 mg twice a day.Pooled results from FIT1 and FIT2 showed that rates of stable response were higher in the fostamatinib arm (18%) than in the placebo arm (2%). Fostamatinib led to greater improvements than placebo for all secondary outcomes, but these benefits appeared to decrease over time. For example, the pooled percentage of people with a platelet count higher than 50x109 per litre at week 12 in the fostamatinib arm was 23% compared with 16% at week 24. The committee concluded that fostamatinib increased platelet levels, but only about 1 in 5 people had a platelet response, which may decrease over time. ## The criteria for non-response and stopping treatment in the FIT trials do not reflect NHS clinical practice Starting from week 12, the criteria used to define non-response in FIT1, FIT2 and the FIT3 extension study were: a platelet count of less than 50x109 per litre or an increase of less than 20x109 per litre for people with baseline platelet counts of less than 15x109 per litre.People with non-response could withdraw from the study. The clinical experts explained that less stringent definitions of response are typically used in practice. This is because platelet counts can vary because of infections or other clinical characteristics and may not affect the overall response to treatment. They noted that they generally consider platelet counts higher than 30x109 per litre and doubling of platelet counts from the treatment starting point as an acceptable response (see section 3.3). They would recommend stopping treatment if: response was not acceptable adverse effects were intolerable or platelet counts dropped to baseline levels or below 20x109 to 30x109 per litre.The committee concluded that the criteria for non-response and stopping treatment in the FIT trials did not reflect clinical practice. ## The results of the FIT clinical trials are likely to be generalisable to NHS clinical practice The average age at baseline in FIT1 and FIT2 was between 53 and 54 years. The ERG was concerned that people enrolled in these trials were about 10 years younger than in clinical practice and had a lower risk of bleeding, which increases with age. The clinical experts highlighted that fostamatinib is likely to work equally well in clinical practice regardless of age. The committee concluded that the results of the FIT clinical trials are likely to be generalisable to NHS practice, but the absolute benefit may differ from the trials. ## Network meta-analyses 2 and 3 have limitations but are considered for decision making The committee recalled that there was no evidence directly comparing fostamatinib with rituximab or mycophenolate. The company's base case discussed at the first committee meeting included rituximab as the only relevant comparator. Clinical efficacy data for rituximab was based on clinical expert opinion, rather than published literature. After consultation, the company did a network meta-analysis comparing fostamatinib with rituximab, with an outcome of overall platelet response. The definition of overall platelet response varied across studies included within the meta-analysis, so the company did 3 separate analyses: Analysis 1 was based on the primary definition of response in each study and included FIT1, FIT2 and 4 rituximab studies. Analysis 2 used alternative definitions for response. Each focused on platelet counts greater than 30x109 per litre and at least doubling from baseline. However, timepoints for measurement and the use of rescue treatments differed. It included the same studies as analysis 1. Analysis 3 used the definition of response as an increase in platelet count greater than 30x109 per litre, at least doubling from baseline and without rescue treatment at 4 weeks. It included only FIT1, FIT2 and the Ghanima et al. (2015) study for rituximab.The company preferred analysis 2 because the endpoints varied less than in analysis 1. The ERG noted that analysis 2 included both randomised and non-randomised evidence, which the Cochrane Handbook (11.3.4, version 6.2, 2021) does not recommend because of bias. The ERG preferred analysis 3, which included only randomised studies. The analyses showed that fostamatinib was more effective than rituximab, and rituximab was no better than placebo. The committee noted that the size of benefit differed between analyses. Analysis 2 showed a 4‑fold increase in the odds of having a response with fostamatinib compared with rituximab, whereas analysis 3 showed a 3‑fold increase. Analyses 1 and 2 included 4 different dosages of rituximab: mg/m2 body surface area per week for 4 weeks mg fixed dose per week for 4 weeks mg/m2 per week for 2 weeks in people with early response and for 4 weeks in the others and mg/m2 perweek for 2 weeks.Analysis 3 included only the rituximab dosage of 375 mg/m2 per week for 4 weeks. The ERG clinical adviser noted that 375 mg/m2 per week for 4 weeks and the 100 mg fixed dose are used in clinical practice and are the most relevant (see section 3.18). The committee noted that the non-randomised study (Zaja et al. 2012) was the only study that included the rituximab 100 mg fixed dose. The ERG explained that when the company used analysis 2 in its model, it did not use the estimates from Zaja et al. to inform the efficacy of the rituximab 100 mg dose. Instead, the company assumed that the efficacy of rituximab 100 mg was the same as that of rituximab 375 mg/m2. The ERG advised that this likely favoured rituximab, although it expected the size of bias to be small. When using analysis 3, the company and the ERG also assumed that both doses of rituximab had the same efficacy. The committee noted that analysis 2 also included Arnold et al. (2012), a randomised controlled trial comparing 375 mg/m2 rituximab with placebo. It noted that the company could have done an additional analysis comparing the FIT trials with only the Ghanima et al. and Arnold et al. trials, because both assessed the efficacy of rituximab 375 mg/m2. The committee agreed that analysis 1 was the least relevant because the endpoint definitions varied most across studies. It concluded that it would consider both analyses 2 and 3 in its decision making but noted they both had limitations. ## The clinical efficacy of mycophenolate is uncertain The company excluded mycophenolate from its network meta-analysis because it did not identify any randomised trials of mycophenolate being used after TPO-RAs. It noted that mycophenolate does not have a marketing authorisation for ITP. The company presented data from the UK ITP registry and a panel of clinical experts, who revealed that a substantial proportion of people do have mycophenolate after TPO-RAs. (The exact proportion is confidential and cannot be reported here.) The committee noted that this further supports its use in NHS clinical practice. The ERG confirmed the lack of evidence for mycophenolate. The committee noted that relevant comparators are selected based on their routine use in NHS clinical practice, regardless of whether they have a marketing authorisation for that indication. It also noted that rituximab does not have a marketing authorisation for ITP, but the company included it as a relevant comparator. The committee maintained that both rituximab and mycophenolate are relevant comparators for fostamatinib (see section 3.5). But it acknowledged that there is no published evidence showing how well mycophenolate works for people with ITP. # The company's economic model ## The company's approach to merging partial and complete response health states has limitations but best reflects clinical practice The company used a Markov cohort state transition model to estimate the cost effectiveness of fostamatinib compared with rituximab. The model cohort was split into 2 groups based on whether a person had intracranial bleeding. The company's original model included 3 health states in each group: response (platelet count higher than 50x109 per litre) partial response (platelet count of 30x109 to 50x109 per litre) and non-response (platelet count lower than 30x109 per litre).The company explained that its thresholds were informed by the latest ITP consensus (2019) and the approach taken in previous NICE submissions for eltrombopag and romiplostim. The company estimated the probability of being in each state on pooled data from FIT1, FIT2 and the FIT3 extension study. The model included a lifetime time horizon. The clinical experts noted that intracranial bleeding is a rare event, but it is associated with substantial disability and morbidity, which may also affect carers' quality of life. The clinical experts explained that health states split into non-response (platelet count lower than 30x109 per litre) and response (platelet count higher than 30x109 per litre) would better reflect clinical practice (see section 3.3). After consultation, the company merged partial and complete response into a single response health state. That is, the company's revised model included only 2 health states, non-response (platelet count lower than 30x109 per litre) and response (platelet count higher than 30x109 per litre). The company did a scenario analysis using the original health states, noting that it had a small impact on cost effectiveness. The ERG agreed that a model with 2 health states better reflected clinical practice than the 3‑health state model. But it had concerns with the company's methodology because the revised model continued to follow a 3‑state structure. The company simply set most inputs for partial response to be equal to the full response health state. The ERG noted that the company should have recalculated how likely people are to move between the 2 health states using data from the FIT trials. Instead, the company used the probabilities of moving between 3 health states from its original model. The ERG explained that these probabilities were based on a low number of events in the FIT trials so were uncertain. These uncertainties were further increased when extrapolating the probabilities over the model's lifetime time horizon and by the approach taken to apply the network meta-analysis results. The committee acknowledged the limitations of the company's approach to merging the health states. But it agreed that it preferred the merged 2‑health state structure because it better reflected clinical practice than the 3‑health state model. ## The company's corrected method for calculating the costs of rescue treatment is appropriate For the rapid review, the company submitted an updated model which corrected an error in the calculation of the cost of rescue treatment. The error resulted in the total acquisition cost of rescue treatment being underestimated. This error had a significant impact on the cost‑effectiveness results. The ERG reviewed the amended model and was satisfied with the company's approach for correcting this error. The committee concluded that the company's corrected method for calculating the cost of rescue treatments was appropriate and it would use the amended model for its decision making in the rapid review. ## The revised model criteria for non-response and stopping treatment are in line with NHS practice but should be applied at 12 weeks The committee recalled that the criteria for non-response and stopping treatment in the FIT trials were not in line with clinical practice (see section 3.7). The company's original model followed the stopping rule from the FIT trials. However, after consultation, for the second committee meeting, the company changed the stopping rule in its economic model to a platelet count lower than 30 x 109 per litre, in line with clinical practice. The ERG explained that the model applied this stopping rule at 12 weeks, with a half-cycle correction. Applying a half-cycle correction effectively means that treatment would be stopped 2 weeks earlier, at 10 weeks, if a platelet count of 30x109 per litre or more was not reached. The company noted this was a conservative assumption because a clinical expert panel advised that treatment could be stopped earlier, by 8 weeks, if platelet response was not reached. The committee noted that fostamatinib's marketing authorisation includes a 12‑week stopping rule if platelet count is 'not sufficient'. The ERG explained that removing the half-cycle correction applied to the stopping rule increased the cost-effectiveness estimates. This was because treatment costs for people whose disease does not respond to treatment are incurred for longer. The committee concluded that the revised criteria for non-response and stopping were in line with clinical practice but should be applied at 12 weeks, without a half-cycle correction. ## The company's revised approach to modelling subsequent treatments is acceptable In the company's original submission, people who had fostamatinib moved to watch and rescue treatment if their platelet count fell below 30x109 per litre (non-response). However, people who had rituximab did not move to watch and rescue treatment. Instead, they remained in the lower than 30x109 per litre health state and could never have a platelet count higher than 30x109 per litre after cycle 4 in the model. This led to a worse modelled outcome than was seen with placebo in the fostamatinib clinical trials. The company explained that its clinical experts had advised that in clinical practice, people do not have other treatments at the same time as rituximab. The clinical experts at the first committee meeting agreed but noted that rituximab is used only for a short time. After that, treatment is offered to raise platelet counts to a level higher than 30x109 per litre. The committee also noted that some people who do not have a response to fostamatinib may get rituximab, instead of watch and rescue treatment. At its first meeting, the committee concluded that subsequent treatments should be modelled consistently between arms and include all relevant sequences. After consultation, at the second committee meeting, the company updated its base case to allow watch and rescue treatment after rituximab, when platelet count is lower than 30x109 per litre. The ERG confirmed that the company applied the change correctly. The committee noted that the company's revised approach did not include all relevant treatment sequences. For example, it did not include an option of having rituximab after fostamatinib. The ERG explained that modelling a full treatment sequence across the pathway was difficult because of evidence limitations. This was a key model limitation and contributed to the overall uncertainty. The committee concluded that the company's revised approach to modelling subsequent treatments had limitations but was acceptable for decision making. ## It is not appropriate to assume that people can taper or stop treatment without any loss of clinical benefit The company explained that its base case did not include tapering dosages or stopping treatment in people with a sustained platelet response. It assumed that those people remain on the full treatment dose until loss of response or death. However, the company stated that tapering was common with other ITP treatments and was likely with fostamatinib. The company did a scenario analysis in which it assumed that 40% of people with a sustained platelet response to fostamatinib (platelet counts above 30x109 per litre after 1 year) stop active treatment, but maintain the full clinical benefit. This scenario improved fostamatinib's cost-effectiveness estimates, as did an ERG scenario in which only people with a sustained platelet count higher than 50x109 per litre taper treatment. But, the company recognised that it did not have data to support tapering or stopping fostamatinib without losing benefit. The committee recognised that maintaining treatment benefit after tapering or stopping treatment was speculative. It also noted that fostamatinib's marketing authorisation does not include treatment tapering or stopping in people with a sustained platelet response. The committee concluded that it is not appropriate to assume that people with sustained platelet response can taper or stop treatment without losing clinical benefit. ## The benefits of fostamatinib may decrease over time and the amount of decline is a source of uncertainty in the model As outlined in section 3.6, the pooled results from FIT1 and FIT2 showed that the benefits of fostamatinib may decrease over time. The company's model captured loss of response for the first 24 weeks by the probabilities of transitioning to the 'no response' health states which were informed by the FIT1 and FIT2 data. The level of sustained response beyond 24 weeks was informed by the extension study (FIT3). The ERG considered the company's approach to inform the loss of fostamatinib response over time was conservative, but noted that it was a source of uncertainty. The committee noted that the model included a stopping rule to reflect the marketing authorisation of fostamatinib. If the condition stopped responding to fostamatinib, that is platelet count was lower than 30x109 per litre, treatment would stop. The committee acknowledged that the model reflects available clinical evidence for fostamatinib over the long term and that people would stop treatment if they were no longer benefiting. But they concluded that any loss of benefit and the timing of any loss of benefit is a source of uncertainty in the cost-effectiveness results. ## Basing the use of rescue treatment on UK ITP registry data is likely to reflect clinical practice In its original base case, the company used FIT trials data to inform the frequency and type of rescue treatments. After consultation, it used the UK ITP registry data instead. The use of rescue treatments in the UK ITP registry depended on platelet count and included IVIgG, intravenous methylprednisolone, platelet transfusion, oral prednisolone, and oral dexamethasone. The company justified using the UK ITP registry because: the FIT trials included locations outside the UK in the trials, people had their platelet counts measured more often than expected in clinical practice and the trial populations had a relatively lower risk of bleeding.In its base case, the company applied frequency and type of rescue treatments separately for each health state defined by platelet count. The non-response health state had greater costs, driven by the increased frequency of events needing rescue treatments and increased use of IVIgG compared with oral prednisolone. The ERG accepted that the UK ITP registry data is likely generalisable to NHS clinical practice and used this source in its base case. However, the ERG was concerned that the company did not provide data comparing the populations in the UK ITP registry and FIT trials. The company explained that it could not get demographic information from the UK ITP registry. But it noted that everyone included in the analysis had previously had treatment with TPO-RAs, consistent with the company's positioning of fostamatinib in the treatment pathway (see section 3.4). The ERG was concerned about using different data sources to inform different parts of the model. For example, using the UK ITP registry for frequency and type of rescue treatment, and the company's network meta-analysis for the probability of reaching platelet response with watch and rescue. To address this, the ERG did a scenario analysis using the FIT trial data to inform all inputs for rescue treatments and for prophylaxis before surgery (see section 3.19). The committee acknowledged the limitations of the company's approach. But it concluded that the UK ITP registry was likely to reflect use of rescue treatment in NHS clinical practice. ## In clinical practice, 2 doses of rituximab are used and both should be included in the model The committee recalled that the trials included 2 doses of rituximab (see section 3.9). In the 2014 NICE evidence summary for rituximab in ITP, most studies included the higher dose of 375 mg/m2 per week. Some used a fixed dose of 100 mg per week. International guidelines for ITP recognised that 100 mg per week is an alternative dosing schedule. Statements from several NHS clinical commissioning groups recommended only the lower dose. One clinical expert explained that they offer a dose of 100 mg per week. They noted that ITP registry data suggested that the effects of this dose are equivalent to the 375 mg/m2 per week dose. The other clinical expert noted that they use the higher dose in practice. After consultation, the company analysed the use of rituximab in the UK ITP registry in people who had prior treatment with TPO‑RAs. It found that both doses were used (exact usage is confidential and cannot be reported here). The company updated its base case to include a mean dose of rituximab calculated from the UK ITP registry. It also did a scenario analysis using the 100 mg rituximab dose. The ERG was concerned that the company may have underestimated the mean rituximab dose in the UK ITP registry. The ERG corrected this, which led to a small increase in the mean dose. However, it explained that it preferred to use the lower, fixed 100 mg dose which was increasingly recommended for use in NHS clinical practice. The committee considered the clinical advice and UK ITP registry data and agreed that both rituximab doses are used in NHS clinical practice. Therefore, it concluded that both doses are relevant and should be included in the model. ## The company's revised approach to modelling prophylaxis before surgery reflects clinical practice People who have a platelet count below 30x109 per litre may need prophylactic treatment to increase platelet count before surgery. In its original submission, the company assumed that prophylactic treatments were the same as rescue treatments. These include IVIgG, intravenous methylprednisolone and platelet transfusions, but not oral prednisolone. At the first committee meeting, the ERG explained that only 1 course of treatment is used, and this is based on the type of surgery (minor or major). It suggested that IVIgG was used for major surgery, which the ERG's clinical expert estimated accounts for 44% of people having surgery. Oral prednisolone was used for minor surgery in the remaining 56% of people. This affected the cost-effectiveness estimates because prednisolone costs much less than IVIgG. The clinical experts explained that oral prednisolone is used in clinical practice, contrary to the company's assumption. Also, they emphasised that the use of prophylaxis before surgery depends on the timing of the surgery. For example, IVIgG works more quickly than oral prednisolone. After consultation, the company asked a panel of 8 clinical experts about which treatments are used as prophylaxis before surgery in NHS clinical practice. Oral prednisolone was the most frequently used treatment for both minor (average use 54% ) and major surgery (62% ). This was followed by IVIgG for both minor (45% ) and major (49% ) surgery. The company assumed the same proportions of minor (56%) and major (44%) surgery as the ERG. The ERG agreed with the company's approach to estimating the use of prophylaxis before surgery and noted it was consistent with its expert opinion. The committee was satisfied that the revised company base case was in line with NHS clinical practice. ## The company's revised approach to modelling adverse events is acceptable The company's base case discussed at the first committee meeting used pooled data from FIT1 and FIT2 for people 65 years and over to estimate the rate of adverse events for fostamatinib. This age group was considered more relevant because it is in line with the starting age in the model. This group had a higher rate of adverse events than the younger people in the trial. The company assumed that the rate of adverse events with rituximab was the same as with fostamatinib. At its first meeting, the committee concluded that adverse events with fostamatinib and rituximab were different and should be modelled separately. After consultation, the company agreed that rituximab was associated with fewer adverse events than fostamatinib and watch and rescue treatments. In its revised base case, adverse events with rituximab were based on a randomised controlled trial comparing 375 mg/m2 rituximab with placebo (Ghanima et al.). The ERG was satisfied with the company's revised approach but noted some limitations. Rituximab can cause very rare fatal progressive multifocal leukoencephalopathy, which the company excluded from its analysis. The median age in the Ghanima et al. trial was 46 years, compared with the starting age in the model of 65 years. Adverse events in older people are likely to be more frequent, as seen with fostamatinib in the FIT trials. The committee noted that these assumptions likely favoured rituximab. The ERG explained that the rate of adverse events with the 100 mg weekly dose was likely to be lower than with the higher dose. The committee recalled that at its first meeting, a clinical expert explained that the 100 mg per week dose is well tolerated. The committee noted that assuming equal rates of adverse events with both doses favours fostamatinib. The ERG also explained that the company applied adverse events for rituximab for as long as response was maintained, even though it is only taken for 4 weeks (see section 3.9). However, the ERG advised that this likely has a small impact on the cost-effectiveness estimates, because cycle-specific costs and disutilities of adverse events with watch and rescue are similar to rituximab. In terms of modelling adverse events with fostamatinib, the company applied the same rate of adverse events for the full duration of treatment when in the response health state. The ERG noted that the company could instead have used the longest available data from the FIT3 extension study to model long-term adverse events with fostamatinib. However, the company explained that this data was not yet available. But it noted that new long-term safety issues were unlikely to emerge because fostamatinib's long-term safety profile in rheumatoid arthritis was consistent with the earlier data for that disease. The committee acknowledged the limitations of the company's approach to modelling adverse events with fostamatinib and rituximab. It noted that overall, it was not clear if this approach favoured rituximab or fostamatinib. However, it concluded that the company's approach was acceptable for decision making. ## The company's revised base case overestimates the risk of dying from ITP In the company's original base case, it estimated the risk of dying in the non-response health state from the General Practice Research Database (Schoonen et al. 2009). The risk of dying was 1.6 times higher than that of the age and sex-matched general population, with 13% of deaths from bleeding and 19% from infection. The risk of death was reported for everyone diagnosed with ITP, that is, it was not reported separately by platelet count. The company assumed all excess deaths happened in the lowest platelet count health state (non-response). All other health states had a risk of death that matched the general population. The ERG noted that assuming all deaths in Schoonen et al. happened in the non-response health state was an important limitation of the company's approach. After consultation, the company identified 2 new studies reporting the risk of dying from ITP and used them in its revised base case. In the 3‑health state model, the hazard ratio for mortality was 4.2 in the non-response state (Portielje et al. 2001), 2.5 in the partial response state (Adelborg et al. 2019) and 1.0 in the complete response health state. The 2-health state model used a hazard ratio for mortality of 4.2 in the non-response health state and 1.0 in the merged response health state. The ERG had concerns with the new sources: Portielje et al. reported hazard ratios for mortality specifically in people with platelet counts below 30 x 109 per litre but had a small sample size and was not based in the UK. Adelborg et al. was a larger study but reported hazard ratios for everyone with a platelet count less than 50x109 per litre.The clinical experts agreed with the ERG that using Adelborg et al. for the partial response (30x109 to 50x109 per litre) health state was not appropriate. This was because most deaths in people with platelet counts below 50x109 per litre could be a result of deaths in people with a platelet count below 30x109 per litre. This meant that the model may overestimate mortality in the partial response state. The committee discussed the 3 potential sources of mortality data, noting that all have limitations. It recalled clinical expert advice that many factors influence the risk of dying from ITP, including platelet count, bleeding, age and treatment. It also recalled advice that treatment had changed over time, and the risk of dying from ITP is now lower than in the past. In the past, deaths related to infection were as high as for bleeding, and likely reflected higher use of splenectomy and heavy immunosuppression. But since the introduction of TPO-RAs, it is rare for people to have chronic platelet counts below 20x109 to 30x109 per litre, and rare to have deaths from ITP treatments. The committee agreed that Portielje et al. may overestimate the current risk of dying from ITP because of the progress in treatment for this disease. It also noted that the risk of dying from intracranial bleeding is already accounted for in the model. So, using hazard ratios for mortality from Portielje et al. would overestimate mortality in people without intracranial bleeding. Also, the committee discussed that the company did not provide any evidence that fostamatinib reduces the risk of dying from ITP. The model predicts such a reduction, based on less time spent in the non-response health state compared with rituximab. But the committee noted that without any evidence to support this, the effect of fostamatinib on the risk of dying was uncertain. It also noted that mortality assumptions have the biggest effect on the cost-effectiveness estimates. The committee concluded that the company's revised approach overestimates the risk of dying from ITP. It preferred the company's original approach, using estimates from the General Practice Research Database (Schoonen et al.). ## The utility values in the model are appropriate, including those for carers The company used utility values for the model health states from published literature because of the low number of responses to the quality-of-life questionnaire used in the FIT clinical trials (SF‑36). The committee noted that the company used utility values for the health states of the group without intracranial bleeding from NICE's technology appraisal guidance on romiplostim. The company's original base case applied a lower utility value for people in the partial and no response health states than in the response health state. This was because the romiplostim appraisal used different utility values for people with platelet counts of 50x109 per litre or more (response) and those with platelet counts below 50x109 per litre (non-response). In its revised base case after consultation, the company applied different utility values to the response (platelets 30x109 per litre or more) and the non-response health states (platelets below 30x109 per litre). The committee acknowledged that people with platelet counts below 30x109 per litre would be unlikely to feel worse than people with platelet counts of 30x109 per litre or above. But if a person knows that they are at higher risk of bleeding, this could cause anxiety and affect their daily life if they avoid their usual activities. For the group who had severe intracranial bleeding and for their carers, the company used published utility values. The ERG noted that because intracranial bleeding is rare, including carer quality of life affected the cost-effectiveness estimates minimally. The company also applied a transient disutility for people with other bleeds, adverse events or when needing rescue treatment. The committee concluded that the utility values in the model, including those for carers of people who had severe intracranial bleeding, were appropriate. ## The ERG's exploratory analysis for mycophenolate assumes equal efficacy and safety to rituximab, which is uncertain The ERG did an analysis for mycophenolate as a comparator, assuming equal efficacy and safety to rituximab. It assumed that mycophenolate is taken twice a day as a 500 mg tablet and stopped at 12 weeks if platelet response is not reached, or later if this response is lost. The analysis predicted that median treatment duration is 12 to 16 weeks, which is longer than the median duration of mycophenolate treatment in the UK ITP registry (exact figures are confidential and cannot be reported here). The model predicted that mycophenolate had higher total treatment costs than 100 mg rituximab at its list price, but lower than 375 mg/m2 rituximab at its list price. The ERG highlighted that this analysis is exploratory, because assuming equal efficacy of rituximab and mycophenolate is uncertain. It noted that there were lower complete and partial responses to mycophenolate in Taylor et al. (2015) compared with responses to rituximab in Ghanima et al. The ERG emphasised that this comparison was highly uncertain because it reflects a naive comparison between 2 different studies, and Taylor et al. was a small, non-randomised, retrospective study. Clinical experts confirmed that assuming equal efficacy of mycophenolate and rituximab is uncertain. They explained that there are no head-to-head comparisons between these 2 treatments, but they expect their efficacy and safety to differ. The 2 drugs are used for different groups of people. Mycophenolate is generally well tolerated and taken as a tablet, so it does not cause infusion-related reactions. The committee agreed that mycophenolate was unlikely to have the same efficacy and safety as rituximab and this was a limitation of the exploratory analysis. It concluded that it would focus on the comparison of fostamatinib with rituximab in its decision making. # Cost-effectiveness estimates ## The most likely cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources The company revised its base case after consultation. The committee noted that it attempted to address its preferences from the first meeting. For the rapid review, the company's revised base case included the committee's preferred assumptions from the time of the original guidance, namely: using clinical effectiveness estimates for the comparators from a network meta-analysis (see section 3.9) stopping fostamatinib at 12 weeks if platelet response had not been reached (see section 3.13) modelling subsequent treatments consistently between arms (see section 3.14) using prophylactic treatments before surgery in line with clinical practice, that is, including both IVIgG and oral prednisolone (see section 3.19) including treatment-specific adverse event rates (see section 3.20) using lower hazard ratios reflecting the association between the non-response health state and mortality (see section 3.21) merging the partial response and response health states (see section 3.11) considering a scenario analysis with 100 mg rituximab (see section 3.18) correcting the error in the calculation of rescue treatment (see section 3.12).For the rapid review, the committee referred to its preferred assumptions from the time of the original guidance including: using both network meta-analysis 2 and 3 results (see section 3.9) using both doses of rituximab used in clinical practice (see section 3.18).The committee recognised that the lack of data increased the uncertainty with modelling chronic ITP that is refractory to other treatments. This is because there were limitations to the indirect treatment comparison and difficulty with modelling a full treatment pathway. Applying confidential discounts for fostamatinib and rituximab, and considering its preferences, the committee noted that all the cost-effectiveness estimates were within what NICE normally considers an acceptable use of NHS resources when either network meta-analysis 2 or 3 were used and when either dose of rituximab was applied. # Other factors ## Fostamatinib has a novel mechanism of action but the benefits are captured in the cost-effectiveness analysis The patient and clinical experts value individualised treatment. The committee noted fostamatinib's novel mechanism of action and the lack of immunosuppression associated with it. This is important because the clinical experts highlighted that the rates of death from infection and from bleeding are similar in people with ITP. This is particularly relevant during the COVID‑19 pandemic because clinicians are being careful about using anti‑CD20 antibody treatments like rituximab which may make people more susceptible to infection. Additionally, treatment options are limited for people who cannot have TPO‑RAs. The committee concluded that while the benefits of treatment are captured in the model (see section 3.18), having alternative treatment options that do not suppress the immune system and could be used when TPO‑RAs are not suitable would be highly beneficial. # Conclusion ## Fostamatinib is recommended after a thrombopoietin receptor agonist or when they are not suitable The committee recognised that people with refractory chronic ITP have benefited from fostamatinib and that the treatment has advantages over other available treatments. It acknowledged that fostamatinib improves outcomes compared with rituximab, but that there are uncertainties over the size of the benefit and its duration. The committee noted that fostamatinib was not compared with mycophenolate, a relevant comparator. But they acknowledged the evidence limitations which underpinned this decision. The committee considered the remaining sources of uncertainty in the model, and also the benefits of fostamatinib which may not be captured in the cost-effectiveness results. The committee concluded that the most plausible ICERs using its preferred modelling assumptions were within the range that NICE normally considers to be a cost-effective use of NHS resources. So, it recommended fostamatinib for treating refractory chronic ITP after TPO‑RAs or when they are not suitable.	{'Recommendations': 'Fostamatinib is recommended as an option for treating refractory chronic immune thrombocytopenia (ITP) in adults, only if:\n\nthey have previously had a thrombopoietin receptor agonist (TPO‑RA), or a TPO‑RA is unsuitable\n\nthe company provides fostamatinib according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with fostamatinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment options for refractory chronic ITP include TPO‑RAs, which are mostly followed by rituximab or mycophenolate. Fostamatinib is licensed for treating refractory chronic ITP, but the company has only provided evidence for using fostamatinib after a TPO‑RA, or when they are not suitable. Fostamatinib would be used at the same point in the treatment pathway as rituximab or mycophenolate.\n\nClinical evidence shows that fostamatinib is effective compared with placebo. There is no clinical trial evidence directly comparing fostamatinib with rituximab or mycophenolate. An indirect comparison shows that fostamatinib works better than rituximab at increasing the number of platelets in the blood (cells that help the blood to clot).\n\nThe cost-effectiveness estimates for fostamatinib compared with rituximab are within what NICE normally considers an acceptable use of NHS resources. So, fostamatinib is recommended.', 'Information about fostamatinib': "# Marketing authorisation indication\n\nFostamatinib (Tavlesse, Grifols) is indicated 'for the treatment of chronic immune thrombocytopenia (ITP) in adult patients who are refractory to other treatments'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for fostamatinib.\n\n# Price\n\nThe list prices of fostamatinib are:\n\n£3,090 per 60‑tablet pack, each tablet contains 100\xa0mg of fostamatinib (excluding VAT; BNF online, accessed August 2022)\n\n£4,635 per 60‑tablet pack, each tablet contains 150\xa0mg of fostamatinib (excluding VAT; BNF online, accessed August 2022).The company has a commercial arrangement. This makes fostamatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Grifols and another submission from Grifols for the rapid review, reviews of these submissions by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## People with chronic ITP and clinicians would welcome an additional treatment option\n\nChronic immune thrombocytopenia (ITP) is an autoimmune condition characterised by platelet destruction, leading to a low number of platelets circulating in the blood. Platelets are a type of cell involved in blood clotting. Thrombocytopenia is usually defined as having a platelet count lower than 100x109\xa0per litre. Signs and symptoms include bruising easily, the appearance of red spots under the skin (petechiae), fatigue and bleeding. Frequency and severity of bleeding may differ in people with similar platelet counts. Some have no bleeding, some bleed from the skin, nose, or urinary tract, and others have more serious intracranial and gastrointestinal bleeding. Because of the risk of bleeding, people may become stressed or depressed. A particular concern is a sudden drop in platelets, which can lead to life‑threatening bleeds. Although treatments called thrombopoietin receptor agonists (TPO‑RAs) are available, they do not work for everyone and some people cannot take them. The patient and clinical experts explained that some of the treatment options suppress the immune system, and increase the risk of infection. The committee concluded that people with chronic ITP and clinicians would welcome an additional treatment option.\n\n# Treatment pathway\n\n## The treatment pathway includes TPO-RAs followed mostly by rituximab and mycophenolate\n\nInitial treatment for ITP involves high-dose oral corticosteroids or intravenous immunoglobulin\xa0G (IVIgG). Later treatments include:\n\nTPO‑RAs (see NICE's technology appraisal guidance on romiplostim and eltrombopag)\n\nrituximab\n\nsurgical removal of the spleen (splenectomy)\n\nazathioprine, mycophenolate, cyclosporine, dapsone and danazol.The clinical experts explained that the choice of treatment after corticosteroids or IVIgG depends on time to relapse, but clinicians are most likely to offer TPO‑RAs. They noted that clinicians avoid offering splenectomy in the first year after diagnosis and are unlikely to offer it as a second line of treatment. After TPO‑RAs, rituximab and mycophenolate are the most common treatments, but azathioprine is offered to people who want to conceive. Cyclosporine is rarely used because of adverse effects, and dapsone is used as a last resort. The committee understood that danazol is no longer available in the UK. For people with platelet counts higher than 30x109\xa0per litre and at low risk of bleeding, clinicians may adopt a 'watch and rescue' approach. A patient expert explained that once his platelet count had stabilised after treatment with IVIgG, he went onto a watch and rescue approach for 15\xa0years. The committee concluded that the treatment pathway after TPO‑RAs includes many treatments, most commonly rituximab and mycophenolate.\n\n## Treatment decisions are based on more than platelet count\n\nThe clinical experts highlighted that they and people with ITP make treatment decisions based on platelet count and other risk factors for bleeding, such as age and use of anti‑platelet treatment. They explained that the objective of treatment is a platelet count higher than 30x109\xa0per litre to reduce the risk of bleeding. Platelet counts higher than 50x109\xa0per litre may be used as a target for maintenance treatment, to avoid fluctuating platelet levels and minimise the chance of counts dropping below 30x109\xa0per litre. The committee appreciated that treatment aims to achieve platelet counts lower than those used to define thrombocytopenia. It concluded that treatment decisions were based on more than platelet count.\n\n## The company's positioning of fostamatinib in the treatment pathway is broadly appropriate\n\nFostamatinib has a marketing authorisation for treating chronic ITP after previous treatments. The company proposed that fostamatinib is used after a TPO‑RA (for example, romiplostim or eltrombopag) or when TPO‑RAs are not suitable. This is narrower than the marketing authorisation. The clinical experts considered the company's proposed positioning to be reasonable. They noted that other treatments such as rituximab and mycophenolate may be used after TPO‑RAs at the point where the company proposed using fostamatinib. The clinical experts noted that rituximab is considered more effective for young women and people with other autoimmune conditions. However, some people may be concerned about rituximab's immunosuppressive effects so would prefer an alternative treatment. The clinical experts also highlighted that for people at risk of blood clots, TPO‑RAs may not be suitable so fostamatinib could be considered instead. They also noted that other treatments such as rituximab and mycophenolate may be used after TPO‑RAs, but before fostamatinib. The committee acknowledged that treatment is individualised. They also noted that people may be cautious about using immunosuppressive drugs during the COVID‑19 pandemic. It concluded that the company's positioning of fostamatinib in the treatment pathway was narrower than the marketing authorisation but broadly appropriate.\n\n## Rituximab and mycophenolate are relevant comparators for fostamatinib\n\nAs relevant comparators, NICE's final scope included the TPO‑RAs romiplostim and eltrombopag, rituximab, splenectomy, cytotoxic agents, dapsone, danazol and 'watch and rescue'. However, the company excluded romiplostim and eltrombopag based on its positioning of fostamatinib after a TPO‑RA, or when TPO‑RAs are unsuitable. The company selected rituximab as the only comparator. For all other comparators, the company argued that there was little evidence to support comparisons with fostamatinib. The clinical experts agreed that many treatments used in practice do not have robust clinical trial data. They also noted that rituximab and mycophenolate are often used in clinical practice at the same point in the treatment pathway as the company proposed for fostamatinib (see section\xa03.4). The committee concluded that the relevant comparators for fostamatinib are rituximab and mycophenolate.\n\n# Clinical effectiveness\n\n## Fostamatinib is effective at increasing platelet count compared with placebo, based on the FIT trials\n\nFIT1 and FIT2 are multinational, double-blind, randomised, phase\xa03 trials of the same design comparing fostamatinib with placebo. Both trials included adults with persistent or chronic ITP that had not responded to at least 1\xa0treatment. Their average platelet count was less than 30x109\xa0per litre. The primary endpoint in both trials was stable platelet response. This was defined as a platelet count of 50x109\xa0per litre or more in at least\xa04 out of 6\xa0assessments between week\xa014 and week\xa024. Secondary outcomes included:\n\nthe percentage of people with a platelet count higher than 50x109\xa0per litre\xa0at week\xa012 and week\xa024\n\nthe percentage of people with a platelet count higher than 30x109\xa0per litre and an increase of at least 20x109\xa0per litre from baseline at week\xa012 and week\xa024, after a platelet count of less than 15x109\xa0per litre at baseline\n\nbleeding frequency and severity, measured by the Immune Thrombocytopenic Purpura Bleeding Scale and World Health Organization bleeding scores.People randomised to fostamatinib had 100\xa0mg twice a day initially. This could be increased to 150\xa0mg twice a day at week\xa04 if platelet count remained below 50x109\xa0per litre and fostamatinib was well tolerated. Rescue treatments were allowed as needed in both treatment arms. People in FIT1 and FIT2 were invited to take part in FIT3, a 5‑year open-label extension study, if they:\n\ncompleted the full 24\xa0weeks of treatment or\n\nstopped the trials after at least 12\xa0weeks of double-blind treatment because of lack of efficacy (including at least 4\xa0weeks at the 150\xa0mg dose of fostamatinib or placebo).In FIT3, the initial fostamatinib dose was the dose that produced a platelet response in FIT1 and FIT2. If there was no platelet response in FIT1 and FIT2, the initial dose was 100\xa0mg twice a day.Pooled results from FIT1 and FIT2 showed that rates of stable response were higher in the fostamatinib arm (18%) than in the placebo arm (2%). Fostamatinib led to greater improvements than placebo for all secondary outcomes, but these benefits appeared to decrease over time. For example, the pooled percentage of people with a platelet count higher than 50x109\xa0per litre at week\xa012 in the fostamatinib arm was 23% compared with 16% at week\xa024. The committee concluded that fostamatinib increased platelet levels, but only about 1 in 5\xa0people had a platelet response, which may decrease over time.\n\n## The criteria for non-response and stopping treatment in the FIT trials do not reflect NHS clinical practice\n\nStarting from week\xa012, the criteria used to define non-response in FIT1, FIT2 and the FIT3 extension study were:\n\na platelet count of less than 50x109\xa0per litre\xa0or\n\nan increase of less than 20x109\xa0per litre for people with baseline platelet counts of less than 15x109\xa0per litre.People with non-response could withdraw from the study. The clinical experts explained that less stringent definitions of response are typically used in practice. This is because platelet counts can vary because of infections or other clinical characteristics and may not affect the overall response to treatment. They noted that they generally consider platelet counts higher than 30x109\xa0per litre and doubling of platelet counts from the treatment starting point as an acceptable response (see section\xa03.3). They would recommend stopping treatment if:\n\nresponse was not acceptable\n\nadverse effects were intolerable or\n\nplatelet counts dropped to baseline levels or below 20x109\xa0to 30x109\xa0per litre.The committee concluded that the criteria for non-response and stopping treatment in the FIT trials did not reflect clinical practice.\n\n## The results of the FIT clinical trials are likely to be generalisable to NHS clinical practice\n\nThe average age at baseline in FIT1 and FIT2 was between 53 and 54\xa0years. The ERG was concerned that people enrolled in these trials were about 10\xa0years younger than in clinical practice and had a lower risk of bleeding, which increases with age. The clinical experts highlighted that fostamatinib is likely to work equally well in clinical practice regardless of age. The committee concluded that the results of the FIT clinical trials are likely to be generalisable to NHS practice, but the absolute benefit may differ from the trials.\n\n## Network meta-analyses 2 and 3 have limitations but are considered for decision making\n\nThe committee recalled that there was no evidence directly comparing fostamatinib with rituximab or mycophenolate. The company's base case discussed at the first committee meeting included rituximab as the only relevant comparator. Clinical efficacy data for rituximab was based on clinical expert opinion, rather than published literature. After consultation, the company did a network meta-analysis comparing fostamatinib with rituximab, with an outcome of overall platelet response. The definition of overall platelet response varied across studies included within the meta-analysis, so the company did 3\xa0separate analyses:\n\nAnalysis\xa01 was based on the primary definition of response in each study and included FIT1, FIT2 and 4\xa0rituximab studies.\n\nAnalysis\xa02 used alternative definitions for response. Each focused on platelet counts greater than 30x109\xa0per litre and at least doubling from baseline. However, timepoints for measurement and the use of rescue treatments differed. It included the same studies as analysis\xa01.\n\nAnalysis\xa03 used the definition of response as an increase in platelet count greater than 30x109\xa0per litre, at least doubling from baseline and without rescue treatment at 4\xa0weeks. It included only FIT1, FIT2 and the Ghanima et al. (2015) study for rituximab.The company preferred analysis\xa02 because the endpoints varied less than in analysis\xa01. The ERG noted that analysis\xa02 included both randomised and non-randomised evidence, which the Cochrane Handbook (11.3.4, version 6.2, 2021) does not recommend because of bias. The ERG preferred analysis\xa03, which included only randomised studies. The analyses showed that fostamatinib was more effective than rituximab, and rituximab was no better than placebo. The committee noted that the size of benefit differed between analyses. Analysis\xa02 showed a 4‑fold increase in the odds of having a response with fostamatinib compared with rituximab, whereas analysis\xa03 showed a 3‑fold increase. Analyses\xa01 and 2 included 4\xa0different dosages of rituximab:\n\nmg/m2 body surface area per week for 4\xa0weeks\n\nmg fixed dose per week for 4\xa0weeks\n\nmg/m2 per week for 2\xa0weeks in people with early response and for 4\xa0weeks in the others and\n\nmg/m2 perweek for 2\xa0weeks.Analysis\xa03 included only the rituximab dosage of 375\xa0mg/m2 per week for 4\xa0weeks. The ERG clinical adviser noted that 375\xa0mg/m2 per week for 4\xa0weeks and the 100\xa0mg fixed dose are used in clinical practice and are the most relevant (see section\xa03.18). The committee noted that the non-randomised study (Zaja et al. 2012) was the only study that included the rituximab 100\xa0mg fixed dose. The ERG explained that when the company used analysis\xa02 in its model, it did not use the estimates from Zaja et al. to inform the efficacy of the rituximab 100\xa0mg dose. Instead, the company assumed that the efficacy of rituximab 100\xa0mg was the same as that of rituximab 375\xa0mg/m2. The ERG advised that this likely favoured rituximab, although it expected the size of bias to be small. When using analysis\xa03, the company and the ERG also assumed that both doses of rituximab had the same efficacy. The committee noted that analysis\xa02 also included Arnold et al. (2012), a randomised controlled trial comparing 375\xa0mg/m2 rituximab with placebo. It noted that the company could have done an additional analysis comparing the FIT trials with only the Ghanima et al. and Arnold et al. trials, because both assessed the efficacy of rituximab 375\xa0mg/m2. The committee agreed that analysis\xa01 was the least relevant because the endpoint definitions varied most across studies. It concluded that it would consider both analyses\xa02 and 3 in its decision making but noted they both had limitations.\n\n## The clinical efficacy of mycophenolate is uncertain\n\nThe company excluded mycophenolate from its network meta-analysis because it did not identify any randomised trials of mycophenolate being used after TPO-RAs. It noted that mycophenolate does not have a marketing authorisation for ITP. The company presented data from the UK ITP registry and a panel of clinical experts, who revealed that a substantial proportion of people do have mycophenolate after TPO-RAs. (The exact proportion is confidential and cannot be reported here.) The committee noted that this further supports its use in NHS clinical practice. The ERG confirmed the lack of evidence for mycophenolate. The committee noted that relevant comparators are selected based on their routine use in NHS clinical practice, regardless of whether they have a marketing authorisation for that indication. It also noted that rituximab does not have a marketing authorisation for ITP, but the company included it as a relevant comparator. The committee maintained that both rituximab and mycophenolate are relevant comparators for fostamatinib (see section\xa03.5). But it acknowledged that there is no published evidence showing how well mycophenolate works for people with ITP.\n\n# The company's economic model\n\n## The company's approach to merging partial and complete response health states has limitations but best reflects clinical practice\n\nThe company used a Markov cohort state transition model to estimate the cost effectiveness of fostamatinib compared with rituximab. The model cohort was split into 2\xa0groups based on whether a person had intracranial bleeding. The company's original model included 3\xa0health states in each group:\n\nresponse (platelet count higher than 50x109\xa0per litre)\n\npartial response (platelet count of 30x109\xa0to 50x109\xa0per litre) and\n\nnon-response (platelet count lower than 30x109\xa0per litre).The company explained that its thresholds were informed by the latest ITP consensus (2019) and the approach taken in previous NICE submissions for eltrombopag and romiplostim. The company estimated the probability of being in each state on pooled data from FIT1, FIT2 and the FIT3 extension study. The model included a lifetime time horizon. The clinical experts noted that intracranial bleeding is a rare event, but it is associated with substantial disability and morbidity, which may also affect carers' quality of life. The clinical experts explained that health states split into non-response (platelet count lower than 30x109\xa0per litre) and response (platelet count higher than\xa030x109\xa0per litre) would better reflect clinical practice (see section\xa03.3). After consultation, the company merged partial and complete response into a single response health state. That is, the company's revised model included only 2\xa0health states, non-response (platelet count lower than 30x109\xa0per litre) and response (platelet count higher than\xa030x109\xa0per litre). The company did a scenario analysis using the original health states, noting that it had a small impact on cost effectiveness. The ERG agreed that a model with 2\xa0health states better reflected clinical practice than the 3‑health state model. But it had concerns with the company's methodology because the revised model continued to follow a 3‑state structure. The company simply set most inputs for partial response to be equal to the full response health state. The ERG noted that the company should have recalculated how likely people are to move between the 2\xa0health states using data from the FIT trials. Instead, the company used the probabilities of moving between 3\xa0health states from its original model. The ERG explained that these probabilities were based on a low number of events in the FIT trials so were uncertain. These uncertainties were further increased when extrapolating the probabilities over the model's lifetime time horizon and by the approach taken to apply the network meta-analysis results. The committee acknowledged the limitations of the company's approach to merging the health states. But it agreed that it preferred the merged 2‑health state structure because it better reflected clinical practice than the 3‑health state model.\n\n## The company's corrected method for calculating the costs of rescue treatment is appropriate\n\nFor the rapid review, the company submitted an updated model which corrected an error in the calculation of the cost of rescue treatment. The error resulted in the total acquisition cost of rescue treatment being underestimated. This error had a significant impact on the cost‑effectiveness results. The ERG reviewed the amended model and was satisfied with the company's approach for correcting this error. The committee concluded that the company's corrected method for calculating the cost of rescue treatments was appropriate and it would use the amended model for its decision making in the rapid review.\n\n## The revised model criteria for non-response and stopping treatment are in line with NHS practice but should be applied at 12\xa0weeks\n\nThe committee recalled that the criteria for non-response and stopping treatment in the FIT trials were not in line with clinical practice (see section\xa03.7). The company's original model followed the stopping rule from the FIT trials. However, after consultation, for the second committee meeting, the company changed the stopping rule in its economic model to a platelet count lower than 30\xa0x\xa0109 per litre, in line with clinical practice. The ERG explained that the model applied this stopping rule at 12\xa0weeks, with a half-cycle correction. Applying a half-cycle correction effectively means that treatment would be stopped 2\xa0weeks earlier, at 10\xa0weeks, if a platelet count of 30x109\xa0per litre or more was not reached. The company noted this was a conservative assumption because a clinical expert panel advised that treatment could be stopped earlier, by 8\xa0weeks, if platelet response was not reached. The committee noted that fostamatinib's marketing authorisation includes a 12‑week stopping rule if platelet count is 'not sufficient'. The ERG explained that removing the half-cycle correction applied to the stopping rule increased the cost-effectiveness estimates. This was because treatment costs for people whose disease does not respond to treatment are incurred for longer. The committee concluded that the revised criteria for non-response and stopping were in line with clinical practice but should be applied at 12\xa0weeks, without a half-cycle correction.\n\n## The company's revised approach to modelling subsequent treatments is acceptable\n\nIn the company's original submission, people who had fostamatinib moved to watch and rescue treatment if their platelet count fell below 30x109\xa0per litre (non-response). However, people who had rituximab did not move to watch and rescue treatment. Instead, they remained in the lower than 30x109\xa0per litre health state and could never have a platelet count higher than 30x109\xa0per litre after cycle\xa04 in the model. This led to a worse modelled outcome than was seen with placebo in the fostamatinib clinical trials. The company explained that its clinical experts had advised that in clinical practice, people do not have other treatments at the same time as rituximab. The clinical experts at the first committee meeting agreed but noted that rituximab is used only for a short time. After that, treatment is offered to raise platelet counts to a level higher than 30x109\xa0per litre. The committee also noted that some people who do not have a response to fostamatinib may get rituximab, instead of watch and rescue treatment. At its first meeting, the committee concluded that subsequent treatments should be modelled consistently between arms and include all relevant sequences. After consultation, at the second committee meeting, the company updated its base case to allow watch and rescue treatment after rituximab, when platelet count is lower than 30x109\xa0per litre. The ERG confirmed that the company applied the change correctly. The committee noted that the company's revised approach did not include all relevant treatment sequences. For example, it did not include an option of having rituximab after fostamatinib. The ERG explained that modelling a full treatment sequence across the pathway was difficult because of evidence limitations. This was a key model limitation and contributed to the overall uncertainty. The committee concluded that the company's revised approach to modelling subsequent treatments had limitations but was acceptable for decision making.\n\n## It is not appropriate to assume that people can taper or stop treatment without any loss of clinical benefit\n\nThe company explained that its base case did not include tapering dosages or stopping treatment in people with a sustained platelet response. It assumed that those people remain on the full treatment dose until loss of response or death. However, the company stated that tapering was common with other ITP treatments and was likely with fostamatinib. The company did a scenario analysis in which it assumed that 40% of people with a sustained platelet response to fostamatinib (platelet counts above 30x109\xa0per litre after 1\xa0year) stop active treatment, but maintain the full clinical benefit. This scenario improved fostamatinib's cost-effectiveness estimates, as did an ERG scenario in which only people with a sustained platelet count higher than 50x109\xa0per litre taper treatment. But, the company recognised that it did not have data to support tapering or stopping fostamatinib without losing benefit. The committee recognised that maintaining treatment benefit after tapering or stopping treatment was speculative. It also noted that fostamatinib's marketing authorisation does not include treatment tapering or stopping in people with a sustained platelet response. The committee concluded that it is not appropriate to assume that people with sustained platelet response can taper or stop treatment without losing clinical benefit.\n\n## The benefits of fostamatinib may decrease over time and the amount of decline is a source of uncertainty in the model\n\nAs outlined in section\xa03.6, the pooled results from FIT1 and FIT2 showed that the benefits of fostamatinib may decrease over time. The company's model captured loss of response for the first 24\xa0weeks by the probabilities of transitioning to the 'no response' health states which were informed by the FIT1 and FIT2 data. The level of sustained response beyond 24\xa0weeks was informed by the extension study (FIT3). The ERG considered the company's approach to inform the loss of fostamatinib response over time was conservative, but noted that it was a source of uncertainty. The committee noted that the model included a stopping rule to reflect the marketing authorisation of fostamatinib. If the condition stopped responding to fostamatinib, that is platelet count was lower than 30x109\xa0per litre, treatment would stop. The committee acknowledged that the model reflects available clinical evidence for fostamatinib over the long term and that people would stop treatment if they were no longer benefiting. But they concluded that any loss of benefit and the timing of any loss of benefit is a source of uncertainty in the cost-effectiveness results.\n\n## Basing the use of rescue treatment on UK ITP registry data is likely to reflect clinical practice\n\nIn its original base case, the company used FIT trials data to inform the frequency and type of rescue treatments. After consultation, it used the UK ITP registry data instead. The use of rescue treatments in the UK ITP registry depended on platelet count and included IVIgG, intravenous methylprednisolone, platelet transfusion, oral prednisolone, and oral dexamethasone. The company justified using the UK ITP registry because:\n\nthe FIT trials included locations outside the UK\n\nin the trials, people had their platelet counts measured more often than expected in clinical practice and\n\nthe trial populations had a relatively lower risk of bleeding.In its base case, the company applied frequency and type of rescue treatments separately for each health state defined by platelet count. The non-response health state had greater costs, driven by the increased frequency of events needing rescue treatments and increased use of IVIgG compared with oral prednisolone. The ERG accepted that the UK ITP registry data is likely generalisable to NHS clinical practice and used this source in its base case. However, the ERG was concerned that the company did not provide data comparing the populations in the UK ITP registry and FIT trials. The company explained that it could not get demographic information from the UK ITP registry. But it noted that everyone included in the analysis had previously had treatment with TPO-RAs, consistent with the company's positioning of fostamatinib in the treatment pathway (see section\xa03.4). The ERG was concerned about using different data sources to inform different parts of the model. For example, using the UK ITP registry for frequency and type of rescue treatment, and the company's network meta-analysis for the probability of reaching platelet response with watch and rescue. To address this, the ERG did a scenario analysis using the FIT trial data to inform all inputs for rescue treatments and for prophylaxis before surgery (see section\xa03.19). The committee acknowledged the limitations of the company's approach. But it concluded that the UK ITP registry was likely to reflect use of rescue treatment in NHS clinical practice.\n\n## In clinical practice, 2\xa0doses of rituximab are used and both should be included in the model\n\nThe committee recalled that the trials included 2\xa0doses of rituximab (see section\xa03.9). In the 2014 NICE evidence summary for rituximab in ITP, most studies included the higher dose of 375\xa0mg/m2 per week. Some used a fixed dose of 100\xa0mg per week. International guidelines for ITP recognised that 100\xa0mg per week is an alternative dosing schedule. Statements from several NHS clinical commissioning groups recommended only the lower dose. One clinical expert explained that they offer a dose of 100\xa0mg per week. They noted that ITP registry data suggested that the effects of this dose are equivalent to the 375\xa0mg/m2 per week dose. The other clinical expert noted that they use the higher dose in practice. After consultation, the company analysed the use of rituximab in the UK ITP registry in people who had prior treatment with TPO‑RAs. It found that both doses were used (exact usage is confidential and cannot be reported here). The company updated its base case to include a mean dose of rituximab calculated from the UK ITP registry. It also did a scenario analysis using the 100\xa0mg rituximab dose. The ERG was concerned that the company may have underestimated the mean rituximab dose in the UK ITP registry. The ERG corrected this, which led to a small increase in the mean dose. However, it explained that it preferred to use the lower, fixed 100\xa0mg dose which was increasingly recommended for use in NHS clinical practice. The committee considered the clinical advice and UK ITP registry data and agreed that both rituximab doses are used in NHS clinical practice. Therefore, it concluded that both doses are relevant and should be included in the model.\n\n## The company's revised approach to modelling prophylaxis before surgery reflects clinical practice\n\nPeople who have a platelet count below 30x109\xa0per litre may need prophylactic treatment to increase platelet count before surgery. In its original submission, the company assumed that prophylactic treatments were the same as rescue treatments. These include IVIgG, intravenous methylprednisolone and platelet transfusions, but not oral prednisolone. At the first committee meeting, the ERG explained that only 1\xa0course of treatment is used, and this is based on the type of surgery (minor or major). It suggested that IVIgG was used for major surgery, which the ERG's clinical expert estimated accounts for 44% of people having surgery. Oral prednisolone was used for minor surgery in the remaining 56% of people. This affected the cost-effectiveness estimates because prednisolone costs much less than IVIgG. The clinical experts explained that oral prednisolone is used in clinical practice, contrary to the company's assumption. Also, they emphasised that the use of prophylaxis before surgery depends on the timing of the surgery. For example, IVIgG works more quickly than oral prednisolone. After consultation, the company asked a panel of 8\xa0clinical experts about which treatments are used as prophylaxis before surgery in NHS clinical practice. Oral prednisolone was the most frequently used treatment for both minor (average use 54% [range 0% to 100%]) and major surgery (62% [0% to 100%]). This was followed by IVIgG for both minor (45% [10% to 75%]) and major (49% [10% to 85%]) surgery. The company assumed the same proportions of minor (56%) and major (44%) surgery as the ERG. The ERG agreed with the company's approach to estimating the use of prophylaxis before surgery and noted it was consistent with its expert opinion. The committee was satisfied that the revised company base case was in line with NHS clinical practice.\n\n## The company's revised approach to modelling adverse events is acceptable\n\nThe company's base case discussed at the first committee meeting used pooled data from FIT1 and FIT2 for people 65\xa0years and over to estimate the rate of adverse events for fostamatinib. This age group was considered more relevant because it is in line with the starting age in the model. This group had a higher rate of adverse events than the younger people in the trial. The company assumed that the rate of adverse events with rituximab was the same as with fostamatinib. At its first meeting, the committee concluded that adverse events with fostamatinib and rituximab were different and should be modelled separately. After consultation, the company agreed that rituximab was associated with fewer adverse events than fostamatinib and watch and rescue treatments. In its revised base case, adverse events with rituximab were based on a randomised controlled trial comparing 375\xa0mg/m2 rituximab with placebo (Ghanima et al.). The ERG was satisfied with the company's revised approach but noted some limitations. Rituximab can cause very rare fatal progressive multifocal leukoencephalopathy, which the company excluded from its analysis. The median age in the Ghanima et al. trial was 46\xa0years, compared with the starting age in the model of 65\xa0years. Adverse events in older people are likely to be more frequent, as seen with fostamatinib in the FIT trials. The committee noted that these assumptions likely favoured rituximab. The ERG explained that the rate of adverse events with the 100\xa0mg weekly dose was likely to be lower than with the higher dose. The committee recalled that at its first meeting, a clinical expert explained that the 100\xa0mg per week dose is well tolerated. The committee noted that assuming equal rates of adverse events with both doses favours fostamatinib. The ERG also explained that the company applied adverse events for rituximab for as long as response was maintained, even though it is only taken for 4\xa0weeks (see section\xa03.9). However, the ERG advised that this likely has a small impact on the cost-effectiveness estimates, because cycle-specific costs and disutilities of adverse events with watch and rescue are similar to rituximab. In terms of modelling adverse events with fostamatinib, the company applied the same rate of adverse events for the full duration of treatment when in the response health state. The ERG noted that the company could instead have used the longest available data from the FIT3 extension study to model long-term adverse events with fostamatinib. However, the company explained that this data was not yet available. But it noted that new long-term safety issues were unlikely to emerge because fostamatinib's long-term safety profile in rheumatoid arthritis was consistent with the earlier data for that disease. The committee acknowledged the limitations of the company's approach to modelling adverse events with fostamatinib and rituximab. It noted that overall, it was not clear if this approach favoured rituximab or fostamatinib. However, it concluded that the company's approach was acceptable for decision making.\n\n## The company's revised base case overestimates the risk of dying from ITP\n\nIn the company's original base case, it estimated the risk of dying in the non-response health state from the General Practice Research Database (Schoonen et al. 2009). The risk of dying was 1.6\xa0times higher than that of the age and sex-matched general population, with 13% of deaths from bleeding and 19% from infection. The risk of death was reported for everyone diagnosed with ITP, that is, it was not reported separately by platelet count. The company assumed all excess deaths happened in the lowest platelet count health state (non-response). All other health states had a risk of death that matched the general population. The ERG noted that assuming all deaths in Schoonen et al. happened in the non-response health state was an important limitation of the company's approach. After consultation, the company identified 2\xa0new studies reporting the risk of dying from ITP and used them in its revised base case. In the 3‑health state model, the hazard ratio for mortality was 4.2 in the non-response state (Portielje et al. 2001), 2.5 in the partial response state (Adelborg et al. 2019) and 1.0 in the complete response health state. The 2-health state model used a hazard ratio for mortality of 4.2 in the non-response health state and 1.0 in the merged response health state. The ERG had concerns with the new sources:\n\nPortielje et al. reported hazard ratios for mortality specifically in people with platelet counts below 30\xa0x\xa0109 per litre but had a small sample size and was not based in the UK.\n\nAdelborg et al. was a larger study but reported hazard ratios for everyone with a platelet count less than 50x109\xa0per litre.The clinical experts agreed with the ERG that using Adelborg et al. for the partial response (30x109 to 50x109\xa0per litre) health state was not appropriate. This was because most deaths in people with platelet counts below 50x109\xa0per litre could be a result of deaths in people with a platelet count below 30x109\xa0per litre. This meant that the model may overestimate mortality in the partial response state. The committee discussed the 3\xa0potential sources of mortality data, noting that all have limitations. It recalled clinical expert advice that many factors influence the risk of dying from ITP, including platelet count, bleeding, age and treatment. It also recalled advice that treatment had changed over time, and the risk of dying from ITP is now lower than in the past. In the past, deaths related to infection were as high as for bleeding, and likely reflected higher use of splenectomy and heavy immunosuppression. But since the introduction of TPO-RAs, it is rare for people to have chronic platelet counts below 20x109 to 30x109\xa0per litre, and rare to have deaths from ITP treatments. The committee agreed that Portielje et al. may overestimate the current risk of dying from ITP because of the progress in treatment for this disease. It also noted that the risk of dying from intracranial bleeding is already accounted for in the model. So, using hazard ratios for mortality from Portielje et al. would overestimate mortality in people without intracranial bleeding. Also, the committee discussed that the company did not provide any evidence that fostamatinib reduces the risk of dying from ITP. The model predicts such a reduction, based on less time spent in the non-response health state compared with rituximab. But the committee noted that without any evidence to support this, the effect of fostamatinib on the risk of dying was uncertain. It also noted that mortality assumptions have the biggest effect on the cost-effectiveness estimates. The committee concluded that the company's revised approach overestimates the risk of dying from ITP. It preferred the company's original approach, using estimates from the General Practice Research Database (Schoonen et al.).\n\n## The utility values in the model are appropriate, including those for carers\n\nThe company used utility values for the model health states from published literature because of the low number of responses to the quality-of-life questionnaire used in the FIT clinical trials (SF‑36). The committee noted that the company used utility values for the health states of the group without intracranial bleeding from NICE's technology appraisal guidance on romiplostim. The company's original base case applied a lower utility value for people in the partial and no response health states than in the response health state. This was because the romiplostim appraisal used different utility values for people with platelet counts of 50x109\xa0per litre or more (response) and those with platelet counts below 50x109\xa0per litre (non-response). In its revised base case after consultation, the company applied different utility values to the response (platelets 30x109\xa0per litre or more) and the non-response health states (platelets below 30x109\xa0per litre). The committee acknowledged that people with platelet counts below 30x109\xa0per litre would be unlikely to feel worse than people with platelet counts of 30x109\xa0per litre or above. But if a person knows that they are at higher risk of bleeding, this could cause anxiety and affect their daily life if they avoid their usual activities. For the group who had severe intracranial bleeding and for their carers, the company used published utility values. The ERG noted that because intracranial bleeding is rare, including carer quality of life affected the cost-effectiveness estimates minimally. The company also applied a transient disutility for people with other bleeds, adverse events or when needing rescue treatment. The committee concluded that the utility values in the model, including those for carers of people who had severe intracranial bleeding, were appropriate.\n\n## The ERG's exploratory analysis for mycophenolate assumes equal efficacy and safety to rituximab, which is uncertain\n\nThe ERG did an analysis for mycophenolate as a comparator, assuming equal efficacy and safety to rituximab. It assumed that mycophenolate is taken twice a day as a 500\xa0mg tablet and stopped at 12\xa0weeks if platelet response is not reached, or later if this response is lost. The analysis predicted that median treatment duration is 12 to 16\xa0weeks, which is longer than the median duration of mycophenolate treatment in the UK ITP registry (exact figures are confidential and cannot be reported here). The model predicted that mycophenolate had higher total treatment costs than 100\xa0mg rituximab at its list price, but lower than 375\xa0mg/m2 rituximab at its list price. The ERG highlighted that this analysis is exploratory, because assuming equal efficacy of rituximab and mycophenolate is uncertain. It noted that there were lower complete and partial responses to mycophenolate in Taylor et al. (2015) compared with responses to rituximab in Ghanima et al. The ERG emphasised that this comparison was highly uncertain because it reflects a naive comparison between 2\xa0different studies, and Taylor et al. was a small, non-randomised, retrospective study. Clinical experts confirmed that assuming equal efficacy of mycophenolate and rituximab is uncertain. They explained that there are no head-to-head comparisons between these 2\xa0treatments, but they expect their efficacy and safety to differ. The 2\xa0drugs are used for different groups of people. Mycophenolate is generally well tolerated and taken as a tablet, so it does not cause infusion-related reactions. The committee agreed that mycophenolate was unlikely to have the same efficacy and safety as rituximab and this was a limitation of the exploratory analysis. It concluded that it would focus on the comparison of fostamatinib with rituximab in its decision making.\n\n# Cost-effectiveness estimates\n\n## The most likely cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources\n\nThe company revised its base case after consultation. The committee noted that it attempted to address its preferences from the first meeting. For the rapid review, the company's revised base case included the committee's preferred assumptions from the time of the original guidance, namely:\n\nusing clinical effectiveness estimates for the comparators from a network meta-analysis (see section\xa03.9)\n\nstopping fostamatinib at 12\xa0weeks if platelet response had not been reached (see section\xa03.13)\n\nmodelling subsequent treatments consistently between arms (see section\xa03.14)\n\nusing prophylactic treatments before surgery in line with clinical practice, that is, including both IVIgG and oral prednisolone (see section\xa03.19)\n\nincluding treatment-specific adverse event rates (see section\xa03.20)\n\nusing lower hazard ratios reflecting the association between the non-response health state and mortality (see section\xa03.21)\n\nmerging the partial response and response health states (see section\xa03.11)\n\nconsidering a scenario analysis with 100\xa0mg rituximab (see section\xa03.18)\n\ncorrecting the error in the calculation of rescue treatment (see section\xa03.12).For the rapid review, the committee referred to its preferred assumptions from the time of the original guidance including:\n\nusing both network meta-analysis\xa02 and\xa03 results (see section\xa03.9)\n\nusing both doses of rituximab used in clinical practice (see section\xa03.18).The committee recognised that the lack of data increased the uncertainty with modelling chronic ITP that is refractory to other treatments. This is because there were limitations to the indirect treatment comparison and difficulty with modelling a full treatment pathway. Applying confidential discounts for fostamatinib and rituximab, and considering its preferences, the committee noted that all the cost-effectiveness estimates were within what NICE normally considers an acceptable use of NHS resources when either network meta-analysis 2 or 3 were used and when either dose of rituximab was applied.\n\n# Other factors\n\n## Fostamatinib has a novel mechanism of action but the benefits are captured in the cost-effectiveness analysis\n\nThe patient and clinical experts value individualised treatment. The committee noted fostamatinib's novel mechanism of action and the lack of immunosuppression associated with it. This is important because the clinical experts highlighted that the rates of death from infection and from bleeding are similar in people with ITP. This is particularly relevant during the COVID‑19 pandemic because clinicians are being careful about using anti‑CD20 antibody treatments like rituximab which may make people more susceptible to infection. Additionally, treatment options are limited for people who cannot have TPO‑RAs. The committee concluded that while the benefits of treatment are captured in the model (see section\xa03.18), having alternative treatment options that do not suppress the immune system and could be used when TPO‑RAs are not suitable would be highly beneficial.\n\n# Conclusion\n\n## Fostamatinib is recommended after a thrombopoietin receptor agonist or when they are not suitable\n\nThe committee recognised that people with refractory chronic ITP have benefited from fostamatinib and that the treatment has advantages over other available treatments. It acknowledged that fostamatinib improves outcomes compared with rituximab, but that there are uncertainties over the size of the benefit and its duration. The committee noted that fostamatinib was not compared with mycophenolate, a relevant comparator. But they acknowledged the evidence limitations which underpinned this decision. The committee considered the remaining sources of uncertainty in the model, and also the benefits of fostamatinib which may not be captured in the cost-effectiveness results. The committee concluded that the most plausible ICERs using its preferred modelling assumptions were within the range that NICE normally considers to be a cost-effective use of NHS resources. So, it recommended fostamatinib for treating refractory chronic ITP after TPO‑RAs or when they are not suitable."}	https://www.nice.org.uk/guidance/ta835	Evidence-based recommendations on fostamatinib (Tavlesse) for chronic refractory chronic immune thrombocytopenia in adults.
313c32d21a6647c4acc12ca3b1a4f942f6357638	nice	Osteoarthritis in over 16s: diagnosis and management	Osteoarthritis in over 16s: diagnosis and management This guideline covers the diagnosis, assessment and non-surgical management of osteoarthritis. It aims to improve management of osteoarthritis and the quality of life for people with osteoarthritis. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Diagnosis Diagnose osteoarthritis clinically without imaging in people who: are 45 or over and have activity-related joint pain and have either no morning joint-related stiffness or morning stiffness that lasts no longer than 30 minutes. Do not routinely use imaging to diagnose osteoarthritis unless there are atypical features or features that suggest an alternative or additional diagnosis. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnosis . Full details of the evidence and the committee's discussion are in evidence review A: additional benefit of imaging in the diagnosis of osteoarthritis. Loading. Please wait. # Information and support When giving information to people with osteoarthritis, their families and carers, tailor it to their individual needs (such as language and culture), ensure it is in an accessible format and follow the recommendations on: enabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services putting shared decision making into practice in NICE's guideline on shared decision making delivering an approach to care that takes account of multimorbidity in NICE's guideline on multimorbidity. Explain to people with osteoarthritis that: it is diagnosed clinically and usually does not need imaging to confirm the diagnosis and management should be guided by symptoms and physical function and the core treatments for the condition are therapeutic exercise and weight management (if appropriate), along with information and support. Advise people with osteoarthritis where they can find further information on: -steoarthritis and how it develops (including flares and progression over time), and information that challenges common misconceptions about the condition specific types of exercise managing their symptoms how to access additional sources of information and support after consultations, such as peer-to-peer support and support groups benefits and limitations of treatment. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support . Full details of the evidence and the committee's discussion are in evidence review B: post-diagnostic information on osteoarthritis for people with osteoarthritis, their family and carers. Loading. Please wait. # Non-pharmacological management ## Therapeutic exercise For all people with osteoarthritis, offer therapeutic exercise tailored to their needs (for example, local muscle strengthening, general aerobic fitness). Consider supervised therapeutic exercise sessions for people with osteoarthritis. Advise people with osteoarthritis that joint pain may increase when they start therapeutic exercise. Explain that: doing regular and consistent exercise, even though this may initially cause pain or discomfort, will be beneficial for their joints long-term adherence to an exercise plan increases its benefits by reducing pain and increasing functioning and quality of life. Consider combining therapeutic exercise with an education programme or behaviour change approaches in a structured treatment package. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on therapeutic exercise . Full details of the evidence and the committee's discussion are in: evidence review C: clinical and cost effectiveness of exercise for the management of osteoarthritis evidence review K: clinical and cost effectiveness of treatment packages for the management of osteoarthritis. Loading. Please wait. ## Weight management For people with osteoarthritis who are living with overweight or obesity: advise them that weight loss will improve their quality of life and physical function, and reduce pain support them to choose a weight loss goal explain that any amount of weight loss is likely to be beneficial, but losing 10% of their body weight is likely to be better than 5%.For guidance and information on weight management, including recommended interventions to support weight loss, see NICE's topic page on obesity. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on weight management . Full details of the evidence and the committee's discussion are in evidence review D: benefit of weight loss for the management of osteoarthritis for people living with overweight or obesity. Loading. Please wait. ## Manual therapy Only consider manual therapy (such as manipulation, mobilisation or soft tissue techniques): for people with hip or knee osteoarthritis and alongside therapeutic exercise. If discussing manual therapy, explain to people with osteoarthritis that there is not enough evidence to support its use alone for managing osteoarthritis. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on manual therapy . Full details of the evidence and the committee's discussion are in evidence review E: clinical and cost-effectiveness of manual therapy for the management of osteoarthritis. Loading. Please wait. ## Acupuncture Do not offer acupuncture or dry needling to manage osteoarthritis. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on acupuncture . Full details of the evidence and the committee's discussion are in evidence review F: clinical and cost-effectiveness of acupuncture for people with osteoarthritis. Loading. Please wait. ## Electrotherapy Do not offer any of the following electrotherapy treatments to people with osteoarthritis because there is insufficient evidence of benefit: transcutaneous electrical nerve stimulation (TENS) ultrasound therapy interferential therapy laser therapy pulsed short-wave therapy neuromuscular electrical stimulation (NMES). For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on electrotherapy . Full details of the evidence and the committee's discussion are in evidence review G: clinical and cost effectiveness of electrotherapy for the management of osteoarthritis. Loading. Please wait. ## Devices Consider walking aids (such as walking sticks) for people with lower limb osteoarthritis. Do not routinely offer insoles, braces, tape, splints or supports to people with osteoarthritis unless: there is joint instability or abnormal biomechanical loading and therapeutic exercise is ineffective or unsuitable without the addition of an aid or device and the addition of an aid or device is likely to improve movement and function. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on devices . Full details of the evidence and the committee's discussion are in evidence review H: clinical and cost effectiveness of devices for the management of osteoarthritis. Loading. Please wait. # Pharmacological management ## Topical, oral and transdermal medicines If pharmacological treatments are needed to manage osteoarthritis, use them: alongside non-pharmacological treatments and to support therapeutic exercise at the lowest effective dose for the shortest possible time. Offer a topical non-steroidal anti-inflammatory drug (NSAID) to people with knee osteoarthritis. Consider a topical NSAID for people with osteoarthritis that affects other joints. If topical medicines are ineffective or unsuitable, consider an oral NSAID for people with osteoarthritis and take account of: potential gastrointestinal, renal, liver and cardiovascular toxicity any risk factors the person may have, including age, pregnancy, current medication and comorbidities.Offer a gastroprotective treatment (such as a proton pump inhibitor) for people with osteoarthritis while they are taking an NSAID. Do not routinely offer paracetamol or weak opioids unless: they are only used infrequently for short-term pain relief and all other pharmacological treatments are contraindicated, not tolerated or ineffective.Explain to people with osteoarthritis that there is no strong evidence of benefit for paracetamol. For more information about opioids, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. Do not offer glucosamine or strong opioids to people to manage osteoarthritis. If the person with osteoarthritis asks about glucosamine or strong opioids, explain that: there is no strong evidence of benefit for glucosamine the risks of strong opioids outweigh the benefits. Review with the person whether to continue treatment. Base the frequency of reviews on clinical need. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on topical, oral and transdermal medicines . Full details of the evidence and the committee's discussion are in evidence review I, evidence review I: appendices A to D, evidence review I: appendices E to J: clinical and cost effectiveness of oral, topical and transdermal medicines for the management of osteoarthritis. Loading. Please wait. ## Intra-articular injections Do not offer intra-articular hyaluronan injections to manage osteoarthritis. Consider intra-articular corticosteroid injections when other pharmacological treatments are ineffective or unsuitable, or to support therapeutic exercise. Explain to the person that these only provide short‑term relief (2 to 10 weeks). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on intra-articular injections . Full details of the evidence and the committee's discussion are in evidence review J: clinical and cost effectiveness of intra-articular injections for the management of osteoarthritis. Loading. Please wait. # Follow-up and review ## Follow-up appointments Consider patient-initiated follow-up for most people with osteoarthritis. Consider planned follow-up for people with osteoarthritis when their individual needs and preferences suggest that this is necessary, taking into account: treatments or interventions that need monitoring their ability to seek help for themselves their occupation and activities the severity of their symptoms or functional limitations.People with multiple long-term conditions are likely to benefit from a tailored approach in line with NICE's guideline on multimorbidity. Advise people with osteoarthritis to seek follow-up if planned management is not working within an agreed follow-up time or they are having difficulties with the agreed approaches. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up and review . Full details of the evidence and the committee's discussion are in evidence review L: regular follow-up and review. Loading. Please wait. ## Imaging for management of osteoarthritis Do not routinely use imaging for follow-up or to guide non-surgical management of osteoarthritis. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on imaging for the management of osteoarthritis . Full details of the evidence and the committee's discussion are in evidence review M: clinical and cost effectiveness of imaging during the management of osteoarthritis. Loading. Please wait. # Referral for joint replacement Consider referring people with hip, knee or shoulder osteoarthritis for joint replacement if: their joint symptoms (such as pain, stiffness, reduced function or progressive joint deformity) are substantially impacting their quality of life and non-surgical management (for example, therapeutic exercise, weight loss, pain relief) is ineffective or unsuitable. Use clinical assessment when deciding to refer someone for joint replacement, instead of systems that numerically score severity of disease. Do not exclude people with osteoarthritis from referral for joint replacement because of: age sex or gender smoking comorbidities -verweight or obesity, based on measurements such as body mass index (BMI). If discussing referral for joint replacement, explain to the person with osteoarthritis that the risks of joint replacement can vary depending on the factors listed in recommendation 1.6.3. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral for joint replacement . Full details of the evidence and the committee's discussion are in: evidence review O: indicators for referral for possible joint replacement surgery evidence review P: outcomes of joint replacement surgery dependent on body mass index Loading. Please wait. # Arthroscopic procedures Do not offer arthroscopic lavage or debridement to people with osteoarthritis. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on arthroscopic procedures . Full details of the evidence and the committee's discussion are in evidence review N: clinical and cost effectiveness of arthroscopic procedures for the management of osteoarthritis. Loading. Please wait. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. ## Atypical features Atypical features could include a history of recent trauma, prolonged morning joint‑related stiffness, rapid worsening of symptoms or deformity, the presence of a hot swollen joint, or concerns that may suggest infection or malignancy. ## Flares A temporary worsening of symptoms (pain, swelling and stiffness) that: is worse than normal may affect sleep, activity, function and psychological wellbeing may lead to change in therapy for at least 24 hours. ## Treatment package A treatment package is defined as any treatment for osteoarthritis (this could include: exercise, manual therapy, devices and pharmacological treatments) combined with one of the following: behaviour change approaches, including ways to reduce pain and straining when using joints, pain coping skills training (including spouse-assisted coping skills training), goal setting; motivational coaching; weight management counselling and workplace risk counselling an education programme given by 1 or more healthcare professionals over multiple sessions, including those based on behavioural theory. ## Walking aids Walking aids include walking sticks, crutches, walking frames and rollators. They support the person with osteoarthritis to move around independently and safely by improving their walking pattern and balance or reducing weight bearing on the affected joint.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Exercise What is the clinical and cost effectiveness of supervised group and individual exercise compared with unsupervised exercise for people with osteoarthritis? For a short explanation of why the committee made the recommendation for research see the rationale section on therapeutic exercise . Full details of the evidence and the committee's discussion are in evidence review C: clinical and cost effectiveness of exercise for the management of osteoarthritis. Loading. Please wait. ## Devices What is the clinical and cost effectiveness of devices compared with usual care for the management of painful foot and or ankle osteoarthritis? For a short explanation of why the committee made the recommendation for research see the rationale section on devices . Full details of the evidence and the committee's discussion are in evidence review H: clinical and cost effectiveness of devices for the management of osteoarthritis. Loading. Please wait. ## Topical medicines What is the clinical and cost effectiveness of topical non-steroidal anti-inflammatory drugs and topical capsaicin for osteoarthritis-affected joints other than the knee? For a short explanation of why the committee made the recommendation for research see the rationale section on topical, oral and transdermal medicines . Full details of the evidence and the committee's discussion are in evidence review I, evidence review I: appendices A to D, evidence review I: appendices E to J: clinical and cost effectiveness of oral, topical and transdermal medicines for the management of osteoarthritis. Loading. Please wait. ## Follow-up strategies What is the clinical and cost effectiveness of patient-initiated follow-up compared with routine follow-up for people with osteoarthritis? For a short explanation of why the committee made the recommendation for research see the rationale section on follow-up and review . Full details of the evidence and the committee's discussion are in evidence review L: regular follow-up and review. Loading. Please wait. # Other recommendations for research ## Patient information What information on the management of flares do people with osteoarthritis, their family and carers need after diagnosis? What information do people with osteoarthritis from different ethnic and socioeconomic groups, and those with learning disabilities, issues with health literacy and severe mental illness (and their family and carers), need? For a short explanation of why the committee made the recommendations for research see the rationale section on information and support . Full details of the evidence and the committee's discussion are in evidence review B: post-diagnostic information on osteoarthritis for people with osteoarthritis, their family and carers. Loading. Please wait. ## Manual therapy What is the clinical and cost effectiveness of manual therapy for people with osteoarthritis, when used alone and when in combination with therapeutic exercise? For a short explanation of why the committee made the recommendation for research see the rationale section on manual therapy . Full details of the evidence and the committee's discussion are in evidence review E: clinical and cost effectiveness of manual therapy for the management of osteoarthritis. Loading. Please wait. ## Electroacupuncture Is electroacupuncture a clinically and cost-effective treatment for any subgroup of people with osteoarthritis? For a short explanation of why the committee made the recommendation for research see the rationale section on acupuncture . Full details of the evidence and the committee's discussion are in evidence review F: clinical and cost effectiveness of acupuncture for people with osteoarthritis. Loading. Please wait. ## Extracorporeal shockwave therapy What is the clinical and cost effectiveness of extracorporeal shockwave therapy for managing osteoarthritis? For a short explanation of why the committee made the recommendation for research see the rationale section on electrotherapy . Full details of the evidence and the committee's discussion are in evidence review G: clinical and cost effectiveness of electrotherapy for the management of osteoarthritis. Loading. Please wait. ## Footwear What is the clinical and cost effectiveness of footwear for managing lower limb osteoarthritis? For a short explanation of why the committee made the recommendation for research see the rationale section on devices . Full details of the evidence and the committee's discussion are in evidence review H: clinical and cost effectiveness of devices for the management of osteoarthritis. Loading. Please wait. ## Topical and oral medicines What is the clinical and cost effectiveness of topical local anaesthetics for people with osteoarthritis? What is the clinical and cost effectiveness of antiepileptics and antidepressants (other than duloxetine) for people with osteoarthritis? What is the clinical and cost effectiveness of weak oral opioids for people with osteoarthritis? For a short explanation of why the committee made the recommendations for research see the rationale section on topical, oral and transdermal medicines . Full details of the evidence and the committee's discussion are in evidence review I, evidence review I: appendices A to D, evidence review I: appendices E to J: clinical and cost effectiveness of oral, topical and transdermal medicines for the management of osteoarthritis. Loading. Please wait. ## Intra-articular injections What is the clinical and cost effectiveness of intra-articular corticosteroids for managing osteoarthritis-affected joints other than the knee? What is the clinical and cost effectiveness of intra-articular stem cells for managing osteoarthritis? For a short explanation of why the committee made the recommendations for research see the rationale section on intra-articular injections . Full details of the evidence and the committee's discussion are in evidence review J: clinical and cost effectiveness of intra-articular injections for the management of osteoarthritis. Loading. Please wait. ## Referral criteria for joint replacement What are the most important indicators that someone with osteoarthritis (including shoulder osteoarthritis) would benefit from joint replacement? For example: presence of night pain non-response to non-pharmacological interventions joint instability symptoms presence of flares numerical summary scores. For a short explanation of why the committee made the recommendation for research see the rationale section on referral for joint replacement . Full details of the evidence and the committee's discussion are in evidence review O: indicators for referral for possible joint replacement surgery. Loading. Please wait. ## Imaging for management of osteoarthritis What is the clinical and cost effectiveness of imaging for informing non-surgical management (for example, exercise or weight loss) in primary care for people with osteoarthritis? What is the clinical and cost effectiveness of imaging for use at different parts of the care pathway (for example, primary care, intermediate care or secondary care) before surgery for people with osteoarthritis? For a short explanation of why the committee made the recommendations for research see the rationale section on imaging for management of osteoarthritis . Full details of the evidence and the committee's discussion are in evidence review M: clinical and cost effectiveness of imaging during the management of osteoarthritis. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Diagnosis Recommendations 1.1.1 and 1.1.2 ## Why the committee made the recommendations There was no evidence showing that imaging is beneficial for diagnosing osteoarthritis. The committee agreed that imaging adds little value and that osteoarthritis can be diagnosed by taking a thorough history and doing an examination. The committee agreed that imaging can be useful if atypical features are present that could suggest an alternative or additional diagnosis, such as other inflammatory forms of arthritis (for example, rheumatoid arthritis) and malignancy. ## How the recommendations might affect practice Imaging is frequently used when diagnosing osteoarthritis, despite uncertainties about its benefit, the resource implications and potential for delays in starting management. The recommendations should reduce unnecessary resource use and be cost saving. Return to recommendations # Information and support Recommendations 1.2.1 to 1.2.3 ## Why the committee made the recommendations Evidence showed that generally people with osteoarthritis wanted more information about their condition. This included information about the causes, what their diagnosis means for the future and where to find more information on self‑management. The committee based their recommendations on the evidence and their experience. They agreed that it is important to tell people that diagnosis is made clinically without imaging, that imaging rarely provides any extra information helpful for diagnosing or planning non-surgical treatment for osteoarthritis, and that it would only be used if there were suspicion of an alternative diagnosis or other complications. This would help reassure and dispel any belief that X-rays or other forms of imaging are needed to diagnose osteoarthritis. The committee noted the importance of information that offers hope for the future and supports self-management strategies (for example, information that emphasises symptom-reducing behaviours, like therapeutic exercise). They agreed that explaining the core treatments for osteoarthritis would help people understand that pharmacological treatments are not a long-term solution. They also agreed that information about recognising flares and how to manage changes in pain would help the person better understand how their condition may vary over time and what they can do about it. The committee noted more evidence was needed on information about managing flares and information for different populations of people with osteoarthritis, and so made recommendations for research on what information people with osteoarthritis need. The committee agreed that each person's experience of osteoarthritis differs and therefore tailoring the information to their needs, as described in NICE's guideline on patient experience in adult NHS services, is important. They also agreed that osteoarthritis is more common in older people who are likely to have other conditions. Therefore, the recommendations on delivering an approach to care that takes account of multimorbidity in NICE's guideline on multimorbidity are particularly relevant to people with osteoarthritis. ## How the recommendations might affect practice The recommendations generally reflect current practice because information is likely to be already provided, but they advise on areas in which practice can be improved. Return to recommendations # Therapeutic exercise Recommendations 1.3.1 to 1.3.4 ## Why the committee made the recommendations The evidence showed that exercise has a clinically important benefit for people with osteoarthritis, as well as general health benefits and a superior safety profile compared with other common treatments, such as analgesia. In particular, the committee highlighted the importance of therapeutic exercise to help manage and reduce symptoms and improve or maintain physical functioning over the long term. For most benefit, they recommended this be tailored to the needs of the person, such as joint-site-specific exercises. Limited evidence showed that supervised exercise had some benefits compared with unsupervised exercise. The committee's expert consensus was that supervised exercise is likely to be of greater benefit than unsupervised exercise for people with osteoarthritis. This is because supervised exercise may enable tailored exercise and social support, which may increase adherence and lead to people with osteoarthritis forming a regular exercise habit. The committee also agreed that shared decision making is important when deciding the form of exercise delivery and type of exercise, as well as considering personal preference and service availability. The committee, acknowledging the importance of exercise, made further recommendations to support people to continue therapeutic exercise by emphasising its benefits while acknowledging that exercise may initially be difficult. They wanted to reassure people with osteoarthritis and healthcare professionals that exercise is not harmful to osteoarthritic joints, and that doing regular and consistent exercise over a long period of time can reduce pain and increase functioning and quality of life. The committee noted that further evidence may be needed and made a recommendation for research to compare the clinical and cost effectiveness of supervised group and individual exercise with unsupervised exercise. Evidence showed that treatment packages had a clinically important benefit on physical function compared with education or behaviour change interventions alone. They also had consistent beneficial changes in quality of life, pain and physical function compared with standard care. However, they showed no superiority to individual therapies (such as exercise, manual therapy and electrotherapy). The committee agreed that a person-centred approach is important. Additional education or behavioural change approaches may help some people achieve their goals, but others may not need this. Therefore, the committee recommended combining therapeutic exercise as part of a structured treatment package because this may be more suitable for some people and motivate them to continue with therapeutic exercise. ## How the recommendations might affect practice Current practice around therapeutic exercise varies. These recommendations may lead to a change in practice by recommending tailored exercise (including supervised exercise) and using treatment packages. Return to recommendations # Weight management Recommendation 1.3.5 ## Why the committee made the recommendation The committee acknowledged that evidence on the effects of weight loss for people with osteoarthritis had limitations. However, for people with knee osteoarthritis, the evidence generally showed that as more weight was lost, the benefits for quality of life, pain and physical function increased. The committee acknowledged the challenges people can have with losing weight and maintaining this weight loss, and recommended that they are supported. The committee acknowledged that, for people who are overweight, losing more than 10% of their body weight may be the most beneficial, but this may not be achievable for all. They wanted to emphasise that losing any amount of weight would be beneficial, but that losing more would have more benefits. They agreed that also explaining that losing 10% of their body weight is likely to be better than 5% might help provide an incentive and encourage weight loss. They also agreed that advising on the amount of weight to lose can help people with osteoarthritis by providing a target for them to work towards. The committee determined that, although evidence was from people with knee osteoarthritis, this could be applied to people with other osteoarthritis-affected joints. This is because of the potential additional benefits of weight loss seen in other populations, such as reducing inflammatory factors, that may be beneficial for all joint sites and general wellbeing. The committee also agreed that osteoarthritis is a multi-joint disease and people presenting with the condition in 1 joint may end up getting it in another. Weight loss may help reduce this risk. ## How the recommendation might affect practice This recommendation somewhat reflects current practice but may lead to a change in how people with osteoarthritis and healthcare professionals discuss weight loss. This is unlikely to have a significant resource impact. Return to recommendation # Manual therapy Recommendations 1.3.6 and 1.3.7 ## Why the committee made the recommendations The committee acknowledged recent evidence that showed some clinical benefits of manual therapy for hip and knee osteoarthritis, with no evidence being identified for other joint sites. However, the benefits were stronger if manual therapy was combined with exercise. Clinical and economic evidence showed that exercise alone was more effective than both manual therapy alone and the combination of manual therapy and exercise. So, the committee concluded that manual therapy should only be considered alongside therapeutic exercise. Most studies provided therapy for less than 3 months and on average for 7 weeks. The committee agreed that the duration of manual therapy would be similar, but would vary according to the person's needs. They agreed that further research was needed, in particular evidence from well‑powered, high-quality studies with adequate blinding and on other osteoarthritis‑affected joints. They made a recommendation for research on manual therapy for people with osteoarthritis used alone and in combination with therapeutic exercise. ## How the recommendations might affect practice Current practice around manual therapy varies. Adding manual therapy to exercise would be a slight change in practice, but it would not have a substantial resource impact because it is not needed long term. Return to recommendations # Acupuncture Recommendation 1.3.8 ## Why the committee made the recommendation The available evidence was predominantly for knee osteoarthritis. This showed a lack of benefits of acupuncture and some evidence of harm. Economic evidence also showed that using acupuncture for osteoarthritis is not cost effective, so the committee did not recommend using acupuncture or dry needling. There was some evidence of clinical benefit and cost effectiveness for electroacupuncture but this was of very low quality because of small study sizes and inconsistency between studies. The evidence for electroacupuncture suggested it showed a benefit compared with sham acupuncture but not compared with acupuncture or no treatment. The committee considered that the inconsistent evidence could be the result of some people responding more to electroacupuncture than others. Because there is uncertainty about who might benefit from electroacupuncture, the committee made a recommendation for research on electroacupuncture for osteoarthritis. ## How the recommendation might affect practice The recommendation reflects current practice so the committee agreed there should be no change in practice or resource impact to the NHS. Return to recommendation # Electrotherapy Recommendation 1.3.9 ## Why the committee made the recommendation Although there were many studies on electrotherapy, the findings were inconsistent and mostly showed little benefit. The committee acknowledged that most studies were small, with fewer than 100 participants, and that evidence from direct comparisons of electrotherapy with other interventions was uncertain. The committee agreed there is not enough evidence to recommend electrotherapy for people with osteoarthritis. Extracorporeal shockwave therapy showed some evidence of benefit compared with a sham intervention. However, this evidence was uncertain because of the small trial sizes and challenges in using appropriate sham techniques. The committee agreed that further research using an appropriate sham with more than 50 participants in each study arm is needed and made a recommendation for research on extracorporeal shockwave therapy. ## How the recommendation might affect practice The committee noted that although the use of some electrotherapy modalities in the NHS has decreased, other modalities with unclear evidence of benefit continue to be used. Also, people with osteoarthritis may self-prescribe electrotherapy devices. This recommendation may reduce the prescription and use of TENS. Return to recommendation # Devices Recommendations 1.3.10 and 1.3.11 ## Why the committee made the recommendations Evidence from a small study on walking aids showed that they benefit quality of life and reduce pain compared with no device. The committee agreed that walking aids have the advantage of reducing the pressure in the leg joints, which helps stability and movement to encourage physical activity and independence. This is particularly the case while waiting for joint replacement or if surgery cannot be undertaken, because the aid helps support exercise and confidence with walking. Overall, they agreed that the evidence, supported by their expert opinion, was enough to recommend walking aids for people with lower limb osteoarthritis. The committee concluded that there was not enough evidence to support the routine use of insoles, braces, tape, splints or supports. They also noted that there is a potential risk that some of these devices could cause significant adverse events, such as blistering and other pressure damage. The committee acknowledged that research on devices has challenges, such as appropriate sham devices for comparisons. The committee agreed that further research is needed on devices, through studies that have a larger number of participants, sufficient blinding and allocation concealment. Because most of the evidence was for knee osteoarthritis, they made a recommendation for research on devices for painful foot and ankle osteoarthritis. The committee also noted that evidence on footwear had limitations and made a recommendation for research on footwear for managing lower limb osteoarthritis. ## How the recommendations might affect practice Use of devices for osteoarthritis is varied in current practice. Currently, insoles, braces, tape or supports may be used by some people with osteoarthritis because they were previously recommended by NICE. The recommendations may change practice with using devices. But the practice of using walking aids is unlikely to change. There is a potential for some cost savings to the NHS. Return to recommendations # Topical, oral and transdermal medicines Recommendations 1.4.1 to 1.4.8 ## Why the committee made the recommendations The committee agreed that pharmacological treatments may be useful for reducing symptoms and supporting people to start other more effective treatments, such as therapeutic exercise. However, they noted that the risks of pharmacological treatments should be understood and that treatments should not be overused or used when they are not needed. The committee agreed that it was difficult to define treatment strengths and durations that would be generalisable to everyone. This is because people with osteoarthritis can have a variety of comorbidities and factors that might influence treatment. Therefore, the committee emphasised that treatments should use the lowest effective dose for the shortest possible time. Topical non-steroidal anti-inflammatory drugs (NSAIDs) were clinically effective in reducing pain for people with knee osteoarthritis and generally the most cost‑effective medicine for osteoarthritis. They were also associated with minimal adverse events. Evidence on topical NSAIDs came from studies including people with knee osteoarthritis and 1 study including people with hand osteoarthritis. The evidence showed no clinically important difference for hand osteoarthritis, but the committee noted this was uncertain because it was based on 1 study. The committee noted that although evidence only showed benefit for knee osteoarthritis, other people with osteoarthritis-affected joints may also benefit from topical NSAIDs. There was some evidence showing that topical capsaicin reduces pain in knee osteoarthritis, but not hand osteoarthritis, and has minimal adverse events. However, capsaicin is more expensive and topical NSAIDs were considered a better option. The committee made a recommendation for research on topical medicines for osteoarthritis-affected joints other than the knee. Oral NSAIDs were found to be cost effective and evidence showed they slightly reduced pain and increased physical function. The committee acknowledged the Medicines and Healthcare products Regulatory Agency (MHRA) safety warnings on NSAIDs for cardiovascular safety, renal safety and gastrointestinal risk. They agreed that NSAIDs, as well as other pharmacological treatments for osteoarthritis, should be used for as short a time as possible and that the potential harms for gastrointestinal, cardiovascular, liver and kidney adverse events should be carefully considered when prescribing. Evidence showed that adding gastroprotection can reduce gastrointestinal bleeding or perforation. However, this was associated with an increase in cardiovascular adverse events compared with oral NSAIDs alone. The committee agreed that this may be unrelated to the addition of gastroprotection and that randomised controlled trial evidence alone may not be the best source for safety evidence, because the population size and length of follow-up are usually limited. Therefore, they also used their clinical experience and guidance from other organisations, including the MHRA. Based on this, the committee agreed that use of gastroprotection should be offered with NSAIDs. Evidence showed that opioids also have the potential for harm, including gastrointestinal and central nervous system adverse events. The committee acknowledged further potential harms such as physical dependence, opioid-induced hyperalgesia and tolerance. Cost-effectiveness evidence showed that buprenorphine, a transdermal opioid, was generally more cost effective than oral strong opioids (such as morphine, oxycodone and tramadol). This evidence was from people having buprenorphine who had not had opioids before, but this was generally not the case for people having oral strong opioids. All people had already tried a type of analgesia such as NSAIDs or paracetamol. However, the committee acknowledged the MHRA safety warning on opioids and recommendations in NICE's guideline on medicines associated with dependence or withdrawal symptoms, which advises against the use of modified-release opioids. Therefore, the committee recommended against the use of strong opioids. Evidence from 1 small study of weak opioids showed a clinically important benefit in reducing pain. The committee agreed that there was not enough evidence of benefit and on potential risks. Although paracetamol has a low potential to cause adverse events, evidence showed that it has no additional benefit in reducing osteoarthritis pain and improving quality of life and physical function compared with placebo. However, the committee discussed that some people cannot use NSAIDS. Therefore, they recommended against the routine use of paracetamol but noted some circumstances where it may be used. Evidence on glucosamine was inconsistent and the largest benefits were shown by smaller studies that were of lower quality. Because glucosamine is not used in current practice and there is no strong evidence of benefit the committee recommended against its use for people with osteoarthritis. The committee determined that there was not enough evidence to make recommendations on antiepileptics, antidepressants, rubefacients and topical local anaesthetics. The committee made recommendations for research on antiepileptics, antidepressants, weak oral opioids and topical local anaesthetics for osteoarthritis. Duloxetine was not included in the recommendation for research because many studies have already investigated its use, but there is less evidence for other antidepressants that may be used more regularly in the NHS to manage pain (such as tricyclic antidepressants). The committee did not make a recommendation for research on rubefacients because they did not think that these would benefit people with osteoarthritis. The committee agreed that pharmacological treatments should be periodically reviewed with the person. They recommended this should be done according to clinical need. ## How the recommendations might affect practice Current practice in pharmacological treatment for osteoarthritis varies in the types of treatments used and how people access treatment (such as buying medicines over the counter instead of accessing them through healthcare services). These recommendations may cause changes in current practice towards using medicines for a shorter time, increasing use of topical NSAIDs, and reducing use of paracetamol and opioids. Return to recommendations # Intra-articular injections Recommendations 1.4.9 and 1.4.10 ## Why the committee made the recommendations There was no evidence showing that hyaluronan injections improved quality of life or physical function, or reduced pain, in people with knee or hip osteoarthritis. Evidence showed a potential harm for hip osteoarthritis. Limited evidence for other osteoarthritis-affected joints showed inconsistent benefits and some potential harms. Based on their expert opinion, the committee agreed that these results were generalisable to other forms of osteoarthritis and that hyaluronan injections should not be offered. Evidence showed that corticosteroid injections had inconsistent benefits on improving quality of life and physical function for people with hip osteoarthritis, and reducing pain for people with knee osteoarthritis. There was no evidence showing long-term benefit beyond 3 months. Given the potential benefits and committee expert opinion, they agreed that intra-articular corticosteroids could be considered for people with osteoarthritis if other treatments have not worked, provided the person was made aware that the injection would only provide short-term relief (2 to 10 weeks). The committee agreed that when used, corticosteroid injections should only be used to supplement and support people to participate in therapeutic exercise where possible. Based on their expert opinion, the committee agreed that this evidence was generalisable to other osteoarthritis-affected joints. The committee acknowledged that there was a lack of consistent evidence on corticosteroids (especially for non-knee joint sites), so they made a recommendation for research on intra-articular corticosteroids. There was some evidence from very small studies that showed a potential benefit of stem cell injections. The committee noted that this is an experimental treatment and agreed that it should not be used outside research. They made a recommendation for research on intra-articular stem cell injections. ## How the recommendations might affect practice The recommendation for intra-articular hyaluronan injections reflects current practice so the committee agreed there should be no change in practice or resource impact to the NHS. Corticosteroid injections are used in current practice, but recommending them only for the short-term relief of symptoms may lead to a reduction in their use and a cost saving to the NHS. Return to recommendations # Follow-up and review Recommendations 1.5.1 to 1.5.3 ## Why the committee made the recommendations There was no evidence on follow-up for people with osteoarthritis. Therefore, the committee based their recommendations on their expert opinion. In current practice, follow-up is mainly symptom-led or people with osteoarthritis raise the condition as a concern during follow-up consultations for other conditions. The committee agreed that symptom-led follow-up is likely to be appropriate for most people with osteoarthritis. This is because they may be able to self-manage their condition effectively after getting information and guidance on management strategies. However, the committee also acknowledged that follow-up should focus on the person's needs, so there are some situations in which planned follow-up may be necessary. The committee noted that agreeing a specific time for people to seek additional help if the management is not improving their symptoms is important. They also agreed that it was important to manage osteoarthritis and other conditions the person may have holistically. Because there was no evidence in this area the committee also made a recommendation for research on the effectiveness of patient-initiated compared with routine follow-up. ## How the recommendations might affect practice These recommendations generally reflect current practice. Because they include self-management and pre-existing appointments for other conditions, they are unlikely to cause a substantial increase in costs. Return to recommendations # Imaging for management of osteoarthritis Recommendation 1.5.4 ## Why the committee made the recommendation There was no evidence on using imaging to manage osteoarthritis. Therefore, the committee used their expertise to inform the recommendation. They acknowledged that imaging was important for confirming the severity of structural joint changes when planning or considering surgery. But it was unclear who should do this imaging because some surgeons may only accept a referral for surgery if they are provided with imaging results, whereas others may prefer to do their own imaging after referral. However, in most cases, imaging should not be needed for managing osteoarthritis because it does not guide how the condition will respond to treatment. The committee made recommendations for research on using imaging to inform non-surgical and pre-surgical management of osteoarthritis. ## How the recommendation might affect practice The recommendation reflects current practice, so the cost impact is likely to be minimal. It may be cost saving by reducing the use of imaging for people with osteoarthritis. Return to recommendation # Referral for joint replacement Recommendations 1.6.1 to 1.6.4 ## Why the committee made the recommendations Evidence on referral criteria for joint replacement was limited. This evidence suggested that non-response to analgesics may be associated with a need for joint replacement. Longer duration of symptoms did not appear to be associated with the need for joint replacement, which may show that the symptom duration is less relevant than non-response to treatments. Evidence for the Oxford Hip and Knee scores and the Knee injury and Osteoarthritis Outcome score (KOOS) and Hip disability and Osteoarthritis Outcome Score (HOOS) summary score showed that these numerical scales alone were unlikely to determine whether someone should have surgery, so they were not recommended for use. The committee agreed that the decision to refer someone for joint replacement should be based on clinical assessment after trying all appropriate treatments for that person. These should have been tried for a sufficient length of time to ensure they are not effective at reducing symptoms before referral happens. Given the absence of evidence, the committee made a recommendation for research on indicators for joint replacement in people with osteoarthritis. Evidence on weight loss before surgery showed that, after hip or knee replacement, there was no difference in outcomes for people in different body mass index (BMI) categories. People who were overweight or obese based on BMI did not have an increased mortality rate after surgery and had improved health-related quality of life and patient-reported outcome measures. For people who were underweight based on BMI, evidence showed an increased mortality rate. However, the committee considered that this may be due to comorbidities and that the effect may be exaggerated by the smaller number of underweight participants in studies. Some studies combined the healthy weight group with the underweight group, which made interpreting the evidence more difficult. The committee acknowledged that BMI can give a false impression of the risks and that other factors need to be considered, such as comorbidities. The committee concluded that BMI, and other measurements of whether someone is overweight or obese, should not be a barrier to joint replacement. Similarly, the committee agreed that everyone should be treated equally, and people should not be excluded from referral for joint replacement based on their age, sex or gender, if they smoke or any comorbidities. They agreed that there are few contraindications to surgery and the surgeon would be best placed to assess and discuss suitability of joint replacement on a case-by-case basis. The committee also recommended that the varying risks of surgery in relation to a person's specific circumstances should be explained. ## How the recommendations might affect practice Current practice is inconsistent. If all centres adopt these recommendations, then it may lead to an increase in the number of referrals for surgery and subsequently more joint replacements done overall. Return to recommendations # Arthroscopic procedures Recommendation 1.7.1 ## Why the committee made the recommendation There was no evidence showing that arthroscopic procedures reduce pain and improve physical function. Evidence also showed possible harms with arthroscopic procedures compared with sham procedures. Cost-effectiveness evidence showed that arthroscopic procedures were more costly than standard care. The committee agreed that arthroscopic procedures were not commonly used in clinical practice for osteoarthritis. ## How the recommendation might affect practice The recommendation reflects current practice, so there should be no change in practice or resource impact. Return to recommendation# Context Osteoarthritis is the most common form of arthritis. It typically presents with joint symptoms such as pain and stiffness, mostly affecting the knee, hip, hand and foot joints. Symptoms vary from mild and intermittent, to more persistent or severe. The condition does not inevitably get worse, but symptoms fluctuate and flares are common. Osteoarthritis has a negative impact on daily activities, quality of life and health outcomes. It can affect people's physical, social and emotional life; more than half of people with osteoarthritis report that it seriously affects their family and working life. Osteoarthritis is more common in women, people living in deprived areas, people aged 45 and over and people living with obesity. The prevalence of osteoarthritis is increasing. Many people with osteoarthritis have multiple long-term conditions, making their care more complex. NICE produced a guideline on the care and management of osteoarthritis in 2014. This updated guideline makes recommendations on diagnosing and managing osteoarthritis, based on new evidence. This includes information and support, non‑pharmacological and pharmacological treatments, follow-up, and referral for joint replacement. The aim of this guideline is to improve management of osteoarthritis and the quality of life for people with the condition.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Diagnosis\n\nDiagnose osteoarthritis clinically without imaging in people who:\n\nare 45 or over and\n\nhave activity-related joint pain and\n\nhave either no morning joint-related stiffness or morning stiffness that lasts no longer than 30\xa0minutes.\n\nDo not routinely use imaging to diagnose osteoarthritis unless there are atypical features or features that suggest an alternative or additional diagnosis.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: additional benefit of imaging in the diagnosis of osteoarthritis.\n\nLoading. Please wait.\n\n# Information and support\n\nWhen giving information to people with osteoarthritis, their families and carers, tailor it to their individual needs (such as language and culture), ensure it is in an accessible format and follow the recommendations on:\n\nenabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services\n\nputting shared decision making into practice in NICE's guideline on shared decision making\n\ndelivering an approach to care that takes account of multimorbidity in NICE's guideline on multimorbidity.\n\nExplain to people with osteoarthritis that:\n\nit is diagnosed clinically and usually does not need imaging to confirm the diagnosis and\n\nmanagement should be guided by symptoms and physical function and\n\nthe core treatments for the condition are therapeutic exercise and weight management (if appropriate), along with information and support.\n\nAdvise people with osteoarthritis where they can find further information on:\n\nosteoarthritis and how it develops (including flares and progression over time), and information that challenges common misconceptions about the condition\n\nspecific types of exercise\n\nmanaging their symptoms\n\nhow to access additional sources of information and support after consultations, such as peer-to-peer support and support groups\n\nbenefits and limitations of treatment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: post-diagnostic information on osteoarthritis for people with osteoarthritis, their family and carers.\n\nLoading. Please wait.\n\n# Non-pharmacological management\n\n## Therapeutic exercise\n\nFor all people with osteoarthritis, offer therapeutic exercise tailored to their needs (for example, local muscle strengthening, general aerobic fitness).\n\nConsider supervised therapeutic exercise sessions for people with osteoarthritis.\n\nAdvise people with osteoarthritis that joint pain may increase when they start therapeutic exercise. Explain that:\n\ndoing regular and consistent exercise, even though this may initially cause pain or discomfort, will be beneficial for their joints\n\nlong-term adherence to an exercise plan increases its benefits by reducing pain and increasing functioning and quality of life.\n\nConsider combining therapeutic exercise with an education programme or behaviour change approaches in a structured treatment package.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on therapeutic exercise\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0C: clinical and cost effectiveness of exercise for the management of osteoarthritis\n\nevidence review K: clinical and cost effectiveness of treatment packages for the management of osteoarthritis.\n\nLoading. Please wait.\n\n## Weight management\n\nFor people with osteoarthritis who are living with overweight or obesity:\n\nadvise them that weight loss will improve their quality of life and physical function, and reduce pain\n\nsupport them to choose a weight loss goal\n\nexplain that any amount of weight loss is likely to be beneficial, but losing 10% of their body weight is likely to be better than 5%.For guidance and information on weight management, including recommended interventions to support weight loss, see NICE's topic page on obesity.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on weight management\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: benefit of weight loss for the management of osteoarthritis for people living with overweight or obesity.\n\nLoading. Please wait.\n\n## Manual therapy\n\nOnly consider manual therapy (such as manipulation, mobilisation or soft tissue techniques):\n\nfor people with hip or knee osteoarthritis and\n\nalongside therapeutic exercise.\n\nIf discussing manual therapy, explain to people with osteoarthritis that there is not enough evidence to support its use alone for managing osteoarthritis.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on manual therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: clinical and cost-effectiveness of manual therapy for the management of osteoarthritis.\n\nLoading. Please wait.\n\n## Acupuncture\n\nDo not offer acupuncture or dry needling to manage osteoarthritis.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on acupuncture\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: clinical and cost-effectiveness of acupuncture for people with osteoarthritis.\n\nLoading. Please wait.\n\n## Electrotherapy\n\nDo not offer any of the following electrotherapy treatments to people with osteoarthritis because there is insufficient evidence of benefit:\n\ntranscutaneous electrical nerve stimulation (TENS)\n\nultrasound therapy\n\ninterferential therapy\n\nlaser therapy\n\npulsed short-wave therapy\n\nneuromuscular electrical stimulation (NMES).\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on electrotherapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: clinical and cost effectiveness of electrotherapy for the management of osteoarthritis.\n\nLoading. Please wait.\n\n## Devices\n\nConsider walking aids (such as walking sticks) for people with lower limb osteoarthritis.\n\nDo not routinely offer insoles, braces, tape, splints or supports to people with osteoarthritis unless:\n\nthere is joint instability or abnormal biomechanical loading and\n\ntherapeutic exercise is ineffective or unsuitable without the addition of an aid or device and\n\nthe addition of an aid or device is likely to improve movement and function.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on devices\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: clinical and cost effectiveness of devices for the management of osteoarthritis.\n\nLoading. Please wait.\n\n# Pharmacological management\n\n## Topical, oral and transdermal medicines\n\nIf pharmacological treatments are needed to manage osteoarthritis, use them:\n\nalongside non-pharmacological treatments and to support therapeutic exercise\n\nat the lowest effective dose for the shortest possible time.\n\nOffer a topical non-steroidal anti-inflammatory drug (NSAID) to people with knee osteoarthritis.\n\nConsider a topical NSAID for people with osteoarthritis that affects other joints.\n\nIf topical medicines are ineffective or unsuitable, consider an oral NSAID for people with osteoarthritis and take account of:\n\npotential gastrointestinal, renal, liver and cardiovascular toxicity\n\nany risk factors the person may have, including age, pregnancy, current medication and comorbidities.Offer a gastroprotective treatment (such as a proton pump inhibitor) for people with osteoarthritis while they are taking an NSAID.\n\nDo not routinely offer paracetamol or weak opioids unless:\n\nthey are only used infrequently for short-term pain relief and\n\nall other pharmacological treatments are contraindicated, not tolerated or ineffective.Explain to people with osteoarthritis that there is no strong evidence of benefit for paracetamol. For more information about opioids, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nDo not offer glucosamine or strong opioids to people to manage osteoarthritis.\n\nIf the person with osteoarthritis asks about glucosamine or strong opioids, explain that:\n\nthere is no strong evidence of benefit for glucosamine\n\nthe risks of strong opioids outweigh the benefits.\n\nReview with the person whether to continue treatment. Base the frequency of reviews on clinical need.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on topical, oral and transdermal medicines\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I, evidence review\xa0I: appendices A to D, evidence review\xa0I: appendices E to J: clinical and cost effectiveness of oral, topical and transdermal medicines for the management of osteoarthritis.\n\nLoading. Please wait.\n\n## Intra-articular injections\n\nDo not offer intra-articular hyaluronan injections to manage osteoarthritis.\n\nConsider intra-articular corticosteroid injections when other pharmacological treatments are ineffective or unsuitable, or to support therapeutic exercise. Explain to the person that these only provide short‑term relief (2 to 10\xa0weeks).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on intra-articular injections\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: clinical and cost effectiveness of intra-articular injections for the management of osteoarthritis.\n\nLoading. Please wait.\n\n# Follow-up and review\n\n## Follow-up appointments\n\nConsider patient-initiated follow-up for most people with osteoarthritis.\n\nConsider planned follow-up for people with osteoarthritis when their individual needs and preferences suggest that this is necessary, taking into account:\n\ntreatments or interventions that need monitoring\n\ntheir ability to seek help for themselves\n\ntheir occupation and activities\n\nthe severity of their symptoms or functional limitations.People with multiple long-term conditions are likely to benefit from a tailored approach in line with NICE's guideline on multimorbidity.\n\nAdvise people with osteoarthritis to seek follow-up if planned management is not working within an agreed follow-up time or they are having difficulties with the agreed approaches.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up and review\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: regular follow-up and review.\n\nLoading. Please wait.\n\n## Imaging for management of osteoarthritis\n\nDo not routinely use imaging for follow-up or to guide non-surgical management of osteoarthritis.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on imaging for the management of osteoarthritis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: clinical and cost effectiveness of imaging during the management of osteoarthritis.\n\nLoading. Please wait.\n\n# Referral for joint replacement\n\nConsider referring people with hip, knee or shoulder osteoarthritis for joint replacement if:\n\ntheir joint symptoms (such as pain, stiffness, reduced function or progressive joint deformity) are substantially impacting their quality of life and\n\nnon-surgical management (for example, therapeutic exercise, weight loss, pain relief) is ineffective or unsuitable.\n\nUse clinical assessment when deciding to refer someone for joint replacement, instead of systems that numerically score severity of disease.\n\nDo not exclude people with osteoarthritis from referral for joint replacement because of:\n\nage\n\nsex or gender\n\nsmoking\n\ncomorbidities\n\noverweight or obesity, based on measurements such as body mass index (BMI).\n\nIf discussing referral for joint replacement, explain to the person with osteoarthritis that the risks of joint replacement can vary depending on the factors listed in recommendation 1.6.3.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral for joint replacement\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0O: indicators for referral for possible joint replacement surgery\n\nevidence review P: outcomes of joint replacement surgery dependent on body mass index\n\nLoading. Please wait.\n\n# Arthroscopic procedures\n\nDo not offer arthroscopic lavage or debridement to people with osteoarthritis.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on arthroscopic procedures\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: clinical and cost effectiveness of arthroscopic procedures for the management of osteoarthritis.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Atypical features\n\nAtypical features could include a history of recent trauma, prolonged morning joint‑related stiffness, rapid worsening of symptoms or deformity, the presence of a hot swollen joint, or concerns that may suggest infection or malignancy.\n\n## Flares\n\nA temporary worsening of symptoms (pain, swelling and stiffness) that:\n\nis worse than normal\n\nmay affect sleep, activity, function and psychological wellbeing\n\nmay lead to change in therapy for at least 24\xa0hours.\n\n## Treatment package\n\nA treatment package is defined as any treatment for osteoarthritis (this could include: exercise, manual therapy, devices and pharmacological treatments) combined with one of the following:\n\nbehaviour change approaches, including ways to reduce pain and straining when using joints, pain coping skills training (including spouse-assisted coping skills training), goal setting; motivational coaching; weight management counselling and workplace risk counselling\n\nan education programme given by 1 or more healthcare professionals over multiple sessions, including those based on behavioural theory.\n\n## Walking aids\n\nWalking aids include walking sticks, crutches, walking frames and rollators. They support the person with osteoarthritis to move around independently and safely by improving their walking pattern and balance or reducing weight bearing on the affected joint.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Exercise\n\nWhat is the clinical and cost effectiveness of supervised group and individual exercise compared with unsupervised exercise for people with osteoarthritis?\n\nFor a short explanation of why the committee made the recommendation for research see the rationale section on therapeutic exercise\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: clinical and cost effectiveness of exercise for the management of osteoarthritis.\n\nLoading. Please wait.\n\n## Devices\n\nWhat is the clinical and cost effectiveness of devices compared with usual care for the management of painful foot and or ankle osteoarthritis?\n\nFor a short explanation of why the committee made the recommendation for research see the rationale section on devices\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: clinical and cost effectiveness of devices for the management of osteoarthritis.\n\nLoading. Please wait.\n\n## Topical medicines\n\nWhat is the clinical and cost effectiveness of topical non-steroidal anti-inflammatory drugs and topical capsaicin for osteoarthritis-affected joints other than the knee?\n\nFor a short explanation of why the committee made the recommendation for research see the rationale section on topical, oral and transdermal medicines\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I, evidence review\xa0I: appendices A to D, evidence review\xa0I: appendices E to J: clinical and cost effectiveness of oral, topical and transdermal medicines for the management of osteoarthritis.\n\nLoading. Please wait.\n\n## Follow-up strategies\n\nWhat is the clinical and cost effectiveness of patient-initiated follow-up compared with routine follow-up for people with osteoarthritis?\n\nFor a short explanation of why the committee made the recommendation for research see the rationale section on follow-up and review\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: regular follow-up and review.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Patient information\n\nWhat information on the management of flares do people with osteoarthritis, their family and carers need after diagnosis?\n\nWhat information do people with osteoarthritis from different ethnic and socioeconomic groups, and those with learning disabilities, issues with health literacy and severe mental illness (and their family and carers), need?\n\nFor a short explanation of why the committee made the recommendations for research see the rationale section on information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: post-diagnostic information on osteoarthritis for people with osteoarthritis, their family and carers.\n\nLoading. Please wait.\n\n## Manual therapy\n\nWhat is the clinical and cost effectiveness of manual therapy for people with osteoarthritis, when used alone and when in combination with therapeutic exercise?\n\nFor a short explanation of why the committee made the recommendation for research see the rationale section on manual therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: clinical and cost effectiveness of manual therapy for the management of osteoarthritis.\n\nLoading. Please wait.\n\n## Electroacupuncture\n\nIs electroacupuncture a clinically and cost-effective treatment for any subgroup of people with osteoarthritis?\n\nFor a short explanation of why the committee made the recommendation for research see the rationale section on acupuncture\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: clinical and cost effectiveness of acupuncture for people with osteoarthritis.\n\nLoading. Please wait.\n\n## Extracorporeal shockwave therapy\n\nWhat is the clinical and cost effectiveness of extracorporeal shockwave therapy for managing osteoarthritis?\n\nFor a short explanation of why the committee made the recommendation for research see the rationale section on electrotherapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: clinical and cost effectiveness of electrotherapy for the management of osteoarthritis.\n\nLoading. Please wait.\n\n## Footwear\n\nWhat is the clinical and cost effectiveness of footwear for managing lower limb osteoarthritis?\n\nFor a short explanation of why the committee made the recommendation for research see the rationale section on devices\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: clinical and cost effectiveness of devices for the management of osteoarthritis.\n\nLoading. Please wait.\n\n## Topical and oral medicines\n\nWhat is the clinical and cost effectiveness of topical local anaesthetics for people with osteoarthritis?\n\nWhat is the clinical and cost effectiveness of antiepileptics and antidepressants (other than duloxetine) for people with osteoarthritis?\n\nWhat is the clinical and cost effectiveness of weak oral opioids for people with osteoarthritis?\n\nFor a short explanation of why the committee made the recommendations for research see the rationale section on topical, oral and transdermal medicines\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I, evidence review\xa0I: appendices A to D, evidence review\xa0I: appendices E to J: clinical and cost effectiveness of oral, topical and transdermal medicines for the management of osteoarthritis.\n\nLoading. Please wait.\n\n## Intra-articular injections\n\nWhat is the clinical and cost effectiveness of intra-articular corticosteroids for managing osteoarthritis-affected joints other than the knee?\n\nWhat is the clinical and cost effectiveness of intra-articular stem cells for managing osteoarthritis?\n\nFor a short explanation of why the committee made the recommendations for research see the rationale section on intra-articular injections\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: clinical and cost effectiveness of intra-articular injections for the management of osteoarthritis.\n\nLoading. Please wait.\n\n## Referral criteria for joint replacement\n\nWhat are the most important indicators that someone with osteoarthritis (including shoulder osteoarthritis) would benefit from joint replacement? For example:\n\npresence of night pain\n\nnon-response to non-pharmacological interventions\n\njoint instability symptoms\n\npresence of flares\n\nnumerical summary scores.\n\nFor a short explanation of why the committee made the recommendation for research see the rationale section on referral for joint replacement\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0O: indicators for referral for possible joint replacement surgery.\n\nLoading. Please wait.\n\n## Imaging for management of osteoarthritis\n\nWhat is the clinical and cost effectiveness of imaging for informing non-surgical management (for example, exercise or weight loss) in primary care for people with osteoarthritis?\n\nWhat is the clinical and cost effectiveness of imaging for use at different parts of the care pathway (for example, primary care, intermediate care or secondary care) before surgery for people with osteoarthritis?\n\nFor a short explanation of why the committee made the recommendations for research see the rationale section on imaging for management of osteoarthritis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: clinical and cost effectiveness of imaging during the management of osteoarthritis.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Diagnosis\n\nRecommendations 1.1.1 and 1.1.2\n\n## Why the committee made the recommendations\n\nThere was no evidence showing that imaging is beneficial for diagnosing osteoarthritis. The committee agreed that imaging adds little value and that osteoarthritis can be diagnosed by taking a thorough history and doing an examination. The committee agreed that imaging can be useful if atypical features are present that could suggest an alternative or additional diagnosis, such as other inflammatory forms of arthritis (for example, rheumatoid arthritis) and malignancy.\n\n## How the recommendations might affect practice\n\nImaging is frequently used when diagnosing osteoarthritis, despite uncertainties about its benefit, the resource implications and potential for delays in starting management. The recommendations should reduce unnecessary resource use and be cost saving.\n\nReturn to recommendations\n\n# Information and support\n\nRecommendations 1.2.1 to 1.2.3\n\n## Why the committee made the recommendations\n\nEvidence showed that generally people with osteoarthritis wanted more information about their condition. This included information about the causes, what their diagnosis means for the future and where to find more information on self‑management. The committee based their recommendations on the evidence and their experience. They agreed that it is important to tell people that diagnosis is made clinically without imaging, that imaging rarely provides any extra information helpful for diagnosing or planning non-surgical treatment for osteoarthritis, and that it would only be used if there were suspicion of an alternative diagnosis or other complications. This would help reassure and dispel any belief that X-rays or other forms of imaging are needed to diagnose osteoarthritis.\n\nThe committee noted the importance of information that offers hope for the future and supports self-management strategies (for example, information that emphasises symptom-reducing behaviours, like therapeutic exercise). They agreed that explaining the core treatments for osteoarthritis would help people understand that pharmacological treatments are not a long-term solution. They also agreed that information about recognising flares and how to manage changes in pain would help the person better understand how their condition may vary over time and what they can do about it. The committee noted more evidence was needed on information about managing flares and information for different populations of people with osteoarthritis, and so made recommendations for research on what information people with osteoarthritis need.\n\nThe committee agreed that each person's experience of osteoarthritis differs and therefore tailoring the information to their needs, as described in NICE's guideline on patient experience in adult NHS services, is important. They also agreed that osteoarthritis is more common in older people who are likely to have other conditions. Therefore, the recommendations on delivering an approach to care that takes account of multimorbidity in NICE's guideline on multimorbidity are particularly relevant to people with osteoarthritis.\n\n## How the recommendations might affect practice\n\nThe recommendations generally reflect current practice because information is likely to be already provided, but they advise on areas in which practice can be improved.\n\nReturn to recommendations\n\n# Therapeutic exercise\n\nRecommendations 1.3.1 to 1.3.4\n\n## Why the committee made the recommendations\n\nThe evidence showed that exercise has a clinically important benefit for people with osteoarthritis, as well as general health benefits and a superior safety profile compared with other common treatments, such as analgesia. In particular, the committee highlighted the importance of therapeutic exercise to help manage and reduce symptoms and improve or maintain physical functioning over the long term. For most benefit, they recommended this be tailored to the needs of the person, such as joint-site-specific exercises.\n\nLimited evidence showed that supervised exercise had some benefits compared with unsupervised exercise. The committee's expert consensus was that supervised exercise is likely to be of greater benefit than unsupervised exercise for people with osteoarthritis. This is because supervised exercise may enable tailored exercise and social support, which may increase adherence and lead to people with osteoarthritis forming a regular exercise habit.\n\nThe committee also agreed that shared decision making is important when deciding the form of exercise delivery and type of exercise, as well as considering personal preference and service availability. The committee, acknowledging the importance of exercise, made further recommendations to support people to continue therapeutic exercise by emphasising its benefits while acknowledging that exercise may initially be difficult. They wanted to reassure people with osteoarthritis and healthcare professionals that exercise is not harmful to osteoarthritic joints, and that doing regular and consistent exercise over a long period of time can reduce pain and increase functioning and quality of life.\n\nThe committee noted that further evidence may be needed and made a recommendation for research to compare the clinical and cost effectiveness of supervised group and individual exercise with unsupervised exercise.\n\nEvidence showed that treatment packages had a clinically important benefit on physical function compared with education or behaviour change interventions alone. They also had consistent beneficial changes in quality of life, pain and physical function compared with standard care. However, they showed no superiority to individual therapies (such as exercise, manual therapy and electrotherapy). The committee agreed that a person-centred approach is important. Additional education or behavioural change approaches may help some people achieve their goals, but others may not need this. Therefore, the committee recommended combining therapeutic exercise as part of a structured treatment package because this may be more suitable for some people and motivate them to continue with therapeutic exercise.\n\n## How the recommendations might affect practice\n\nCurrent practice around therapeutic exercise varies. These recommendations may lead to a change in practice by recommending tailored exercise (including supervised exercise) and using treatment packages.\n\nReturn to recommendations\n\n# Weight management\n\nRecommendation 1.3.5\n\n## Why the committee made the recommendation\n\nThe committee acknowledged that evidence on the effects of weight loss for people with osteoarthritis had limitations. However, for people with knee osteoarthritis, the evidence generally showed that as more weight was lost, the benefits for quality of life, pain and physical function increased. The committee acknowledged the challenges people can have with losing weight and maintaining this weight loss, and recommended that they are supported.\n\nThe committee acknowledged that, for people who are overweight, losing more than 10% of their body weight may be the most beneficial, but this may not be achievable for all. They wanted to emphasise that losing any amount of weight would be beneficial, but that losing more would have more benefits. They agreed that also explaining that losing 10% of their body weight is likely to be better than 5% might help provide an incentive and encourage weight loss. They also agreed that advising on the amount of weight to lose can help people with osteoarthritis by providing a target for them to work towards.\n\nThe committee determined that, although evidence was from people with knee osteoarthritis, this could be applied to people with other osteoarthritis-affected joints. This is because of the potential additional benefits of weight loss seen in other populations, such as reducing inflammatory factors, that may be beneficial for all joint sites and general wellbeing. The committee also agreed that osteoarthritis is a multi-joint disease and people presenting with the condition in 1 joint may end up getting it in another. Weight loss may help reduce this risk.\n\n## How the recommendation might affect practice\n\nThis recommendation somewhat reflects current practice but may lead to a change in how people with osteoarthritis and healthcare professionals discuss weight loss. This is unlikely to have a significant resource impact.\n\nReturn to recommendation\n\n# Manual therapy\n\nRecommendations 1.3.6 and 1.3.7\n\n## Why the committee made the recommendations\n\nThe committee acknowledged recent evidence that showed some clinical benefits of manual therapy for hip and knee osteoarthritis, with no evidence being identified for other joint sites. However, the benefits were stronger if manual therapy was combined with exercise. Clinical and economic evidence showed that exercise alone was more effective than both manual therapy alone and the combination of manual therapy and exercise. So, the committee concluded that manual therapy should only be considered alongside therapeutic exercise. Most studies provided therapy for less than 3\xa0months and on average for 7\xa0weeks. The committee agreed that the duration of manual therapy would be similar, but would vary according to the person's needs. They agreed that further research was needed, in particular evidence from well‑powered, high-quality studies with adequate blinding and on other osteoarthritis‑affected joints. They made a recommendation for research on manual therapy for people with osteoarthritis used alone and in combination with therapeutic exercise.\n\n## How the recommendations might affect practice\n\nCurrent practice around manual therapy varies. Adding manual therapy to exercise would be a slight change in practice, but it would not have a substantial resource impact because it is not needed long term.\n\nReturn to recommendations\n\n# Acupuncture\n\nRecommendation 1.3.8\n\n## Why the committee made the recommendation\n\nThe available evidence was predominantly for knee osteoarthritis. This showed a lack of benefits of acupuncture and some evidence of harm. Economic evidence also showed that using acupuncture for osteoarthritis is not cost effective, so the committee did not recommend using acupuncture or dry needling. There was some evidence of clinical benefit and cost effectiveness for electroacupuncture but this was of very low quality because of small study sizes and inconsistency between studies. The evidence for electroacupuncture suggested it showed a benefit compared with sham acupuncture but not compared with acupuncture or no treatment. The committee considered that the inconsistent evidence could be the result of some people responding more to electroacupuncture than others. Because there is uncertainty about who might benefit from electroacupuncture, the committee made a recommendation for research on electroacupuncture for osteoarthritis.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice so the committee agreed there should be no change in practice or resource impact to the NHS.\n\nReturn to recommendation\n\n# Electrotherapy\n\nRecommendation 1.3.9\n\n## Why the committee made the recommendation\n\nAlthough there were many studies on electrotherapy, the findings were inconsistent and mostly showed little benefit. The committee acknowledged that most studies were small, with fewer than 100\xa0participants, and that evidence from direct comparisons of electrotherapy with other interventions was uncertain. The committee agreed there is not enough evidence to recommend electrotherapy for people with osteoarthritis.\n\nExtracorporeal shockwave therapy showed some evidence of benefit compared with a sham intervention. However, this evidence was uncertain because of the small trial sizes and challenges in using appropriate sham techniques. The committee agreed that further research using an appropriate sham with more than 50\xa0participants in each study arm is needed and made a recommendation for research on extracorporeal shockwave therapy.\n\n## How the recommendation might affect practice\n\nThe committee noted that although the use of some electrotherapy modalities in the NHS has decreased, other modalities with unclear evidence of benefit continue to be used. Also, people with osteoarthritis may self-prescribe electrotherapy devices. This recommendation may reduce the prescription and use of TENS.\n\nReturn to recommendation\n\n# Devices\n\nRecommendations 1.3.10 and 1.3.11\n\n## Why the committee made the recommendations\n\nEvidence from a small study on walking aids showed that they benefit quality of life and reduce pain compared with no device. The committee agreed that walking aids have the advantage of reducing the pressure in the leg joints, which helps stability and movement to encourage physical activity and independence. This is particularly the case while waiting for joint replacement or if surgery cannot be undertaken, because the aid helps support exercise and confidence with walking. Overall, they agreed that the evidence, supported by their expert opinion, was enough to recommend walking aids for people with lower limb osteoarthritis.\n\nThe committee concluded that there was not enough evidence to support the routine use of insoles, braces, tape, splints or supports. They also noted that there is a potential risk that some of these devices could cause significant adverse events, such as blistering and other pressure damage. The committee acknowledged that research on devices has challenges, such as appropriate sham devices for comparisons.\n\nThe committee agreed that further research is needed on devices, through studies that have a larger number of participants, sufficient blinding and allocation concealment. Because most of the evidence was for knee osteoarthritis, they made a recommendation for research on devices for painful foot and ankle osteoarthritis. The committee also noted that evidence on footwear had limitations and made a recommendation for research on footwear for managing lower limb osteoarthritis.\n\n## How the recommendations might affect practice\n\nUse of devices for osteoarthritis is varied in current practice. Currently, insoles, braces, tape or supports may be used by some people with osteoarthritis because they were previously recommended by NICE. The recommendations may change practice with using devices. But the practice of using walking aids is unlikely to change. There is a potential for some cost savings to the NHS.\n\nReturn to recommendations\n\n# Topical, oral and transdermal medicines\n\nRecommendations 1.4.1 to 1.4.8\n\n## Why the committee made the recommendations\n\nThe committee agreed that pharmacological treatments may be useful for reducing symptoms and supporting people to start other more effective treatments, such as therapeutic exercise. However, they noted that the risks of pharmacological treatments should be understood and that treatments should not be overused or used when they are not needed. The committee agreed that it was difficult to define treatment strengths and durations that would be generalisable to everyone. This is because people with osteoarthritis can have a variety of comorbidities and factors that might influence treatment. Therefore, the committee emphasised that treatments should use the lowest effective dose for the shortest possible time.\n\nTopical non-steroidal anti-inflammatory drugs (NSAIDs) were clinically effective in reducing pain for people with knee osteoarthritis and generally the most cost‑effective medicine for osteoarthritis. They were also associated with minimal adverse events. Evidence on topical NSAIDs came from studies including people with knee osteoarthritis and 1\xa0study including people with hand osteoarthritis. The evidence showed no clinically important difference for hand osteoarthritis, but the committee noted this was uncertain because it was based on 1\xa0study. The committee noted that although evidence only showed benefit for knee osteoarthritis, other people with osteoarthritis-affected joints may also benefit from topical NSAIDs. There was some evidence showing that topical capsaicin reduces pain in knee osteoarthritis, but not hand osteoarthritis, and has minimal adverse events. However, capsaicin is more expensive and topical NSAIDs were considered a better option. The committee made a recommendation for research on topical medicines for osteoarthritis-affected joints other than the knee.\n\nOral NSAIDs were found to be cost effective and evidence showed they slightly reduced pain and increased physical function. The committee acknowledged the Medicines and Healthcare products Regulatory Agency (MHRA) safety warnings on NSAIDs for cardiovascular safety, renal safety and gastrointestinal risk. They agreed that NSAIDs, as well as other pharmacological treatments for osteoarthritis, should be used for as short a time as possible and that the potential harms for gastrointestinal, cardiovascular, liver and kidney adverse events should be carefully considered when prescribing.\n\nEvidence showed that adding gastroprotection can reduce gastrointestinal bleeding or perforation. However, this was associated with an increase in cardiovascular adverse events compared with oral NSAIDs alone. The committee agreed that this may be unrelated to the addition of gastroprotection and that randomised controlled trial evidence alone may not be the best source for safety evidence, because the population size and length of follow-up are usually limited. Therefore, they also used their clinical experience and guidance from other organisations, including the MHRA. Based on this, the committee agreed that use of gastroprotection should be offered with NSAIDs.\n\nEvidence showed that opioids also have the potential for harm, including gastrointestinal and central nervous system adverse events. The committee acknowledged further potential harms such as physical dependence, opioid-induced hyperalgesia and tolerance. Cost-effectiveness evidence showed that buprenorphine, a transdermal opioid, was generally more cost effective than oral strong opioids (such as morphine, oxycodone and tramadol). This evidence was from people having buprenorphine who had not had opioids before, but this was generally not the case for people having oral strong opioids. All people had already tried a type of analgesia such as NSAIDs or paracetamol. However, the committee acknowledged the MHRA safety warning on opioids and recommendations in NICE's guideline on medicines associated with dependence or withdrawal symptoms, which advises against the use of modified-release opioids. Therefore, the committee recommended against the use of strong opioids. Evidence from 1 small study of weak opioids showed a clinically important benefit in reducing pain. The committee agreed that there was not enough evidence of benefit and on potential risks.\n\nAlthough paracetamol has a low potential to cause adverse events, evidence showed that it has no additional benefit in reducing osteoarthritis pain and improving quality of life and physical function compared with placebo. However, the committee discussed that some people cannot use NSAIDS. Therefore, they recommended against the routine use of paracetamol but noted some circumstances where it may be used.\n\nEvidence on glucosamine was inconsistent and the largest benefits were shown by smaller studies that were of lower quality. Because glucosamine is not used in current practice and there is no strong evidence of benefit the committee recommended against its use for people with osteoarthritis.\n\nThe committee determined that there was not enough evidence to make recommendations on antiepileptics, antidepressants, rubefacients and topical local anaesthetics. The committee made recommendations for research on antiepileptics, antidepressants, weak oral opioids and topical local anaesthetics for osteoarthritis. Duloxetine was not included in the recommendation for research because many studies have already investigated its use, but there is less evidence for other antidepressants that may be used more regularly in the NHS to manage pain (such as tricyclic antidepressants). The committee did not make a recommendation for research on rubefacients because they did not think that these would benefit people with osteoarthritis.\n\nThe committee agreed that pharmacological treatments should be periodically reviewed with the person. They recommended this should be done according to clinical need.\n\n## How the recommendations might affect practice\n\nCurrent practice in pharmacological treatment for osteoarthritis varies in the types of treatments used and how people access treatment (such as buying medicines over the counter instead of accessing them through healthcare services). These recommendations may cause changes in current practice towards using medicines for a shorter time, increasing use of topical NSAIDs, and reducing use of paracetamol and opioids.\n\nReturn to recommendations\n\n# Intra-articular injections\n\nRecommendations 1.4.9 and 1.4.10\n\n## Why the committee made the recommendations\n\nThere was no evidence showing that hyaluronan injections improved quality of life or physical function, or reduced pain, in people with knee or hip osteoarthritis. Evidence showed a potential harm for hip osteoarthritis. Limited evidence for other osteoarthritis-affected joints showed inconsistent benefits and some potential harms. Based on their expert opinion, the committee agreed that these results were generalisable to other forms of osteoarthritis and that hyaluronan injections should not be offered.\n\nEvidence showed that corticosteroid injections had inconsistent benefits on improving quality of life and physical function for people with hip osteoarthritis, and reducing pain for people with knee osteoarthritis. There was no evidence showing long-term benefit beyond 3\xa0months. Given the potential benefits and committee expert opinion, they agreed that intra-articular corticosteroids could be considered for people with osteoarthritis if other treatments have not worked, provided the person was made aware that the injection would only provide short-term relief (2\xa0to\xa010\xa0weeks). The committee agreed that when used, corticosteroid injections should only be used to supplement and support people to participate in therapeutic exercise where possible. Based on their expert opinion, the committee agreed that this evidence was generalisable to other osteoarthritis-affected joints.\n\nThe committee acknowledged that there was a lack of consistent evidence on corticosteroids (especially for non-knee joint sites), so they made a recommendation for research on intra-articular corticosteroids.\n\nThere was some evidence from very small studies that showed a potential benefit of stem cell injections. The committee noted that this is an experimental treatment and agreed that it should not be used outside research. They made a recommendation for research on intra-articular stem cell injections.\n\n## How the recommendations might affect practice\n\nThe recommendation for intra-articular hyaluronan injections reflects current practice so the committee agreed there should be no change in practice or resource impact to the NHS. Corticosteroid injections are used in current practice, but recommending them only for the short-term relief of symptoms may lead to a reduction in their use and a cost saving to the NHS.\n\nReturn to recommendations\n\n# Follow-up and review\n\nRecommendations 1.5.1 to 1.5.3\n\n## Why the committee made the recommendations\n\nThere was no evidence on follow-up for people with osteoarthritis. Therefore, the committee based their recommendations on their expert opinion. In current practice, follow-up is mainly symptom-led or people with osteoarthritis raise the condition as a concern during follow-up consultations for other conditions. The committee agreed that symptom-led follow-up is likely to be appropriate for most people with osteoarthritis. This is because they may be able to self-manage their condition effectively after getting information and guidance on management strategies. However, the committee also acknowledged that follow-up should focus on the person's needs, so there are some situations in which planned follow-up may be necessary. The committee noted that agreeing a specific time for people to seek additional help if the management is not improving their symptoms is important. They also agreed that it was important to manage osteoarthritis and other conditions the person may have holistically. Because there was no evidence in this area the committee also made a recommendation for research on the effectiveness of patient-initiated compared with routine follow-up.\n\n## How the recommendations might affect practice\n\nThese recommendations generally reflect current practice. Because they include self-management and pre-existing appointments for other conditions, they are unlikely to cause a substantial increase in costs.\n\nReturn to recommendations\n\n# Imaging for management of osteoarthritis\n\nRecommendation 1.5.4\n\n## Why the committee made the recommendation\n\nThere was no evidence on using imaging to manage osteoarthritis. Therefore, the committee used their expertise to inform the recommendation. They acknowledged that imaging was important for confirming the severity of structural joint changes when planning or considering surgery. But it was unclear who should do this imaging because some surgeons may only accept a referral for surgery if they are provided with imaging results, whereas others may prefer to do their own imaging after referral. However, in most cases, imaging should not be needed for managing osteoarthritis because it does not guide how the condition will respond to treatment. The committee made recommendations for research on using imaging to inform non-surgical and pre-surgical management of osteoarthritis.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice, so the cost impact is likely to be minimal. It may be cost saving by reducing the use of imaging for people with osteoarthritis.\n\nReturn to recommendation\n\n# Referral for joint replacement\n\nRecommendations 1.6.1 to 1.6.4\n\n## Why the committee made the recommendations\n\nEvidence on referral criteria for joint replacement was limited. This evidence suggested that non-response to analgesics may be associated with a need for joint replacement. Longer duration of symptoms did not appear to be associated with the need for joint replacement, which may show that the symptom duration is less relevant than non-response to treatments. Evidence for the Oxford Hip and Knee scores and the Knee injury and Osteoarthritis Outcome score (KOOS) and Hip disability and Osteoarthritis Outcome Score (HOOS) summary score showed that these numerical scales alone were unlikely to determine whether someone should have surgery, so they were not recommended for use. The committee agreed that the decision to refer someone for joint replacement should be based on clinical assessment after trying all appropriate treatments for that person. These should have been tried for a sufficient length of time to ensure they are not effective at reducing symptoms before referral happens. Given the absence of evidence, the committee made a recommendation for research on indicators for joint replacement in people with osteoarthritis.\n\nEvidence on weight loss before surgery showed that, after hip or knee replacement, there was no difference in outcomes for people in different body mass index (BMI) categories. People who were overweight or obese based on BMI did not have an increased mortality rate after surgery and had improved health-related quality of life and patient-reported outcome measures. For people who were underweight based on BMI, evidence showed an increased mortality rate. However, the committee considered that this may be due to comorbidities and that the effect may be exaggerated by the smaller number of underweight participants in studies. Some studies combined the healthy weight group with the underweight group, which made interpreting the evidence more difficult. The committee acknowledged that BMI can give a false impression of the risks and that other factors need to be considered, such as comorbidities. The committee concluded that BMI, and other measurements of whether someone is overweight or obese, should not be a barrier to joint replacement.\n\nSimilarly, the committee agreed that everyone should be treated equally, and people should not be excluded from referral for joint replacement based on their age, sex or gender, if they smoke or any comorbidities. They agreed that there are few contraindications to surgery and the surgeon would be best placed to assess and discuss suitability of joint replacement on a case-by-case basis. The committee also recommended that the varying risks of surgery in relation to a person's specific circumstances should be explained.\n\n## How the recommendations might affect practice\n\nCurrent practice is inconsistent. If all centres adopt these recommendations, then it may lead to an increase in the number of referrals for surgery and subsequently more joint replacements done overall.\n\nReturn to recommendations\n\n# Arthroscopic procedures\n\nRecommendation 1.7.1\n\n## Why the committee made the recommendation\n\nThere was no evidence showing that arthroscopic procedures reduce pain and improve physical function. Evidence also showed possible harms with arthroscopic procedures compared with sham procedures. Cost-effectiveness evidence showed that arthroscopic procedures were more costly than standard care.\n\nThe committee agreed that arthroscopic procedures were not commonly used in clinical practice for osteoarthritis.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice, so there should be no change in practice or resource impact.\n\nReturn to recommendation", 'Context': "Osteoarthritis is the most common form of arthritis. It typically presents with joint symptoms such as pain and stiffness, mostly affecting the knee, hip, hand and foot joints. Symptoms vary from mild and intermittent, to more persistent or severe. The condition does not inevitably get worse, but symptoms fluctuate and flares are common. Osteoarthritis has a negative impact on daily activities, quality of life and health outcomes. It can affect people's physical, social and emotional life; more than half of people with osteoarthritis report that it seriously affects their family and working life.\n\nOsteoarthritis is more common in women, people living in deprived areas, people aged 45 and over and people living with obesity. The prevalence of osteoarthritis is increasing. Many people with osteoarthritis have multiple long-term conditions, making their care more complex.\n\nNICE produced a guideline on the care and management of osteoarthritis in 2014. This updated guideline makes recommendations on diagnosing and managing osteoarthritis, based on new evidence. This includes information and support, non‑pharmacological and pharmacological treatments, follow-up, and referral for joint replacement. The aim of this guideline is to improve management of osteoarthritis and the quality of life for people with the condition."}	https://www.nice.org.uk/guidance/ng226	This guideline covers the diagnosis, assessment and non-surgical management of osteoarthritis. It aims to improve management of osteoarthritis and the quality of life for people with osteoarthritis.
34b6febaef5580881ee7d58913433aac268f4da1	nice	Oral azacitidine for maintenance treatment of acute myeloid leukaemia after induction therapy	Oral azacitidine for maintenance treatment of acute myeloid leukaemia after induction therapy Evidence-based recommendations on azacitidine (Onureg) for maintenance treatment of acute myeloid leukaemia after induction therapy in adults. # Recommendations Oral azacitidine is recommended, within its marketing authorisation, as an option for maintenance treatment for acute myeloid leukaemia (AML) in adults who: are in complete remission, or complete remission with incomplete blood count recovery, after induction therapy with or without consolidation treatment, and cannot have or do not want a haematopoietic stem cell transplant.It is recommended only if the company provides oral azacitidine according to the commercial arrangement. Why the committee made these recommendations There are no standard maintenance treatment options for most people with AML who cannot have or do not want a haematopoietic stem cell transplant. Some people with FLT3-mutation-positive AML can have targeted maintenance treatment with midostaurin. Therefore, oral azacitidine would likely be of most benefit to people whose AML does not have an FLT3-mutation. The clinical trial evidence shows that if people take oral azacitidine it takes longer for their cancer to relapse, and they live longer than if they have placebo. Oral azacitidine meets NICE's criteria to be considered a life-extending treatment at the end of life. The most likely cost-effectiveness estimates for oral azacitidine are within what NICE normally considers an acceptable use of NHS resources for end of life treatments. So, oral azacitidine is recommended.# Information about oral azacitidine # Marketing authorisation indication Oral azacitidine (Onureg, Celgene, a Bristol Myers Squibb company) is indicated 'as maintenance therapy in adult patients with acute myeloid leukaemia (AML) who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following induction therapy with or without consolidation treatment and who are not candidates for, including those who choose not to proceed to, hematopoietic stem cell transplantation (HSCT)'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for oral azacitidine. # Price The list price for oral azacitidine is £5,867 for a 200‑mg or 300‑mg pack of 7 tablets (excluding VAT; price confirmed by the company). The company has a commercial arrangement. This makes oral azacitidine available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by the company, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # New treatment option ## People with acute myeloid leukaemia would welcome a new treatment option Acute myeloid leukaemia (AML) is a rapidly progressing cancer of the blood and bone marrow that is usually diagnosed in older people. Treatment options for AML include chemotherapy and a stem cell transplant (see section 3.2). The committee understood the substantial psychological, social and physical impact of living with AML for people with the condition and their carers and families. The patient expert described how being diagnosed with AML and the potential prospect of living for only a few months, had a significant emotional impact on them and their family. The clinical experts explained how intensive chemotherapy is associated with morbidity and that each treatment cycle often requires a prolonged hospital stay over several weeks. They explained that because a person's immune system is likely to weaken with chemotherapy, this increases their likelihood of contracting a life-threatening infection, which is an additional worry for people having treatment. The clinical experts explained that for people who are well enough to have intensive chemotherapy, a stem cell transplant remains the most effective treatment option. The committee understood that the decision to have a transplant depends on a person's fitness, choice, response to chemotherapy, and donor availability. The clinical experts highlighted that most people with AML are aged over 60 and are often unable to have a transplant because of co-morbidities and frailty. They also explained that there is a lack of donor availability for people from a minority ethnic family background. Therefore, some people cannot have, or do not want to have a stem cell transplant. The clinical experts explained that the risk of relapse in people who do not have a transplant is around 70% to 80%. They added that this would most likely occur within the first year after reaching complete remission. They highlighted that there are no effective treatment options after relapse in this population and that their prognosis and quality of life is poor. The committee noted that while stem cell transplants have the potential to be curative, they are associated with significant morbidity and mortality. The patient expert described how their treatment in preparation for a stem cell transplant was painful and invasive and made them feel too unwell to carry out their regular activities. The committee heard how the financial implications of having a transplant, such as regular travel to hospital and having to take time off work, can have a significant impact on quality of life for people with AML, their carers and families. It understood that oral azacitidine would benefit people who cannot have, or do not want to have a stem cell transplant because it can be taken at home. The committee concluded that people with AML would welcome a new treatment option that would improve their life expectancy and quality of life. # Comparators ## Low dose cytarabine and subcutaneous azacitidine are not routinely used for maintenance treatment Treatment for AML depends on whether a person is able to have intensive chemotherapy. If intensive chemotherapy is unsuitable, low dose chemotherapy may be given. If intensive chemotherapy is suitable, induction chemotherapy is initially given to achieve complete remission followed by consolidation chemotherapy. After induction or consolidation chemotherapy, some people may be able to have a stem cell transplant. People who have FLT3-mutation-positive AML may also have concomitant treatment with midostaurin during induction and consolidation chemotherapy and continue with midostaurin alone as maintenance treatment to prolong their remission (see NICE's technology appraisal guidance on midostaurin for untreated acute myeloid leukaemia). The committee discussed the company's positioning of oral azacitidine as a maintenance treatment for people who are in complete remission after induction chemotherapy, with or without consolidation chemotherapy, and who cannot have or do not want a stem cell transplant. The final scope for this appraisal included established clinical management without oral azacitidine (which may include a watch and wait strategy with best supportive care, low dose cytarabine or subcutaneous azacitidine) as a comparator. The committee noted that the company had not included low dose cytarabine and subcutaneous azacitidine as part of established clinical management. The company's clinical experts considered that these treatments are not used as maintenance treatment in the population who would be considered for treatment with oral azacitidine. The committee discussed the stakeholder comments that low dose cytarabine and subcutaneous azacitidine are not used routinely after induction and consolidation chemotherapy but are used when intensive chemotherapy is unsuitable. It noted the company's response to technical engagement which referenced data from the Haematological Malignancy Research Network (HMRN), which is an ongoing UK population-based cohort. The company presented subgroup data from the HMRN which was aligned to the eligibility criteria of the key clinical trial of oral azacitidine (see section 3.4). This indicated that very few people had maintenance treatment with low dose cytarabine and subcutaneous azacitidine (actual figures are confidential and cannot be reported here). Therefore, the committee concluded that these treatments would not likely be used routinely as maintenance treatment in people who are in complete remission. ## Midostaurin is a relevant comparator for people with FLT3-mutation-positive AML The committee noted that the company's clinical experts considered that around 25% of people with AML have FLT3-mutation-positive AML. Most of these people will have a stem cell transplant after reaching remission, leaving around 10% who would likely have maintenance therapy with midostaurin. The clinical experts explained that most people with FLT3-mutation positive AML would have targeted treatment with midostaurin during induction, consolidation and maintenance treatment and would be unlikely to switch to oral azacitidine. The committee heard how midostaurin is often not well tolerated, so having an alternative treatment option such as oral azacitidine would be important for this population. It recognised that the proportion of people with FLT3-mutation-positive AML who would have oral azacitidine in clinical practice would likely be small, but that it was still a relevant population. Therefore, the committee concluded that midostaurin was a relevant comparator for people with FLT3-mutation-positive AML. # Clinical evidence ## Oral azacitidine improves overall survival and relapse-free survival compared with placebo The clinical evidence came from QUAZAR AML‑001 (from now, referred to as QUAZAR), a phase 3, double-blind, randomised controlled trial that compared oral azacitidine plus best supportive care (from now, referred to as oral azacitidine) with placebo plus best supportive care (from now, referred to as placebo). The company considered that the placebo arm represented the watch and wait comparator. The population included adults with AML in complete remission after intensive induction chemotherapy with or without consolidation chemotherapy, who were not able to have a stem cell transplant. The company reported data from the trial's first data cut (July 2019, median follow up 41.2 months) for all outcomes. It also reported data from a second data cut (September 2020, median follow up 51.7 months) for the primary outcome of overall survival. In the intention-to-treat (ITT) population, oral azacitidine increased median overall survival compared with placebo from 14.8 months to 24.7 months (hazard ratio 0.69; 95% confidence interval 0.56 to 0.86, p value 0.0008). In the ITT population, oral azacitidine increased median relapse-free survival compared with placebo from 4.8 months to 10.2 months (hazard ratio 0.65; 95% confidence interval 0.52 to 0.81, p value 0.0001). The committee welcomed the mature trial data from QUAZAR and concluded that oral azacitidine improves overall survival and relapse-free survival compared with placebo. ## The results from the QUAZAR EU-subgroup are generalisable to clinical practice in England and should be used for decision-making The QUAZAR trial included 148 sites and included a large number of people from Europe (known as the EU-subgroup) and a small number of people from the UK (the actual numbers are considered confidential by the company and cannot be reported here). The EU-subgroup was part of the company's pre-specified subgroup analyses. The company considered that the baseline characteristics of people in QUAZAR aligned to the AML population in the UK who cannot have a transplant, with some exceptions: age (the trial was limited to people aged 55 and over) cytogenetic risk (the trial included people with intermediate and poor risk cytogenetics, but people with favourable risk cytogenetics are less likely to have a transplant in first complete remission).The clinical experts explained that the treatment pathway for younger people would be the same as for those aged over 55 years. They explained that because of the toxicity associated with intensive chemotherapy, many younger people are also unable to have a transplant because they are not well enough or do not have a suitable donor. The ERG highlighted differences between the UK subgroup and other populations analysed in the trial (specifically the EU-subgroup and the ITT population). This included the proportion of people who were unable to have a stem cell transplant because of not having an appropriate donor. The ERG also noted inconsistencies between the number of pre-trial consolidation cycles observed in the UK subgroup and the company's clinical expert estimates of consolidation therapy use in people with AML who cannot have a transplant. Because of these differences, and because only a small number of people from the UK were included in the trial, the ERG considered that the EU-subgroup may be more relevant to UK clinical practice. In response to technical engagement, the company revised its base case to use data for the EU-subgroup (rather than the original ITT population) which reduced the incremental cost-effectiveness ratio (ICER). The company highlighted that the baseline characteristics of the subgroup from the HMRN report (aligned to the QUAZAR trial eligibility criteria) were in line with the EU-subgroup. The committee noted that stakeholders had commented that the QUAZAR trial was generally representative of UK clinical practice. The clinical experts considered that there was no strong evidence to suggest that the UK subgroup in the trial was not representative of the UK population, but they noted that the numbers in this subgroup were small. They explained that the QUAZAR study included European people, and that the baseline characteristics for this subgroup reflected the population who would have oral azacitidine in the NHS. The committee concluded that the trial results from the EU-subgroup were generalisable to clinical practice in England and should be used for decision-making. ## The number of cycles of pre-trial consolidation therapy in QUAZAR likely reflects NHS clinical practice The ERG noted that in QUAZAR, most people had 1 or no cycles of pre-trial consolidation therapy. The committee understood that 20% of people in the trial did not have any pre-trial consolidation therapy (based on the ITT population). The ERG considered that previous NICE technology appraisals for untreated AML imply that consolidation therapy is standard practice, but the number of cycles of consolidation is unclear. In response to technical engagement, the company's clinical experts suggested that there is variability in the number of consolidation cycles and that up to 60% of people in the UK are likely to have only 1 or no cycles in routine practice. The company presented data from the HMRN report which highlighted that in the NHS, a proportion of people whose cancer responded to intensive induction therapy did not have any cycles of consolidation chemotherapy (actual numbers are confidential and cannot be reported here). The ERG considered that there is some disparity between the HMRN report findings and the NHS website which suggests that all people with AML have consolidation therapy. It noted that the European Society for Medical Oncology's (ESMO) clinical practice guideline on acute myeloid leukaemia in adult patients (2020) recommends that people should have consolidation therapy after reaching complete remission after induction treatment. The ERG considered that consolidation therapy is expected so it initially preferred to use a subpopulation of the EU-subgroup who had had at least 1 cycle of consolidation therapy for its base case. This subpopulation was known as the EU-consolidation subgroup. The committee noted that the EU-consolidation subgroup slightly increased the ICER. The clinical experts explained that in clinical practice, many people can only have a single course of consolidation chemotherapy, because of delayed blood count recovery, toxicity or patient choice. They described how optimum best practice includes 3 to 4 cycles of consolidation chemotherapy; however, this is difficult to achieve particularly in an older population. The clinical expert described that around 20% of people will have the optimum number of consolidation cycles. They explained that the QUAZAR trial reflects the use of consolidation chemotherapy in clinical practice. The committee noted that data from the trial suggested that overall survival was improved irrespective of whether a person had consolidation treatment. The committee concluded that although most people would likely have at least 1 cycle of consolidation therapy, there may be people who would not have any consolidation treatment after induction chemotherapy. It concluded that the number of cycles of pre-trial consolidation therapy in QUAZAR likely reflects NHS clinical practice. ## The results of the company's indirect treatment comparison in people with FLT3-mutation-positive AML are highly uncertain The company did not identify any direct evidence comparing the efficacy of oral azacitidine to midostaurin as maintenance treatment in people with FLT3-mutation-positive AML. Therefore, it did an anchored indirect treatment comparison using data from QUAZAR and a phase 3, randomised, placebo-controlled study of midostaurin plus standard chemotherapy in adults with newly diagnosed FLT3-mutation-positive AML (known as RATIFY). Because individual patient data was available from QUAZAR, the company matched the population in QUAZAR to the eligibility criteria in RATIFY, so that only people with FLT3-mutation-positive AML in complete remission were included in the analysis. The company considers the results of the indirect treatment comparison to be confidential and so they cannot be reported here. However, the company noted significant differences between QUAZAR and RATIFY including differences in: Trial design: RATIFY was not prospectively designed to assess the efficacy of midostaurin as maintenance therapy but as an addition to induction and consolidation therapy. The QUAZAR trial was designed to specifically assess oral azacitidine in the maintenance setting. Time to randomisation: RATIFY included a maintenance therapy phase but people in the trial were not re-randomised before the start of maintenance therapy. In QUAZAR, people were randomised to have maintenance treatment. Age and AML status: RATIFY mainly included younger people (aged 18 to 59) and only included people with FLT3-mutation-positive AML unlike QUAZAR. Cytogenetic risk: people with favourable cytogenetic risk were included in RATIFY but not in QUAZAR. Stem cell transplant eligibility: this was not a formal exclusion criterion in the RATIFY trial but was in QUAZAR History of consolidation therapy and definitions of time-to-event outcomes.The company considered that many of these variables are known prognostic factors and potential effect modifiers and so the indirect estimates of oral azacitidine and midostaurin are likely limited in their validity and generalisability. The ERG also considered that survival analyses for this population are likely to be biased because of limitations associated with the indirect treatment comparison. The committee concluded that the results of the indirect treatment comparison comparing oral azacitidine with midostaurin were highly uncertain and considered this in its decision making. # Cost effectiveness ## There is uncertainty about whether the company's model captures the long-term benefit after a stem cell transplant The company presented a partitioned survival model with 3 health states: relapse-free survival, relapse and death. In the relapse-free health state, people could either be on or off treatment with oral azacitidine (the same utility value was applied). All people in the watch and wait plus best supportive care arm (from now, referred to as best supportive care), were assumed to be off treatment. The model included a cycle length of 28 days with a half-cycle correction over a lifetime time horizon. In the model, stem cell transplant was not included as a separate health state but was implicitly included in the modelling through the survival analysis of the QUAZAR ITT population. The company considered that because oral azacitidine has a marketing authorisation for people who cannot have a transplant, it would be unlikely in clinical practice that people will go on to have a transplant after oral azacitidine unless they had relapsed. In the trial, 6.3% of people in the oral azacitidine arm and 13.7% in the placebo arm had a transplant after stopping treatment. Costs and a temporary disutility associated with stem cell transplant were included in the model. The committee noted that the ERG's preference was to include stem cell transplant as a health state in the model. In response to technical engagement, the company stated that the QUAZAR trial did not collect sufficient data to allow modelling of stem cell transplant as a separate health state and this data is not available in the literature. Instead, it provided a scenario analysis which calculated a weighted average utility value for each treatment arm in the relapse health state. This was to account for the potential long-term health-related quality-of-life benefits of a transplant. The committee noted that the company's scenario analysis suggested only a small impact on the ICER. The ERG considered that it was unclear whether the model captured the long-term benefits of a stem cell transplant on a person's health-related quality of life (including after the company's scenario analysis). The committee agreed with the ERG's preference to remove the temporary disutility associated with a transplant, given that no benefit in health-related quality of life after having a transplant had been included in the model. It noted that the removal of this disutility had a small impact on the ICER. The committee considered the ERG's scenario analysis which included a utility increment for people who went on to have a stem cell transplant and noted that this slightly increased the ICER. The committee considered that it would have preferred the company to have included stem cell transplant as a health state in the model in line with NICE's technology appraisal guidance on midostaurin for untreated acute myeloid leukaemia. It noted that the company did not provide an updated model or any new evidence to support its approach to modelling a stem cell transplant in response to consultation. Therefore, the committee concluded that there is still uncertainty about whether the company's model captures the long-term benefits after a stem cell transplant. ## Health-related quality of life after relapse should be calculated using data from the Tremblay (2018) study The company considered that the QUAZAR trial did not capture health-related quality of life after relapse, except in some people who may have had an extended dose of oral azacitidine. This included people with a bone marrow blast count of 6% to 15% but not those with advanced disease (blast count greater than 15%). The company considered that using a utility value derived from this small cohort of people would be inappropriate and may overestimate the quality of life for people who relapse. Therefore, the company calculated the relapse utility based on a study by Joshi (2019) which used the composite time trade-off method to elicit utility values for AML from the UK general population. In the model, relapse utility was calculated as the difference between the relapse-free survival and relapse utilities in Joshi (2019) which was then applied to the relapse-free utility from QUAZAR. The ERG noted that the sample size in Joshi (2019) was small which resulted in a large standard error. The committee understood that the company considered alternative sources for relapse utilities including studies by Stein (2019) and Tremblay (2018). The ERG considered that both sources were not ideal because utility values were derived from US populations. In response to technical engagement, the company explained why the study by Joshi (2019) had been selected. It considered the utility elicitation methodology to be preferred by NICE, utility values were from individuals in the UK, and the utility value was clinically plausible. The ERG was unclear why the company preferred the composite time trade-off methodology, given that it was not part of the reference case in NICE's guide to the methods of technology appraisal 2013. In line with NICE's technology appraisal guidance on midostaurin for untreated acute myeloid leukaemia, the ERG used Tremblay (2018) to calculate health-related quality of life after relapse in its base case. This was because it considered that the method used to elicit utility values was more appropriate than Joshi (2019). The committee noted the company's scenario analyses using relapse utility values from Tremblay (2018) and Stein (2019) had a small impact on the ICER in the EU-subgroup. The company did not provide any new evidence to support its preferred approach to calculating utility after relapse in response to the appraisal consultation document. The committee agreed with the ERG's approach and concluded that health-related quality of life after relapse should be calculated using data from Tremblay (2018). ## Utility for the relapse-free survival health state should be capped at age- and sex-matched general population values The committee understood that the company had adjusted health state utility values for age in the model. It discussed the ERG's critique that the relapse-free survival utility was higher than the age-adjusted population norm in the UK. The committee considered that this did not make sense because it would mean that people with AML had a better quality of life than people without the disease. It noted that the ERG had asked the company to provide a scenario analysis capping the utility at general population levels which slightly increased the ICER (based on the ITT population). The company did not provide any new evidence on utility for the relapse-free survival health state in response to consultation. The committee noted the ERG's analysis which capped the utility value for the relapse-free survival health state at general population levels in the EU-subgroup. The results of the analysis suggested only a small impact on the ICER. The committee concluded that the utility value for the relapse-free survival health state in the model should be capped at age- and sex-matched general population levels. ## Joint survival models are appropriate for estimating overall survival and relapse-free survival in the EU-subgroup The company used joint models (joint models apply a single distribution to both treatment arms) to estimate overall survival and relapse-free survival based on QUAZAR trial data. It used the generalised gamma accelerated failure time model for overall survival and the log-logistic accelerated failure time model for relapse-free survival in the ITT population. The company considered that the survival analyses in the EU-subgroup were aligned with the assessment for the ITT population. The committee considered that the joint modelled curves showed that the survival function was being underestimated in the model for the comparator arm (best supportive care) when compared with the Kaplan–Meier curves from the trial (based on the ITT population). It considered that this may be because accelerated failure time models assume that the treatment effect is constant over the entire lifetime of the model. In response to consultation, the company stated that the joint models selected in its base case did not overestimate the expected treatment benefit with oral azacitidine for the EU-subgroup. It presented a scenario analysis exploring the impact of using the best-fitting individual models for the EU-subgroup (generalised gamma models for overall survival and log-logistic models for relapse-free survival). The committee noted that the company's scenario analysis suggested only a small impact on the ICER. It discussed the ERG's scenario analysis which explored the impact of using the same individual parametric models and the committee's preferred assumptions from the first meeting, which also had a small impact on the ICER. The committee noted the ERG's critique that the company's joint and individual modelling results were comparable and that the impact of choosing between these approaches was likely minor. It was reassured that both approaches reflected the trial data and resulted in similar extrapolations. Therefore, the committee concluded that the company's joint modelling approach was appropriate for estimating overall survival and relapse-free survival in the EU-subgroup. ## The company's approach to modelling treatment effect waning does not have a significant impact on the cost-effectiveness results The company's base-case analysis assumed no treatment effect waning for oral azacitidine. The committee initially considered that it was highly optimistic to assume a constant treatment benefit with oral azacitidine based on the observed trial data. The committee understood that the company had presented a scenario analysis which tried to explore the impact of treatment effect waning. It did this using individual log-normal models for overall survival and log-logistic models for relapse-free survival (based on the ITT population). The results of the scenario analysis increased the ICER by 11%. The committee considered that this was not explored fully and it would be preferable to include an assumption that the relative treatment effectiveness would decline over time. Therefore, the committee considered that it would be helpful to see a range of scenarios for both the overall population (based on the EU-subgroup) and for people with FLT3-mutation-positive AML including: using individually fitted parametric models without any additional treatment effect waning (and comparing the risks of overall survival and relapse-free survival in each cycle between the treatment groups). adding treatment effect waning in the above scenario to assume that the treatment benefit with oral azacitidine is lost at a range of clinically plausible time points (for example, after stopping treatment).In response to consultation, the company considered that the impact of treatment effect waning during the trial was already captured in the survival estimates. This was because the end of the trial follow up was 90 months (7.5 years) at which point no people remained on treatment with oral azacitidine. The company and ERG presented analyses exploring the relative treatment effect over time by comparing the risks of overall survival and relapse-free survival between treatment groups. This was based on using the best-fitting individual models for the EU-subgroup (see section 3.11). The results from both analyses showed a similar risk of death and relapse between treatment arms over time (actual numbers are considered confidential by the company and cannot be reported here). The committee noted that this suggested that treatment effect waning may be implicitly included when using an individual modelling approach. It discussed the ERG's scenario analyses which included the committee's preferred assumptions and explored the impact of using individual models with treatment effect waning at various timepoints (3 years, 5 years and 7.5 years) after randomisation. The results of the scenario analyses suggested only a small impact on the ICER. The committee recalled that the company's joint and individual modelling results were comparable (see section 3.11). Therefore, it considered that the impact of treatment effect waning using a joint modelling approach would also likely have a similar effect on the ICER based on its preferred assumptions. The committee concluded that the company's approach to modelling treatment effect waning did not have a significant impact on the cost-effectiveness results. # End of life ## Oral azacitidine extends life by at least 3 months The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal 2013. The committee agreed that based on the trial evidence and the views of clinical experts, the overall survival gain with oral azacitidine would likely be more than 3 months. The company's model suggested that there was an increase in mean overall survival of 12.8 months (median 9.9 months in QUAZAR) for the ITT population. For the EU-subgroup, the company's model suggested that there was an increase in mean overall survival of 16.2 months (median overall survival gain was greater than 3 months in QUAZAR but the exact figure is confidential so cannot be reported here). The committee agreed that oral azacitidine meets the criterion for a life-extending treatment because it increases overall survival by more than 3 months. ## The short life expectancy criterion is also met so oral azacitidine is considered to be a life-extending treatment at the end of life The company confirmed that mean estimates were not available from QUAZAR, but the median overall survival for people who had placebo was 14.8 months (ITT population). The company's original base case for the ITT population predicted a mean overall survival of 33.6 months for people having best supportive care. The company's revised base case using the EU-subgroup predicted a mean overall survival of 31.5 months for people having best supportive care (median overall survival from QUAZAR for the EU-subgroup was also less than 24 months but the exact figure is confidential and so cannot be reported here). The committee acknowledged that using extrapolation models to estimate mean values involves assumptions and uncertainty. However, the committee noted that the mean estimates were higher than 24 months and that the cost-effectiveness analyses are based on mean survival estimates. The clinical experts explained that a significant number of people with AML are unable to have a stem cell transplant and that they have a high risk of relapse in the first year. After relapse, they would have palliative treatment within 12 months and a life expectancy of around 3 months at this point. The clinical experts explained that around 20% of people may be cured after intensive chemotherapy, and reach long-term survival. The ERG considered that because some people will live for much longer, this will skew the survival distribution where the mean is often higher than the median. The committee recalled that while the short-term prognosis for most people would be poor, a proportion of people (around 20%) would be cured and would therefore be expected to live beyond 2 years. It initially considered that the short life expectancy criterion had not been met. The committee considered comments received in response to consultation from the company, a clinical expert and a patient group which strongly reiterated that life expectancy for most people in this population is less than 24 months. The company highlighted the appeal decision in NICE's technology appraisal guidance on avelumab for maintenance treatment of locally advanced or metastatic urothelial cancer after platinum-based chemotherapy (TA788). The appeal panel for TA788 concluded that it would be unreasonable to state that life expectancy was not normally less than 24 months given that the modelled mean life expectancy indicated that most people (65%) did not survive after 24 months. In this appraisal, the company highlighted that a similar proportion in the EU-subgroup did not survive beyond 24 months (the exact figure is considered confidential by the company and so cannot be reported here). The committee believed that the best estimate of life expectancy came from the mean survival for the relevant patient population, based on the decision model submitted by the company. However, it accepted a consultation comment that the NICE methods guide does not specifically state how this criterion should be assessed. It noted the appeal panel's conclusion for TA788 that the totality of evidence should be considered when assessing whether a technology meets the short life expectancy criterion. The committee took into consideration the mean and median survival estimates, clinical opinion from the first committee meeting and consultation comments from all stakeholders. It also recalled that the data from the QUAZAR trial was mature and this reduced the uncertainty in the results. The committee discussed that although there are different ways to estimate life expectancy, it is likely that the population who would be considered for treatment with oral azacitidine would live on average less than 24 months. Therefore, it accepted that the short life expectancy criterion was met and concluded that oral azacitidine meets the criteria to be considered a life-extending treatment at the end of life. # Cost-effectiveness estimates ## The cost-effectiveness estimates are within the range that NICE considers to be an acceptable use of NHS resources NICE's guide to the methods of technology appraisal 2013 notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. At the first meeting, the committee considered that there was uncertainty around some of the assumptions used in the model which made the cost-effectiveness results uncertain. It considered that analyses which explored the use of individual models for extrapolating overall survival and treatment effect waning would reduce the uncertainty that the expected treatment benefit with oral azacitidine had been overestimated in the model (see section 3.11 and section 3.12). At the second committee meeting, the company and ERG presented these analyses which suggested that the cost-effectiveness results are robust to changes in survival modelling assumptions (see section 3.11 and section 3.12). The committee was therefore reassured that this uncertainty had now been adequately addressed. The ERG updated its base-case assumptions to align with the committee's preferences which remained unchanged from the first committee meeting. This included the following assumptions: using the EU-subgroup of the QUAZAR trial for the total population (see section 3.5) removing the temporary disutility associated with a stem cell transplant (see section 3.8) calculating health-related quality of life after relapse using data from Tremblay (2018; see section 3.9) capping the utility value for the relapse-free survival health state at matched general population levels (see section 3.10).The ERG's updated analyses included the committee's preferred deterministic and probabilistic ICERs for oral azacitidine compared with best supportive care, which were slightly above £30,000 per QALY gained. Exact ICERs are confidential and cannot be reported here, because they include the confidential patient access scheme for oral azacitidine and confidential comparator discounts. The committee considered that the most plausible ICERs were within the range that NICE considers to be an acceptable use of NHS resources for end of life treatments. It also noted the ICERs for all the scenarios presented for oral azacitidine compared with best supportive care and for oral azacitidine compared with midostaurin for the FLT3 subgroup. All the ICERs were within the range that NICE considers to be an acceptable use of NHS resources (including the confidential patient access scheme for oral azacitidine and confidential comparator discounts). It noted that the cost-effectiveness estimates for oral azacitidine compared with midostaurin were uncertain because of the limitations in the clinical evidence informing this treatment comparison (see section 3.7). However, the committee recalled that the proportion of people with FLT3-mutation-positive AML who would have oral azacitidine in clinical practice would be small. The committee also acknowledged that oral azacitidine could potentially address some of the equality issues raised by stakeholders (see section 3.16). Therefore, it recommended oral azacitidine as an option for people with AML. # Other factors ## The recommendation for oral azacitidine may reduce some of the equality issues for people with AML The committee discussed the potential equality issues raised during the appraisal. It noted a stakeholder comment that some people may struggle financially to have current treatment (such as a transplant) because of the cost of regular travel to hospital and reduced income from having to take time off work. Having a transplant may be especially difficult for people with caring responsibilities because of the significant time commitment needed. The stakeholder considered that these people should not be denied treatment and oral azacitidine would be a viable alternative to a transplant. The committee recognised that because oral azacitidine can be taken at home it may be more convenient and reduce the amount of time spent in hospital compared with having a transplant. It noted comments from stakeholders that many people with AML who are in complete remission are unable to have a transplant because of a lack of donor availability. Therefore, this results in an inequity of access to curative treatment and disproportionately affects people with a minority ethnic family background. The clinical experts explained that after a transplant there is a 70% reduction in the risk of relapse. They explained that in people of white family background, the likelihood of finding a suitably matched donor is around 80%, which reduces to around 30% to 40% in people with a minority ethnic family background. Stakeholders and clinical experts highlighted that oral azacitidine should therefore be available to all people who are not able to have a transplant, including those with a minority ethnic family background who do not have a suitable donor. The committee noted that this issue had been reiterated in comments received in response to the appraisal consultation document. The committee acknowledged that unequal access to transplants because of ethnicity was a relevant consideration and it was mindful of its obligations in relation to the Equality Act 2010. It noted that the company had also highlighted that there may be geographical barriers to accessing a stem cell transplant based on how far away a person lives from an allograft transplant centre. The committee considered that issues around healthcare implementation cannot be addressed in a technology appraisal. It concluded that because it had recommended oral azacitidine for people with AML that this may help to reduce some of the potential equality issues raised during the appraisal. ## The benefits of oral azacitidine are captured in the cost-effectiveness analysis The company and stakeholders considered oral azacitidine to be innovative because it improves survival, is well tolerated and because of its oral formulation. The committee recalled how treatment with oral azacitidine would offer benefits because people would be able to have treatment at home (see section 3.1). It heard how this would reduce time spent in hospital and allow people to spend more time with their family and friends. The committee agreed that these are important benefits and noted that oral azacitidine is the first maintenance treatment licensed for all people with AML. However, it concluded that it had not been presented with evidence of any additional benefits that could not be captured in the QALY calculations.	{'Recommendations': "Oral azacitidine is recommended, within its marketing authorisation, as an option for maintenance treatment for acute myeloid leukaemia (AML) in adults who:\n\nare in complete remission, or complete remission with incomplete blood count recovery, after induction therapy with or without consolidation treatment, and\n\ncannot have or do not want a haematopoietic stem cell transplant.It is recommended only if the company provides oral azacitidine according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThere are no standard maintenance treatment options for most people with AML who cannot have or do not want a haematopoietic stem cell transplant. Some people with FLT3-mutation-positive AML can have targeted maintenance treatment with midostaurin. Therefore, oral azacitidine would likely be of most benefit to people whose AML does not have an FLT3-mutation. The clinical trial evidence shows that if people take oral azacitidine it takes longer for their cancer to relapse, and they live longer than if they have placebo.\n\nOral azacitidine meets NICE's criteria to be considered a life-extending treatment at the end of life. The most likely cost-effectiveness estimates for oral azacitidine are within what NICE normally considers an acceptable use of NHS resources for end of life treatments. So, oral azacitidine is recommended.", 'Information about oral azacitidine': "# Marketing authorisation indication\n\nOral azacitidine (Onureg, Celgene, a Bristol Myers Squibb company) is indicated 'as maintenance therapy in adult patients with acute myeloid leukaemia (AML) who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following induction therapy with or without consolidation treatment and who are not candidates for, including those who choose not to proceed to, hematopoietic stem cell transplantation (HSCT)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for oral azacitidine.\n\n# Price\n\nThe list price for oral azacitidine is £5,867 for a 200‑mg or 300‑mg pack of 7\xa0tablets (excluding VAT; price confirmed by the company). The company has a commercial arrangement. This makes oral azacitidine available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by the company, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with acute myeloid leukaemia would welcome a new treatment option\n\nAcute myeloid leukaemia (AML) is a rapidly progressing cancer of the blood and bone marrow that is usually diagnosed in older people. Treatment options for AML include chemotherapy and a stem cell transplant (see section 3.2). The committee understood the substantial psychological, social and physical impact of living with AML for people with the condition and their carers and families. The patient expert described how being diagnosed with AML and the potential prospect of living for only a few months, had a significant emotional impact on them and their family. The clinical experts explained how intensive chemotherapy is associated with morbidity and that each treatment cycle often requires a prolonged hospital stay over several weeks. They explained that because a person's immune system is likely to weaken with chemotherapy, this increases their likelihood of contracting a life-threatening infection, which is an additional worry for people having treatment. The clinical experts explained that for people who are well enough to have intensive chemotherapy, a stem cell transplant remains the most effective treatment option. The committee understood that the decision to have a transplant depends on a person's fitness, choice, response to chemotherapy, and donor availability. The clinical experts highlighted that most people with AML are aged over 60 and are often unable to have a transplant because of co-morbidities and frailty. They also explained that there is a lack of donor availability for people from a minority ethnic family background. Therefore, some people cannot have, or do not want to have a stem cell transplant. The clinical experts explained that the risk of relapse in people who do not have a transplant is around 70% to 80%. They added that this would most likely occur within the first year after reaching complete remission. They highlighted that there are no effective treatment options after relapse in this population and that their prognosis and quality of life is poor. The committee noted that while stem cell transplants have the potential to be curative, they are associated with significant morbidity and mortality. The patient expert described how their treatment in preparation for a stem cell transplant was painful and invasive and made them feel too unwell to carry out their regular activities. The committee heard how the financial implications of having a transplant, such as regular travel to hospital and having to take time off work, can have a significant impact on quality of life for people with AML, their carers and families. It understood that oral azacitidine would benefit people who cannot have, or do not want to have a stem cell transplant because it can be taken at home. The committee concluded that people with AML would welcome a new treatment option that would improve their life expectancy and quality of life.\n\n# Comparators\n\n## Low dose cytarabine and subcutaneous azacitidine are not routinely used for maintenance treatment\n\nTreatment for AML depends on whether a person is able to have intensive chemotherapy. If intensive chemotherapy is unsuitable, low dose chemotherapy may be given. If intensive chemotherapy is suitable, induction chemotherapy is initially given to achieve complete remission followed by consolidation chemotherapy. After induction or consolidation chemotherapy, some people may be able to have a stem cell transplant. People who have FLT3-mutation-positive AML may also have concomitant treatment with midostaurin during induction and consolidation chemotherapy and continue with midostaurin alone as maintenance treatment to prolong their remission (see NICE's technology appraisal guidance on midostaurin for untreated acute myeloid leukaemia). The committee discussed the company's positioning of oral azacitidine as a maintenance treatment for people who are in complete remission after induction chemotherapy, with or without consolidation chemotherapy, and who cannot have or do not want a stem cell transplant. The final scope for this appraisal included established clinical management without oral azacitidine (which may include a watch and wait strategy with best supportive care, low dose cytarabine or subcutaneous azacitidine) as a comparator. The committee noted that the company had not included low dose cytarabine and subcutaneous azacitidine as part of established clinical management. The company's clinical experts considered that these treatments are not used as maintenance treatment in the population who would be considered for treatment with oral azacitidine. The committee discussed the stakeholder comments that low dose cytarabine and subcutaneous azacitidine are not used routinely after induction and consolidation chemotherapy but are used when intensive chemotherapy is unsuitable. It noted the company's response to technical engagement which referenced data from the Haematological Malignancy Research Network (HMRN), which is an ongoing UK population-based cohort. The company presented subgroup data from the HMRN which was aligned to the eligibility criteria of the key clinical trial of oral azacitidine (see section 3.4). This indicated that very few people had maintenance treatment with low dose cytarabine and subcutaneous azacitidine (actual figures are confidential and cannot be reported here). Therefore, the committee concluded that these treatments would not likely be used routinely as maintenance treatment in people who are in complete remission.\n\n## Midostaurin is a relevant comparator for people with FLT3-mutation-positive AML\n\nThe committee noted that the company's clinical experts considered that around 25% of people with AML have FLT3-mutation-positive AML. Most of these people will have a stem cell transplant after reaching remission, leaving around 10% who would likely have maintenance therapy with midostaurin. The clinical experts explained that most people with FLT3-mutation positive AML would have targeted treatment with midostaurin during induction, consolidation and maintenance treatment and would be unlikely to switch to oral azacitidine. The committee heard how midostaurin is often not well tolerated, so having an alternative treatment option such as oral azacitidine would be important for this population. It recognised that the proportion of people with FLT3-mutation-positive AML who would have oral azacitidine in clinical practice would likely be small, but that it was still a relevant population. Therefore, the committee concluded that midostaurin was a relevant comparator for people with FLT3-mutation-positive AML.\n\n# Clinical evidence\n\n## Oral azacitidine improves overall survival and relapse-free survival compared with placebo\n\nThe clinical evidence came from QUAZAR AML‑001 (from now, referred to as QUAZAR), a phase\xa03, double-blind, randomised controlled trial that compared oral azacitidine plus best supportive care (from now, referred to as oral azacitidine) with placebo plus best supportive care (from now, referred to as placebo). The company considered that the placebo arm represented the watch and wait comparator. The population included adults with AML in complete remission after intensive induction chemotherapy with or without consolidation chemotherapy, who were not able to have a stem cell transplant. The company reported data from the trial's first data cut (July\xa02019, median follow up 41.2\xa0months) for all outcomes. It also reported data from a second data cut (September\xa02020, median follow up 51.7\xa0months) for the primary outcome of overall survival. In the intention-to-treat (ITT) population, oral azacitidine increased median overall survival compared with placebo from 14.8\xa0months to 24.7\xa0months (hazard ratio 0.69; 95% confidence interval 0.56 to 0.86, p\xa0value 0.0008). In the ITT population, oral azacitidine increased median relapse-free survival compared with placebo from 4.8\xa0months to 10.2\xa0months (hazard ratio 0.65; 95% confidence interval 0.52 to 0.81, p\xa0value 0.0001). The committee welcomed the mature trial data from QUAZAR and concluded that oral azacitidine improves overall survival and relapse-free survival compared with placebo.\n\n## The results from the QUAZAR EU-subgroup are generalisable to clinical practice in England and should be used for decision-making\n\nThe QUAZAR trial included 148\xa0sites and included a large number of people from Europe (known as the EU-subgroup) and a small number of people from the UK (the actual numbers are considered confidential by the company and cannot be reported here). The EU-subgroup was part of the company's pre-specified subgroup analyses. The company considered that the baseline characteristics of people in QUAZAR aligned to the AML population in the UK who cannot have a transplant, with some exceptions:\n\nage (the trial was limited to people aged 55\xa0and over)\n\ncytogenetic risk (the trial included people with intermediate and poor risk cytogenetics, but people with favourable risk cytogenetics are less likely to have a transplant in first complete remission).The clinical experts explained that the treatment pathway for younger people would be the same as for those aged over 55\xa0years. They explained that because of the toxicity associated with intensive chemotherapy, many younger people are also unable to have a transplant because they are not well enough or do not have a suitable donor. The ERG highlighted differences between the UK subgroup and other populations analysed in the trial (specifically the EU-subgroup and the ITT population). This included the proportion of people who were unable to have a stem cell transplant because of not having an appropriate donor. The ERG also noted inconsistencies between the number of pre-trial consolidation cycles observed in the UK subgroup and the company's clinical expert estimates of consolidation therapy use in people with AML who cannot have a transplant. Because of these differences, and because only a small number of people from the UK were included in the trial, the ERG considered that the EU-subgroup may be more relevant to UK clinical practice. In response to technical engagement, the company revised its base case to use data for the EU-subgroup (rather than the original ITT population) which reduced the incremental cost-effectiveness ratio (ICER). The company highlighted that the baseline characteristics of the subgroup from the HMRN report (aligned to the QUAZAR trial eligibility criteria) were in line with the EU-subgroup. The committee noted that stakeholders had commented that the QUAZAR trial was generally representative of UK clinical practice. The clinical experts considered that there was no strong evidence to suggest that the UK subgroup in the trial was not representative of the UK population, but they noted that the numbers in this subgroup were small. They explained that the QUAZAR study included European people, and that the baseline characteristics for this subgroup reflected the population who would have oral azacitidine in the NHS. The committee concluded that the trial results from the EU-subgroup were generalisable to clinical practice in England and should be used for decision-making.\n\n## The number of cycles of pre-trial consolidation therapy in QUAZAR likely reflects NHS clinical practice\n\nThe ERG noted that in QUAZAR, most people had 1 or no cycles of pre-trial consolidation therapy. The committee understood that 20% of people in the trial did not have any pre-trial consolidation therapy (based on the ITT population). The ERG considered that previous NICE technology appraisals for untreated AML imply that consolidation therapy is standard practice, but the number of cycles of consolidation is unclear. In response to technical engagement, the company's clinical experts suggested that there is variability in the number of consolidation cycles and that up to 60% of people in the UK are likely to have only 1 or no cycles in routine practice. The company presented data from the HMRN report which highlighted that in the NHS, a proportion of people whose cancer responded to intensive induction therapy did not have any cycles of consolidation chemotherapy (actual numbers are confidential and cannot be reported here). The ERG considered that there is some disparity between the HMRN report findings and the NHS website which suggests that all people with AML have consolidation therapy. It noted that the European Society for Medical Oncology's (ESMO) clinical practice guideline on acute myeloid leukaemia in adult patients (2020) recommends that people should have consolidation therapy after reaching complete remission after induction treatment. The ERG considered that consolidation therapy is expected so it initially preferred to use a subpopulation of the EU-subgroup who had had at least 1\xa0cycle of consolidation therapy for its base case. This subpopulation was known as the EU-consolidation subgroup. The committee noted that the EU-consolidation subgroup slightly increased the ICER. The clinical experts explained that in clinical practice, many people can only have a single course of consolidation chemotherapy, because of delayed blood count recovery, toxicity or patient choice. They described how optimum best practice includes 3\xa0to\xa04 cycles of consolidation chemotherapy; however, this is difficult to achieve particularly in an older population. The clinical expert described that around 20% of people will have the optimum number of consolidation cycles. They explained that the QUAZAR trial reflects the use of consolidation chemotherapy in clinical practice. The committee noted that data from the trial suggested that overall survival was improved irrespective of whether a person had consolidation treatment. The committee concluded that although most people would likely have at least 1\xa0cycle of consolidation therapy, there may be people who would not have any consolidation treatment after induction chemotherapy. It concluded that the number of cycles of pre-trial consolidation therapy in QUAZAR likely reflects NHS clinical practice.\n\n## The results of the company's indirect treatment comparison in people with FLT3-mutation-positive AML are highly uncertain\n\nThe company did not identify any direct evidence comparing the efficacy of oral azacitidine to midostaurin as maintenance treatment in people with FLT3-mutation-positive AML. Therefore, it did an anchored indirect treatment comparison using data from QUAZAR and a phase\xa03, randomised, placebo-controlled study of midostaurin plus standard chemotherapy in adults with newly diagnosed FLT3-mutation-positive AML (known as RATIFY). Because individual patient data was available from QUAZAR, the company matched the population in QUAZAR to the eligibility criteria in RATIFY, so that only people with FLT3-mutation-positive AML in complete remission were included in the analysis. The company considers the results of the indirect treatment comparison to be confidential and so they cannot be reported here. However, the company noted significant differences between QUAZAR and RATIFY including differences in:\n\nTrial design: RATIFY was not prospectively designed to assess the efficacy of midostaurin as maintenance therapy but as an addition to induction and consolidation therapy. The QUAZAR trial was designed to specifically assess oral azacitidine in the maintenance setting.\n\nTime to randomisation: RATIFY included a maintenance therapy phase but people in the trial were not re-randomised before the start of maintenance therapy. In QUAZAR, people were randomised to have maintenance treatment.\n\nAge and AML status: RATIFY mainly included younger people (aged 18\xa0to\xa059) and only included people with FLT3-mutation-positive AML unlike QUAZAR.\n\nCytogenetic risk: people with favourable cytogenetic risk were included in RATIFY but not in QUAZAR.\n\nStem cell transplant eligibility: this was not a formal exclusion criterion in the RATIFY trial but was in QUAZAR\n\nHistory of consolidation therapy and definitions of time-to-event outcomes.The company considered that many of these variables are known prognostic factors and potential effect modifiers and so the indirect estimates of oral azacitidine and midostaurin are likely limited in their validity and generalisability. The ERG also considered that survival analyses for this population are likely to be biased because of limitations associated with the indirect treatment comparison. The committee concluded that the results of the indirect treatment comparison comparing oral azacitidine with midostaurin were highly uncertain and considered this in its decision making.\n\n# Cost effectiveness\n\n## There is uncertainty about whether the company's model captures the long-term benefit after a stem cell transplant\n\nThe company presented a partitioned survival model with 3\xa0health states: relapse-free survival, relapse and death. In the relapse-free health state, people could either be on or off treatment with oral azacitidine (the same utility value was applied). All people in the watch and wait plus best supportive care arm (from now, referred to as best supportive care), were assumed to be off treatment. The model included a cycle length of 28\xa0days with a half-cycle correction over a lifetime time horizon. In the model, stem cell transplant was not included as a separate health state but was implicitly included in the modelling through the survival analysis of the QUAZAR ITT population. The company considered that because oral azacitidine has a marketing authorisation for people who cannot have a transplant, it would be unlikely in clinical practice that people will go on to have a transplant after oral azacitidine unless they had relapsed. In the trial, 6.3% of people in the oral azacitidine arm and 13.7% in the placebo arm had a transplant after stopping treatment. Costs and a temporary disutility associated with stem cell transplant were included in the model. The committee noted that the ERG's preference was to include stem cell transplant as a health state in the model. In response to technical engagement, the company stated that the QUAZAR trial did not collect sufficient data to allow modelling of stem cell transplant as a separate health state and this data is not available in the literature. Instead, it provided a scenario analysis which calculated a weighted average utility value for each treatment arm in the relapse health state. This was to account for the potential long-term health-related quality-of-life benefits of a transplant. The committee noted that the company's scenario analysis suggested only a small impact on the ICER. The ERG considered that it was unclear whether the model captured the long-term benefits of a stem cell transplant on a person's health-related quality of life (including after the company's scenario analysis). The committee agreed with the ERG's preference to remove the temporary disutility associated with a transplant, given that no benefit in health-related quality of life after having a transplant had been included in the model. It noted that the removal of this disutility had a small impact on the ICER. The committee considered the ERG's scenario analysis which included a utility increment for people who went on to have a stem cell transplant and noted that this slightly increased the ICER. The committee considered that it would have preferred the company to have included stem cell transplant as a health state in the model in line with NICE's technology appraisal guidance on midostaurin for untreated acute myeloid leukaemia. It noted that the company did not provide an updated model or any new evidence to support its approach to modelling a stem cell transplant in response to consultation. Therefore, the committee concluded that there is still uncertainty about whether the company's model captures the long-term benefits after a stem cell transplant.\n\n## Health-related quality of life after relapse should be calculated using data from the Tremblay (2018) study\n\nThe company considered that the QUAZAR trial did not capture health-related quality of life after relapse, except in some people who may have had an extended dose of oral azacitidine. This included people with a bone marrow blast count of 6% to 15% but not those with advanced disease (blast count greater than 15%). The company considered that using a utility value derived from this small cohort of people would be inappropriate and may overestimate the quality of life for people who relapse. Therefore, the company calculated the relapse utility based on a study by Joshi (2019) which used the composite time trade-off method to elicit utility values for AML from the UK general population. In the model, relapse utility was calculated as the difference between the relapse-free survival and relapse utilities in Joshi (2019) which was then applied to the relapse-free utility from QUAZAR. The ERG noted that the sample size in Joshi (2019) was small which resulted in a large standard error. The committee understood that the company considered alternative sources for relapse utilities including studies by Stein (2019) and Tremblay (2018). The ERG considered that both sources were not ideal because utility values were derived from US populations. In response to technical engagement, the company explained why the study by Joshi (2019) had been selected. It considered the utility elicitation methodology to be preferred by NICE, utility values were from individuals in the UK, and the utility value was clinically plausible. The ERG was unclear why the company preferred the composite time trade-off methodology, given that it was not part of the reference case in NICE's guide to the methods of technology appraisal 2013. In line with NICE's technology appraisal guidance on midostaurin for untreated acute myeloid leukaemia, the ERG used Tremblay (2018) to calculate health-related quality of life after relapse in its base case. This was because it considered that the method used to elicit utility values was more appropriate than Joshi (2019). The committee noted the company's scenario analyses using relapse utility values from Tremblay (2018) and Stein (2019) had a small impact on the ICER in the EU-subgroup. The company did not provide any new evidence to support its preferred approach to calculating utility after relapse in response to the appraisal consultation document. The committee agreed with the ERG's approach and concluded that health-related quality of life after relapse should be calculated using data from Tremblay (2018).\n\n## Utility for the relapse-free survival health state should be capped at age- and sex-matched general population values\n\nThe committee understood that the company had adjusted health state utility values for age in the model. It discussed the ERG's critique that the relapse-free survival utility was higher than the age-adjusted population norm in the UK. The committee considered that this did not make sense because it would mean that people with AML had a better quality of life than people without the disease. It noted that the ERG had asked the company to provide a scenario analysis capping the utility at general population levels which slightly increased the ICER (based on the ITT population). The company did not provide any new evidence on utility for the relapse-free survival health state in response to consultation. The committee noted the ERG's analysis which capped the utility value for the relapse-free survival health state at general population levels in the EU-subgroup. The results of the analysis suggested only a small impact on the ICER. The committee concluded that the utility value for the relapse-free survival health state in the model should be capped at age- and sex-matched general population levels.\n\n## Joint survival models are appropriate for estimating overall survival and relapse-free survival in the EU-subgroup\n\nThe company used joint models (joint models apply a single distribution to both treatment arms) to estimate overall survival and relapse-free survival based on QUAZAR trial data. It used the generalised gamma accelerated failure time model for overall survival and the log-logistic accelerated failure time model for relapse-free survival in the ITT population. The company considered that the survival analyses in the EU-subgroup were aligned with the assessment for the ITT population. The committee considered that the joint modelled curves showed that the survival function was being underestimated in the model for the comparator arm (best supportive care) when compared with the Kaplan–Meier curves from the trial (based on the ITT population). It considered that this may be because accelerated failure time models assume that the treatment effect is constant over the entire lifetime of the model. In response to consultation, the company stated that the joint models selected in its base case did not overestimate the expected treatment benefit with oral azacitidine for the EU-subgroup. It presented a scenario analysis exploring the impact of using the best-fitting individual models for the EU-subgroup (generalised gamma models for overall survival and log-logistic models for relapse-free survival). The committee noted that the company's scenario analysis suggested only a small impact on the ICER. It discussed the ERG's scenario analysis which explored the impact of using the same individual parametric models and the committee's preferred assumptions from the first meeting, which also had a small impact on the ICER. The committee noted the ERG's critique that the company's joint and individual modelling results were comparable and that the impact of choosing between these approaches was likely minor. It was reassured that both approaches reflected the trial data and resulted in similar extrapolations. Therefore, the committee concluded that the company's joint modelling approach was appropriate for estimating overall survival and relapse-free survival in the EU-subgroup.\n\n## The company's approach to modelling treatment effect waning does not have a significant impact on the cost-effectiveness results\n\nThe company's base-case analysis assumed no treatment effect waning for oral azacitidine. The committee initially considered that it was highly optimistic to assume a constant treatment benefit with oral azacitidine based on the observed trial data. The committee understood that the company had presented a scenario analysis which tried to explore the impact of treatment effect waning. It did this using individual log-normal models for overall survival and log-logistic models for relapse-free survival (based on the ITT population). The results of the scenario analysis increased the ICER by 11%. The committee considered that this was not explored fully and it would be preferable to include an assumption that the relative treatment effectiveness would decline over time. Therefore, the committee considered that it would be helpful to see a range of scenarios for both the overall population (based on the EU-subgroup) and for people with FLT3-mutation-positive AML including:\n\nusing individually fitted parametric models without any additional treatment effect waning (and comparing the risks of overall survival and relapse-free survival in each cycle between the treatment groups).\n\nadding treatment effect waning in the above scenario to assume that the treatment benefit with oral azacitidine is lost at a range of clinically plausible time points (for example, after stopping treatment).In response to consultation, the company considered that the impact of treatment effect waning during the trial was already captured in the survival estimates. This was because the end of the trial follow up was 90\xa0months (7.5\xa0years) at which point no people remained on treatment with oral azacitidine. The company and ERG presented analyses exploring the relative treatment effect over time by comparing the risks of overall survival and relapse-free survival between treatment groups. This was based on using the best-fitting individual models for the EU-subgroup (see section\xa03.11). The results from both analyses showed a similar risk of death and relapse between treatment arms over time (actual numbers are considered confidential by the company and cannot be reported here). The committee noted that this suggested that treatment effect waning may be implicitly included when using an individual modelling approach. It discussed the ERG's scenario analyses which included the committee's preferred assumptions and explored the impact of using individual models with treatment effect waning at various timepoints (3\xa0years, 5\xa0years and\xa07.5\xa0years) after randomisation. The results of the scenario analyses suggested only a small impact on the ICER. The committee recalled that the company's joint and individual modelling results were comparable (see section 3.11). Therefore, it considered that the impact of treatment effect waning using a joint modelling approach would also likely have a similar effect on the ICER based on its preferred assumptions. The committee concluded that the company's approach to modelling treatment effect waning did not have a significant impact on the cost-effectiveness results.\n\n# End of life\n\n## Oral azacitidine extends life by at least 3\xa0months\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal 2013. The committee agreed that based on the trial evidence and the views of clinical experts, the overall survival gain with oral azacitidine would likely be more than 3\xa0months. The company's model suggested that there was an increase in mean overall survival of 12.8\xa0months (median 9.9\xa0months in QUAZAR) for the ITT population. For the EU-subgroup, the company's model suggested that there was an increase in mean overall survival of 16.2\xa0months (median overall survival gain was greater than 3\xa0months in QUAZAR but the exact figure is confidential so cannot be reported here). The committee agreed that oral azacitidine meets the criterion for a life-extending treatment because it increases overall survival by more than 3\xa0months.\n\n## The short life expectancy criterion is also met so oral azacitidine is considered to be a life-extending treatment at the end of life\n\nThe company confirmed that mean estimates were not available from QUAZAR, but the median overall survival for people who had placebo was 14.8\xa0months (ITT population). The company's original base case for the ITT population predicted a mean overall survival of 33.6\xa0months for people having best supportive care. The company's revised base case using the EU-subgroup predicted a mean overall survival of 31.5\xa0months for people having best supportive care (median overall survival from QUAZAR for the EU-subgroup was also less than 24\xa0months but the exact figure is confidential and so cannot be reported here). The committee acknowledged that using extrapolation models to estimate mean values involves assumptions and uncertainty. However, the committee noted that the mean estimates were higher than 24\xa0months and that the cost-effectiveness analyses are based on mean survival estimates. The clinical experts explained that a significant number of people with AML are unable to have a stem cell transplant and that they have a high risk of relapse in the first year. After relapse, they would have palliative treatment within 12\xa0months and a life expectancy of around 3\xa0months at this point. The clinical experts explained that around 20% of people may be cured after intensive chemotherapy, and reach long-term survival. The ERG considered that because some people will live for much longer, this will skew the survival distribution where the mean is often higher than the median. The committee recalled that while the short-term prognosis for most people would be poor, a proportion of people (around 20%) would be cured and would therefore be expected to live beyond 2\xa0years. It initially considered that the short life expectancy criterion had not been met. The committee considered comments received in response to consultation from the company, a clinical expert and a patient group which strongly reiterated that life expectancy for most people in this population is less than 24\xa0months. The company highlighted the appeal decision in NICE's technology appraisal guidance on avelumab for maintenance treatment of locally advanced or metastatic urothelial cancer after platinum-based chemotherapy (TA788). The appeal panel for TA788 concluded that it would be unreasonable to state that life expectancy was not normally less than 24\xa0months given that the modelled mean life expectancy indicated that most people (65%) did not survive after 24\xa0months. In this appraisal, the company highlighted that a similar proportion in the EU-subgroup did not survive beyond 24\xa0months (the exact figure is considered confidential by the company and so cannot be reported here). The committee believed that the best estimate of life expectancy came from the mean survival for the relevant patient population, based on the decision model submitted by the company. However, it accepted a consultation comment that the NICE methods guide does not specifically state how this criterion should be assessed. It noted the appeal panel's conclusion for TA788 that the totality of evidence should be considered when assessing whether a technology meets the short life expectancy criterion. The committee took into consideration the mean and median survival estimates, clinical opinion from the first committee meeting and consultation comments from all stakeholders. It also recalled that the data from the QUAZAR trial was mature and this reduced the uncertainty in the results. The committee discussed that although there are different ways to estimate life expectancy, it is likely that the population who would be considered for treatment with oral azacitidine would live on average less than 24\xa0months. Therefore, it accepted that the short life expectancy criterion was met and concluded that oral azacitidine meets the criteria to be considered a life-extending treatment at the end of life.\n\n# Cost-effectiveness estimates\n\n## The cost-effectiveness estimates are within the range that NICE considers to be an acceptable use of NHS resources\n\nNICE's guide to the methods of technology appraisal 2013 notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. At the first meeting, the committee considered that there was uncertainty around some of the assumptions used in the model which made the cost-effectiveness results uncertain. It considered that analyses which explored the use of individual models for extrapolating overall survival and treatment effect waning would reduce the uncertainty that the expected treatment benefit with oral azacitidine had been overestimated in the model (see section 3.11 and section 3.12). At the second committee meeting, the company and ERG presented these analyses which suggested that the cost-effectiveness results are robust to changes in survival modelling assumptions (see section 3.11 and section 3.12). The committee was therefore reassured that this uncertainty had now been adequately addressed. The ERG updated its base-case assumptions to align with the committee's preferences which remained unchanged from the first committee meeting. This included the following assumptions:\n\nusing the EU-subgroup of the QUAZAR trial for the total population (see section 3.5)\n\nremoving the temporary disutility associated with a stem cell transplant (see section 3.8)\n\ncalculating health-related quality of life after relapse using data from Tremblay (2018; see section 3.9)\n\ncapping the utility value for the relapse-free survival health state at matched general population levels (see section 3.10).The ERG's updated analyses included the committee's preferred deterministic and probabilistic ICERs for oral azacitidine compared with best supportive care, which were slightly above £30,000 per QALY gained. Exact ICERs are confidential and cannot be reported here, because they include the confidential patient access scheme for oral azacitidine and confidential comparator discounts. The committee considered that the most plausible ICERs were within the range that NICE considers to be an acceptable use of NHS resources for end of life treatments. It also noted the ICERs for all the scenarios presented for oral azacitidine compared with best supportive care and for oral azacitidine compared with midostaurin for the FLT3 subgroup. All the ICERs were within the range that NICE considers to be an acceptable use of NHS resources (including the confidential patient access scheme for oral azacitidine and confidential comparator discounts). It noted that the cost-effectiveness estimates for oral azacitidine compared with midostaurin were uncertain because of the limitations in the clinical evidence informing this treatment comparison (see section\xa03.7). However, the committee recalled that the proportion of people with FLT3-mutation-positive AML who would have oral azacitidine in clinical practice would be small. The committee also acknowledged that oral azacitidine could potentially address some of the equality issues raised by stakeholders (see section\xa03.16). Therefore, it recommended oral azacitidine as an option for people with AML.\n\n# Other factors\n\n## The recommendation for oral azacitidine may reduce some of the equality issues for people with AML\n\nThe committee discussed the potential equality issues raised during the appraisal. It noted a stakeholder comment that some people may struggle financially to have current treatment (such as a transplant) because of the cost of regular travel to hospital and reduced income from having to take time off work. Having a transplant may be especially difficult for people with caring responsibilities because of the significant time commitment needed. The stakeholder considered that these people should not be denied treatment and oral azacitidine would be a viable alternative to a transplant. The committee recognised that because oral azacitidine can be taken at home it may be more convenient and reduce the amount of time spent in hospital compared with having a transplant. It noted comments from stakeholders that many people with AML who are in complete remission are unable to have a transplant because of a lack of donor availability. Therefore, this results in an inequity of access to curative treatment and disproportionately affects people with a minority ethnic family background. The clinical experts explained that after a transplant there is a 70% reduction in the risk of relapse. They explained that in people of white family background, the likelihood of finding a suitably matched donor is around 80%, which reduces to around 30% to 40% in people with a minority ethnic family background. Stakeholders and clinical experts highlighted that oral azacitidine should therefore be available to all people who are not able to have a transplant, including those with a minority ethnic family background who do not have a suitable donor. The committee noted that this issue had been reiterated in comments received in response to the appraisal consultation document. The committee acknowledged that unequal access to transplants because of ethnicity was a relevant consideration and it was mindful of its obligations in relation to the Equality Act\xa02010. It noted that the company had also highlighted that there may be geographical barriers to accessing a stem cell transplant based on how far away a person lives from an allograft transplant centre. The committee considered that issues around healthcare implementation cannot be addressed in a technology appraisal. It concluded that because it had recommended oral azacitidine for people with AML that this may help to reduce some of the potential equality issues raised during the appraisal.\n\n## The benefits of oral azacitidine are captured in the cost-effectiveness analysis\n\nThe company and stakeholders considered oral azacitidine to be innovative because it improves survival, is well tolerated and because of its oral formulation. The committee recalled how treatment with oral azacitidine would offer benefits because people would be able to have treatment at home (see section 3.1). It heard how this would reduce time spent in hospital and allow people to spend more time with their family and friends. The committee agreed that these are important benefits and noted that oral azacitidine is the first maintenance treatment licensed for all people with AML. However, it concluded that it had not been presented with evidence of any additional benefits that could not be captured in the QALY calculations."}	https://www.nice.org.uk/guidance/ta827	Evidence-based recommendations on azacitidine (Onureg) for maintenance treatment of acute myeloid leukaemia after induction therapy in adults.
1696ff629386891c211508067fd29c4d378436d6	nice	Ozanimod for treating moderately to severely active ulcerative colitis	Ozanimod for treating moderately to severely active ulcerative colitis Evidence-based recommendations on ozanimod (Zeposia) for treating moderately to severely active ulcerative colitis in adults when conventional or biological treatments cannot be tolerated or are not working well enough. # Recommendations Ozanimod is recommended as an option for treating moderately to severely active ulcerative colitis in adults, only if: conventional treatment cannot be tolerated or is not working well enough and infliximab is not suitable, or biological treatment cannot be tolerated or is not working well enough, and the company provides it according to the commercial arrangement. This recommendation is not intended to affect treatment with ozanimod that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Standard treatments for moderately to severely active ulcerative colitis after conventional treatments are biological treatments (adalimumab, golimumab, infliximab, ustekinumab or vedolizumab) or tofacitinib. Clinical trial evidence shows that ozanimod is more effective than placebo for treating moderately to severely active ulcerative colitis. There is no direct evidence comparing ozanimod with standard treatments that are offered after conventional treatment, but indirect comparisons suggest that it is likely to be as effective as some of them. When conventional treatment is not tolerated or not working well enough, infliximab is more cost effective than ozanimod. But the most likely cost-effectiveness estimates for ozanimod compared with most other treatments are within the range that NICE normally considers an acceptable use of NHS resources. So, ozanimod is recommended, but only if conventional treatment cannot be tolerated or is not working well enough, and only if infliximab is not suitable. Ozanimod is also recommended if a biological treatment cannot be tolerated or is not working well enough.# Information about ozanimod # Marketing authorisation indication Ozanimod (Zeposia, Celgene, a Bristol Myers Squibb Company) is indicated for 'the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for ozanimod. # Price The price of an ozanimod induction pack is £343 (4 capsules of 0.23 mg and 3 capsules of 0.46 mg per pack). The price of a maintenance pack is £1,373 (0.92 mg, 28‑capsule pack) or £4,806 (0.92 mg, 98‑capsule pack; all prices excluding VAT; company submission). The estimated cost for the induction and maintenance phases of treatment is £17,910 per person per year (company submission, excluding VAT). The company has a commercial arrangement. This makes ozanimod available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Celgene, a Bristol Myers Squibb Company, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Ulcerative colitis is a lifelong condition affecting all aspects of a person's life Ulcerative colitis is a chronic, unpredictable condition characterised by relapsing and remitting periods of inflammation of the rectal and colonic lining. The patient experts explained that the symptoms of the condition and the side effects of treatments can have a profound and devastating impact on all aspects of a person's life. Symptoms can affect the ability to work, study, socialise, take part in leisure activities and have intimate relationships. They explained that fears of needing surgery or developing cancer or even dying can affect a person's mental and emotional wellbeing, leading to feelings of anxiety, stress, depression and hopelessness. They explained that the impact of living with ulcerative colitis can be exacerbated because of the stigma of having the condition and frustration from a lack of understanding of the condition by others. Unlike symptoms of gastroenteritis that may last for 1 or 2 days, symptoms of active ulcerative colitis can last for months. People with active disease may experience debilitating, multiple daily episodes of explosive, painful diarrhoea with blood loss and pus. The committee concluded that symptoms of ulcerative colitis and the side effects of treatments for moderately to severely active ulcerative colitis can have a profound impact on quality of life. # Clinical management ## Management of ulcerative colitis is highly individualised and there is an unmet need for new treatments The clinical experts explained that management of ulcerative colitis is highly individualised. Factors including previous therapies, the need for concomitant medicines such as corticosteroids and thiopurines, tolerability, and personal preferences and circumstances such as planned pregnancy can affect treatment options. They explained that current treatments are not very effective at achieving and maintaining clinical remission, so treatment switching often occurs. Some treatments also have serious side effects, for example thiopurines are associated with an increased risk of cancer, and there are also some serious side effects associated with biological treatments. At initial diagnosis, people typically have conventional treatments such as corticosteroids, mesalazine and thiopurines (azathioprine and mercaptopurine). If the condition does not respond well enough or stops responding to conventional treatment, a biological treatment, usually a tumour necrosis factor (TNF)‑alpha inhibitor, commonly infliximab, is most often offered. The clinical experts explained that TNF‑alpha inhibitors should be used with thiopurines to be most effective. In about 30% of people, the condition does not respond to a TNF‑alpha inhibitor (primary non-response), and about 40% of people with the condition will lose response over 12 months (secondary non-response). For a minority of people, another TNF‑alpha inhibitor such as adalimumab or golimumab may be offered, but other options include vedolizumab, ustekinumab, tofacitinib, and filgotinib. These treatments have different mechanisms of action to TNF‑alpha inhibitors which people may benefit from. However, the clinical experts explained that at this point in the treatment pathway, response to further treatment, regardless of its mechanism of action, is likely to be lower. They emphasised the importance of using the most effective option for the person in the first instance. They explained that medicines that result in clinical remission are not stopped if they continue to be effective. They highlighted that an oral treatment, such as tofacitinib, is attractive because it is easy to take and any response can be judged after 1 or 2 weeks. However, response is usually assessed after a few months for TNF‑alpha inhibitors and ustekinumab. Importantly, tofacitinib can be used without corticosteroids or thiopurines. They highlighted that tofacitinib use is variable across England and suggested that uptake may have been affected by safety concerns about deep vein thrombosis (DVT). They explained that under-treated ulcerative colitis also increases the risk of DVTs and that tofacitinib has been effectively used in carefully selected people. The patient experts emphasised the importance of having access to a range of effective treatment options to avoid or delay the need for surgery. The committee acknowledged the need for new treatments that can be taken without concomitant medicines and that are fast-acting, well tolerated and easy to administer. The committee concluded that treatment options are highly individualised and that there is an unmet need for new treatments with different mechanisms of action. ## Ozanimod could be used after conventional treatment or after a TNF-alpha inhibitor The marketing authorisation for ozanimod is for people with moderately to severely active ulcerative colitis whose condition had an inadequate response, lost response, or were intolerant to either conventional therapy or a biological treatment. The company submission presented ozanimod at 2 positions in the treatment pathway: A treatment for 'TNF‑alpha inhibitor-naive': people who have never had a TNF‑alpha inhibitor, but have had conventional treatment and their condition has not responded or has lost response to it or it cannot be tolerated. A treatment for 'TNF‑alpha inhibitor-experienced': people who have had at least 1 TNF‑alpha inhibitor and their condition has not responded or has lost response to it, or it cannot be tolerated.The clinical experts confirmed that it was reasonable to divide people according to TNF‑alpha inhibitor experience, rather than biological treatment experience because TNF‑alpha inhibitors are more commonly used than other treatments after conventional treatment stops being effective. The committee concluded that the company's categorisation based on TNF‑alpha inhibitor experience was appropriate. ## TNF-alpha inhibitors, vedolizumab, ustekinumab and tofacitinib are all relevant comparators because management of ulcerative colitis is highly individualised The company proposed the following comparators: For the TNF‑alpha inhibitor-naive subgroup: TNF‑alpha inhibitors and vedolizumab. For the TNF‑alpha inhibitor-experienced subgroup: ustekinumab and vedolizumab.The company considered tofacitinib was not a relevant comparator because of safety concerns. The committee recalled the clinical experts' testimony that tofacitinib is used, although variably, across the NHS. It also recalled that a second TNF‑alpha inhibitor may be used when there has been a secondary non-response to a first TNF‑alpha inhibitor (see section 3.2). It also recalled that a highly individualised approach to management is adopted for ulcerative colitis. The committee was aware of the recently published NICE technology appraisal guidance on filgotinib for treating moderately to severely active ulcerative colitis (June 2022). It noted that filgotinib has not yet been routinely used in clinical practice and was not included in the scope of this appraisal. It concluded that although the order in which treatments are given may vary in practice, the relevant comparators are: For the TNF‑alpha inhibitor-naive subgroup: TNF‑alpha inhibitors (usually infliximab), vedolizumab and tofacitinib. For the TNF‑alpha inhibitor-experienced subgroup: TNF‑alpha inhibitors (usually adalimumab), ustekinumab, vedolizumab and tofacitinib. # Clinical evidence ## The key clinical trial, TRUENORTH, shows that ozanimod improves clinical remission compared with placebo The main clinical evidence for ozanimod came from a phase 3, double-blind, randomised, placebo-controlled, multicentre trial that included a 10‑week induction phase and a 42‑week maintenance phase. It included 1,012 adults (18 to 75 years) with moderately to severely active ulcerative colitis. This was defined by a 4‑component Mayo score of between 6 and 12, and component subscores of at least 1 for stool frequency and rectal bleeding, and at least 2 for endoscopic findings. It had a re‑randomised design and included 2 cohorts. Cohort 1 included 645 adults who were randomised to either ozanimod or placebo. Cohort 2 included an open-label group of 367 adults who had ozanimod. People taking corticosteroids maintained their dose during induction, and then tapered their dose on entering the maintenance phase. The key primary end point, the proportion of people in clinical remission at induction (week 10) and maintenance (week 52) used data from Cohort 1. In addition to results for the overall population, the company presented the results based on the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups. The clinical experts confirmed that the most important clinical end point is clinical remission. For both the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups, a greater proportion of people who had ozanimod experienced clinical remission than those in the placebo group at the end of induction and maintenance. These findings were all statistically significant except for the TNF‑alpha inhibitor-experienced subgroup at the end of induction. These results are considered academic in confidence by the company and cannot be presented here. The committee concluded that ozanimod improved clinical remission compared with placebo for both the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups. ## People in TRUENORTH are representative of people likely to have ozanimod in NHS clinical practice The company confirmed that some people in the TNF‑alpha inhibitor-experienced subgroup had received more than 1 biological treatment. The committee noted that the company had not further stratified the TNF‑alpha inhibitor-experienced subgroup based on the number of previous biological treatments, that is, for second-line or third-line biological treatment. The ERG highlighted that an older group of adults may be missing in the trial. The clinical experts confirmed that people seen in the NHS are unlikely to be much older than people in the trial. They considered that the people in TRUENORTH are representative of people likely to have ozanimod in clinical practice. They explained that people in the TNF‑alpha inhibitor-experienced subgroup are likely to have more severe ulcerative colitis and that any treatment is likely to be less effective at this stage. The committee concluded that the people in TRUENORTH are representative of people that would be treated in NHS clinical practice. ## A high placebo response is commonly seen in trials of ulcerative colitis The committee noted the high placebo response in TRUENORTH for both the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups. The clinical experts explained that high placebo responses are typically seen in these trials and that concomitant corticosteroid use may have a large impact on placebo response. The ERG noted that there was little detail on the use of concomitant medicines in the company submission. The committee noted that placebo response contributed to the heterogeneity across trials in the network meta-analysis. ## The company's revised network meta-analysis is appropriate for decision making Because there were no head-to-head trials, the company did network meta-analyses to compare the effectiveness of ozanimod with TNF‑alpha inhibitors (adalimumab, infliximab, golimumab), vedolizumab, ustekinumab, and tofacitinib. The network meta-analyses included 25 trials stratified by TNF‑alpha inhibitor experience (TNF‑alpha inhibitor-naive compared with TNF‑alpha inhibitor-experienced) and treatment phase (induction 6 to 14 weeks compared with maintenance 52 to 60 weeks). This was done using random effects ordinal models with a probit link to assess clinical remission and clinical response. The company assessed baseline risk in the placebo arm of its revised network meta-analyses using data from single trials in the network meta-analyses that it considered representative of UK clinical practice. This was in line with the ERG's approach. The ERG explained that overall, the company's revised network meta-analyses are in line with recommended practice and have accounted for some potential effect modifiers (mainly previous TNF‑alpha inhibitor treatment and differences in trial design). But it considered that there is uncertainty as to whether the most suitable source of evidence had been used to estimate baseline placebo risk. The committee recognised that the company tried to address the limitation of identifying suitable data sources to estimate baseline placebo risk during technical engagement but was unsuccessful. It concluded that although the approach to estimate baseline placebo risk was suboptimal, overall the company's revised network meta-analyses were appropriate for decision making. ## Ozanimod is likely to be as effective as some comparators The results of the company's induction and maintenance network meta-analyses showed that ozanimod is likely to be as effective as some comparators in the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups. The results are considered academic in confidence by the company and cannot be presented here. The clinical experts highlighted that different network meta-analyses may provide different rankings, and that it is difficult to choose a specific treatment based only on small differences in efficacy. They explained that this is because people respond differently, and no single treatment is very effective in terms of maintaining clinical remission. They emphasised that treatment choice is highly dependent on individual needs and preferences. The committee concluded that in the network meta-analyses, ozanimod did not stand out as being substantially more or less effective than the comparators. # The company's economic model ## The company's economic model is appropriate for decision making The company used a Markov model to estimate the cost effectiveness of ozanimod compared with adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab for the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups. The company's model structure was similar to those used in previous ulcerative colitis technology appraisals. It included health states defined by the type of treatment and degree of disease control, to replicate the relapsing and remitting nature of ulcerative colitis. The types of treatment were active treatment (including both induction and maintenance phases), post-active treatment (including surgery and post-surgery), and best supportive care, comprising components of conventional treatment. Degrees of disease control were remission, response without remission, and active ulcerative colitis. The Markov model had a lifetime time horizon and a cycle length of 2 weeks and included clinical response, clinical remission and serious infections. The ERG agreed that the company captured all relevant health states and that its approach was appropriate. The committee concluded that the company's model was appropriate for decision making. # Assumptions in the model ## Using subgroup-specific data to model efficacy estimates for best supportive care in the post-active treatment phase is preferred The company modelled efficacy estimates for best supportive care in the post-active treatment phase. It used data from the placebo arms of the trials included in the network meta-analysis from the TNF‑alpha inhibitor-experienced subgroup to inform the transition probabilities for the TNF‑alpha inhibitor-naive subgroup. The company considered that the data from the TNF‑alpha inhibitor-experienced subgroup was more appropriate for the TNF‑alpha inhibitor-naive subgroup because people in the post-active treatment phase had already had at least 1 TNF‑alpha inhibitor. The ERG considered that subgroup-specific data should inform transition probabilities in the best supportive care arm. It considered that the loss of response and loss of response (no remission) transition probabilities should be based on both the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced estimates. The committee noted that the 2 approaches resulted in only a modest difference in the incremental cost-effectiveness ratio (ICER), but considered that subgroup-specific data is preferred. # Cost-effectiveness estimates ## Ozanimod is considered cost effective, except in comparison with infliximab in the TNF-alpha inhibitor-naive subgroup The committee considered the cost effectiveness of ozanimod compared with adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab for the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups. The company's and ERG's base case results included confidential commercial discounts, so they cannot be reported here. The committee considered that the ICERs are potentially unstable because of very small and uncertain differences in efficacy between the treatments that were used in the economic model. However, considering the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups separately, the committee concluded that overall, ozanimod could be considered a cost-effective option when conventional or biological treatments are not tolerated or working well enough. The committee noted the exception that infliximab was more cost effective than ozanimod in the TNF‑alpha inhibitor-naive subgroup. It concluded that ozanimod should only be offered to people in the TNF‑alpha inhibitor-naive subgroup if infliximab cannot be tolerated or is contraindicated. # Other factors ## There are no equality issues relevant to the recommendations The patient experts explained that for some religious groups the impact of active disease and the effects of surgery may interfere with religious practices and cause distress. The committee did not consider this an equality issue that could be resolved by this appraisal. No other equality or social value judgement issues were identified. ## The benefits of ozanimod are adequately captured in the cost-effectiveness analysis The company considered ozanimod to be innovative because it has a novel mechanism of action that uses sphingosine 1‑phosphate (S1P) receptors to decrease circulating lymphocytes to reduce inflammation. Ozanimod addresses an unmet need by providing people with a new therapeutic oral option to treat symptoms and induce remission. The committee acknowledged the benefits offered by ozanimod and that people value an oral treatment. But it noted that it had not been presented with evidence of any additional benefits that were not captured in the quality-adjusted life year (QALY) measurements. The committee concluded that the benefits of ozanimod were adequately captured in the model.	{'Recommendations': 'Ozanimod is recommended as an option for treating moderately to severely active ulcerative colitis in adults, only if:\n\nconventional treatment cannot be tolerated or is not working well enough and infliximab is not suitable, or\n\nbiological treatment cannot be tolerated or is not working well enough, and\n\nthe company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with ozanimod that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard treatments for moderately to severely active ulcerative colitis after conventional treatments are biological treatments (adalimumab, golimumab, infliximab, ustekinumab or vedolizumab) or tofacitinib.\n\nClinical trial evidence shows that ozanimod is more effective than placebo for treating moderately to severely active ulcerative colitis. There is no direct evidence comparing ozanimod with standard treatments that are offered after conventional treatment, but indirect comparisons suggest that it is likely to be as effective as some of them.\n\nWhen conventional treatment is not tolerated or not working well enough, infliximab is more cost effective than ozanimod. But the most likely cost-effectiveness estimates for ozanimod compared with most other treatments are within the range that NICE normally considers an acceptable use of NHS resources. So, ozanimod is recommended, but only if conventional treatment cannot be tolerated or is not working well enough, and only if infliximab is not suitable. Ozanimod is also recommended if a biological treatment cannot be tolerated or is not working well enough.', 'Information about ozanimod': "# Marketing authorisation indication\n\nOzanimod (Zeposia, Celgene, a Bristol Myers Squibb Company) is indicated for 'the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for ozanimod.\n\n# Price\n\nThe price of an ozanimod induction pack is £343 (4\xa0capsules of 0.23\xa0mg and 3\xa0capsules of 0.46\xa0mg per pack). The price of a maintenance pack is £1,373 (0.92\xa0mg, 28‑capsule pack)\xa0or £4,806 (0.92\xa0mg, 98‑capsule pack; all prices excluding VAT; company submission). The estimated cost for the induction and maintenance phases of treatment is £17,910 per person per year (company submission, excluding VAT).\n\nThe company has a commercial arrangement. This makes ozanimod available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Celgene, a Bristol Myers Squibb Company, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Ulcerative colitis is a lifelong condition affecting all aspects of a person's life\n\nUlcerative colitis is a chronic, unpredictable condition characterised by relapsing and remitting periods of inflammation of the rectal and colonic lining. The patient experts explained that the symptoms of the condition and the side effects of treatments can have a profound and devastating impact on all aspects of a person's life. Symptoms can affect the ability to work, study, socialise, take part in leisure activities and have intimate relationships. They explained that fears of needing surgery or developing cancer or even dying can affect a person's mental and emotional wellbeing, leading to feelings of anxiety, stress, depression and hopelessness. They explained that the impact of living with ulcerative colitis can be exacerbated because of the stigma of having the condition and frustration from a lack of understanding of the condition by others. Unlike symptoms of gastroenteritis that may last for 1\xa0or 2\xa0days, symptoms of active ulcerative colitis can last for months. People with active disease may experience debilitating, multiple daily episodes of explosive, painful diarrhoea with blood loss and pus. The committee concluded that symptoms of ulcerative colitis and the side effects of treatments for moderately to severely active ulcerative colitis can have a profound impact on quality of life.\n\n# Clinical management\n\n## Management of ulcerative colitis is highly individualised and there is an unmet need for new treatments\n\nThe clinical experts explained that management of ulcerative colitis is highly individualised. Factors including previous therapies, the need for concomitant medicines such as corticosteroids and thiopurines, tolerability, and personal preferences and circumstances such as planned pregnancy can affect treatment options. They explained that current treatments are not very effective at achieving and maintaining clinical remission, so treatment switching often occurs. Some treatments also have serious side effects, for example thiopurines are associated with an increased risk of cancer, and there are also some serious side effects associated with biological treatments. At initial diagnosis, people typically have conventional treatments such as corticosteroids, mesalazine and thiopurines (azathioprine and mercaptopurine). If the condition does not respond well enough or stops responding to conventional treatment, a biological treatment, usually a tumour necrosis factor (TNF)‑alpha inhibitor, commonly infliximab, is most often offered. The clinical experts explained that TNF‑alpha inhibitors should be used with thiopurines to be most effective. In about 30% of people, the condition does not respond to a TNF‑alpha inhibitor (primary non-response), and about 40% of people with the condition will lose response over 12\xa0months (secondary non-response). For a minority of people, another TNF‑alpha inhibitor such as adalimumab or golimumab may be offered, but other options include vedolizumab, ustekinumab, tofacitinib, and filgotinib. These treatments have different mechanisms of action to TNF‑alpha inhibitors which people may benefit from. However, the clinical experts explained that at this point in the treatment pathway, response to further treatment, regardless of its mechanism of action, is likely to be lower. They emphasised the importance of using the most effective option for the person in the first instance. They explained that medicines that result in clinical remission are not stopped if they continue to be effective. They highlighted that an oral treatment, such as tofacitinib, is attractive because it is easy to take and any response can be judged after 1\xa0or 2\xa0weeks. However, response is usually assessed after a few months for TNF‑alpha inhibitors and ustekinumab. Importantly, tofacitinib can be used without corticosteroids or thiopurines. They highlighted that tofacitinib use is variable across England and suggested that uptake may have been affected by safety concerns about deep vein thrombosis (DVT). They explained that under-treated ulcerative colitis also increases the risk of DVTs and that tofacitinib has been effectively used in carefully selected people. The patient experts emphasised the importance of having access to a range of effective treatment options to avoid or delay the need for surgery. The committee acknowledged the need for new treatments that can be taken without concomitant medicines and that are fast-acting, well tolerated and easy to administer. The committee concluded that treatment options are highly individualised and that there is an unmet need for new treatments with different mechanisms of action.\n\n## Ozanimod could be used after conventional treatment or after a TNF-alpha inhibitor\n\nThe marketing authorisation for ozanimod is for people with moderately to severely active ulcerative colitis whose condition had an inadequate response, lost response, or were intolerant to either conventional therapy or a biological treatment. The company submission presented ozanimod at 2\xa0positions in the treatment pathway:\n\nA treatment for 'TNF‑alpha inhibitor-naive': people who have never had a TNF‑alpha inhibitor, but have had conventional treatment and their condition has not responded or has lost response to it or it cannot be tolerated.\n\nA treatment for 'TNF‑alpha inhibitor-experienced': people who have had at least 1\xa0TNF‑alpha inhibitor and their condition has not responded or has lost response to it, or it cannot be tolerated.The clinical experts confirmed that it was reasonable to divide people according to TNF‑alpha inhibitor experience, rather than biological treatment experience because TNF‑alpha inhibitors are more commonly used than other treatments after conventional treatment stops being effective. The committee concluded that the company's categorisation based on TNF‑alpha inhibitor experience was appropriate.\n\n## TNF-alpha inhibitors, vedolizumab, ustekinumab and tofacitinib are all relevant comparators because management of ulcerative colitis is highly individualised\n\nThe company proposed the following comparators:\n\nFor the TNF‑alpha inhibitor-naive subgroup: TNF‑alpha inhibitors and vedolizumab.\n\nFor the TNF‑alpha inhibitor-experienced subgroup: ustekinumab and vedolizumab.The company considered tofacitinib was not a relevant comparator because of safety concerns. The committee recalled the clinical experts' testimony that tofacitinib is used, although variably, across the NHS. It also recalled that a second TNF‑alpha inhibitor may be used when there has been a secondary non-response to a first TNF‑alpha inhibitor (see section\xa03.2). It also recalled that a highly individualised approach to management is adopted for ulcerative colitis. The committee was aware of the recently published NICE technology appraisal guidance on filgotinib for treating moderately to severely active ulcerative colitis (June\xa02022). It noted that filgotinib has not yet been routinely used in clinical practice and was not included in the scope of this appraisal. It concluded that although the order in which treatments are given may vary in practice, the relevant comparators are:\n\nFor the TNF‑alpha inhibitor-naive subgroup: TNF‑alpha inhibitors (usually infliximab), vedolizumab and tofacitinib.\n\nFor the TNF‑alpha inhibitor-experienced subgroup: TNF‑alpha inhibitors (usually adalimumab), ustekinumab, vedolizumab and tofacitinib.\n\n# Clinical evidence\n\n## The key clinical trial, TRUENORTH, shows that ozanimod improves clinical remission compared with placebo\n\nThe main clinical evidence for ozanimod came from a phase\xa03, double-blind, randomised, placebo-controlled, multicentre trial that included a 10‑week induction phase and a 42‑week maintenance phase. It included 1,012\xa0adults (18\xa0to\xa075\xa0years) with moderately to severely active ulcerative colitis. This was defined by a 4‑component Mayo score of between 6\xa0and\xa012, and component subscores of at least 1 for stool frequency and rectal bleeding, and at least 2 for endoscopic findings. It had a re‑randomised design and included 2\xa0cohorts. Cohort\xa01 included 645\xa0adults who were randomised to either ozanimod or placebo. Cohort\xa02 included an open-label group of 367\xa0adults who had ozanimod. People taking corticosteroids maintained their dose during induction, and then tapered their dose on entering the maintenance phase. The key primary end point, the proportion of people in clinical remission at induction (week\xa010) and maintenance (week\xa052) used data from Cohort\xa01. In addition to results for the overall population, the company presented the results based on the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups. The clinical experts confirmed that the most important clinical end point is clinical remission. For both the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups, a greater proportion of people who had ozanimod experienced clinical remission than those in the placebo group at the end of induction and maintenance. These findings were all statistically significant except for the TNF‑alpha inhibitor-experienced subgroup at the end of induction. These results are considered academic in confidence by the company and cannot be presented here. The committee concluded that ozanimod improved clinical remission compared with placebo for both the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups.\n\n## People in TRUENORTH are representative of people likely to have ozanimod in NHS clinical practice\n\nThe company confirmed that some people in the TNF‑alpha inhibitor-experienced subgroup had received more than 1\xa0biological treatment. The committee noted that the company had not further stratified the TNF‑alpha inhibitor-experienced subgroup based on the number of previous biological treatments, that is, for second-line or third-line biological treatment. The ERG highlighted that an older group of adults may be missing in the trial. The clinical experts confirmed that people seen in the NHS are unlikely to be much older than people in the trial. They considered that the people in TRUENORTH are representative of people likely to have ozanimod in clinical practice. They explained that people in the TNF‑alpha inhibitor-experienced subgroup are likely to have more severe ulcerative colitis and that any treatment is likely to be less effective at this stage. The committee concluded that the people in TRUENORTH are representative of people that would be treated in NHS clinical practice.\n\n## A high placebo response is commonly seen in trials of ulcerative colitis\n\nThe committee noted the high placebo response in TRUENORTH for both the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups. The clinical experts explained that high placebo responses are typically seen in these trials and that concomitant corticosteroid use may have a large impact on placebo response. The ERG noted that there was little detail on the use of concomitant medicines in the company submission. The committee noted that placebo response contributed to the heterogeneity across trials in the network meta-analysis.\n\n## The company's revised network meta-analysis is appropriate for decision making\n\nBecause there were no head-to-head trials, the company did network meta-analyses to compare the effectiveness of ozanimod with TNF‑alpha inhibitors (adalimumab, infliximab, golimumab), vedolizumab, ustekinumab, and tofacitinib. The network meta-analyses included 25\xa0trials stratified by TNF‑alpha inhibitor experience (TNF‑alpha inhibitor-naive compared with TNF‑alpha inhibitor-experienced) and treatment phase (induction 6\xa0to\xa014\xa0weeks compared with maintenance 52\xa0to\xa060\xa0weeks). This was done using random effects ordinal models with a probit link to assess clinical remission and clinical response. The company assessed baseline risk in the placebo arm of its revised network meta-analyses using data from single trials in the network meta-analyses that it considered representative of UK clinical practice. This was in line with the ERG's approach. The ERG explained that overall, the company's revised network meta-analyses are in line with recommended practice and have accounted for some potential effect modifiers (mainly previous TNF‑alpha inhibitor treatment and differences in trial design). But it considered that there is uncertainty as to whether the most suitable source of evidence had been used to estimate baseline placebo risk. The committee recognised that the company tried to address the limitation of identifying suitable data sources to estimate baseline placebo risk during technical engagement but was unsuccessful. It concluded that although the approach to estimate baseline placebo risk was suboptimal, overall the company's revised network meta-analyses were appropriate for decision making.\n\n## Ozanimod is likely to be as effective as some comparators\n\nThe results of the company's induction and maintenance network meta-analyses showed that ozanimod is likely to be as effective as some comparators in the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups. The results are considered academic in confidence by the company and cannot be presented here. The clinical experts highlighted that different network meta-analyses may provide different rankings, and that it is difficult to choose a specific treatment based only on small differences in efficacy. They explained that this is because people respond differently, and no single treatment is very effective in terms of maintaining clinical remission. They emphasised that treatment choice is highly dependent on individual needs and preferences. The committee concluded that in the network meta-analyses, ozanimod did not stand out as being substantially more or less effective than the comparators.\n\n# The company's economic model\n\n## The company's economic model is appropriate for decision making\n\nThe company used a Markov model to estimate the cost effectiveness of ozanimod compared with adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab for the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups. The company's model structure was similar to those used in previous ulcerative colitis technology appraisals. It included health states defined by the type of treatment and degree of disease control, to replicate the relapsing and remitting nature of ulcerative colitis. The types of treatment were active treatment (including both induction and maintenance phases), post-active treatment (including surgery and post-surgery), and best supportive care, comprising components of conventional treatment. Degrees of disease control were remission, response without remission, and active ulcerative colitis. The Markov model had a lifetime time horizon and a cycle length of 2\xa0weeks and included clinical response, clinical remission and serious infections. The ERG agreed that the company captured all relevant health states and that its approach was appropriate. The committee concluded that the company's model was appropriate for decision making.\n\n# Assumptions in the model\n\n## Using subgroup-specific data to model efficacy estimates for best supportive care in the post-active treatment phase is preferred\n\nThe company modelled efficacy estimates for best supportive care in the post-active treatment phase. It used data from the placebo arms of the trials included in the network meta-analysis from the TNF‑alpha inhibitor-experienced subgroup to inform the transition probabilities for the TNF‑alpha inhibitor-naive subgroup. The company considered that the data from the TNF‑alpha inhibitor-experienced subgroup was more appropriate for the TNF‑alpha inhibitor-naive subgroup because people in the post-active treatment phase had already had at least 1\xa0TNF‑alpha inhibitor. The ERG considered that subgroup-specific data should inform transition probabilities in the best supportive care arm. It considered that the loss of response and loss of response (no remission) transition probabilities should be based on both the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced estimates. The committee noted that the 2\xa0approaches resulted in only a modest difference in the incremental cost-effectiveness ratio (ICER), but considered that subgroup-specific data is preferred.\n\n# Cost-effectiveness estimates\n\n## Ozanimod is considered cost effective, except in comparison with infliximab in the TNF-alpha inhibitor-naive subgroup\n\nThe committee considered the cost effectiveness of ozanimod compared with adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab for the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups. The company's and ERG's base case results included confidential commercial discounts, so they cannot be reported here. The committee considered that the ICERs are potentially unstable because of very small and uncertain differences in efficacy between the treatments that were used in the economic model. However, considering the TNF‑alpha inhibitor-naive and TNF‑alpha inhibitor-experienced subgroups separately, the committee concluded that overall, ozanimod could be considered a cost-effective option when conventional or biological treatments are not tolerated or working well enough. The committee noted the exception that infliximab was more cost effective than ozanimod in the TNF‑alpha inhibitor-naive subgroup. It concluded that ozanimod should only be offered to people in the TNF‑alpha inhibitor-naive subgroup if infliximab cannot be tolerated or is contraindicated.\n\n# Other factors\n\n## There are no equality issues relevant to the recommendations\n\nThe patient experts explained that for some religious groups the impact of active disease and the effects of surgery may interfere with religious practices and cause distress. The committee did not consider this an equality issue that could be resolved by this appraisal. No other equality or social value judgement issues were identified.\n\n## The benefits of ozanimod are adequately captured in the cost-effectiveness analysis\n\nThe company considered ozanimod to be innovative because it has a novel mechanism of action that uses sphingosine 1‑phosphate (S1P) receptors to decrease circulating lymphocytes to reduce inflammation. Ozanimod addresses an unmet need by providing people with a new therapeutic oral option to treat symptoms and induce remission. The committee acknowledged the benefits offered by ozanimod and that people value an oral treatment. But it noted that it had not been presented with evidence of any additional benefits that were not captured in the quality-adjusted life year (QALY) measurements. The committee concluded that the benefits of ozanimod were adequately captured in the model."}	https://www.nice.org.uk/guidance/ta828	Evidence-based recommendations on ozanimod (Zeposia) for treating moderately to severely active ulcerative colitis in adults when conventional or biological treatments cannot be tolerated or are not working well enough.
403405df5e227720746396a0d70f946a098e3aa2	nice	Magtrace and Sentimag system for locating sentinel lymph nodes for breast cancer	Magtrace and Sentimag system for locating sentinel lymph nodes for breast cancer Evidence-based recommendations on Magtrace and Sentimag system for locating sentinel lymph nodes for breast cancer. # Recommendations Magtrace and Sentimag is recommended as an option to locate sentinel lymph nodes for breast cancer in hospitals with limited or no access to radiopharmacy. Further data collection is recommended to monitor the number of additional sentinel lymph node biopsies done in each hospital after the technology is adopted in clinical practice. Why the committee made these recommendations Evidence shows that Magtrace and Sentimag is likely to be as effective at detecting sentinel lymph nodes as the radioactive isotope tracer and blue dye dual technique used in standard practice. Standard practice requires nuclear medicine safety procedures and facilities. Clinical expert advice suggested that hospitals with limited or no access to radiopharmacy are more likely to realise the opportunity costs that make this technology a cost-saving option. These hospitals are likely to be able to do more procedures because scheduling is less dependent on external supply chain and staffing resources. Because the potential cost saving depends on the opportunity costs, and the economic evidence is limited, data collection is recommended to understand if cost savings are made once the technology is adopted in clinical practice.# The technology # Technology The Magtrace and Sentimag system (Endomag) comprises a magnetic liquid tracer (Magtrace) and a handheld magnetic sensing probe (Sentimag). Magtrace is intended for use only with the Sentimag system. Magtrace is a non-radioactive dark brown liquid containing superparamagnetic iron oxide with a carboxydextran coating. It is both a magnetic marker and a visual dye. Magtrace is injected into the tissue beneath the areola or interstitial tissue around a tumour. The particles are then absorbed into lymphatics and become trapped in sentinel lymph nodes that can then be detected by the magnetic sensing probe and also by visualisation to assist with biopsy. During surgery, the Sentimag probe detects the tracer trapped in the lymph nodes and guides the surgeon to remove them for biopsy. Sentimag uses a visual reading and sounds of different pitches to indicate how close the surgeon is to the magnetic tracer. The nodes often appear dark brown or black in colour, which also helps identification. # Care pathway A sentinel lymph node biopsy helps to stage cancer that has spread to the lymph nodes and is followed by a surgical procedure to remove 1 or more of the nodes. NICE's guideline on early and locally advanced breast cancer recommends sentinel lymph node biopsy as the preferred technique to stage the axilla for people with invasive breast cancer and no evidence of lymph involvement on ultrasound or a negative ultrasound-guided needle biopsy. The guideline also recommends that sentinel lymph node biopsy should be offered to people who are having a mastectomy for ductal carcinoma in-situ breast cancer and people with a preoperative diagnosis of ductal carcinoma in-situ who are considered to be at high risk of invasive disease. The recommended treatment option for locating sentinel lymph nodes during biopsy is a dual technique combination of a tracer containing a radioactive isotope, and blue dye. When the radioactive isotope is not available, some centres report using blue dye on its own, but this can reduce the detection rate of sentinel lymph nodes. # Innovative aspects The key innovative feature of the Magtrace and Sentimag system is its magnetic mechanism of action. This means that unlike the dual technique, the system can be used without the need for nuclear medicine safety procedures and facilities. Magtrace can also be injected up to 30 days before surgery, whereas the radioactive tracers can be given no more than 24 hours before the sentinel lymph node biopsy procedure. # Intended use Magtrace and Sentimag are intended to help locate sentinel lymph nodes during biopsy procedures for cancer staging. Magtrace can be injected by a nurse or surgeon up to 30 days before a biopsy or in the operating theatre 20 minutes before surgery. Sentimag is then used by the surgeon during the biopsy procedure to detect the tracer trapped in the lymph nodes. # Contraindications Known contraindications to Magtrace include people with known hypersensitivity to iron oxide or dextran compounds, people with iron overload disease and people with a metal implant in the axilla or in the chest. Sentimag is contraindicated for use within 15 mm of a working pacemaker. # Costs Magtrace costs £226 per unit (excluding VAT). The Sentimag probe costs £24,900 to purchase. However, NHS trusts entering a consumable commitment of 100 to 120 units per annum receive the Sentimag system free of charge.For more details, see the webpage for Magtrace and Sentimag at the Endomag UK website.# Evidence NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website. # Clinical evidence ## The main clinical evidence comprises 36 studies The EAC included a total of 36 studies which included 18 non-randomised controlled trials, 16 cohort studies, 1 prospective paired comparison study and 1 validation study. The 36 studies included a total of 4,202 people who had procedures in which Magtrace and Sentimag was used. Nine studies were reported in conference abstracts only. For full details of the clinical evidence, see section 4 of the assessment report in the supporting documentation. ## Studies comparing Magtrace and Sentimag with the dual technique are considered most relevant The published clinical evidence on Magtrace and Sentimag included several comparators. Five studies compared the dual technique radioisotope with Magtrace and Sentimag, and were considered most relevant to the decision problem. These studies were powered to show non-inferiority compared with the dual technique. Eleven studies compared Magtrace and Sentimag with radioisotope alone. Six studies included both the dual technique and radioisotope only but did not report outcomes separately for each comparator. Fourteen non-comparative studies were included for patient reported outcome measures and adverse events only. Studies comparing Magtrace with blue dye alone were not included because of high false negative rates and known inferiority of blue dye when compared with the dual technique. ## The evidence supports the non-inferiority of Magtrace and Sentimag compared with standard care for detecting sentinel and malignant lymph nodes The published evidence for the detection rates of Magtrace and Sentimag compared with standard care is based on non-inferiority trials. Twelve studies were statistically powered to show non-inferiority, only 1 of which reported dual technique outcomes exclusively. The detection rates per patient for Magtrace ranged from 89.7% to 100% compared with 83.3% to 100% for radioactive isotope with and without blue dye. Detection rates per patient for malignant lymph nodes for Magtrace and technetium‑99m with and without blue dye were also comparable, with ranges of 91.7% to 100% and 90.8% to 100% respectively. ## Future imaging studies may be affected by artefacts after Magtrace administration Six studies noted future MRI of the injection and drainage sites being affected by artefacts for up to 5 years after using Magtrace. Chapman et al. (2021) reported the outcome of MRI in 16 people after Magtrace injection. MRI image quality was impaired in all studies and 5 people had non-diagnostic MRI results. Krischer et al. (2017) evaluated MRI done 42 months after Magtrace injection in a sample of 25 people. Imaging interpretation was not restricted in 12 cases, impaired in 10 cases and not possible in 3 cases because of Magtrace residues. There is no longitudinal evidence to determine the effect of this on future diagnoses or treatment. ## The main adverse event associated with using Magtrace is the incidence of skin staining Warnberg et al. (2019) assessed skin staining up to 36 months postoperatively. People who had retro-areolar Magtrace injections were more likely to experience skin staining compared with those who had peritumoral Magtrace injection, with 67.3% and 37.8% incidence reported at 3 weeks respectively. These figures decreased to 46.2% and 9.4% at 36 months. Karakatsanis et al. (2017) and Karakatsanis et al. (2016) reported that 39.9% and 35.5% of people having breast conserving surgery presented with skin staining. People having mastectomy rarely experienced skin staining. No evidence was identified which directly compared skin staining outcomes of Magtrace with blue dye. A small number of studies that investigated patient reported outcomes did not identify skin staining as a significant problem for patients. For full details of the adverse events, see section 5.3 of the assessment report in the supporting documentation. ## Most studies reported intraoperative administration of Magtrace Of the 36 included studies, 18 administered Magtrace intraoperatively or on the day of surgery, 7 injected Magtrace within 1 to 3 days of surgery, 5 included people injected more than 3 days before surgery and 6 did not report injection timing. Clinical experts report that Magtrace is usually injected at a routine clinical visit within 30 days of surgery rather than intraoperatively because this gives an improved visual and magnetic signal during surgery. Karakatsanis et al. (2017) note a higher tracer-specific sentinel lymph node detection rate with preoperative administration of Magtrace compared with perioperative administration, with 95.3% and 86.0% respectively (p=0.031). From the available studies, there is no evidence to support a significantly improved detection rate with earlier Magtrace administration. # Cost evidence ## The company's cost modelling finds Magtrace and Sentimag to be cost saving compared with the dual technique The company developed a de-novo cost-minimisation analysis from an NHS perspective, which compared Magtrace and Sentimag with the dual technique. The time horizon of the model is from the time the person attends the hospital for sentinel lymph node biopsy to the end of the procedure. The company received resource use data from 3 NHS trusts without on-site access to radiopharmacy or nuclear medicine. The data stated that 30 minutes of theatre time was lost for 20% of all sentinel lymph node biopsies because of delays in surgery or staff shortages. The company model also assumed that 1 additional sentinel lymph node biopsy procedure could be done each week with Magtrace. These 2 factors were included as opportunity costs in the model by measuring the number of sentinel lymph node biopsy procedures foregone, with only 50% of potential additional procedures being realised. The company's base case showed a cost saving of £105 per person using Magtrace and Sentimag. For full details of the cost evidence, see section 9 of the assessment report in the supporting documentation. ## The company's cost model is appropriate, but the EAC made changes to the structure and parameters of the model Although the EAC accepted most of the assumptions and parameters in the company's base-case analysis, the model was reformulated into a decision tree to improve the clarity of the clinical pathway and allow probabilistic sensitivity analysis. The EAC included 3 arms to represent the different timings and settings of the tracer injections. This included 1 arm for administration of the radioisotope and blue dye, 1 arm for intraoperative Magtrace injection and 1 arm for Magtrace injected at a separate clinic. The model assumes that intraoperative Magtrace injection needs 20 minutes additional theatre time to allow drainage to the axilla. The EAC did not include opportunity costs associated with a lack of availability of radioisotope but did include an opportunity cost for 1 additional sentinel lymph node biopsy procedure each week. The EAC assumes that the opportunity costs are achieved in 50% of hospitals. ## Magtrace and Sentimag is still cost saving compared with the dual technique with the EAC's changes to the model When using the EAC's base-case model, Magtrace and Sentimag remains cost saving by £78.90 per person compared with the dual technique. The EAC did a sensitivity analysis to determine the effect of Magtrace injection timing on the cost of the sentinel lymph node biopsy procedure. When time for intraoperative Magtrace injection was more than 29 minutes, Magtrace was cost incurring. The EAC included additional scenario analyses that explored the cost impact of contraindications for Magtrace and the effect on future MRI. Assuming 1% of people cannot have Magtrace because of contraindications and need the dual technique instead, Magtrace remains cost saving by £78.11 per person. If 1% of people in both arms need future MRI and 5% of those who have had Magtrace then have uninterpretable MRI and need gadolinium-enhanced MRI, Magtrace remains cost saving by £78.82. ## Opportunity costs are the key cost driver The key cost driver in the model was the opportunity cost associated with being able to do more sentinel lymph node biopsy procedures each week. Cost savings were dependent on the number of centres that can realise these opportunity costs in clinical practice. It was assumed that using Magtrace would lead to 1 additional sentinel lymph node biopsy per week because of improved management of operating lists. Based on centres doing 400 biopsies annually and 50% of centres realising the opportunity costs, the threshold at which Magtrace became cost incurring was 0.42 additional procedures each week. If no additional procedures are realised, Magtrace would be cost incurring by £58.17 per procedure. If less than 21% of hospitals using Magtrace can do 1 additional sentinel lymph node biopsy procedure each week, Magtrace would be cost incurring.# Committee discussion # Clinical-effectiveness overview ## Magtrace and Sentimag is as effective as standard care for locating sentinel lymph nodes for breast cancer The committee noted that the clinical evidence showed Magtrace and Sentimag to be as effective as the dual technique for detecting sentinel lymph nodes, including malignant nodes. Other clinically relevant outcome measures such as the number of nodes retrieved per procedure and pain scores were deemed to be equivalent when compared with standard care. The committee considered the non-inferiority studies to be well conducted. The evidence base includes studies that have been done in a UK and NHS context. The committee concluded that the clinical evidence supports non-inferiority of Magtrace and Sentimag compared with current standard care. ## Magtrace can be injected much earlier than the radioisotope used in standard care The committee was advised that although Magtrace can be injected in the theatre 20 minutes before the start of a sentinel lymph node biopsy procedure, injection is more commonly done at a standard clinical appointment up to 30 days before surgery to give a better detection signal. The clinical experts highlighted the advantages of earlier injection in terms of improved theatre scheduling and convenience. An ongoing study is exploring the earliest appropriate time point for Magtrace injection before sentinel lymph node biopsy. The committee accepted the maximum time period for injecting Magtrace of 30 days as stated in the manufacturer's information for use and concluded that Magtrace allows for significantly earlier injection than the radioisotope used in standard practice. # Side effects and adverse events ## Future MRI can be affected after using Magtrace, so Magtrace should be carefully considered for people who are likely to need follow-up MRI studies The committee acknowledged that future MRI of the breast could be affected by residual Magtrace that remains in the body after a sentinel lymph node biopsy procedure. The EAC explained that the clinical evidence shows that follow-up MRI can be impaired for as long as 5 years after the procedure. There is 1 study that shows that a mammography was also affected after an injection of Magtrace. The clinical experts highlighted that follow-up MRI studies are becoming more common, particularly in the following groups: young people under the age of 40, people with occult cancers and people with dense breasts. Consensus from clinical experts is that Magtrace would not be advised for people who are likely to need MRI within 3 months after sentinel lymph node biopsy. Contrast-enhanced digital mammography or gadolinium-enhanced MRI could be used as alternative imaging techniques for these people, but they are associated with higher radiation or higher costs. The committee queried whether residual Magtrace would remain localised in lymph nodes in the breasts or whether it would spread throughout the body over time and affect imaging of other areas. The company clarified that this would remain residually in the breast tissue and that any particles outside of this would be engulfed by macrophages and excreted. The clinical experts stated that issues with mammography had not been identified after 3 years of using Magtrace. The committee concluded that future imaging is an important issue for clinicians to consider, so Magtrace should be carefully considered for people who are likely to need follow-up MRI studies after having a sentinel lymph node biopsy procedure. ## Magtrace and Sentimag is safe to use, but skin staining is a common adverse event The committee noted that the clinical evidence identified skin staining as the most common adverse event associated with Magtrace. The patient expert commented that skin staining was not a key issue, and that people find the brown staining is preferable to the blue staining associated with blue dye. The company provided data on patient experience, stating that 90% of people did not worry about skin staining caused by Magtrace. The clinical experts commented that from their experience, the size of the breasts and method of injection affects the rate of staining. A deeper peritumoral breast injection causes less staining, and this has been adopted by clinicians in practice. The committee concluded that skin staining is also an issue with the dual technique comparator and is not a significant concern for people having the injection. # Other patient benefits or issues ## People should have information made available to them before having sentinel lymph node biopsy with Magtrace and Sentimag The patient expert explained that people can be quite worried before having a sentinel lymph node biopsy procedure because of the need for radioactive material to be injected into the body and the risk of anaphylaxis associated with blue dye. The patient expert highlighted that these risks do not exist with Magtrace, but there are other considerations which are important for people having the procedure. Some people with breast cancer will have yearly follow-up imaging, and these could be affected by artefacts because of residual Magtrace. People may also experience skin staining and pass darker coloured urine after having Magtrace injected. Therefore, the patient expert suggested that people would prefer to have information before having sentinel lymph node biopsy with Magtrace and Sentimag. The committee agreed with the patient expert and concluded that it is important for people to be appropriately informed of the adverse events associated with the technology before the procedure. # Cost modelling ## If the opportunity costs are realised, Magtrace and Sentimag is cost saving compared with standard care The committee considered that the EAC base-case model was appropriate for decision making. They agreed with the parameters included in the model but were uncertain about whether the opportunity costs associated with additional sentinel lymph node biopsy procedures would be realised in practice. Opportunity costs were identified as the key cost driver for Magtrace and Sentimag. In the EAC's base-case analysis, Magtrace and Sentimag is cost saving by £78.90 per procedure, but cost incurring by £58.16 per procedure when opportunity costs are excluded from the model. # NHS considerations overview ## The efficiency gains from using Magtrace will depend on where the procedure is done The EAC highlighted that there are currently 3 scenarios to consider when looking at the different hospitals in which sentinel lymph node biopsies are done. The differentiating factor is whether radiopharmacy and nuclear medicine facilities exist on the same site as where the sentinel lymph node biopsy is being done. Some hospitals can produce the radioisotope injection on the same site as the procedure, whereas other hospitals need the radioisotope to be transported to their site for injection before the procedures. The third scenario needs people to travel to 1 site for the radioisotope injection, then a different site where the biopsy is done. Clinical experts work at centres with and without access to radiopharmacy and explained there was general agreement that hospitals with limited or no access to radiopharmacy and nuclear medicine would be most likely to realise the opportunity costs which make Magtrace and Sentimag cost saving. The EAC highlighted that 55.9% of centres performing sentinel lymph node biopsy procedures have radiopharmacy and nuclear medicine facilities on site or are already using Magtrace and Sentimag, and would therefore be less likely to realise the opportunity costs included in the economic model. The committee concluded that hospitals without access to on-site radiopharmacy and nuclear medicine are likely to benefit from Magtrace because of the efficiency gains related to theatre scheduling and reduced supply chain issues. The committee acknowledged that Magtrace and Sentimag could also be an option for some hospitals with on-site radiopharmacy which still have challenges with theatre scheduling or experience delays. # Device compatibility ## The Sentimag probe needs regular recalibration and is similar to the gamma probes used in current practice The company explained that the Sentimag probe has a 5‑year lifespan and is supplied with a calibration cap which is used to calibrate the device each day before starting surgery. This takes about 20 seconds and is logged. During the procedure, the probe also needs to be reset each time it is moved out of the operation field, which takes around 3 seconds. In the event of an issue with the Sentimag probe, there is a contact procedure in place to report this to the company. The committee was advised that the gamma probes used in current practice need similar calibration. The lifespan of a gamma probe is around 2 years. The clinical experts did not consider calibration of the Sentimag probe to cause any inconvenience to clinicians. They also noted that the gamma probe was smaller and had a softer feel than the Sentimag probe. The committee concluded that the Sentimag probe is broadly similar to the gamma probes used in current practice. ## Metal and magnetic materials interfere with the Sentimag probe so alternative instruments may have to be used by the surgeon One clinical study (Pinero-Madrona et al. 2015) mentioned the possible interference of surgical instruments when using Magtrace and Sentimag. The manufacturer's information for use states that the Sentimag probe head should be at least 0.5 metres away from any metal or magnetic objects. Clinical experts explained that metal and magnetic materials affect the signal detection on the Sentimag system, so plastic surgical instruments (for example, single-use disposable forceps and retractors) may need to be used. The committee was told that this can potentially make operating more difficult and time consuming, although it was also told that with more experience the need for alternative instruments can be avoided. The company explained that plastic instruments are provided with the technology at no extra charge and that titanium instruments can also be used. The committee concluded that some surgeons may need to use alternative surgical instruments with Magtrace and Sentimag. They acknowledged that this may take some time to get used to, but with experience it does not add any significant time to the procedure and using such instruments can potentially be avoided altogether. # Training ## There is a learning curve associated with using Magtrace and Sentimag The company commented that a minimum of 5 procedures were needed to build familiarity with Magtrace and Sentimag. The company suggested that representatives from the manufacturer are usually present for the first few procedures to support clinicians. Online resources and surgical footage are also available, as well as an annual retraining session for sites which regularly use the technology. The clinical experts stated it takes around 50 procedures or 2 years to be fully competent with Magtrace. The committee concluded that a learning curve is associated with using Magtrace and Sentimag, and the company has processes in place to support clinicians during this time. # Further research ## Further data collection on the number of sentinel lymph node biopsies being done would help to understand the efficiency gains associated with Magtrace and Sentimag The committee stated that further data collection was needed to monitor the difference in the number of sentinel lymph node biopsies being done in each hospital once Magtrace and Sentimag have been adopted into clinical practice. The realisation of the efficiency gains and opportunity costs is defined as being able to do additional procedures each week with Magtrace. Adverse events should also be reported. More evidence is needed on the impact of Magtrace on future MRI of the breast.	{'Recommendations': 'Magtrace and Sentimag is recommended as an option to locate sentinel lymph nodes for breast cancer in hospitals with limited or no access to radiopharmacy.\n\nFurther data collection is recommended to monitor the number of additional sentinel lymph node biopsies done in each hospital after the technology is adopted in clinical practice.\n\nWhy the committee made these recommendations\n\nEvidence shows that Magtrace and Sentimag is likely to be as effective at detecting sentinel lymph nodes as the radioactive isotope tracer and blue dye dual technique used in standard practice. Standard practice requires nuclear medicine safety procedures and facilities.\n\nClinical expert advice suggested that hospitals with limited or no access to radiopharmacy are more likely to realise the opportunity costs that make this technology a cost-saving option. These hospitals are likely to be able to do more procedures because scheduling is less dependent on external supply chain and staffing resources.\n\nBecause the potential cost saving depends on the opportunity costs, and the economic evidence is limited, data collection is recommended to understand if cost savings are made once the technology is adopted in clinical practice.', 'The technology': "# Technology\n\nThe Magtrace and Sentimag system (Endomag) comprises a magnetic liquid tracer (Magtrace) and a handheld magnetic sensing probe (Sentimag). Magtrace is intended for use only with the Sentimag system. Magtrace is a non-radioactive dark brown liquid containing superparamagnetic iron oxide with a carboxydextran coating. It is both a magnetic marker and a visual dye. Magtrace is injected into the tissue beneath the areola or interstitial tissue around a tumour. The particles are then absorbed into lymphatics and become trapped in sentinel lymph nodes that can then be detected by the magnetic sensing probe and also by visualisation to assist with biopsy.\n\nDuring surgery, the Sentimag probe detects the tracer trapped in the lymph nodes and guides the surgeon to remove them for biopsy. Sentimag uses a visual reading and sounds of different pitches to indicate how close the surgeon is to the magnetic tracer. The nodes often appear dark brown or black in colour, which also helps identification.\n\n# Care pathway\n\nA sentinel lymph node biopsy helps to stage cancer that has spread to the lymph nodes and is followed by a surgical procedure to remove 1 or more of the nodes. NICE's guideline on early and locally advanced breast cancer recommends sentinel lymph node biopsy as the preferred technique to stage the axilla for people with invasive breast cancer and no evidence of lymph involvement on ultrasound or a negative ultrasound-guided needle biopsy. The guideline also recommends that sentinel lymph node biopsy should be offered to people who are having a mastectomy for ductal carcinoma in-situ breast cancer and people with a preoperative diagnosis of ductal carcinoma in-situ who are considered to be at high risk of invasive disease.\n\nThe recommended treatment option for locating sentinel lymph nodes during biopsy is a dual technique combination of a tracer containing a radioactive isotope, and blue dye. When the radioactive isotope is not available, some centres report using blue dye on its own, but this can reduce the detection rate of sentinel lymph nodes.\n\n# Innovative aspects\n\nThe key innovative feature of the Magtrace and Sentimag system is its magnetic mechanism of action. This means that unlike the dual technique, the system can be used without the need for nuclear medicine safety procedures and facilities. Magtrace can also be injected up to 30\xa0days before surgery, whereas the radioactive tracers can be given no more than 24\xa0hours before the sentinel lymph node biopsy procedure.\n\n# Intended use\n\nMagtrace and Sentimag are intended to help locate sentinel lymph nodes during biopsy procedures for cancer staging. Magtrace can be injected by a nurse or surgeon up to 30\xa0days before a biopsy or in the operating theatre 20\xa0minutes before surgery. Sentimag is then used by the surgeon during the biopsy procedure to detect the tracer trapped in the lymph nodes.\n\n# Contraindications\n\nKnown contraindications to Magtrace include people with known hypersensitivity to iron oxide or dextran compounds, people with iron overload disease and people with a metal implant in the axilla or in the chest. Sentimag is contraindicated for use within 15\xa0mm of a working pacemaker.\n\n# Costs\n\nMagtrace costs £226 per unit (excluding VAT). The Sentimag probe costs £24,900 to purchase. However, NHS trusts entering a consumable commitment of 100\xa0to 120\xa0units per annum receive the Sentimag system free of charge.For more details, see the webpage for Magtrace and Sentimag at the Endomag UK website.", 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## The main clinical evidence comprises 36 studies\n\nThe EAC included a total of 36\xa0studies which included 18\xa0non-randomised controlled trials, 16\xa0cohort studies, 1\xa0prospective paired comparison study and 1\xa0validation study. The 36\xa0studies included a total of 4,202\xa0people who had procedures in which Magtrace and Sentimag was used. Nine studies were reported in conference abstracts only. For full details of the clinical evidence, see section\xa04 of the assessment report in the supporting documentation.\n\n## Studies comparing Magtrace and Sentimag with the dual technique are considered most relevant\n\nThe published clinical evidence on Magtrace and Sentimag included several comparators. Five studies compared the dual technique radioisotope with Magtrace and Sentimag, and were considered most relevant to the decision problem. These studies were powered to show non-inferiority compared with the dual technique. Eleven studies compared Magtrace and Sentimag with radioisotope alone. Six studies included both the dual technique and radioisotope only but did not report outcomes separately for each comparator. Fourteen non-comparative studies were included for patient reported outcome measures and adverse events only. Studies comparing Magtrace with blue dye alone were not included because of high false negative rates and known inferiority of blue dye when compared with the dual technique.\n\n## The evidence supports the non-inferiority of Magtrace and Sentimag compared with standard care for detecting sentinel and malignant lymph nodes\n\nThe published evidence for the detection rates of Magtrace and Sentimag compared with standard care is based on non-inferiority trials. Twelve studies were statistically powered to show non-inferiority, only 1 of which reported dual technique outcomes exclusively. The detection rates per patient for Magtrace ranged from 89.7% to 100% compared with 83.3% to 100% for radioactive isotope with and without blue dye. Detection rates per patient for malignant lymph nodes for Magtrace and technetium‑99m with and without blue dye were also comparable, with ranges of 91.7% to 100% and 90.8% to 100% respectively.\n\n## Future imaging studies may be affected by artefacts after Magtrace administration\n\nSix studies noted future MRI of the injection and drainage sites being affected by artefacts for up to 5\xa0years after using Magtrace. Chapman et al. (2021) reported the outcome of MRI in 16\xa0people after Magtrace injection. MRI image quality was impaired in all studies and 5\xa0people had non-diagnostic MRI results. Krischer et al. (2017) evaluated MRI done 42\xa0months after Magtrace injection in a sample of 25\xa0people. Imaging interpretation was not restricted in 12\xa0cases, impaired in 10\xa0cases and not possible in 3\xa0cases because of Magtrace residues. There is no longitudinal evidence to determine the effect of this on future diagnoses or treatment.\n\n## The main adverse event associated with using Magtrace is the incidence of skin staining\n\nWarnberg et al. (2019) assessed skin staining up to 36\xa0months postoperatively. People who had retro-areolar Magtrace injections were more likely to experience skin staining compared with those who had peritumoral Magtrace injection, with 67.3% and 37.8% incidence reported at 3\xa0weeks respectively. These figures decreased to 46.2% and 9.4% at 36\xa0months. Karakatsanis et al. (2017) and Karakatsanis et al. (2016) reported that 39.9% and 35.5% of people having breast conserving surgery presented with skin staining. People having mastectomy rarely experienced skin staining. No evidence was identified which directly compared skin staining outcomes of Magtrace with blue dye. A small number of studies that investigated patient reported outcomes did not identify skin staining as a significant problem for patients. For full details of the adverse events, see section\xa05.3 of the assessment report in the supporting documentation.\n\n## Most studies reported intraoperative administration of Magtrace\n\nOf the 36 included studies, 18\xa0administered Magtrace intraoperatively or on the day of surgery, 7 injected Magtrace within 1 to 3\xa0days of surgery, 5 included people injected more than 3\xa0days before surgery and 6 did not report injection timing. Clinical experts report that Magtrace is usually injected at a routine clinical visit within 30\xa0days of surgery rather than intraoperatively because this gives an improved visual and magnetic signal during surgery. Karakatsanis et al. (2017) note a higher tracer-specific sentinel lymph node detection rate with preoperative administration of Magtrace compared with perioperative administration, with 95.3% and 86.0% respectively (p=0.031). From the available studies, there is no evidence to support a significantly improved detection rate with earlier Magtrace administration.\n\n# Cost evidence\n\n## The company's cost modelling finds Magtrace and Sentimag to be cost saving compared with the dual technique\n\nThe company developed a de-novo cost-minimisation analysis from an NHS perspective, which compared Magtrace and Sentimag with the dual technique. The time horizon of the model is from the time the person attends the hospital for sentinel lymph node biopsy to the end of the procedure. The company received resource use data from 3\xa0NHS trusts without on-site access to radiopharmacy or nuclear medicine. The data stated that 30\xa0minutes of theatre time was lost for 20% of all sentinel lymph node biopsies because of delays in surgery or staff shortages. The company model also assumed that 1 additional sentinel lymph node biopsy procedure could be done each week with Magtrace. These 2 factors were included as opportunity costs in the model by measuring the number of sentinel lymph node biopsy procedures foregone, with only 50% of potential additional procedures being realised. The company's base case showed a cost saving of £105 per person using Magtrace and Sentimag. For full details of the cost evidence, see section\xa09 of the assessment report in the supporting documentation.\n\n## The company's cost model is appropriate, but the EAC made changes to the structure and parameters of the model\n\nAlthough the EAC accepted most of the assumptions and parameters in the company's base-case analysis, the model was reformulated into a decision tree to improve the clarity of the clinical pathway and allow probabilistic sensitivity analysis. The EAC included 3\xa0arms to represent the different timings and settings of the tracer injections. This included 1\xa0arm for administration of the radioisotope and blue dye, 1\xa0arm for intraoperative Magtrace injection and 1\xa0arm for Magtrace injected at a separate clinic. The model assumes that intraoperative Magtrace injection needs 20\xa0minutes additional theatre time to allow drainage to the axilla. The EAC did not include opportunity costs associated with a lack of availability of radioisotope but did include an opportunity cost for 1 additional sentinel lymph node biopsy procedure each week. The EAC assumes that the opportunity costs are achieved in 50% of hospitals.\n\n## Magtrace and Sentimag is still cost saving compared with the dual technique with the EAC's changes to the model\n\nWhen using the EAC's base-case model, Magtrace and Sentimag remains cost saving by £78.90 per person compared with the dual technique. The EAC did a sensitivity analysis to determine the effect of Magtrace injection timing on the cost of the sentinel lymph node biopsy procedure. When time for intraoperative Magtrace injection was more than 29\xa0minutes, Magtrace was cost incurring. The EAC included additional scenario analyses that explored the cost impact of contraindications for Magtrace and the effect on future MRI. Assuming 1% of people cannot have Magtrace because of contraindications and need the dual technique instead, Magtrace remains cost saving by £78.11 per person. If 1% of people in both arms need future MRI and 5% of those who have had Magtrace then have uninterpretable MRI and need gadolinium-enhanced MRI, Magtrace remains cost saving by £78.82.\n\n## Opportunity costs are the key cost driver\n\nThe key cost driver in the model was the opportunity cost associated with being able to do more sentinel lymph node biopsy procedures each week. Cost savings were dependent on the number of centres that can realise these opportunity costs in clinical practice. It was assumed that using Magtrace would lead to 1 additional sentinel lymph node biopsy per week because of improved management of operating lists. Based on centres doing 400\xa0biopsies annually and 50% of centres realising the opportunity costs, the threshold at which Magtrace became cost incurring was 0.42 additional procedures each week. If no additional procedures are realised, Magtrace would be cost incurring by £58.17 per procedure. If less than 21% of hospitals using Magtrace can do 1 additional sentinel lymph node biopsy procedure each week, Magtrace would be cost incurring.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## Magtrace and Sentimag is as effective as standard care for locating sentinel lymph nodes for breast cancer\n\nThe committee noted that the clinical evidence showed Magtrace and Sentimag to be as effective as the dual technique for detecting sentinel lymph nodes, including malignant nodes. Other clinically relevant outcome measures such as the number of nodes retrieved per procedure and pain scores were deemed to be equivalent when compared with standard care. The committee considered the non-inferiority studies to be well conducted. The evidence base includes studies that have been done in a UK and NHS context. The committee concluded that the clinical evidence supports non-inferiority of Magtrace and Sentimag compared with current standard care.\n\n## Magtrace can be injected much earlier than the radioisotope used in standard care\n\nThe committee was advised that although Magtrace can be injected in the theatre 20\xa0minutes before the start of a sentinel lymph node biopsy procedure, injection is more commonly done at a standard clinical appointment up to 30\xa0days before surgery to give a better detection signal. The clinical experts highlighted the advantages of earlier injection in terms of improved theatre scheduling and convenience. An ongoing study is exploring the earliest appropriate time point for Magtrace injection before sentinel lymph node biopsy. The committee accepted the maximum time period for injecting Magtrace of 30\xa0days as stated in the manufacturer's information for use and concluded that Magtrace allows for significantly earlier injection than the radioisotope used in standard practice.\n\n# Side effects and adverse events\n\n## Future MRI can be affected after using Magtrace, so Magtrace should be carefully considered for people who are likely to need follow-up MRI studies\n\nThe committee acknowledged that future MRI of the breast could be affected by residual Magtrace that remains in the body after a sentinel lymph node biopsy procedure. The EAC explained that the clinical evidence shows that follow-up MRI can be impaired for as long as 5\xa0years after the procedure. There is 1\xa0study that shows that a mammography was also affected after an injection of Magtrace. The clinical experts highlighted that follow-up MRI studies are becoming more common, particularly in the following groups: young people under the age of 40, people with occult cancers and people with dense breasts. Consensus from clinical experts is that Magtrace would not be advised for people who are likely to need MRI within 3\xa0months after sentinel lymph node biopsy. Contrast-enhanced digital mammography or gadolinium-enhanced MRI could be used as alternative imaging techniques for these people, but they are associated with higher radiation or higher costs. The committee queried whether residual Magtrace would remain localised in lymph nodes in the breasts or whether it would spread throughout the body over time and affect imaging of other areas. The company clarified that this would remain residually in the breast tissue and that any particles outside of this would be engulfed by macrophages and excreted. The clinical experts stated that issues with mammography had not been identified after 3\xa0years of using Magtrace. The committee concluded that future imaging is an important issue for clinicians to consider, so Magtrace should be carefully considered for people who are likely to need follow-up MRI studies after having a sentinel lymph node biopsy procedure.\n\n## Magtrace and Sentimag is safe to use, but skin staining is a common adverse event\n\nThe committee noted that the clinical evidence identified skin staining as the most common adverse event associated with Magtrace. The patient expert commented that skin staining was not a key issue, and that people find the brown staining is preferable to the blue staining associated with blue dye. The company provided data on patient experience, stating that 90% of people did not worry about skin staining caused by Magtrace. The clinical experts commented that from their experience, the size of the breasts and method of injection affects the rate of staining. A deeper peritumoral breast injection causes less staining, and this has been adopted by clinicians in practice. The committee concluded that skin staining is also an issue with the dual technique comparator and is not a significant concern for people having the injection.\n\n# Other patient benefits or issues\n\n## People should have information made available to them before having sentinel lymph node biopsy with Magtrace and Sentimag\n\nThe patient expert explained that people can be quite worried before having a sentinel lymph node biopsy procedure because of the need for radioactive material to be injected into the body and the risk of anaphylaxis associated with blue dye. The patient expert highlighted that these risks do not exist with Magtrace, but there are other considerations which are important for people having the procedure. Some people with breast cancer will have yearly follow-up imaging, and these could be affected by artefacts because of residual Magtrace. People may also experience skin staining and pass darker coloured urine after having Magtrace injected. Therefore, the patient expert suggested that people would prefer to have information before having sentinel lymph node biopsy with Magtrace and Sentimag. The committee agreed with the patient expert and concluded that it is important for people to be appropriately informed of the adverse events associated with the technology before the procedure.\n\n# Cost modelling\n\n## If the opportunity costs are realised, Magtrace and Sentimag is cost saving compared with standard care\n\nThe committee considered that the EAC base-case model was appropriate for decision making. They agreed with the parameters included in the model but were uncertain about whether the opportunity costs associated with additional sentinel lymph node biopsy procedures would be realised in practice. Opportunity costs were identified as the key cost driver for Magtrace and Sentimag. In the EAC's base-case analysis, Magtrace and Sentimag is cost saving by £78.90 per procedure, but cost incurring by £58.16 per procedure when opportunity costs are excluded from the model.\n\n# NHS considerations overview\n\n## The efficiency gains from using Magtrace will depend on where the procedure is done\n\nThe EAC highlighted that there are currently 3 scenarios to consider when looking at the different hospitals in which sentinel lymph node biopsies are done. The differentiating factor is whether radiopharmacy and nuclear medicine facilities exist on the same site as where the sentinel lymph node biopsy is being done. Some hospitals can produce the radioisotope injection on the same site as the procedure, whereas other hospitals need the radioisotope to be transported to their site for injection before the procedures. The third scenario needs people to travel to 1 site for the radioisotope injection, then a different site where the biopsy is done. Clinical experts work at centres with and without access to radiopharmacy and explained there was general agreement that hospitals with limited or no access to radiopharmacy and nuclear medicine would be most likely to realise the opportunity costs which make Magtrace and Sentimag cost saving. The EAC highlighted that 55.9% of centres performing sentinel lymph node biopsy procedures have radiopharmacy and nuclear medicine facilities on site or are already using Magtrace and Sentimag, and would therefore be less likely to realise the opportunity costs included in the economic model. The committee concluded that hospitals without access to on-site radiopharmacy and nuclear medicine are likely to benefit from Magtrace because of the efficiency gains related to theatre scheduling and reduced supply chain issues. The committee acknowledged that Magtrace and Sentimag could also be an option for some hospitals with on-site radiopharmacy which still have challenges with theatre scheduling or experience delays.\n\n# Device compatibility\n\n## The Sentimag probe needs regular recalibration and is similar to the gamma probes used in current practice\n\nThe company explained that the Sentimag probe has a 5‑year lifespan and is supplied with a calibration cap which is used to calibrate the device each day before starting surgery. This takes about 20\xa0seconds and is logged. During the procedure, the probe also needs to be reset each time it is moved out of the operation field, which takes around 3\xa0seconds. In the event of an issue with the Sentimag probe, there is a contact procedure in place to report this to the company. The committee was advised that the gamma probes used in current practice need similar calibration. The lifespan of a gamma probe is around 2\xa0years. The clinical experts did not consider calibration of the Sentimag probe to cause any inconvenience to clinicians. They also noted that the gamma probe was smaller and had a softer feel than the Sentimag probe. The committee concluded that the Sentimag probe is broadly similar to the gamma probes used in current practice.\n\n## Metal and magnetic materials interfere with the Sentimag probe so alternative instruments may have to be used by the surgeon\n\nOne clinical study (Pinero-Madrona et al. 2015) mentioned the possible interference of surgical instruments when using Magtrace and Sentimag. The manufacturer's information for use states that the Sentimag probe head should be at least 0.5\xa0metres away from any metal or magnetic objects. Clinical experts explained that metal and magnetic materials affect the signal detection on the Sentimag system, so plastic surgical instruments (for example, single-use disposable forceps and retractors) may need to be used. The committee was told that this can potentially make operating more difficult and time consuming, although it was also told that with more experience the need for alternative instruments can be avoided. The company explained that plastic instruments are provided with the technology at no extra charge and that titanium instruments can also be used. The committee concluded that some surgeons may need to use alternative surgical instruments with Magtrace and Sentimag. They acknowledged that this may take some time to get used to, but with experience it does not add any significant time to the procedure and using such instruments can potentially be avoided altogether.\n\n# Training\n\n## There is a learning curve associated with using Magtrace and Sentimag\n\nThe company commented that a minimum of 5\xa0procedures were needed to build familiarity with Magtrace and Sentimag. The company suggested that representatives from the manufacturer are usually present for the first few procedures to support clinicians. Online resources and surgical footage are also available, as well as an annual retraining session for sites which regularly use the technology. The clinical experts stated it takes around 50\xa0procedures or 2\xa0years to be fully competent with Magtrace. The committee concluded that a learning curve is associated with using Magtrace and Sentimag, and the company has processes in place to support clinicians during this time.\n\n# Further research\n\n## Further data collection on the number of sentinel lymph node biopsies being done would help to understand the efficiency gains associated with Magtrace and Sentimag\n\nThe committee stated that further data collection was needed to monitor the difference in the number of sentinel lymph node biopsies being done in each hospital once Magtrace and Sentimag have been adopted into clinical practice. The realisation of the efficiency gains and opportunity costs is defined as being able to do additional procedures each week with Magtrace. Adverse events should also be reported. More evidence is needed on the impact of Magtrace on future MRI of the breast."}	https://www.nice.org.uk/guidance/mtg72	Evidence-based recommendations on Magtrace and Sentimag system for locating sentinel lymph nodes for breast cancer.
c3e1169986bd2a85794b49843e9042c614f0498c	nice	Upadacitinib for treating active ankylosing spondylitis	Upadacitinib for treating active ankylosing spondylitis Evidence-based recommendations on upadacitinib (Rinvoq) for treating active ankylosing spondylitis that is not controlled well enough with conventional therapy in adults. # Recommendations Upadacitinib is recommended as an option for treating active ankylosing spondylitis that is not controlled well enough with conventional therapy in adults, only if: tumour necrosis factor (TNF)-alpha inhibitors are not suitable or do not control the condition well enough and the company provides upadacitinib according to the commercial arrangement. If patients and their clinicians consider upadacitinib to be one of a range of suitable treatments (including secukinumab and ixekizumab), choose the least expensive treatment, taking into account administration costs, dosage, price per dose and commercial arrangements. Assess response to upadacitinib after 16 weeks of treatment. Continue treatment only if there is clear evidence of response, defined as: a reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2 or more units and a reduction in the spinal pain visual analogue scale (VAS) by 2 cm or more. Take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the BASDAI and spinal pain VAS and make any adjustments needed. These recommendations are not intended to affect treatment with upadacitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Usual treatment for active ankylosing spondylitis in adults that is not controlled well enough with conventional therapy, and when TNF-alpha inhibitors are not suitable or do not control the condition well enough, is secukinumab or ixekizumab. Upadacitinib is another treatment that works in a similar way. Evidence from clinical trials shows that upadacitinib is more effective than placebo. Indirect comparisons of upadacitinib with secukinumab and ixekizumab suggest they have similar clinical effectiveness. A cost comparison suggests upadacitinib has similar costs and overall health benefits as secukinumab and ixekizumab. So upadacitinib is recommended for treating active ankylosing spondylitis in adults if it is used in the same population as secukinumab and ixekizumab.# Information about upadacitinib # Marketing authorisation indication Upadacitinib (Rinvoq, AbbVie) is 'indicated for the treatment of active ankylosing spondylitis in adult patients who have responded inadequately to conventional therapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for upadacitinib. # Price The list price is £805.56 per 28‑tablet pack, with each tablet containing 15 mg of upadacitinib (excluding VAT; BNF online, accessed June 2022). The annual cost of treatment with one 15‑mg tablet per day is £10,501.05 (excluding VAT; BNF online, accessed June 2022) The company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Decision problem ## A cost-comparison analysis with secukinumab as the comparator was the most appropriate decision problem The company proposed that upadacitinib should be considered in adults as an alternative to the currently NICE-recommended interleukin (IL)‑17 inhibitors secukinumab and ixekizumab for ankylosing spondylitis that is not controlled well enough with conventional therapy and when tumour necrosis factor (TNF)-alpha inhibitors are not suitable (biological-naive population) or do not control the condition well enough (biological-experienced population). The company's proposed decision problem was narrower than upadacitinib's marketing authorisation because it excluded people who had had TNF-alpha inhibitors. However, the committee agreed that the proposed population was consistent with previous NICE recommendations for IL‑17 inhibitors for ankylosing spondylitis, and with their use in clinical practice. The company presented a comparison with 2 NICE-recommended IL-17 inhibitors (NICE technology appraisal guidance on secukinumab for active ankylosing spondylitis and ixekizumab for treating axial spondyloarthritis). The committee agreed that this was consistent with the criteria for a cost-comparison appraisal (see section 3.7). The clinical expert explained that secukinumab was likely to be chosen over ixekizumab by clinicians. The committee was aware that secukinumab was recommended for ankylosing spondylitis in 2016, while ixekizumab was recommended in 2021. It considered both comparators relevant but reasoned that secukinumab is more established in NHS clinical practice than ixekizumab. The committee recalled that NICE's technology appraisal guidance on secukinumab and ixekizumab recommend that treatment should stop if there is an inadequate response at 16 weeks or after 16 to 20 weeks, respectively. An adequate response is defined as: a reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2 or more units and a reduction in the spinal pain visual analogue scale (VAS) by 2 cm or more.The committee considered that it would be reasonable to apply the same approach for this appraisal. It concluded that secukinumab was the more relevant comparator and represented the decision problem that had the most validity to NHS clinical practice. # Clinical effectiveness ## Upadacitinib is more clinically effective at reducing symptom burden than placebo Upadacitinib has been compared with placebo in 2 randomised controlled trials in ankylosing spondylitis: SELECT‑AXIS 1, which included 187 people who had not previously had biological disease-modifying antirheumatic drugs (DMARDs), and study 1 of SELECT‑AXIS 2, which included 420 adults with active ankylosing spondylitis who had had previous treatment with biological DMARDs. In both trials, upadacitinib was associated with statistically significant improvements compared with placebo in primary and secondary outcomes, including the Assessment in Spondyloarthritis International Society 40% (ASAS40) response and BASDAI 50 score. The clinical expert explained that the ASAS40 score is mostly used in clinical trials as a measure of treatment effect. In clinical practice, the BASDAI 50 or back pain score are used to assess treatment response (see section 3.1). In study 1 of SELECT‑AXIS 2, people having upadacitinib also had statistically significantly higher scores in the Ankylosing Spondylitis Quality of Life (ASQoL) measure. The committee concluded that upadacitinib was more clinically effective at reducing symptom burden than placebo. ## The company's network meta-analyses are suitable for decision making The company did a series of network meta-analyses comparing upadacitinib with secukinumab on measures of efficacy, including ASAS40 and BASDAI 50 response rates. It provided results with fixed effect and random effects models for people with ankylosing spondylitis that has not been treated with biological therapies (biological-naive population). The company did scenario analyses comparing upadacitinib with secukinumab for people with ankylosing spondylitis that has been treated with 1 or more biological DMARD (biological-experienced population). It acknowledged the lack of robust data for secukinumab in people who have had biological treatments. The company highlighted that the published secukinumab trials included few people with ankylosing spondylitis who had had biological DMARDs. Also, it indicated that the inclusion criteria and patient populations in the secukinumab trials were different from the study 1 of the SELECT‑AXIS 2 trial. The network meta-analyses for the biological-naive population did not find any significant differences between upadacitinib and secukinumab for any of the outcomes analysed. However, the ERG indicated that the results were uncertain and that this could favour upadacitinib. The company extrapolated the results of the biological-naive population analyses to the biological-experienced population based on clinician opinion that upadacitinib would have similar efficacy in both populations. The clinical expert confirmed that they would expect upadacitinib to have similar efficacy in both populations. The committee concluded that the network meta-analyses estimates were uncertain, but they supported the company's position that upadacitinib is likely to have similar clinical effectiveness to secukinumab. ## It is plausible that the long-term efficacy of upadacitinib is equivalent to that of secukinumab, but this is uncertain The methods guide states that a cost-comparison analysis requires that the technology have similar health benefits to the comparator over the average time on treatment. The company network meta-analyses compared upadacitinib with secukinumab for outcomes measured between 12 and 16 weeks and found no significant differences (see section 3.3). The ERG indicated that there is limited long-term data available for upadacitinib's efficacy, which adds uncertainty to the assumption of clinical equivalence between upadacitinib and secukinumab. The ERG also noted that in previous appraisals in ankylosing spondylitis, companies presented trial data for 2 to 5 years of follow up which showed that drug responses were maintained in the long term. The company stated that there is evidence available for upadacitinib's efficacy in the long term (up to 2 years) which shows maintenance of response, but only for biological-naive populations. The clinical expert stated that long-term efficacy of upadacitinib (a small molecule drug) was expected to be similar or greater than that of biological drugs such as secukinumab. This is because biological drugs can cause an immune response that can lead to their gradual destruction and loss of efficacy over time. However, this is less likely to happen with small molecules such as upadacitinib. The committee considered this explanation biologically plausible. However, it concluded that there was still substantial uncertainty around long-term efficacy because of potential safety concerns and whether people will take upadacitinib as intended (see section 3.5 and section 3.6). # The company's economic model ## There is uncertainty about whether upadacitinib has an equivalent discontinuation rate to secukinumab Differences in treatment discontinuation can lead to differences in efficacy and costs between the technology and comparators. The company assumed upadacitinib has an annual discontinuation rate of 11%, based on the rate used in the appraisal of secukinumab. However, it presented limited data on discontinuation rates. The ERG indicated there may be differences in adherence between upadacitinib and secukinumab because upadacitinib is taken daily and this may affect adherence. The company stated that there is no evidence to support the assumption of worse adherence with upadacitinib compared with secukinumab. The clinical expert added that, in their experience, if a drug is working then adherence is likely to be high. The patient expert confirmed this and stated it is unlikely for someone to forget to take the drug because the effect of the disease on all parts of life was so substantial. They also explained that the effect of injectable biologicals wears off in the days before the next dose and symptoms worsen as a result. The committee concluded that, although there was no evidence to suggest that discontinuation rates would be different between upadacitinib and secukinumab, there was uncertainty that could favour either technology. ## There may be additional monitoring costs for upadacitinib that the company did not include in the cost-comparison model The company base case in the cost-comparison model included only drug acquisition, administration and monitoring costs. The ERG raised the issue that the costs of adverse effects and some monitoring costs were excluded. The company did not include annual lipid monitoring in its base case but provided a scenario with these costs included. The ERG base case included these costs and also had slightly different drug acquisition costs, because of differences in the assumed duration of a trimester (13.04 weeks compared with 12 weeks assumed by the company). These differences meant that the calculated number of doses of secukinumab in a year were higher in the ERG base case. Also, the ERG excluded administration costs from its base case because people would receive training to self-administer subcutaneous injections when they first start treatment, but do not need training for later lines of subcutaneous treatment. The company stated that it agreed with the ERG base case. The committee considered that the changes proposed in the ERG base case did not have a large effect on the cost-comparison estimates. The ERG also considered that the exclusion of the costs of adverse events could bias the analysis in favour of upadacitinib if the adverse event profile was different to those of the comparators in the long term. The clinical expert explained that it was unlikely that adverse events with upadacitinib would be different from those of secukinumab. They highlighted that even if incidence of some viral infections was higher with upadacitinib, this would be made up by the lack of inflammatory bowel issues associated with IL‑17 inhibitors such as secukinumab. The committee accepted this but questioned whether, in light of the Medicines and Healthcare products Regulatory Agency (MHRA) safety warning for tofacitinib, there may be additional monitoring costs for upadacitinib, such as electrocardiograms for cardiovascular monitoring or screening for malignancies, which could incur substantial additional costs. The clinical expert stated that they would take into account the MHRA safety warning, and the individual risk of each patient before deciding whether to use upadacitinib. So it is unlikely that additional monitoring costs would be incurred. The committee noted this but concluded that it was still highly uncertain if upadacitinib would incur additional monitoring costs in the longer term as many of these costs were tied to long-term safety, which it also considered uncertain. # Cost comparison ## The total costs associated with upadacitinib are similar to or lower than those associated with secukinumab and ixekizumab The company presented a cost-comparison analysis that modelled the total costs of upadacitinib and secukinumab over 10 years. The committee considered that the comparison against secukinumab was the most important and represented the most valid decision problem. It considered that the clinical evidence available supported the assumption of clinical equivalence between upadacitinib and secukinumab. The committee preferred the ERG's base case model. Taking into account the confidential patient access schemes for upadacitinib and secukinumab, the committee concluded that the total costs associated with upadacitinib were similar to or lower than those associated with secukinumab (the exact results cannot be reported here because the discounts are confidential). ## Upadacitinib is recommended as an option for treating active ankylosing spondylitis in adults The committee concluded that the criteria for a positive cost comparison were met because: upadacitinib provided similar overall health benefits to secukinumab or ixekizumab and the total costs associated with upadacitinib were similar to or lower than the total costs associated with secukinumab or ixekizumab.The committee therefore recommended upadacitinib as an option for treating active ankylosing spondylitis in adults. It concluded that the recommendations for upadacitinib should be consistent with the company's proposal and NICE's technology appraisal guidance recommendations for secukinumab and ixekizumab, that is: when the condition has not responded to conventional therapy and when TNF-alpha inhibitors are not suitable or do not control the condition well enough and when treatment is stopped at 16 weeks if the condition has not responded adequately. # Other factors ## Equality No equality issues were identified that were not addressed in recommendation 1.4.	{'Recommendations': 'Upadacitinib is recommended as an option for treating active ankylosing spondylitis that is not controlled well enough with conventional therapy in adults, only if:\n\ntumour necrosis factor (TNF)-alpha inhibitors are not suitable or do not control the condition well enough and\n\nthe company provides upadacitinib according to the commercial arrangement.\n\nIf patients and their clinicians consider upadacitinib to be one of a range of suitable treatments (including secukinumab and ixekizumab), choose the least expensive treatment, taking into account administration costs, dosage, price per dose and commercial arrangements.\n\nAssess response to upadacitinib after 16\xa0weeks of treatment. Continue treatment only if there is clear evidence of response, defined as:\n\na reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2\xa0or more units and\n\na reduction in the spinal pain visual analogue scale (VAS) by 2\xa0cm or more.\n\nTake into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the BASDAI and spinal pain VAS and make any adjustments needed.\n\nThese recommendations are not intended to affect treatment with upadacitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nUsual treatment for active ankylosing spondylitis in adults that is not controlled well enough with conventional therapy, and when TNF-alpha inhibitors are not suitable or do not control the condition well enough, is secukinumab or ixekizumab. Upadacitinib is another treatment that works in a similar way.\n\nEvidence from clinical trials shows that upadacitinib is more effective than placebo. Indirect comparisons of upadacitinib with secukinumab and ixekizumab suggest they have similar clinical effectiveness.\n\nA cost comparison suggests upadacitinib has similar costs and overall health benefits as secukinumab and ixekizumab. So upadacitinib is recommended for treating active ankylosing spondylitis in adults if it is used in the same population as secukinumab and ixekizumab.', 'Information about upadacitinib': "# Marketing authorisation indication\n\nUpadacitinib (Rinvoq, AbbVie) is 'indicated for the treatment of active ankylosing spondylitis in adult patients who have responded inadequately to conventional therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for upadacitinib.\n\n# Price\n\nThe list price is £805.56 per 28‑tablet pack, with each tablet containing 15\xa0mg of upadacitinib (excluding VAT; BNF online, accessed June 2022). The annual cost of treatment with one 15‑mg tablet per day is £10,501.05 (excluding VAT; BNF online, accessed June 2022)\n\nThe company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Decision problem\n\n## A cost-comparison analysis with secukinumab as the comparator was the most appropriate decision problem\n\nThe company proposed that upadacitinib should be considered in adults as an alternative to the currently NICE-recommended interleukin (IL)‑17 inhibitors secukinumab and ixekizumab for ankylosing spondylitis that is not controlled well enough with conventional therapy and when tumour necrosis factor (TNF)-alpha inhibitors are not suitable (biological-naive population) or do not control the condition well enough (biological-experienced population). The company's proposed decision problem was narrower than upadacitinib's marketing authorisation because it excluded people who had had TNF-alpha inhibitors. However, the committee agreed that the proposed population was consistent with previous NICE recommendations for IL‑17 inhibitors for ankylosing spondylitis, and with their use in clinical practice. The company presented a comparison with 2 NICE-recommended IL-17 inhibitors (NICE technology appraisal guidance on secukinumab for active ankylosing spondylitis and ixekizumab for treating axial spondyloarthritis). The committee agreed that this was consistent with the criteria for a cost-comparison appraisal (see section\xa03.7). The clinical expert explained that secukinumab was likely to be chosen over ixekizumab by clinicians. The committee was aware that secukinumab was recommended for ankylosing spondylitis in 2016, while ixekizumab was recommended in 2021. It considered both comparators relevant but reasoned that secukinumab is more established in NHS clinical practice than ixekizumab. The committee recalled that NICE's technology appraisal guidance on secukinumab and ixekizumab recommend that treatment should stop if there is an inadequate response at 16\xa0weeks or after 16\xa0to 20\xa0weeks, respectively. An adequate response is defined as:\n\na reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2\xa0or more units and\n\na reduction in the spinal pain visual analogue scale (VAS) by 2\xa0cm or more.The committee considered that it would be reasonable to apply the same approach for this appraisal. It concluded that secukinumab was the more relevant comparator and represented the decision problem that had the most validity to NHS clinical practice.\n\n# Clinical effectiveness\n\n## Upadacitinib is more clinically effective at reducing symptom burden than placebo\n\nUpadacitinib has been compared with placebo in 2\xa0randomised controlled trials in ankylosing spondylitis: SELECT‑AXIS\xa01, which included 187\xa0people who had not previously had biological disease-modifying antirheumatic drugs (DMARDs), and study 1 of SELECT‑AXIS\xa02, which included 420\xa0adults with active ankylosing spondylitis who had had previous treatment with biological DMARDs. In both trials, upadacitinib was associated with statistically significant improvements compared with placebo in primary and secondary outcomes, including the Assessment in Spondyloarthritis International Society 40% (ASAS40) response and BASDAI\xa050 score. The clinical expert explained that the ASAS40 score is mostly used in clinical trials as a measure of treatment effect. In clinical practice, the BASDAI\xa050 or back pain score are used to assess treatment response (see section 3.1). In study 1 of SELECT‑AXIS\xa02, people having upadacitinib also had statistically significantly higher scores in the Ankylosing Spondylitis Quality of Life (ASQoL) measure. The committee concluded that upadacitinib was more clinically effective at reducing symptom burden than placebo.\n\n## The company's network meta-analyses are suitable for decision making\n\nThe company did a series of network meta-analyses comparing upadacitinib with secukinumab on measures of efficacy, including ASAS40 and BASDAI\xa050 response rates. It provided results with fixed effect and random effects models for people with ankylosing spondylitis that has not been treated with biological therapies (biological-naive population). The company did scenario analyses comparing upadacitinib with secukinumab for people with ankylosing spondylitis that has been treated with 1 or more biological DMARD (biological-experienced population). It acknowledged the lack of robust data for secukinumab in people who have had biological treatments. The company highlighted that the published secukinumab trials included few people with ankylosing spondylitis who had had biological DMARDs. Also, it indicated that the inclusion criteria and patient populations in the secukinumab trials were different from the study 1 of the SELECT‑AXIS\xa02 trial. The network meta-analyses for the biological-naive population did not find any significant differences between upadacitinib and secukinumab for any of the outcomes analysed. However, the ERG indicated that the results were uncertain and that this could favour upadacitinib. The company extrapolated the results of the biological-naive population analyses to the biological-experienced population based on clinician opinion that upadacitinib would have similar efficacy in both populations. The clinical expert confirmed that they would expect upadacitinib to have similar efficacy in both populations. The committee concluded that the network meta-analyses estimates were uncertain, but they supported the company's position that upadacitinib is likely to have similar clinical effectiveness to secukinumab.\n\n## It is plausible that the long-term efficacy of upadacitinib is equivalent to that of secukinumab, but this is uncertain\n\nThe methods guide states that a cost-comparison analysis requires that the technology have similar health benefits to the comparator over the average time on treatment. The company network meta-analyses compared upadacitinib with secukinumab for outcomes measured between 12\xa0and 16\xa0weeks and found no significant differences (see section 3.3). The ERG indicated that there is limited long-term data available for upadacitinib's efficacy, which adds uncertainty to the assumption of clinical equivalence between upadacitinib and secukinumab. The ERG also noted that in previous appraisals in ankylosing spondylitis, companies presented trial data for 2\xa0to 5\xa0years of follow up which showed that drug responses were maintained in the long term. The company stated that there is evidence available for upadacitinib's efficacy in the long term (up to 2\xa0years) which shows maintenance of response, but only for biological-naive populations. The clinical expert stated that long-term efficacy of upadacitinib (a small molecule drug) was expected to be similar or greater than that of biological drugs such as secukinumab. This is because biological drugs can cause an immune response that can lead to their gradual destruction and loss of efficacy over time. However, this is less likely to happen with small molecules such as upadacitinib. The committee considered this explanation biologically plausible. However, it concluded that there was still substantial uncertainty around long-term efficacy because of potential safety concerns and whether people will take upadacitinib as intended (see section 3.5 and section 3.6).\n\n# The company's economic model\n\n## There is uncertainty about whether upadacitinib has an equivalent discontinuation rate to secukinumab\n\nDifferences in treatment discontinuation can lead to differences in efficacy and costs between the technology and comparators. The company assumed upadacitinib has an annual discontinuation rate of 11%, based on the rate used in the appraisal of secukinumab. However, it presented limited data on discontinuation rates. The ERG indicated there may be differences in adherence between upadacitinib and secukinumab because upadacitinib is taken daily and this may affect adherence. The company stated that there is no evidence to support the assumption of worse adherence with upadacitinib compared with secukinumab. The clinical expert added that, in their experience, if a drug is working then adherence is likely to be high. The patient expert confirmed this and stated it is unlikely for someone to forget to take the drug because the effect of the disease on all parts of life was so substantial. They also explained that the effect of injectable biologicals wears off in the days before the next dose and symptoms worsen as a result. The committee concluded that, although there was no evidence to suggest that discontinuation rates would be different between upadacitinib and secukinumab, there was uncertainty that could favour either technology.\n\n## There may be additional monitoring costs for upadacitinib that the company did not include in the cost-comparison model\n\nThe company base case in the cost-comparison model included only drug acquisition, administration and monitoring costs. The ERG raised the issue that the costs of adverse effects and some monitoring costs were excluded. The company did not include annual lipid monitoring in its base case but provided a scenario with these costs included. The ERG base case included these costs and also had slightly different drug acquisition costs, because of differences in the assumed duration of a trimester (13.04\xa0weeks compared with 12\xa0weeks assumed by the company). These differences meant that the calculated number of doses of secukinumab in a year were higher in the ERG base case. Also, the ERG excluded administration costs from its base case because people would receive training to self-administer subcutaneous injections when they first start treatment, but do not need training for later lines of subcutaneous treatment. The company stated that it agreed with the ERG base case. The committee considered that the changes proposed in the ERG base case did not have a large effect on the cost-comparison estimates. The ERG also considered that the exclusion of the costs of adverse events could bias the analysis in favour of upadacitinib if the adverse event profile was different to those of the comparators in the long term. The clinical expert explained that it was unlikely that adverse events with upadacitinib would be different from those of secukinumab. They highlighted that even if incidence of some viral infections was higher with upadacitinib, this would be made up by the lack of inflammatory bowel issues associated with IL‑17 inhibitors such as secukinumab. The committee accepted this but questioned whether, in light of the Medicines and Healthcare products Regulatory Agency (MHRA) safety warning for tofacitinib, there may be additional monitoring costs for upadacitinib, such as electrocardiograms for cardiovascular monitoring or screening for malignancies, which could incur substantial additional costs. The clinical expert stated that they would take into account the MHRA safety warning, and the individual risk of each patient before deciding whether to use upadacitinib. So it is unlikely that additional monitoring costs would be incurred. The committee noted this but concluded that it was still highly uncertain if upadacitinib would incur additional monitoring costs in the longer term as many of these costs were tied to long-term safety, which it also considered uncertain.\n\n# Cost comparison\n\n## The total costs associated with upadacitinib are similar to or lower than those associated with secukinumab and ixekizumab\n\nThe company presented a cost-comparison analysis that modelled the total costs of upadacitinib and secukinumab over 10\xa0years. The committee considered that the comparison against secukinumab was the most important and represented the most valid decision problem. It considered that the clinical evidence available supported the assumption of clinical equivalence between upadacitinib and secukinumab. The committee preferred the ERG's base case model. Taking into account the confidential patient access schemes for upadacitinib and secukinumab, the committee concluded that the total costs associated with upadacitinib were similar to or lower than those associated with secukinumab (the exact results cannot be reported here because the discounts are confidential).\n\n## Upadacitinib is recommended as an option for treating active ankylosing spondylitis in adults\n\nThe committee concluded that the criteria for a positive cost comparison were met because:\n\nupadacitinib provided similar overall health benefits to secukinumab or ixekizumab and\n\nthe total costs associated with upadacitinib were similar to or lower than the total costs associated with secukinumab or ixekizumab.The committee therefore recommended upadacitinib as an option for treating active ankylosing spondylitis in adults. It concluded that the recommendations for upadacitinib should be consistent with the company's proposal and NICE's technology appraisal guidance recommendations for secukinumab and ixekizumab, that is:\n\nwhen the condition has not responded to conventional therapy and\n\nwhen TNF-alpha inhibitors are not suitable or do not control the condition well enough and\n\nwhen treatment is stopped at 16\xa0weeks if the condition has not responded adequately.\n\n# Other factors\n\n## Equality\n\nNo equality issues were identified that were not addressed in recommendation\xa01.4."}	https://www.nice.org.uk/guidance/ta829	Evidence-based recommendations on upadacitinib (Rinvoq) for treating active ankylosing spondylitis that is not controlled well enough with conventional therapy in adults.
8a1cf7e965b3b3265acea0a5d96df769161e0656	nice	Atezolizumab for adjuvant treatment of resected non-small-cell lung cancer	Atezolizumab for adjuvant treatment of resected non-small-cell lung cancer Evidence-based recommendations on atezolizumab (Tecentriq) for adjuvant treatment of resected non-small-cell lung cancer in adults. # Recommendations Atezolizumab is recommended for use within the Cancer Drugs Fund as an option for adjuvant treatment after complete tumour resection in adults with stage 2 to 3a non-small-cell lung cancer (NSCLC) whose: tumours have the programmed cell death ligand‑1 (PD‑L1) biomarker expression on 50% or more of their tumour cells and whose disease has not progressed after platinum-based adjuvant chemotherapy.It is recommended only if the company provides atezolizumab according to the managed access agreement. This recommendation is not intended to affect treatment with atezolizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations There are no immunotherapy treatments available in England for NSCLC after complete tumour resection. Clinical trial evidence shows that compared with active monitoring, atezolizumab reduces the risk of the disease coming back. It may also lower the risk of death. However, this evidence is uncertain because the available data is still immature. Also, the company's model structure did not fully capture expected outcomes from more advanced disease health states. Because of this, the cost-effectiveness estimates for atezolizumab are also uncertain. It has the potential to be cost effective, but more evidence is needed to address these uncertainties before it can be recommended for routine use. Because more data is being collected that addresses these uncertainties, atezolizumab is recommended for use in the Cancer Drugs Fund.# Information about atezolizumab # Marketing authorisation indication Atezolizumab (Tecentriq, Roche) is indicated for 'adjuvant treatment following complete resection for adult patients with stage II to IIIA (7th edition of the UICC/AJCC-staging system) non-small-cell lung cancer (NSCLC) whose tumours have programmed cell death ligand-1 (PD‑L1) expression on ≥50% of tumour cells and whose disease has not progressed following platinum-based adjuvant chemotherapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for atezolizumab. # Price The list price is £3,807.69 for a (1,200 mg) 20‑ml vial and £2,665.38 for a (840 mg) 14‑ml vial (excluding VAT; BNF online accessed July 2022). The company has a commercial arrangement. This makes atezolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # New treatment option ## People with early-stage non-small-cell lung cancer would welcome new effective treatments that reduce the risk of recurrence Surgical removal of tumours is the preferred treatment for many people with early-stage non-small-cell lung cancer (NSCLC) because it is potentially a cure, and can be followed by adjuvant chemotherapy. But despite the curative intent of complete resection, recurrence rates in people with early NSCLC (stage 1 to 3) remain high. The disease comes back within about 5 years of surgery in 17% to 29% of people with stage 1, 38% to 46% of people with stage 2, and 47% to 64% of people with stage 3, regardless of using adjuvant chemotherapy. Clinical experts stated that outcomes after surgical resection remain poor, and this highlights the need to reduce the incidence of recurrence after surgery and improve outcomes for people with early-stage NSCLC in this potentially curative setting. The clinical experts stated that the availability of atezolizumab would be welcomed by people with early-stage NSCLC, because it addresses a high unmet need. The committee concluded that new, effective treatments that reduce the risk of recurrence would be welcomed. # Treatment pathway ## Atezolizumab is the first immunotherapy available at this point in the pathway The only treatment routinely available in England as adjuvant therapy for NSCLC after complete resection is chemotherapy (platinum-based combination therapy), which provides a small benefit in overall survival. NICE's technology appraisal on osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer recommends it for use through the Cancer Drugs Fund, but epidermal growth factor receptor (EGFR) mutation-positive NSCLC only accounts for a small subset of people with NSCLC. After adjuvant chemotherapy, standard care is active monitoring. The clinical experts stated that adjuvant atezolizumab after chemotherapy could prevent or delay disease recurrence in people with programmed cell death ligand-1 (PD‑L1) positive early-stage NSCLC, increasing the number of people whose disease is considered cured. The committee concluded that atezolizumab is the first immunotherapy at this point in the pathway for adjuvant treatment of people with PD‑L1 positive NSCLC after chemotherapy. ## Retreatment with atezolizumab would be offered to some people whose disease has progressed At the first committee meeting, the company assumed that people who have adjuvant treatment with atezolizumab and develop metastatic disease recurrence, would not have any subsequent immunotherapy treatment. The Cancer Drugs Fund clinical lead explained that if disease relapsed after treatment with atezolizumab was stopped, then retreatment with an immunotherapy would be commissioned in the NHS. They explained that this would depend on the time since finishing atezolizumab and the onset of metastatic disease. If this time gap was short, then retreatment would be unlikely to provide significant benefit. The ERG provided an analysis which assumed the same treatments would be given after metastatic disease recurrence in both the atezolizumab and active monitoring groups. The ERG explained that this scenario was likely to be appropriate because of the 1‑year treatment stopping rule for atezolizumab. This is because only a minority of people had experienced disease progression in the IMpower010 trial in the atezolizumab group while either having treatment or shortly after stopping treatment. The committee agreed that the ERG's retreatment scenario should be considered in its decision making but acknowledged that it may assume a slightly higher rate of immunotherapy retreatment than may happen in NHS clinical practice. At the second committee meeting, the company updated its analysis to include the assumption of immunotherapy retreatment in line with comments from the Cancer Drugs Fund clinical lead at the first meeting. The committee concluded that retreatment with atezolizumab would be offered to some people whose disease has progressed after having atezolizumab as an adjuvant treatment. # Clinical evidence ## The clinical evidence for atezolizumab is from IMpower010, a phase 3, randomised, placebo-controlled trial The clinical-effectiveness evidence for atezolizumab came from the IMpower010 trial. This is a phase 3, multicentre, open-label, clinical trial comparing atezolizumab with active monitoring after resection and cisplatin-based adjuvant chemotherapy in adults with completely resected stage 1b to 3a NSCLC. IMpower010 compared adjuvant atezolizumab treatment for up to approximately 1 year with active monitoring which comprised regular observations and scans for disease recurrence. The trial population which was covered by the marketing authorisation were those people with stages 2 to 3a and PD‑L1 positive (tumour expression of 50% or more) NSCLC. This reduced the number of people included in the analysis to 115 for atezolizumab and 114 for active monitoring. The unstratified clinical trial results showed that atezolizumab reduces the relative risk of experiencing disease recurrence or death (disease-free survival) by 57% compared with active monitoring (hazard ratio (HR) 0.43, 95% confidence interval 0.27 to 0.68). Median disease-free survival was 35.7 months for the active monitoring group but it was not reached for the atezolizumab group. The overall survival results are immature as few events happened in the interim trial data, but suggested a survival benefit in favour of atezolizumab (HR 0.37, 95% CI 0.18 to 0.74). The committee concluded that data from IMpower010 suggests that atezolizumab could be clinically effective. However, the disease-free survival data is immature and there have been very few events from which to calculate overall survival. ## It is not certain to what extent disease-free survival improves overall survival The company stated that although overall survival data from IMpower010 was not mature and very limited number of events had happened, atezolizumab was likely to increase survival based on the improvements seen in disease-free survival. The committee was aware that overall survival data would take longer to mature because of the nature of early-stage NSCLC. The overall survival results from IMpower010 showed that atezolizumab was associated with a relative risk reduction of death compared with active monitoring (the exact results are confidential and cannot be reported here). The ERG explained that although these results seem encouraging, they should be interpreted with caution given that median overall survival was not reached in either arm and a very low number of deaths had happened in the interim trial data. The clinical experts noted that while data on overall survival was not robust, the improvements in disease-free survival were significant and clinically important. The company explained that further analysis including more data on both disease-free and overall survival will become available from IMpower010. After the first committee meeting, the company provided an updated analysis of IMpower010 overall survival data for people with stages 2 to 3a and PD‑L1 positive (tumour expression of 50% or more) NSCLC (the exact results are confidential and cannot be reported here). However, it did not provide a corresponding updated analysis of disease-free survival data since it will not be available until 2023. The committee concluded that data from IMpower010 is still immature and it was not certain to what extent disease-free survival improves overall survival. # The company's economic model ## The company's original economic modelling approach was not appropriate for decision making The company used a cohort-level, discrete-time model. The model includes 8 disease-free survival health states: locoregional recurrence; first metastatic recurrence; second metastatic recurrence; and death. The locoregional and metastatic recurrence health states included both on and off active treatment states. In the model, people enter the disease-free survival state. The proportion of individuals in each health state model cycle varies with time as per the extrapolations of the disease-free survival Kaplan–Meier data from people with stage 2 or 3a PD‑L1 positive (tumour expression of 50% or more) NSCLC in IMpower010, and adjustments to these extrapolations (see section 3.9). The ERG explained that using a cohort-level analysis meant it was difficult to track events that usually vary with time. This meant that most of the transitions in the model were assumed to be constant. The ERG also noted that the model transitions were mostly informed by external sources rather than IMpower010 data. It explained that some of these sources covered heterogenous populations and some were based on small numbers within the studies. The company highlighted that the model structure was consistent with that used in NICE's technology appraisal guidance on osimertinib for adjuvant treatment of EGFR mutation-positive non-small-cell lung cancer after complete tumour resection (TA761). The ERG noted that the company's model was comparable to the model used in TA761 in terms of model health states. However, it relied on stronger assumptions than the model used in TA761. This is because the model used in TA761 allowed the risk of having locoregional and distant metastasis health states to be varied with time, by tracking the time that people have been in a particular health state in the model. The ERG also noted that the company's model did not allow transitions between locoregional recurrence and metastatic recurrence. The committee was aware that the modelled overall survival estimates were affected by a combination of all transitions in the model. It noted that the projected overall survival outcomes in the company's base case appeared to be underestimated when compared with IMpower010 trial data in both treatment groups. The ERG highlighted that the company's model did not appear to capture the expected outcomes from the metastatic disease recurrence states, because the incremental quality-adjusted life years (QALYs) accrued in these states were lower than in previous NICE technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic non-small-cell lung cancer (TA531), atezolizumab in combination for treating metastatic non-squamous non-small-cell lung cancer (TA584), pembrolizumab with pemetrexed and platinum chemotherapy for untreated, metastatic, non-squamous non-small-cell lung cancer (TA683) and atezolizumab monotherapy for untreated advanced non-small-cell lung cancer (TA705) at this part of the treatment pathway. The committee concluded that the company's original model was not appropriate for decision making and it needed further analyses after the first committee meeting. ## The company's updated economic modelling approach is acceptable for decision making At the second committee meeting, the company updated its economic modelling approach to align with previous NICE technology appraisal guidance (TA531, TA584, TA683 and TA705). It adjusted the post disease-free survival transition probabilities to better fit the modelled overall survival data to the observed overall survival data in IMpower010. The ERG stated that making the post disease-free survival transitions match 1 arm's Kaplan−Meier overall survival curve did not produce a good visual fit to the other arm's Kaplan–Meier overall survival curve. The committee was concerned that the model may not represent observed disease-free survival and overall survival data by making the trial data fit the model. The survival benefit seems to be maintained but this is uncertain owing to a lack of data. The company provided a further scenario which allows people with PD‑L1 positive early-stage NSCLC to enter the first metastatic disease recurrence state after cycle 1. It compared the resulting QALYs with metastatic NSCLC models which were previously submitted to NICE. In addition, the company presented additional evidence including justification of external resources for transitions in the model and the risk of having a locoregional recurrence state. The ERG noted that the company's updated approach to explore the consistency of the model with previous NICE appraisal guidance on treatments for metastatic lung cancer was useful. However, the approach is likely to underestimate the benefits of immunotherapy for metastatic lung cancer. The committee concluded that the company's updated economic modelling approach was acceptable for decision making. ## There is uncertainty about the company's cure assumptions In its original model, the company used a study by Sonoda et al. (2019) to assume that 91.5% of people who were in the disease-free survival health state at 5 years could be assumed to be cured and no longer at risk of disease recurrence. The ERG explained that this study used data from a single Japanese hospital between 1990 and 2006, and included 53% of people with stage 1a disease. It queried the appropriateness of the source to inform a cure assumption. The ERG provided analysis which assumed a longer time before a cure was assumed (8 years in both model arms). One of the clinical experts stated that the higher proportion of early-stage lung cancer in Sonoda et al. (2019) may not be an issue as these people tend to experience disease recurrence later, and therefore may give a good estimate on long-term recurrence. The committee noted that it would have preferred to have seen a more recent study which more closely aligned to the population in this appraisal. The clinical experts stated that in clinical practice people are followed up for 5 years after surgery. The committee agreed that while a cure assumption may be plausible, the point at which this should be applied in the model was uncertain. After the first committee meeting, the committee requested that the company explore other sources of literature reporting the proportion cured after resection and do a sensitivity analysis of the cure assumptions. In response, the company included 2 more studies (Shin 2021 and Maeda 2010a) to inform the cure assumptions, but they also had similar issues to Sonoda et al. (2019) around applicability to UK clinical practice. Therefore, the committee agreed that assuming a cure proportion from either Sonada et al. (2019), Shin (2021) or Maeda (2010a) was uncertain because the 2 new studies provided no better information. The committee noted the uncertainty around the proportion of people who could be assumed to be effectively cured as well as the cure timepoint because of the limitations of the data. It agreed that it was appropriate to have differential cure timepoints between the 2 arms. The Cancer Drugs Fund clinical lead suggested that 1 to 2 years difference is plausible because most disease relapses occur after 12 months or at most after 18 months after the surgery and adjuvant treatment. Therefore, a cure timepoint of 6 years or 7 years for atezolizumab and a cure timepoint of 5 years for active monitoring was a reasonable assumption. The ERG provided analyses which assumed these alternative cure timepoints. The committee concluded that there was significant uncertainty about the company's cure assumptions, and it would consider both of the ERG's approaches in its decision making. ## Some of the company's adjustments to the disease-free survival extrapolation are not appropriate The company's original base-case analysis made several adjustments to the disease-free survival curves. The company applied a linearly increasing cure rate from 0% to 91.5% between years 3 and 6, to account for the effect of the 5‑year cure assumption on the disease-free survival curve (see section 3.8). The ERG believed that this adjustment was not appropriate because it was not justified by the company, and removed it in its analysis. In addition, the company applied a treatment effect limitation, in which the probability of an event in the atezolizumab arm equalled that of the active monitoring arm at 5 years. The ERG noted that this improved the cost effectiveness of atezolizumab because the Kaplan−Meier data initially separates between the trial arms but this trend starts to reverse. The company also assumed a different proportion of transitions from the disease-free survival health state to locoregional and first-line metastatic health states between the atezolizumab and active monitoring arms based on data from IMpower010. The ERG highlighted that this assumption was based on a post-hoc analysis and was not justified by the company. The clinical experts stated that they were not aware of a biologically plausible explanation of why the proportion of people experiencing either a locoregional or first-line metastatic recurrence would differ between treatment arms. The committee agreed with the ERG and did not consider these assumptions in its preferred assumptions (see section 3.14). After the first committee meeting, the committee requested that the company provide analyses and commentary on alternative extrapolations of disease-free survival. In response, the company provided justification for the disease-free survival extrapolation and presented scenario analyses using different parametric models. The ERG noted that the company fitted the data from each trial arm separately to the parametric models. The projections in each parametric model had a tendency to converge across arms because of the different shapes of the Kaplan–Meier curves across arms. The 5‑year disease-free survival estimates the company assumed were broadly consistent with the 5‑year estimates from all parametric survival models of active monitoring tested, except the generalised gamma model. Therefore, the ERG was concerned about the long-term benefit of disease-free survival provided by adjuvant atezolizumab from the variations of different structural parametric model assumptions. The committee concluded that some of the company's adjustments to the disease-free survival extrapolation are not appropriate. ## Using a log-logistic, Weibull or log-normal distribution to model disease-free survival may be plausible but the data is limited The company stated that it had followed the advice outlined in NICE Decision Support Unit Technical Support Document 14 (TSD14) when selecting which distribution to use to extrapolate disease-free survival. It highlighted that there was no clearly best fitting model for extrapolating disease-free survival. The company explained that it chose the log-logistic distribution because the outcomes produced by this curve were validated by its clinical experts and reflected outcomes seen in Pignon et al. (2008). The ERG noted that the Weibull distribution was also a potentially plausible choice and provided a scenario analysis using this distribution. It also noted that Pignon et al. (2008) included 38% of people with stage 1a or stage 1b NSCLC, which raised generalisability issues. The committee agreed that because the disease-free survival data was limited and many distributions could potentially be used to extrapolate, this increased the uncertainty in the cost-effectiveness results. At the second committee meeting, the company updated its analyses to include the log-normal extrapolation with cure adjustments for disease-free survival modelling, but they did not use either log-logistic or Weibull distributions from the ERG preferred analyses. The committee noted that the log-normal extrapolation from the company was no better fit than other distributions. The company explained that it researched the plausibility of different distributions systematically and chose the log-normal distribution by statistical ranking compared with other distributions. The committee noted that using the log-normal distribution to model disease-free survival generated better results compared with log-logistic and Weibull distributions which were used in ERG preferred analyses, but the results are highly uncertain because of the limitations of the evidence. It noted that varying structural parametric model assumptions leads to uncertainties around cost-effectiveness results. The committee concluded that using either a log-logistic, Weibull or log-normal distribution to model disease-free survival may be plausible but the data informing this choice is limited. ## The ERG's approach to the treatment pathway is more appropriate In the company's model, a proportion of people were assumed to have further treatment after metastatic disease progression. The company assumed these people would have subsequent treatments based on clinical expert input. The ERG considered that the company's approach did not reflect the complexity of the treatment pathway, and the ERG exploratory analysis updated the assumed treatment pathway informed by their clinical expert and an NHS treatment algorithm. In the second committee meeting, the company included immunotherapy retreatment in its analysis but did not reflect other aspects noted by the ERG in the treatment pathway. The committee considered that the ERG's approach was more appropriate and concluded that it would use this analysis for decision making. ## Some of the costs in the company's analysis are not appropriate The ERG did not agree with some aspects of the company's cost analysis. In particular, it queried the following company assumptions: No treatment discontinuation in metastatic recurrence health states, except for assuming a 2‑year stopping rule for pembrolizumab. Only people who experience a disease-related death incur a terminal care cost. A lower adjuvant atezolizumab NHS and patient treatment burden is assumed than expected by the ERG's clinical expert. Double counting of some intravenous treatment administration costs and assuming no atezolizumab batch remakes.In its analysis, the ERG preferred to assume that people would stay on treatment for half of the time until disease progression or death. It also included terminal care costs for all patients and included additional resource costs for adjuvant atezolizumab. The committee agreed with the ERG's costing analysis but noted the company had stated that the cost of any atezolizumab batch remakes would be covered by the company. At the second committee meeting, the company's updated base-case analysis included terminal care costs and removed the double administration costing for combination treatments. It did not explain the reason why the rest of the ERG preferred costing assumptions were not included. The committee concluded that some of the costs in the company's analysis are not appropriate and it preferred the ERG's assumptions. ## There are still uncertainties in the company's updated analyses because of the immaturity of the trial data At the first committee meeting, the committee noted that the model had several limitations which increased the uncertainty in the cost-effectiveness results. Using exponential models to inform health state transitions was not properly justified (and unlikely to be appropriate, see section 3.6). In addition, using external sources to inform model transitions increased uncertainty in the post disease-free survival model state transitions (see section 3.6). The QALY gains from health states post disease-free survival and the time to stopping treatment in these health states were lower than those seen in recent NICE technology appraisal guidance in this part of the treatment pathway (see section 3.6). In addition, the committee noted there were other uncertainties in the analysis, including the cure assumption implemented in the analysis (see section 3.8) and the limited data on disease-free and overall survival (see section 3.4). After the first appraisal committee meeting, NICE requested that the company provide additional analyses to improve its modelling approaches. In response, the company updated its analyses to include a scenario in which people were retreated with atezolizumab 3 months after stopping treatment. It also updated the approach to post disease-free survival by adjusting the transition probabilities, comparing metastatic health state QALY gains with previous NICE appraisals and converting the model to a metastatic model (see section 3.7). The company updated its cure assumptions (see section 3.8) but the committee noted that the company's updated cure proportions and cure timing assumptions are still uncertain.This may be because there is limited data and evidence existing in this area. The committee recognised that the updated analyses done by the company may address some of the concerns around the company's original economic model but there still were some uncertainties around its approach. The committee concluded that in the absence of an alternative model, the company's updated model could be used for decision making. However, it noted that the model added uncertainty because of the immaturity of the trial data. # Cost-effectiveness estimate ## The most plausible incremental cost-effectiveness ratios are highly uncertain Because of confidential discounts for subsequent treatments, the cost-effectiveness results are commercial in confidence and cannot be reported here. The ERG's optimistic base case included a cure assumption of 5 years for both the atezolizumab and active monitoring groups and a log-logistic distribution to model disease-free survival. The ERG's alternative base case included a cure assumption of 8 years for both the atezolizumab and active monitoring groups and a Weibull distribution to model disease-free survival. Both analyses produced incremental cost-effectiveness ratios (ICERs) below £20,000 per QALY gained. The committee considered several assumptions were plausible: A cure assumption of 6 years in the atezolizumab arm and 5 years in active monitoring arm. A cure assumption of 7 years in the atezolizumab arm and 5 years in active monitoring arm. Including retreatment with atezolizumab at 3 months after stopping treatment.The committee considered these assumptions when applied to the updated analysis from the company (which included a log-normal distribution to model disease-free survival), the ERG's optimistic and alternative base cases. Combining any of these assumptions with the ERG's optimistic base case resulted in ICERs of below £20,000 per QALY gained. However, combining them with the ERG's alternative base case at cure point of 7 years in the atezolizumab arm resulted in ICERs above £30,000 per QALY gained. Using these preferred assumptions, the committee considered that the most plausible ICERs for atezolizumab were in the range of less than £20,000 per QALY gained to more than £30,000 per QALY gained. The committee concluded that the most plausible ICER range may be within or above the range usually considered a cost-effective use of resource, but it is associated with high uncertainty because of the immaturity of the current trial data. ## Atezolizumab is not recommended for routine use in the NHS The committee recognised that disease-free survival and overall survival data for atezolizumab from IMpower010 was immature. It also noted that the most plausible ICER range may be within or above the range considered cost effective for routine use in the NHS (see section 3.14). After considering the uncertainty of the clinical evidence along with its preferred assumptions, the committee agreed that the additional data being collected from IMpower010 may reduce the uncertainties around the modelling. The committee concluded it could not recommend atezolizumab for the adjuvant treatment of stage 2 to 3a NSCLC after complete resection in adults whose tumours have PD‑L1 expression on 50% or more of their tumour cells and whose disease has not progressed after platinum-based adjuvant chemotherapy for routine use in the NHS. ## Atezolizumab is recommended for use in the Cancer Drugs Fund Having concluded that atezolizumab could not be recommended for routine use, the committee then considered if it could be recommended for treating stage 2 to 3a NSCLC within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee acknowledged that the disease-free survival and overall survival data from IMpower010 was not mature and the evidence is limited to prefer either the log-logistic, Weibull or log-normal curves for disease-free survival extrapolations, so that further data collection may help address uncertainty. In addition, there are still many limitations with the approaches in the company's economic modelling. The committee considered that an updated model from the company is needed to address the modelling issues. The committee was aware that, although a period of time in the Cancer Drugs Fund may not produce enough mature overall survival and disease-free survival data for the modelling, there will still be benefits: The disease-free survival data and overall survival data will be more mature. More data will be available to estimate the extent of the cure proportion and cure timing assumption.The committee considered that further data collection in the Cancer Drugs Fund could address some of the uncertainty in the cost-effectiveness estimates. Most analyses resulted in ICERs showing that atezolizumab was cost effective within and above the range normally considered a cost-effective use of NHS resources. However, the uncertainties around the ICERs are high. The committee concluded that atezolizumab met the criteria to be considered for inclusion in the Cancer Drugs Fund. It recommended atezolizumab for use within the Cancer Drugs Fund as an option for people with stage 2 to 3a NSCLC after complete resection in adults whose tumours have PD‑L1 expression on 50% or more of their tumour cells and whose disease has not progressed after platinum-based adjuvant chemotherapy, if the conditions in the managed access agreement are followed. When the guidance is next reviewed the company should use the committee's preferred assumptions and provide an updated model (unless new evidence indicates otherwise), as set out in section 3.13. # Innovation ## Atezolizumab is an innovative treatment for people with PD-L1 positive early-stage NSCLC in the adjuvant setting The company stated that atezolizumab is innovative because there has been little innovation in adjuvant treatment for early NSCLC. It highlighted that there are no treatment options for most people at this part of the treatment pathway apart from adjuvant chemotherapy, which has shown to provide limited benefits. The clinical experts considered atezolizumab is a step change in the management of early-stage NSCLC with PD‑L1 expression on 50% or more of their tumour cells and represents a significant improvement in outcomes for this population. The committee was aware that atezolizumab has been reviewed as part of Project Orbis because it is considered an innovative adjuvant treatment. In addition, atezolizumab has been granted an 'Innovation Passport' through the Medicines and Healthcare products Regulatory Agency's Innovative Licensing and Access Pathway (ILAP). The committee considered that atezolizumab was an innovative treatment for people with PD‑L1 positive early-stage NSCLC but considered that all related health benefits had been captured in the model. # Other factors No equality or social value judgement issues were identified. NICE's advice about life-extending treatments for people with a short life expectancy did not apply. # Conclusion The committee recognises that atezolizumab is a promising treatment option at this point in the pathway. However, there is not enough clinical and cost-effectiveness evidence to recommend it for routine use in the NHS. Therefore, atezolizumab is recommended for use in the Cancer Drugs Fund as an adjuvant treatment of stage 2 to 3a NSCLC after complete tumour resection, in adults whose tumours have PD‑L1 expression on 50% or more of their tumour cells and whose disease has not progressed after platinum-based adjuvant chemotherapy. The committee recognised that the IMpower010 trial used American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) TNM 7th edition lung cancer staging criteria and that this evidence underpinned the marketing authorisation. It was aware that these criteria had been recently updated and that the 8th edition is also now used in NHS clinical practice. It understood from the Cancer Drugs Fund clinical lead that the population as per 7th edition (stages 2 to 3a – as specified in the marketing authorisation) corresponds to stages 2 to N2 only stage 3b in the 8th edition. It also understood that the Cancer Drugs Fund would ensure patient access in accordance with this translation from the 7th to the 8th edition lung cancer staging criteria.	{'Recommendations': "Atezolizumab is recommended for use within the Cancer Drugs Fund as an option for adjuvant treatment after complete tumour resection in adults with stage\xa02 to\xa03a non-small-cell lung cancer (NSCLC) whose:\n\ntumours have the programmed cell death ligand‑1 (PD‑L1) biomarker expression on 50% or more of their tumour cells and\n\nwhose disease has not progressed after platinum-based adjuvant chemotherapy.It is recommended only if the company provides atezolizumab according to the managed access agreement.\n\nThis recommendation is not intended to affect treatment with atezolizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThere are no immunotherapy treatments available in England for NSCLC after complete tumour resection.\n\nClinical trial evidence shows that compared with active monitoring, atezolizumab reduces the risk of the disease coming back. It may also lower the risk of death. However, this evidence is uncertain because the available data is still immature. Also, the company's model structure did not fully capture expected outcomes from more advanced disease health states.\n\nBecause of this, the cost-effectiveness estimates for atezolizumab are also uncertain. It has the potential to be cost effective, but more evidence is needed to address these uncertainties before it can be recommended for routine use.\n\nBecause more data is being collected that addresses these uncertainties, atezolizumab is recommended for use in the Cancer Drugs Fund.", 'Information about atezolizumab': "# Marketing authorisation indication\n\nAtezolizumab (Tecentriq, Roche) is indicated for 'adjuvant treatment following complete resection for adult patients with stage\xa0II to\xa0IIIA (7th\xa0edition of the UICC/AJCC-staging system) non-small-cell lung cancer (NSCLC) whose tumours have programmed cell death ligand-1 (PD‑L1) expression on ≥50% of tumour cells and whose disease has not progressed following platinum-based adjuvant chemotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for atezolizumab.\n\n# Price\n\nThe list price is £3,807.69 for a (1,200\xa0mg) 20‑ml vial and £2,665.38 for a (840\xa0mg) 14‑ml vial (excluding VAT; BNF online accessed July\xa02022).\n\nThe company has a commercial arrangement. This makes atezolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with early-stage non-small-cell lung cancer would welcome new effective treatments that reduce the risk of recurrence\n\nSurgical removal of tumours is the preferred treatment for many people with early-stage non-small-cell lung cancer (NSCLC) because it is potentially a cure, and can be followed by adjuvant chemotherapy. But despite the curative intent of complete resection, recurrence rates in people with early NSCLC (stage\xa01 to\xa03) remain high. The disease comes back within about 5\xa0years of surgery in 17% to 29% of people with stage\xa01, 38% to 46% of people with stage\xa02, and 47% to 64% of people with stage\xa03, regardless of using adjuvant chemotherapy. Clinical experts stated that outcomes after surgical resection remain poor, and this highlights the need to reduce the incidence of recurrence after surgery and improve outcomes for people with early-stage NSCLC in this potentially curative setting. The clinical experts stated that the availability of atezolizumab would be welcomed by people with early-stage NSCLC, because it addresses a high unmet need. The committee concluded that new, effective treatments that reduce the risk of recurrence would be welcomed.\n\n# Treatment pathway\n\n## Atezolizumab is the first immunotherapy available at this point in the pathway\n\nThe only treatment routinely available in England as adjuvant therapy for NSCLC after complete resection is chemotherapy (platinum-based combination therapy), which provides a small benefit in overall survival. NICE's technology appraisal on osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer recommends it for use through the Cancer Drugs Fund, but epidermal growth factor receptor (EGFR) mutation-positive NSCLC only accounts for a small subset of people with NSCLC. After adjuvant chemotherapy, standard care is active monitoring. The clinical experts stated that adjuvant atezolizumab after chemotherapy could prevent or delay disease recurrence in people with programmed cell death ligand-1 (PD‑L1) positive early-stage NSCLC, increasing the number of people whose disease is considered cured. The committee concluded that atezolizumab is the first immunotherapy at this point in the pathway for adjuvant treatment of people with PD‑L1 positive NSCLC after chemotherapy.\n\n## Retreatment with atezolizumab would be offered to some people whose disease has progressed\n\nAt the first committee meeting, the company assumed that people who have adjuvant treatment with atezolizumab and develop metastatic disease recurrence, would not have any subsequent immunotherapy treatment. The Cancer Drugs Fund clinical lead explained that if disease relapsed after treatment with atezolizumab was stopped, then retreatment with an immunotherapy would be commissioned in the NHS. They explained that this would depend on the time since finishing atezolizumab and the onset of metastatic disease. If this time gap was short, then retreatment would be unlikely to provide significant benefit. The ERG provided an analysis which assumed the same treatments would be given after metastatic disease recurrence in both the atezolizumab and active monitoring groups. The ERG explained that this scenario was likely to be appropriate because of the 1‑year treatment stopping rule for atezolizumab. This is because only a minority of people had experienced disease progression in the IMpower010 trial in the atezolizumab group while either having treatment or shortly after stopping treatment. The committee agreed that the ERG's retreatment scenario should be considered in its decision making but acknowledged that it may assume a slightly higher rate of immunotherapy retreatment than may happen in NHS clinical practice. At the second committee meeting, the company updated its analysis to include the assumption of immunotherapy retreatment in line with comments from the Cancer Drugs Fund clinical lead at the first meeting. The committee concluded that retreatment with atezolizumab would be offered to some people whose disease has progressed after having atezolizumab as an adjuvant treatment.\n\n# Clinical evidence\n\n## The clinical evidence for atezolizumab is from IMpower010, a phase\xa03, randomised, placebo-controlled trial\n\nThe clinical-effectiveness evidence for atezolizumab came from the IMpower010 trial. This is a phase\xa03, multicentre, open-label, clinical trial comparing atezolizumab with active monitoring after resection and cisplatin-based adjuvant chemotherapy in adults with completely resected stage\xa01b to\xa03a NSCLC. IMpower010 compared adjuvant atezolizumab treatment for up to approximately 1\xa0year with active monitoring which comprised regular observations and scans for disease recurrence. The trial population which was covered by the marketing authorisation were those people with stages\xa02 to\xa03a and PD‑L1 positive (tumour expression of 50% or more) NSCLC. This reduced the number of people included in the analysis to 115 for atezolizumab and 114 for active monitoring. The unstratified clinical trial results showed that atezolizumab reduces the relative risk of experiencing disease recurrence or death (disease-free survival) by 57% compared with active monitoring (hazard ratio (HR) 0.43, 95% confidence interval [CI] 0.27 to 0.68). Median disease-free survival was 35.7\xa0months for the active monitoring group but it was not reached for the atezolizumab group. The overall survival results are immature as few events happened in the interim trial data, but suggested a survival benefit in favour of atezolizumab (HR 0.37, 95% CI 0.18 to 0.74). The committee concluded that data from IMpower010 suggests that atezolizumab could be clinically effective. However, the disease-free survival data is immature and there have been very few events from which to calculate overall survival.\n\n## It is not certain to what extent disease-free survival improves overall survival\n\nThe company stated that although overall survival data from IMpower010 was not mature and very limited number of events had happened, atezolizumab was likely to increase survival based on the improvements seen in disease-free survival. The committee was aware that overall survival data would take longer to mature because of the nature of early-stage NSCLC. The overall survival results from IMpower010 showed that atezolizumab was associated with a relative risk reduction of death compared with active monitoring (the exact results are confidential and cannot be reported here). The ERG explained that although these results seem encouraging, they should be interpreted with caution given that median overall survival was not reached in either arm and a very low number of deaths had happened in the interim trial data. The clinical experts noted that while data on overall survival was not robust, the improvements in disease-free survival were significant and clinically important. The company explained that further analysis including more data on both disease-free and overall survival will become available from IMpower010. After the first committee meeting, the company provided an updated analysis of IMpower010 overall survival data for people with stages\xa02 to\xa03a and PD‑L1 positive (tumour expression of 50% or more) NSCLC (the exact results are confidential and cannot be reported here). However, it did not provide a corresponding updated analysis of disease-free survival data since it will not be available until 2023. The committee concluded that data from IMpower010 is still immature and it was not certain to what extent disease-free survival improves overall survival.\n\n# The company's economic model\n\n## The company's original economic modelling approach was not appropriate for decision making\n\nThe company used a cohort-level, discrete-time model. The model includes 8\xa0disease-free survival health states: locoregional recurrence; first metastatic recurrence; second metastatic recurrence; and death. The locoregional and metastatic recurrence health states included both on and off active treatment states. In the model, people enter the disease-free survival state. The proportion of individuals in each health state model cycle varies with time as per the extrapolations of the disease-free survival Kaplan–Meier data from people with stage\xa02 or\xa03a PD‑L1 positive (tumour expression of 50% or more) NSCLC in IMpower010, and adjustments to these extrapolations (see section\xa03.9). The ERG explained that using a cohort-level analysis meant it was difficult to track events that usually vary with time. This meant that most of the transitions in the model were assumed to be constant. The ERG also noted that the model transitions were mostly informed by external sources rather than IMpower010 data. It explained that some of these sources covered heterogenous populations and some were based on small numbers within the studies. The company highlighted that the model structure was consistent with that used in NICE's technology appraisal guidance on osimertinib for adjuvant treatment of EGFR mutation-positive non-small-cell lung cancer after complete tumour resection (TA761). The ERG noted that the company's model was comparable to the model used in TA761 in terms of model health states. However, it relied on stronger assumptions than the model used in TA761. This is because the model used in TA761 allowed the risk of having locoregional and distant metastasis health states to be varied with time, by tracking the time that people have been in a particular health state in the model. The ERG also noted that the company's model did not allow transitions between locoregional recurrence and metastatic recurrence. The committee was aware that the modelled overall survival estimates were affected by a combination of all transitions in the model. It noted that the projected overall survival outcomes in the company's base case appeared to be underestimated when compared with IMpower010 trial data in both treatment groups. The ERG highlighted that the company's model did not appear to capture the expected outcomes from the metastatic disease recurrence states, because the incremental quality-adjusted life years (QALYs) accrued in these states were lower than in previous NICE technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic non-small-cell lung cancer (TA531), atezolizumab in combination for treating metastatic non-squamous non-small-cell lung cancer (TA584), pembrolizumab with pemetrexed and platinum chemotherapy for untreated, metastatic, non-squamous non-small-cell lung cancer (TA683) and atezolizumab monotherapy for untreated advanced non-small-cell lung cancer (TA705) at this part of the treatment pathway. The committee concluded that the company's original model was not appropriate for decision making and it needed further analyses after the first committee meeting.\n\n## The company's updated economic modelling approach is acceptable for decision making\n\nAt the second committee meeting, the company updated its economic modelling approach to align with previous NICE technology appraisal guidance (TA531, TA584, TA683 and TA705). It adjusted the post disease-free survival transition probabilities to better fit the modelled overall survival data to the observed overall survival data in IMpower010. The ERG stated that making the post disease-free survival transitions match 1 arm's Kaplan−Meier overall survival curve did not produce a good visual fit to the other arm's Kaplan–Meier overall survival curve. The committee was concerned that the model may not represent observed disease-free survival and overall survival data by making the trial data fit the model. The survival benefit seems to be maintained but this is uncertain owing to a lack of data. The company provided a further scenario which allows people with PD‑L1 positive early-stage NSCLC to enter the first metastatic disease recurrence state after cycle\xa01. It compared the resulting QALYs with metastatic NSCLC models which were previously submitted to NICE. In addition, the company presented additional evidence including justification of external resources for transitions in the model and the risk of having a locoregional recurrence state. The ERG noted that the company's updated approach to explore the consistency of the model with previous NICE appraisal guidance on treatments for metastatic lung cancer was useful. However, the approach is likely to underestimate the benefits of immunotherapy for metastatic lung cancer. The committee concluded that the company's updated economic modelling approach was acceptable for decision making.\n\n## There is uncertainty about the company's cure assumptions\n\nIn its original model, the company used a study by Sonoda et al. (2019) to assume that 91.5% of people who were in the disease-free survival health state at 5\xa0years could be assumed to be cured and no longer at risk of disease recurrence. The ERG explained that this study used data from a single Japanese hospital between 1990 and 2006, and included 53% of people with stage\xa01a disease. It queried the appropriateness of the source to inform a cure assumption. The ERG provided analysis which assumed a longer time before a cure was assumed (8\xa0years in both model arms). One of the clinical experts stated that the higher proportion of early-stage lung cancer in Sonoda et al. (2019) may not be an issue as these people tend to experience disease recurrence later, and therefore may give a good estimate on long-term recurrence. The committee noted that it would have preferred to have seen a more recent study which more closely aligned to the population in this appraisal. The clinical experts stated that in clinical practice people are followed up for 5\xa0years after surgery. The committee agreed that while a cure assumption may be plausible, the point at which this should be applied in the model was uncertain. After the first committee meeting, the committee requested that the company explore other sources of literature reporting the proportion cured after resection and do a sensitivity analysis of the cure assumptions. In response, the company included 2 more studies (Shin 2021 and Maeda 2010a) to inform the cure assumptions, but they also had similar issues to Sonoda et al. (2019) around applicability to UK clinical practice. Therefore, the committee agreed that assuming a cure proportion from either Sonada et al. (2019), Shin (2021) or Maeda (2010a) was uncertain because the 2 new studies provided no better information. The committee noted the uncertainty around the proportion of people who could be assumed to be effectively cured as well as the cure timepoint because of the limitations of the data. It agreed that it was appropriate to have differential cure timepoints between the 2 arms. The Cancer Drugs Fund clinical lead suggested that 1\xa0to 2\xa0years difference is plausible because most disease relapses occur after 12\xa0months or at most after 18\xa0months after the surgery and adjuvant treatment. Therefore, a cure timepoint of 6\xa0years or 7\xa0years for atezolizumab and a cure timepoint of 5\xa0years for active monitoring was a reasonable assumption. The ERG provided analyses which assumed these alternative cure timepoints. The committee concluded that there was significant uncertainty about the company's cure assumptions, and it would consider both of the ERG's approaches in its decision making.\n\n## Some of the company's adjustments to the disease-free survival extrapolation are not appropriate\n\nThe company's original base-case analysis made several adjustments to the disease-free survival curves. The company applied a linearly increasing cure rate from 0% to 91.5% between years 3 and 6, to account for the effect of the 5‑year cure assumption on the disease-free survival curve (see section\xa03.8). The ERG believed that this adjustment was not appropriate because it was not justified by the company, and removed it in its analysis. In addition, the company applied a treatment effect limitation, in which the probability of an event in the atezolizumab arm equalled that of the active monitoring arm at 5\xa0years. The ERG noted that this improved the cost effectiveness of atezolizumab because the Kaplan−Meier data initially separates between the trial arms but this trend starts to reverse. The company also assumed a different proportion of transitions from the disease-free survival health state to locoregional and first-line metastatic health states between the atezolizumab and active monitoring arms based on data from IMpower010. The ERG highlighted that this assumption was based on a post-hoc analysis and was not justified by the company. The clinical experts stated that they were not aware of a biologically plausible explanation of why the proportion of people experiencing either a locoregional or first-line metastatic recurrence would differ between treatment arms. The committee agreed with the ERG and did not consider these assumptions in its preferred assumptions (see section\xa03.14). After the first committee meeting, the committee requested that the company provide analyses and commentary on alternative extrapolations of disease-free survival. In response, the company provided justification for the disease-free survival extrapolation and presented scenario analyses using different parametric models. The ERG noted that the company fitted the data from each trial arm separately to the parametric models. The projections in each parametric model had a tendency to converge across arms because of the different shapes of the Kaplan–Meier curves across arms. The 5‑year disease-free survival estimates the company assumed were broadly consistent with the 5‑year estimates from all parametric survival models of active monitoring tested, except the generalised gamma model. Therefore, the ERG was concerned about the long-term benefit of disease-free survival provided by adjuvant atezolizumab from the variations of different structural parametric model assumptions. The committee concluded that some of the company's adjustments to the disease-free survival extrapolation are not appropriate.\n\n## Using a log-logistic, Weibull or log-normal distribution to model disease-free survival may be plausible but the data is limited\n\nThe company stated that it had followed the advice outlined in NICE Decision Support Unit Technical Support Document 14 (TSD14) when selecting which distribution to use to extrapolate disease-free survival. It highlighted that there was no clearly best fitting model for extrapolating disease-free survival. The company explained that it chose the log-logistic distribution because the outcomes produced by this curve were validated by its clinical experts and reflected outcomes seen in Pignon et al. (2008). The ERG noted that the Weibull distribution was also a potentially plausible choice and provided a scenario analysis using this distribution. It also noted that Pignon et al. (2008) included 38% of people with stage\xa01a or stage\xa01b NSCLC, which raised generalisability issues. The committee agreed that because the disease-free survival data was limited and many distributions could potentially be used to extrapolate, this increased the uncertainty in the cost-effectiveness results. At the second committee meeting, the company updated its analyses to include the log-normal extrapolation with cure adjustments for disease-free survival modelling, but they did not use either log-logistic or Weibull distributions from the ERG preferred analyses. The committee noted that the log-normal extrapolation from the company was no better fit than other distributions. The company explained that it researched the plausibility of different distributions systematically and chose the log-normal distribution by statistical ranking compared with other distributions. The committee noted that using the log-normal distribution to model disease-free survival generated better results compared with log-logistic and Weibull distributions which were used in ERG preferred analyses, but the results are highly uncertain because of the limitations of the evidence. It noted that varying structural parametric model assumptions leads to uncertainties around cost-effectiveness results. The committee concluded that using either a log-logistic, Weibull or log-normal distribution to model disease-free survival may be plausible but the data informing this choice is limited.\n\n## The ERG's approach to the treatment pathway is more appropriate\n\nIn the company's model, a proportion of people were assumed to have further treatment after metastatic disease progression. The company assumed these people would have subsequent treatments based on clinical expert input. The ERG considered that the company's approach did not reflect the complexity of the treatment pathway, and the ERG exploratory analysis updated the assumed treatment pathway informed by their clinical expert and an NHS treatment algorithm. In the second committee meeting, the company included immunotherapy retreatment in its analysis but did not reflect other aspects noted by the ERG in the treatment pathway. The committee considered that the ERG's approach was more appropriate and concluded that it would use this analysis for decision making.\n\n## Some of the costs in the company's analysis are not appropriate\n\nThe ERG did not agree with some aspects of the company's cost analysis. In particular, it queried the following company assumptions:\n\nNo treatment discontinuation in metastatic recurrence health states, except for assuming a 2‑year stopping rule for pembrolizumab.\n\nOnly people who experience a disease-related death incur a terminal care cost.\n\nA lower adjuvant atezolizumab NHS and patient treatment burden is assumed than expected by the ERG's clinical expert.\n\nDouble counting of some intravenous treatment administration costs and assuming no atezolizumab batch remakes.In its analysis, the ERG preferred to assume that people would stay on treatment for half of the time until disease progression or death. It also included terminal care costs for all patients and included additional resource costs for adjuvant atezolizumab. The committee agreed with the ERG's costing analysis but noted the company had stated that the cost of any atezolizumab batch remakes would be covered by the company. At the second committee meeting, the company's updated base-case analysis included terminal care costs and removed the double administration costing for combination treatments. It did not explain the reason why the rest of the ERG preferred costing assumptions were not included. The committee concluded that some of the costs in the company's analysis are not appropriate and it preferred the ERG's assumptions.\n\n## There are still uncertainties in the company's updated analyses because of the immaturity of the trial data\n\nAt the first committee meeting, the committee noted that the model had several limitations which increased the uncertainty in the cost-effectiveness results. Using exponential models to inform health state transitions was not properly justified (and unlikely to be appropriate, see section\xa03.6). In addition, using external sources to inform model transitions increased uncertainty in the post disease-free survival model state transitions (see section\xa03.6). The QALY gains from health states post disease-free survival and the time to stopping treatment in these health states were lower than those seen in recent NICE technology appraisal guidance in this part of the treatment pathway (see section\xa03.6). In addition, the committee noted there were other uncertainties in the analysis, including the cure assumption implemented in the analysis (see section\xa03.8) and the limited data on disease-free and overall survival (see section\xa03.4). After the first appraisal committee meeting, NICE requested that the company provide additional analyses to improve its modelling approaches. In response, the company updated its analyses to include a scenario in which people were retreated with atezolizumab 3\xa0months after stopping treatment. It also updated the approach to post disease-free survival by adjusting the transition probabilities, comparing metastatic health state QALY gains with previous NICE appraisals and converting the model to a metastatic model (see section\xa03.7). The company updated its cure assumptions (see section\xa03.8) but the committee noted that the company's updated cure proportions and cure timing assumptions are still uncertain.This may be because there is limited data and evidence existing in this area. The committee recognised that the updated analyses done by the company may address some of the concerns around the company's original economic model but there still were some uncertainties around its approach. The committee concluded that in the absence of an alternative model, the company's updated model could be used for decision making. However, it noted that the model added uncertainty because of the immaturity of the trial data.\n\n# Cost-effectiveness estimate\n\n## The most plausible incremental cost-effectiveness ratios are highly uncertain\n\nBecause of confidential discounts for subsequent treatments, the cost-effectiveness results are commercial in confidence and cannot be reported here. The ERG's optimistic base case included a cure assumption of 5\xa0years for both the atezolizumab and active monitoring groups and a log-logistic distribution to model disease-free survival. The ERG's alternative base case included a cure assumption of 8\xa0years for both the atezolizumab and active monitoring groups and a Weibull distribution to model disease-free survival. Both analyses produced incremental cost-effectiveness ratios (ICERs) below £20,000 per QALY gained. The committee considered several assumptions were plausible:\n\nA cure assumption of 6\xa0years in the atezolizumab arm and 5\xa0years in active monitoring arm.\n\nA cure assumption of 7\xa0years in the atezolizumab arm and 5\xa0years in active monitoring arm.\n\nIncluding retreatment with atezolizumab at 3\xa0months after stopping treatment.The committee considered these assumptions when applied to the updated analysis from the company (which included a log-normal distribution to model disease-free survival), the ERG's optimistic and alternative base cases. Combining any of these assumptions with the ERG's optimistic base case resulted in ICERs of below £20,000 per QALY gained. However, combining them with the ERG's alternative base case at cure point of 7\xa0years in the atezolizumab arm resulted in ICERs above £30,000 per QALY gained. Using these preferred assumptions, the committee considered that the most plausible ICERs for atezolizumab were in the range of less than £20,000 per QALY gained to more than £30,000 per QALY gained. The committee concluded that the most plausible ICER range may be within or above the range usually considered a cost-effective use of resource, but it is associated with high uncertainty because of the immaturity of the current trial data.\n\n## Atezolizumab is not recommended for routine use in the NHS\n\nThe committee recognised that disease-free survival and overall survival data for atezolizumab from IMpower010 was immature. It also noted that the most plausible ICER range may be within or above the range considered cost effective for routine use in the NHS (see section\xa03.14). After considering the uncertainty of the clinical evidence along with its preferred assumptions, the committee agreed that the additional data being collected from IMpower010 may reduce the uncertainties around the modelling. The committee concluded it could not recommend atezolizumab for the adjuvant treatment of stage\xa02 to\xa03a NSCLC after complete resection in adults whose tumours have PD‑L1 expression on 50% or more of their tumour cells and whose disease has not progressed after platinum-based adjuvant chemotherapy for routine use in the NHS.\n\n## Atezolizumab is recommended for use in the Cancer Drugs Fund\n\nHaving concluded that atezolizumab could not be recommended for routine use, the committee then considered if it could be recommended for treating stage\xa02 to\xa03a NSCLC within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee acknowledged that the disease-free survival and overall survival data from IMpower010 was not mature and the evidence is limited to prefer either the log-logistic, Weibull or log-normal curves for disease-free survival extrapolations, so that further data collection may help address uncertainty. In addition, there are still many limitations with the approaches in the company's economic modelling. The committee considered that an updated model from the company is needed to address the modelling issues. The committee was aware that, although a period of time in the Cancer Drugs Fund may not produce enough mature overall survival and disease-free survival data for the modelling, there will still be benefits:\n\nThe disease-free survival data and overall survival data will be more mature.\n\nMore data will be available to estimate the extent of the cure proportion and cure timing assumption.The committee considered that further data collection in the Cancer Drugs Fund could address some of the uncertainty in the cost-effectiveness estimates. Most analyses resulted in ICERs showing that atezolizumab was cost effective within and above the range normally considered a cost-effective use of NHS resources. However, the uncertainties around the ICERs are high. The committee concluded that atezolizumab met the criteria to be considered for inclusion in the Cancer Drugs Fund. It recommended atezolizumab for use within the Cancer Drugs Fund as an option for people with stage\xa02 to\xa03a NSCLC after complete resection in adults whose tumours have PD‑L1 expression on 50% or more of their tumour cells and whose disease has not progressed after platinum-based adjuvant chemotherapy, if the conditions in the managed access agreement are followed. When the guidance is next reviewed the company should use the committee's preferred assumptions and provide an updated model (unless new evidence indicates otherwise), as set out in section 3.13.\n\n# Innovation\n\n## Atezolizumab is an innovative treatment for people with PD-L1 positive early-stage NSCLC in the adjuvant setting\n\nThe company stated that atezolizumab is innovative because there has been little innovation in adjuvant treatment for early NSCLC. It highlighted that there are no treatment options for most people at this part of the treatment pathway apart from adjuvant chemotherapy, which has shown to provide limited benefits. The clinical experts considered atezolizumab is a step change in the management of early-stage NSCLC with PD‑L1 expression on 50% or more of their tumour cells and represents a significant improvement in outcomes for this population. The committee was aware that atezolizumab has been reviewed as part of Project Orbis because it is considered an innovative adjuvant treatment. In addition, atezolizumab has been granted an 'Innovation Passport' through the Medicines and Healthcare products Regulatory Agency's Innovative Licensing and Access Pathway (ILAP). The committee considered that atezolizumab was an innovative treatment for people with PD‑L1 positive early-stage NSCLC but considered that all related health benefits had been captured in the model.\n\n# Other factors\n\nNo equality or social value judgement issues were identified.\n\nNICE's advice about life-extending treatments for people with a short life expectancy did not apply.\n\n# Conclusion\n\nThe committee recognises that atezolizumab is a promising treatment option at this point in the pathway. However, there is not enough clinical and cost-effectiveness evidence to recommend it for routine use in the NHS. Therefore, atezolizumab is recommended for use in the Cancer Drugs Fund as an adjuvant treatment of stage\xa02 to 3a NSCLC after complete tumour resection, in adults whose tumours have PD‑L1 expression on 50% or more of their tumour cells and whose disease has not progressed after platinum-based adjuvant chemotherapy. The committee recognised that the IMpower010 trial used American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) TNM 7th edition lung cancer staging criteria and that this evidence underpinned the marketing authorisation. It was aware that these criteria had been recently updated and that the 8th edition is also now used in NHS clinical practice. It understood from the Cancer Drugs Fund clinical lead that the population as per 7th edition (stages\xa02 to\xa03a – as specified in the marketing authorisation) corresponds to stages\xa02 to N2 only stage\xa03b in the 8th edition. It also understood that the Cancer Drugs Fund would ensure patient access in accordance with this translation from the 7th to the 8th edition lung cancer staging criteria."}	https://www.nice.org.uk/guidance/ta823	Evidence-based recommendations on atezolizumab (Tecentriq) for adjuvant treatment of resected non-small-cell lung cancer in adults.
6887de2136ef7dca7e2e56991610a3e804c51685	nice	Neurostimulation of lumbar muscles for refractory non-specific chronic low back pain	Neurostimulation of lumbar muscles for refractory non-specific chronic low back pain Evidence-based recommendations on neurostimulation of lumbar muscles for refractory non-specific chronic low back pain in adults. This involves implanting a pulse generator under the skin of the upper buttock or lower back, which the person can use to manage their pain. # Recommendations Evidence on the efficacy and safety of neurostimulation of lumbar muscles for refractory non-specific chronic low back pain is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do neurostimulation of lumbar muscles for refractory non-specific chronic low back pain should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Ensure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Enter details about everyone having neurostimulation of lumbar muscles for refractory non-specific chronic low back pain onto the National Neuromodulation Registry and review local clinical outcomes. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Patient selection should be done by a multidisciplinary team with experience in pain management and neuromodulation stimulation procedures. Further research should include suitably powered randomised controlled trials comparing the procedure with current best practice with appropriate duration. It should report details of patient selection and long-term outcomes.# The condition, current treatments and procedure # The condition Non-specific severe long-term chronic refractory low back pain can present in various ways, including as neuropathic pain (associated with damage to the nervous system) or nociceptive pain (associated with physical damage to joints, muscles and ligaments). In some people, it is associated with dysfunction of the lumbar multifidus (large muscles that support the lower back) and arthrogenic muscle inhibition. This treatment is not intended for neuropathic pain. # Current treatments Treatments for low back pain are described in NICE's guideline on low back pain and sciatica in over 16s: assessment and management. Conservative pain management includes pharmacological treatments (such as oral non-steroidal anti-inflammatory drugs, and weak opioids with or without paracetamol) and non-interventional treatments (such as self-management advice and education, exercise, manual therapies, and combined physical and psychological therapy). People with severe chronic low back pain that is refractory to conservative treatments may be offered interventional procedures (such as radiofrequency denervation and epidural injections) or surgery (such as spinal fusion procedures). # The procedure The procedure is done under general anaesthesia, or local anaesthesia with sedation. A pulse generator (neurostimulator) is implanted in a pocket created under the skin of the upper buttock or lower back. Under fluoroscopic guidance through a midline approach, 2 stimulating leads are inserted. The distal end of each lead has stimulation electrodes. They are positioned next to the spinal column, near the medial branch of the L2 motor nerve supply (dorsal ramus nerve) to the multifidus muscles, and fixed using flexible tines. The leads are tunnelled internally, then the proximal ends are connected to the pulse generator and the position is checked radiographically. Approximately 14 days after the implantation procedure, the patient can start to use the device to manage their pain. While lying prone, they use a handheld wireless remote control to deliver stimulation to the nerve supply of the lumbar multifidus muscles, which causes them to contract. This is usually done twice a day for about 30 minutes each time. The pulse generator can be programmed to deliver stimulation between any pair of electrodes on each lead if needed. The aim of neurostimulation is to help the body regain multifidus neuromuscular control by 'activating' the lumbar muscles and stabilising the spinal column, reducing chronic pain. The procedure is reversible.	{'Recommendations': "Evidence on the efficacy and safety of neurostimulation of lumbar muscles for refractory non-specific chronic low back pain is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do neurostimulation of lumbar muscles for refractory non-specific chronic low back pain should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nEnter details about everyone having neurostimulation of lumbar muscles for refractory non-specific chronic low back pain onto the National Neuromodulation Registry and review local clinical outcomes.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a multidisciplinary team with experience in pain management and neuromodulation stimulation procedures.\n\nFurther research should include suitably powered randomised controlled trials comparing the procedure with current best practice with appropriate duration. It should report details of patient selection and long-term outcomes.", 'The condition, current treatments and procedure': "# The condition\n\nNon-specific severe long-term chronic refractory low back pain can present in various ways, including as neuropathic pain (associated with damage to the nervous system) or nociceptive pain (associated with physical damage to joints, muscles and ligaments). In some people, it is associated with dysfunction of the lumbar multifidus (large muscles that support the lower back) and arthrogenic muscle inhibition. This treatment is not intended for neuropathic pain.\n\n# Current treatments\n\nTreatments for low back pain are described in NICE's guideline on low back pain and sciatica in over 16s: assessment and management. Conservative pain management includes pharmacological treatments (such as oral non-steroidal anti-inflammatory drugs, and weak opioids with or without paracetamol) and non-interventional treatments (such as self-management advice and education, exercise, manual therapies, and combined physical and psychological therapy). People with severe chronic low back pain that is refractory to conservative treatments may be offered interventional procedures (such as radiofrequency denervation and epidural injections) or surgery (such as spinal fusion procedures).\n\n# The procedure\n\nThe procedure is done under general anaesthesia, or local anaesthesia with sedation. A pulse generator (neurostimulator) is implanted in a pocket created under the skin of the upper buttock or lower back. Under fluoroscopic guidance through a midline approach, 2 stimulating leads are inserted. The distal end of each lead has stimulation electrodes. They are positioned next to the spinal column, near the medial branch of the L2 motor nerve supply (dorsal ramus nerve) to the multifidus muscles, and fixed using flexible tines. The leads are tunnelled internally, then the proximal ends are connected to the pulse generator and the position is checked radiographically.\n\nApproximately 14\xa0days after the implantation procedure, the patient can start to use the device to manage their pain. While lying prone, they use a handheld wireless remote control to deliver stimulation to the nerve supply of the lumbar multifidus muscles, which causes them to contract. This is usually done twice a day for about 30\xa0minutes each time. The pulse generator can be programmed to deliver stimulation between any pair of electrodes on each lead if needed.\n\nThe aim of neurostimulation is to help the body regain multifidus neuromuscular control by 'activating' the lumbar muscles and stabilising the spinal column, reducing chronic pain. The procedure is reversible."}	https://www.nice.org.uk/guidance/ipg739	Evidence-based recommendations on neurostimulation of lumbar muscles for refractory non-specific chronic low back pain in adults. This involves implanting a pulse generator under the skin of the upper buttock or lower back, which the person can use to manage their pain.
f02d90d0cdb0161451fc16b87de016a8bc6e3a17	nice	Prostatic urethral temporary implant insertion for lower urinary tract symptoms caused by benign prostatic hyperplasia	Prostatic urethral temporary implant insertion for lower urinary tract symptoms caused by benign prostatic hyperplasia Evidence-based recommendations on prostatic urethral temporary implant insertion for lower urinary tract symptoms caused by benign prostatic hyperplasia. This involves positioning a temporary implant in the urethra to increase the flow of urine. # Recommendations Evidence on the safety and efficacy of prostatic urethral temporary implant insertion for lower urinary tract symptoms caused by benign prostatic hyperplasia is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do prostatic urethral temporary implant insertion for lower urinary tract symptoms caused by benign prostatic hyperplasia should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Ensure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Patient selection should be done by a team experienced in managing benign prostatic hyperplasia. The procedure should only be done by clinicians with specific training in the technique. Further research could include registry data or randomised controlled trials using a suitable comparator. It should report details of patient selection, including size of prostate, and longer-term outcomes, including the need for reintervention.# The condition, current treatments and procedure # The condition Lower urinary tract symptoms caused by benign prostatic hyperplasia commonly affect men aged over 50. Benign prostatic hyperplasia results from an increased number of stromal and epithelial cells. These cells are typically in the periurethral region of the prostate, with large discrete nodules compressing the urethra. Symptoms include hesitancy during micturition, interrupted or decreased urine stream (volume and flow rate), nocturia, incomplete voiding and urinary retention. # Current treatments NICE's guideline on lower urinary tract symptoms in men describes current treatment options. Mild symptoms are usually managed conservatively. Medicines such as alpha blockers and 5‑alpha‑reductase inhibitors may also be used. If other treatments have not worked, there are several possible surgical options, including transurethral resection of the prostate, transurethral vaporisation, holmium laser enucleation, prostatic urethral lift implant insertion, prostatic artery embolisation and prostatectomy. Potential complications of some of these surgical procedures include bleeding, infection, urethral strictures, incontinence and sexual dysfunction. # The procedure The aim of prostatic urethral temporary implant insertion is to relieve symptoms of benign prostatic hyperplasia by creating new channels in the urethra to increase the flow of urine. The aim of using a temporary implant is to avoid complications from an implant left in place long term. Local anaesthesia or light sedation is used. A folded device made from nitinol is deployed into the bladder under direct visualisation using a cystoscope. The device is opened in the bladder and retracted into the prostatic urethra. Over the following days, the pressure applied by struts in the device creates areas of ischaemia in the prostatic urethra and bladder neck. This makes new longitudinal channels through which urine can flow. After 5 to 7 days, lidocaine gel and a flexible silicone extraction catheter are inserted into the urethra and the device is removed. Insertion of the device is usually done as a day-case procedure and removal is done as a day-case or outpatient procedure.	{'Recommendations': "Evidence on the safety and efficacy of prostatic urethral temporary implant insertion for lower urinary tract symptoms caused by benign prostatic hyperplasia is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do prostatic urethral temporary implant insertion for lower urinary tract symptoms caused by benign prostatic hyperplasia should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a team experienced in managing benign prostatic hyperplasia. The procedure should only be done by clinicians with specific training in the technique.\n\nFurther research could include registry data or randomised controlled trials using a suitable comparator. It should report details of patient selection, including size of prostate, and longer-term outcomes, including the need for reintervention.", 'The condition, current treatments and procedure': "# The condition\n\nLower urinary tract symptoms caused by benign prostatic hyperplasia commonly affect men aged over\xa050. Benign prostatic hyperplasia results from an increased number of stromal and epithelial cells. These cells are typically in the periurethral region of the prostate, with large discrete nodules compressing the urethra. Symptoms include hesitancy during micturition, interrupted or decreased urine stream (volume and flow rate), nocturia, incomplete voiding and urinary retention.\n\n# Current treatments\n\nNICE's guideline on lower urinary tract symptoms in men describes current treatment options. Mild symptoms are usually managed conservatively. Medicines such as alpha blockers and 5‑alpha‑reductase inhibitors may also be used. If other treatments have not worked, there are several possible surgical options, including transurethral resection of the prostate, transurethral vaporisation, holmium laser enucleation, prostatic urethral lift implant insertion, prostatic artery embolisation and prostatectomy. Potential complications of some of these surgical procedures include bleeding, infection, urethral strictures, incontinence and sexual dysfunction.\n\n# The procedure\n\nThe aim of prostatic urethral temporary implant insertion is to relieve symptoms of benign prostatic hyperplasia by creating new channels in the urethra to increase the flow of urine. The aim of using a temporary implant is to avoid complications from an implant left in place long term.\n\nLocal anaesthesia or light sedation is used. A folded device made from nitinol is deployed into the bladder under direct visualisation using a cystoscope. The device is opened in the bladder and retracted into the prostatic urethra. Over the following days, the pressure applied by struts in the device creates areas of ischaemia in the prostatic urethra and bladder neck. This makes new longitudinal channels through which urine can flow. After 5\xa0to\xa07\xa0days, lidocaine gel and a flexible silicone extraction catheter are inserted into the urethra and the device is removed. Insertion of the device is usually done as a day-case procedure and removal is done as a day-case or outpatient procedure."}	https://www.nice.org.uk/guidance/ipg737	Evidence-based recommendations on prostatic urethral temporary implant insertion for lower urinary tract symptoms caused by benign prostatic hyperplasia. This involves positioning a temporary implant in the urethra to increase the flow of urine.
63c1a43ed269300fa298925bc954235d022a7f17	nice	Removal, preservation and subsequent reimplantation of ovarian tissue to prevent symptoms from the menopause	Removal, preservation and subsequent reimplantation of ovarian tissue to prevent symptoms from the menopause Evidence-based recommendations on removal, preservation and subsequent reimplantation of ovarian tissue to prevent symptoms from the menopause. This involves removing a small piece of ovarian tissue using keyhole surgery, freezing and storing it. After menopause starts, the tissue is thawed and transplanted under the skin of the armpit, abdomen or forearm, with the aim of producing oestrogen. # Recommendations Evidence on the safety and efficacy of removal, preservation and subsequent reimplantation of ovarian tissue to prevent symptoms from the menopause is inadequate in quality and quantity. Therefore, this procedure should not be done unless it is part of a formal research study, with appropriate governance and ethics approval. Find out what only in research means on the NICE interventional procedures guidance page. Research should include randomised controlled trials and should report details of: patient selection, including the age at which ovarian tissue is removed the procedure, including the techniques used for harvesting tissue and cryopreservation, the timing and the frequency of reimplantation of ovarian tissue, and the association between the amount of tissue removed and reimplanted and subsequent endocrine function endocrine function in the period between removing and reimplanting ovarian tissue a comparator group who have pharmacological hormone replacement therapy (HRT). Patient selection should be done by a multidisciplinary team including clinicians with specialist expertise in managing menopause. The procedure should only be done by surgeons with specialist expertise in the procedure.# The condition, current treatments and procedure # The condition Menopause occurs with the final menstrual period and is usually diagnosed clinically after 12 months of amenorrhoea. It usually happens when someone is between 45 and 55, although around 1% of women have early (premature) menopause before 40. As oestrogen levels reduce, most people have some symptoms, which can affect quality of life. Most commonly, these are hot flushes and night sweats. Other symptoms are mood changes, memory and concentration loss, vaginal dryness, a lack of interest in sex, headaches, and joint and muscle stiffness. Menopause can also increase the risk of osteoporosis and cardiovascular disease. # Current treatments Symptoms can be treated with pharmacological hormone replacement therapy (HRT). For someone with a uterus, HRT usually consists of an oestrogen and a progestogen. For someone who has had their uterus removed, it is usually oestrogen only. HRT aims to replace the hormones that are no longer produced by the ovaries because of menopause. Non-hormonal treatments can also be used. # The procedure The level of reproductive hormones and ovarian reserve is assessed first. If this is adequate, one-third to one-half of the outer cortex of 1 ovary is removed laparoscopically under general anaesthesia and cryopreserved in thin slices. When menopause starts, a slice of the ovarian tissue is thawed and regrafted under the skin in a heterotopic site (for example, the forearm or axilla) with the aim of restoring normal ovarian endocrine function. The transplantation process is reversible and may be repeated to maintain endocrine function. The aim is to prevent the symptoms associated with the menopause.	{'Recommendations': 'Evidence on the safety and efficacy of removal, preservation and subsequent reimplantation of ovarian tissue to prevent symptoms from the menopause is inadequate in quality and quantity. Therefore, this procedure should not be done unless it is part of a formal research study, with appropriate governance and ethics approval. Find out what only in research means on the NICE interventional procedures guidance page.\n\nResearch should include randomised controlled trials and should report details of:\n\npatient selection, including the age at which ovarian tissue is removed\n\nthe procedure, including the techniques used for harvesting tissue and cryopreservation, the timing and the frequency of reimplantation of ovarian tissue, and the association between the amount of tissue removed and reimplanted and subsequent endocrine function\n\nendocrine function in the period between removing and reimplanting ovarian tissue\n\na comparator group who have pharmacological hormone replacement therapy (HRT).\n\nPatient selection should be done by a multidisciplinary team including clinicians with specialist expertise in managing menopause.\n\nThe procedure should only be done by surgeons with specialist expertise in the procedure.', 'The condition, current treatments and procedure': '# The condition\n\nMenopause occurs with the final menstrual period and is usually diagnosed clinically after 12\xa0months of amenorrhoea. It usually happens when someone is between 45\xa0and\xa055, although around 1% of women have early (premature) menopause before\xa040.\n\nAs oestrogen levels reduce, most people have some symptoms, which can affect quality of life. Most commonly, these are hot flushes and night sweats. Other symptoms are mood changes, memory and concentration loss, vaginal dryness, a lack of interest in sex, headaches, and joint and muscle stiffness. Menopause can also increase the risk of osteoporosis and cardiovascular disease.\n\n# Current treatments\n\nSymptoms can be treated with pharmacological hormone replacement therapy (HRT). For someone with a uterus, HRT usually consists of an oestrogen and a progestogen. For someone who has had their uterus removed, it is usually oestrogen only. HRT aims to replace the hormones that are no longer produced by the ovaries because of menopause. Non-hormonal treatments can also be used.\n\n# The procedure\n\nThe level of reproductive hormones and ovarian reserve is assessed first. If this is adequate, one-third to one-half of the outer cortex of 1\xa0ovary is removed laparoscopically under general anaesthesia and cryopreserved in thin slices. When menopause starts, a slice of the ovarian tissue is thawed and regrafted under the skin in a heterotopic site (for example, the forearm or axilla) with the aim of restoring normal ovarian endocrine function. The transplantation process is reversible and may be repeated to maintain endocrine function. The aim is to prevent the symptoms associated with the menopause.'}	https://www.nice.org.uk/guidance/ipg738	Evidence-based recommendations on removal, preservation and subsequent reimplantation of ovarian tissue to prevent symptoms from the menopause. This involves removing a small piece of ovarian tissue using keyhole surgery, freezing and storing it. After menopause starts, the tissue is thawed and transplanted under the skin of the armpit, abdomen or forearm, with the aim of producing oestrogen.
0c42d452d5fab14de659f413804ce5921bde02b9	nice	Neuropad for detecting preclinical diabetic peripheral neuropathy	Neuropad for detecting preclinical diabetic peripheral neuropathy Evidence-based recommendations on Neuropad for detecting preclinical diabetic peripheral neuropathy. # Recommendations The case for adopting Neuropad to detect preclinical diabetic peripheral neuropathy is not supported by the evidence. Why the committee made these recommendations Neuropad detects abnormal sweating in people with diabetes. But the clinical importance of this is poorly defined. There is insufficient evidence to support the use of Neuropad in people in whom 10 g monofilament testing for diabetic peripheral neuropathy is not possible. Using Neuropad instead of 10 g monofilament testing would likely increase costs because Neuropad has a lower specificity for detecting diabetic peripheral neuropathy. Cost modelling is uncertain because of the limited clinical-effectiveness evidence. Further research is needed on the benefits and consequences of detecting preclinical diabetic peripheral neuropathy.# The technology # Description of the technology Neuropad (TRIGOcare International) is a point-of-care test for use in people with diabetes. The test detects sudomotor dysfunction (inadequate sweat production), which may indicate that a person is in the early stages of developing diabetic peripheral neuropathy (DPN). The 10‑minute test is non-invasive and involves applying a single-size plaster to the sole of the foot. The plaster contains cobalt chloride, which changes colour as it absorbs sweat. The colour changing from blue to pink indicates normal sweat production and implies preserved autonomic nerve function. If the plaster stays blue or does not turn fully pink, it is assumed that there is reduced sweating which carries with it an increased risk of diabetic foot complications. The Neuropad test can be done in a clinic by a healthcare professional during a routine foot check, or at home by the person themselves or their carer. Neuropad can be used either as a standalone test or in conjunction with other standard sensory neuropathy testing. Neuropad is a class I diagnostic device. The cost of Neuropad stated in the company's submission is £7.28 (excluding VAT). The summary of claimed benefits of Neuropad in the case for adoption presented by the company are that it: is simple and can be done at home by the person with diabetes or their carer, or in a clinic by a healthcare professional is non-invasive, painless and safe provides results in 10 minutes that are easy to interpret can detect DPN earlier than monofilament and vibration tests, so is useful for the early identification of people at the greatest risk of complications. # Current management NICE's guideline on diabetic foot problems recommends that adults with diabetes should have a risk assessment for diabetic foot problems at diagnosis, at least every year thereafter, whenever foot problems arise and at the time of any admission to hospital. During the risk assessment, both feet should be examined for any risk factors, including manifestations of DPN, which should be tested using a 10 g monofilament as part of a foot sensory examination. If DPN is detected, a person's risk is classified as being moderate or high (depending on the presence or absence of other comorbidities). This should trigger referral to a foot protection service and more frequent subsequent foot assessments. NICE's medical technologies guidance on VibraTip for testing vibration perception to detect DPN states that the technology shows potential but more research is needed. NICE's guideline on diabetic foot problems does not refer specifically to testing for preclinical DPN using, for example, sudomotor function (on which Neuropad is based) or any other modality. Preclinical DPN refers to the early-stage development of the condition before it becomes clinically apparent (see section 4.2).# Evidence # Summary of clinical evidence The evidence for Neuropad assessed by the external assessment centre (EAC) comprised 18 studies, of which 13 were full text articles and 5 were abstracts. Of the 18 studies, 17 investigated the diagnostic accuracy of Neuropad against a reference standard and 1 reported its ability to predict the risk of diabetic foot ulceration. In addition to examining diagnostic accuracy, 1 study looked at the reproducibility of results when using Neuropad and 3 assessed the association between Neuropad testing and developing foot ulcers. The most common reference standard used was the neuropathy disability score. All the studies were prospective observational, cross-sectional or longitudinal cohort studies. For full details of the clinical evidence, see section 3 of the assessment report. # EAC's analysis of the clinical evidence The EAC considered that the 2 published UK studies (Ponirakis et al. 2014 and Quattrini et al. 2008) were fully relevant to the scope. The EAC also did a meta-analysis of 5 diagnostic accuracy studies that used a neuropathy disability score of 5 or more as the reference standard: Freitas et al. 2009, Kamenov et al. 2010, Liatis et al. 2007, Manes et al. 2016 and Tentolouris et al. 2008. The EAC used its meta-analysis results comparing Neuropad with a neuropathy disability score of 5 or more with the results obtained for 10 g monofilament. It concluded that Neuropad may be more sensitive than 10 g monofilament testing in detecting diabetic peripheral neuropathy (DPN) but has lower specificity. In addition, the EAC noted that the current care pathway includes interventions that are triggered only by clinically apparent DPN, which would be regarded as moderate or advanced, so the benefit of detecting preclinical DPN in the current care pathway is uncertain. # guidance review: summary of clinical evidence ## New evidence was not robust to support the use of Neuropad as an alternative to monofilament The EAC reviewed evidence published since April 2017. There were 8 publications, including 7 comparative clinical studies, on Neuropad. None of the studies used a single comparator, with all using multiple tests to diagnose diabetic peripheral neuropathy, which indicates variation in the care pathway. The EAC found that the new evidence was heterogeneous and did not help to clarify Neuropad's position in the care pathway. The most common comparators (reference tests) were in line with the final scope (for details see the review report – August 2022). Four studies reported the diagnostic accuracy of using Neuropad to diagnose diabetic peripheral neuropathy compared with standard care (10 g monofilament alone). Neuropad's sensitivity ranged between 24.3% (Gomez-Banoy et al. 2017, n=93) and 95% (Zografou et al. 2020, n=174) with a specificity ranging between 29% (Lorenzini et al. 2020, n=42) and 94.2% (Gomez-Banoy et al. 2017, n=93). It is unclear to the EAC why the sensitivity and specificity reported by Gomez-Banoy et al. (2017) were outliers to the other 3 studies. The EAC concluded that the new evidence was not sufficiently robust to support the use of Neuropad in people who would currently undergo testing with monofilament. This is because the evidence reported a wide variation in sensitivity and specificity for Neuropad, compared with monofilament. ## None of the new evidence showed particular benefits of Neuropad for specific population groups, including people in care homes The EAC reported that Zografou et al. (2020) claimed Neuropad was a useful screening tool for diagnosing diabetic peripheral neuropathy in terms of time saving and objectivity during clinical examination and educational benefit for the patient. However, none of the new evidence explicitly measured and compared the time taken with Neuropad against a comparator. And none of the new evidence demonstrated particular benefits for specific patient groups, including people in care homes. # Summary of economic evidence Neither the company nor the EAC identified any relevant published economic evidence. The company submitted a Markov model with 2 comparisons: Neuropad testing compared with 10 g monofilament testing, and Neuropad testing compared with Neuropad testing then 10 g monofilament testing. The time horizon of the model was 3 years. The EAC made a number of changes, including: adding the implications of false-negative and false‑positive results; adding a death state; extending the time horizon to 10 years; and adding a third comparison of Neuropad testing with no testing. For full details of the economic evidence, see section 4 of the assessment report. # EAC's analysis of the economic evidence The EAC disagreed with a number of the sources used to generate parameter values in the company's model. It also noted discrepancies between the values used in the model and those quoted in the referenced sources. Moreover, the EAC considered that the cost of 10 g monofilament testing in the model had been overestimated, because it included the cost of the reusable holder. For full details of the EAC's changes to the company's economic model, see sections 4.2 and 4.3 of the assessment report. Results from the EAC's revised model showed that Neuropad testing incurs additional cost over a 10‑year time horizon compared with all other comparators: £775 per patient compared with 10 g monofilament testing £1,075 per patient compared with Neuropad testing then 10 g monofilament testing £1,792 per patient compared with no testing.The EAC did sensitivity analyses which showed that Neuropad testing alone was not cost saving in any considered scenario. # guidance review: summary of economic evidence ## The new evidence did not address the issues in the original cost model An economic study was published after the original guidance was published (Rodriguez-Sanchez et al. 2020). The EAC reviewed it and noted that it was a cost-effectiveness analysis. The EAC did not consider that the study fully addressed the issues outlined by the original EAC (King's College Technology Evaluation Centre ; for details see the review report – August 2022). It concluded that the results of Rodriguez-Sanchez et al. (2020) were consistent with the findings presented in the original assessment report, and the economic case remains unchanged. # Committee discussion # Clinical effectiveness The evidence for the accuracy of Neuropad in diagnosing preclinical diabetic peripheral neuropathy (DPN) comprises longitudinal observational studies that mainly compared testing in terms of neuropathy scoring systems (most commonly the neuropathy disability score). The committee was aware that the external assessment centre (EAC) had rejected the study by Tsapas et al. (2014; a meta-analysis identified by the company) because of overlapping populations in the studies included and differences in the reference standards used, and had, instead, done its own meta-analysis. The results from the EAC's meta‑analysis showed that Neuropad has a sensitivity of 89.4% (95% confidence interval 83.2 to 93.5) and a specificity of 60.3% (95% CI 50.9 to 69.0), when using a neuropathy disability score of 5 or more as a reference standard for the diagnosis of DPN. Based on this, the committee concluded that Neuropad demonstrates good sensitivity but poor specificity as a diagnostic test for DPN. Although no direct comparative data were available for 10 g monofilament, the committee and EAC agreed that it was appropriate to use the sensitivity (84%) and specificity (83%) estimates for 10 g monofilament that were used in NICE's medical technologies guidance on VibraTip. The committee concluded, therefore, that the current evidence for Neuropad is insufficient to support its effectiveness as an alternative test to 10 g monofilament for detecting DPN. # Pathway positioning The clinical experts advised the committee that patients with diabetes are offered foot checks every year, during which physical examination, 10 g monofilament testing and vibration testing are used to test for DPN and therefore the clinical risk of future complications. The clinical experts explained that patients who test positive for DPN at these foot checks (and who are therefore at moderate or high risk of foot complications) are referred to community podiatrists for ongoing foot care. The clinical experts explained that Neuropad tests different nerve fibres and functions to a 10 g monofilament test: Neuropad tests sudomotor dysfunction, which is a feature of small fibre, preclinical DPN, whereas 10 g monofilaments are used to test for the loss of fine touch, which is a distinctive symptom of clinically apparent DPN. They explained that because it is uncertain how well autonomic testing (such as testing for sudomotor dysfunction) predicts progressive neuropathy or the development of complications, it is not included in current DPN scoring systems. This means that it would be difficult to understand, on the basis of current evidence, how Neuropad testing may affect diabetic foot risk assessment and referral practice. Specifically, the clinical experts advised that a positive Neuropad test alone would currently not lead to a change in management, because it would not alter the definition of risk status in a patient with diabetes. A patient diagnosed with preclinical DPN using Neuropad testing could be offered more attentive foot care, but it is unclear to what extent this would lead to beneficial clinical consequences. # Patient selection The clinical experts explained that Neuropad has particular promise for patients who have difficulty in engaging with testing for DPN. Monofilament testing requires the patient to confirm when they feel a fine touch on their foot or toes, but for some people with cognitive impairment or communication difficulties, this may not be possible. The clinical experts estimated that between 5% and 10% of all patients with diabetes may have difficulty engaging with 10 g monofilament testing for these reasons. The committee acknowledged that because Neuropad testing does not need patient feedback, it may be of particular value for patients with cognitive impairment or communication difficulties if future evidence supports its case for adoption in the NHS. The committee also heard that some patients, such as older and frailer people, may not be able to easily access foot clinics. The clinical experts explained that type 2 diabetes, which accounts for 90% of all diabetes, is much more common in older people. Many of these patients do not always attend their yearly foot checks and so do not have the benefit of foot care programmes. The clinical experts also explained that DPN progression may be prevented if it is detected early and appropriate treatment is started. Consequently, limited access to regular testing may increase the risks of progressive DPN and its clinical complications in a vulnerable patient group. The committee acknowledged that a test such as Neuropad, which can be done easily in the community, may be of particular value to people with limited access to foot clinics but concluded that this has not been tested in clinical studies and cannot be inferred from the evidence available. # NHS considerations The clinical experts stated that Neuropad might be considered as part of a community-delivered DPN detection and management service. However, they acknowledged that for this to be successful, changes would be needed to other important parts of the community package of care for people with diabetes. Having heard from the experts about the existing deficiencies in DPN detection and foot care services in the UK, the committee concluded that addressing these deficiencies in the current pathway would be needed before any potential benefits associated with detecting preclinical DPN could be realised. The committee considered the importance of foot preparation before Neuropad testing in order to ensure a reliable result. It heard from the clinical experts that the foot needs to be completely dry and that the test strip should not be placed on calluses or dry skin for the result to be meaningful. It concluded that, were Neuropad introduced into the community, clear guidance on its use would be needed to avoid misleading results. # Cost savings The committee noted the differences between the company's and EAC's revised cost models and their base-case estimates. It agreed with the EAC's changes and concluded that the revised model most accurately represented the cost consequences of adopting Neuropad. The committee noted that Neuropad's low diagnostic specificity (based on the evidence presented and current diagnostic criteria) means that its use alone would increase the rate of false-positive results for DPN. Because of the current uncertainty about whether patients with diagnosed preclinical DPN would benefit from referral to a foot care service, the committee concluded that a positive result with Neuropad would probably lead to further 10 g monofilament testing. The committee understood that the results of this dual-testing strategy in the EAC model should be treated with caution, because it assumed that the 2 tests are done completely independently (that is, the sensitivity and specificity of the 10 g monofilament test are not affected by the results of the Neuropad test). The committee was also aware there is no evidence to support the merits of such a dual-testing approach. It concluded that the cost modelling for Neuropad is uncertain, but that it is most likely that Neuropad testing alone would be cost incurring compared with conventional testing with a 10 g monofilament. # Potential research In its assessment report, the EAC identified a number of possible priorities for future research on the comparative effectiveness of Neuropad and 10 g monofilament testing, and on the effectiveness of foot care programmes. The clinical experts also highlighted areas for future research that could be considered. They proposed a multicentre, longitudinal study with at least 5 years' follow up, comparing point-of-care testing strategies (including Neuropad) in predicting future diabetic complications, including DPN, using a reference standard (such as the neuropathy disability score). The experts also proposed a community-based study to explore the benefits of using Neuropad to detect preclinical DPN in populations that include vulnerable people, in whom 10 g monofilament testing is not possible. Such a study could also define the benefits to people with diabetes of improved access to DPN diagnostic and treatment services. The committee considered that research into the wider benefits of detecting preclinical DPN and how to address the deficiencies in the current care pathway would be valuable but acknowledged that these are issues beyond the scope of this assessment. Such research would also help to clarify Neuropad's effectiveness in detecting preclinical DPN.	{'Recommendations': 'The case for adopting Neuropad to detect preclinical diabetic peripheral neuropathy is not supported by the evidence.\n\nWhy the committee made these recommendations\n\nNeuropad detects abnormal sweating in people with diabetes. But the clinical importance of this is poorly defined. There is insufficient evidence to support the use of Neuropad in people in whom 10\xa0g monofilament testing for diabetic peripheral neuropathy is not possible.\n\nUsing Neuropad instead of 10\xa0g monofilament testing would likely increase costs because Neuropad has a lower specificity for detecting diabetic peripheral neuropathy. Cost modelling is uncertain because of the limited clinical-effectiveness evidence. Further research is needed on the benefits and consequences of detecting preclinical diabetic peripheral neuropathy.', 'The technology': "# Description of the technology\n\nNeuropad (TRIGOcare International) is a point-of-care test for use in people with diabetes. The test detects sudomotor dysfunction (inadequate sweat production), which may indicate that a person is in the early stages of developing diabetic peripheral neuropathy (DPN). The 10‑minute test is non-invasive and involves applying a single-size plaster to the sole of the foot. The plaster contains cobalt chloride, which changes colour as it absorbs sweat. The colour changing from blue to pink indicates normal sweat production and implies preserved autonomic nerve function. If the plaster stays blue or does not turn fully pink, it is assumed that there is reduced sweating which carries with it an increased risk of diabetic foot complications. The Neuropad test can be done in a clinic by a healthcare professional during a routine foot check, or at home by the person themselves or their carer. Neuropad can be used either as a standalone test or in conjunction with other standard sensory neuropathy testing.\n\nNeuropad is a class I diagnostic device. The cost of Neuropad stated in the company's submission is £7.28 (excluding VAT).\n\nThe summary of claimed benefits of Neuropad in the case for adoption presented by the company are that it:\n\nis simple and can be done at home by the person with diabetes or their carer, or in a clinic by a healthcare professional\n\nis non-invasive, painless and safe\n\nprovides results in 10\xa0minutes that are easy to interpret\n\ncan detect DPN earlier than monofilament and vibration tests, so is useful for the early identification of people at the greatest risk of complications.\n\n# Current management\n\nNICE's guideline on diabetic foot problems recommends that adults with diabetes should have a risk assessment for diabetic foot problems at diagnosis, at least every year thereafter, whenever foot problems arise and at the time of any admission to hospital. During the risk assessment, both feet should be examined for any risk factors, including manifestations of DPN, which should be tested using a 10\xa0g monofilament as part of a foot sensory examination. If DPN is detected, a person's risk is classified as being moderate or high (depending on the presence or absence of other comorbidities). This should trigger referral to a foot protection service and more frequent subsequent foot assessments.\n\nNICE's medical technologies guidance on VibraTip for testing vibration perception to detect DPN states that the technology shows potential but more research is needed.\n\nNICE's guideline on diabetic foot problems does not refer specifically to testing for preclinical DPN using, for example, sudomotor function (on which Neuropad is based) or any other modality. Preclinical DPN refers to the early-stage development of the condition before it becomes clinically apparent (see section\xa04.2).", 'Evidence': "# Summary of clinical evidence\n\nThe evidence for Neuropad assessed by the external assessment centre (EAC) comprised 18\xa0studies, of which 13 were full text articles and 5 were abstracts. Of the 18\xa0studies, 17 investigated the diagnostic accuracy of Neuropad against a reference standard and 1 reported its ability to predict the risk of diabetic foot ulceration. In addition to examining diagnostic accuracy, 1\xa0study looked at the reproducibility of results when using Neuropad and 3 assessed the association between Neuropad testing and developing foot ulcers. The most common reference standard used was the neuropathy disability score. All the studies were prospective observational, cross-sectional or longitudinal cohort studies. For full details of the clinical evidence, see section\xa03 of the assessment report.\n\n# EAC's analysis of the clinical evidence\n\nThe EAC considered that the 2\xa0published UK studies (Ponirakis\xa0et\xa0al. 2014 and Quattrini\xa0et\xa0al. 2008) were fully relevant to the scope. The EAC also did a meta-analysis of 5\xa0diagnostic accuracy studies that used a neuropathy disability score of 5 or more as the reference standard: Freitas et al. 2009, Kamenov\xa0et\xa0al.\xa02010, Liatis et al. 2007, Manes et al. 2016 and Tentolouris\xa0et\xa0al.\xa02008.\n\nThe EAC used its meta-analysis results comparing Neuropad with a neuropathy disability score of 5 or more with the results obtained for 10\xa0g monofilament. It concluded that Neuropad may be more sensitive than 10\xa0g monofilament testing in detecting diabetic peripheral neuropathy (DPN) but has lower specificity. In addition, the EAC noted that the current care pathway includes interventions that are triggered only by clinically apparent DPN, which would be regarded as moderate or advanced, so the benefit of detecting preclinical DPN in the current care pathway is uncertain.\n\n# guidance review: summary of clinical evidence\n\n## New evidence was not robust to support the use of Neuropad as an alternative to monofilament\n\nThe EAC reviewed evidence published since April\xa02017. There were 8\xa0publications, including 7 comparative clinical studies, on Neuropad. None of the studies used a single comparator, with all using multiple tests to diagnose diabetic peripheral neuropathy, which indicates variation in the care pathway. The EAC found that the new evidence was heterogeneous and did not help to clarify Neuropad's position in the care pathway. The most common comparators (reference tests) were in line with the final scope (for details see the review report – August 2022). Four studies reported the diagnostic accuracy of using Neuropad to diagnose diabetic peripheral neuropathy compared with standard care (10\xa0g monofilament alone). Neuropad's sensitivity ranged between 24.3% (Gomez-Banoy et al. 2017, n=93) and 95% (Zografou et al. 2020, n=174) with a specificity ranging between 29% (Lorenzini et al. 2020, n=42) and 94.2% (Gomez-Banoy et al. 2017, n=93). It is unclear to the EAC why the sensitivity and specificity reported by Gomez-Banoy et al. (2017) were outliers to the other 3\xa0studies. The EAC concluded that the new evidence was not sufficiently robust to support the use of Neuropad in people who would currently undergo testing with monofilament. This is because the evidence reported a wide variation in sensitivity and specificity for Neuropad, compared with monofilament. \n\n## None of the new evidence showed particular benefits of Neuropad for specific population groups, including people in care homes\n\nThe EAC reported that Zografou et al. (2020) claimed Neuropad was a useful screening tool for diagnosing diabetic peripheral neuropathy in terms of time saving and objectivity during clinical examination and educational benefit for the patient. However, none of the new evidence explicitly measured and compared the time taken with Neuropad against a comparator. And none of the new evidence demonstrated particular benefits for specific patient groups, including people in care homes. \n\n# Summary of economic evidence\n\nNeither the company nor the EAC identified any relevant published economic evidence. The company submitted a Markov model with 2\xa0comparisons: Neuropad testing compared with 10\xa0g monofilament testing, and Neuropad testing compared with Neuropad testing then 10\xa0g monofilament testing. The time horizon of the model was 3\xa0years. The EAC made a number of changes, including: adding the implications of false-negative and false‑positive results; adding a death state; extending the time horizon to 10\xa0years; and adding a third comparison of Neuropad testing with no testing. For full details of the economic evidence, see section\xa04 of the assessment report.\n\n# EAC's analysis of the economic evidence\n\nThe EAC disagreed with a number of the sources used to generate parameter values in the company's model. It also noted discrepancies between the values used in the model and those quoted in the referenced sources. Moreover, the EAC considered that the cost of 10\xa0g monofilament testing in the model had been overestimated, because it included the cost of the reusable holder. For full details of the EAC's changes to the company's economic model, see sections\xa04.2 and\xa04.3 of the assessment report.\n\nResults from the EAC's revised model showed that Neuropad testing incurs additional cost over a 10‑year time horizon compared with all other comparators:\n\n£775 per patient compared with 10\xa0g monofilament testing\n\n£1,075 per patient compared with Neuropad testing then 10\xa0g monofilament testing\n\n£1,792 per patient compared with no testing.The EAC did sensitivity analyses which showed that Neuropad testing alone was not cost saving in any considered scenario.\n\n# guidance review: summary of economic evidence\n\n## The new evidence did not address the issues in the original cost model\n\nAn economic study was published after the original guidance was published (Rodriguez-Sanchez et al. 2020). The EAC reviewed it and noted that it was a cost-effectiveness analysis. The EAC did not consider that the study fully addressed the issues outlined by the original EAC (King's College Technology Evaluation Centre [KiTEC]; for details see the review report – August 2022). It concluded that the results of Rodriguez-Sanchez et al. (2020) were consistent with the findings presented in the original assessment report, and the economic case remains unchanged. ", 'Committee discussion': "# Clinical effectiveness\n\nThe evidence for the accuracy of Neuropad in diagnosing preclinical diabetic peripheral neuropathy (DPN) comprises longitudinal observational studies that mainly compared testing in terms of neuropathy scoring systems (most commonly the neuropathy disability score). The committee was aware that the external assessment centre (EAC) had rejected the study by Tsapas\xa0et\xa0al. (2014; a meta-analysis identified by the company) because of overlapping populations in the studies included and differences in the reference standards used, and had, instead, done its own meta-analysis. The results from the EAC's meta‑analysis showed that Neuropad has a sensitivity of 89.4% (95% confidence interval [CI] 83.2 to 93.5) and a specificity of 60.3% (95% CI 50.9 to 69.0), when using a neuropathy disability score of 5\xa0or more as a reference standard for the diagnosis of DPN. Based on this, the committee concluded that Neuropad demonstrates good sensitivity but poor specificity as a diagnostic test for DPN. Although no direct comparative data were available for 10\xa0g monofilament, the committee and EAC agreed that it was appropriate to use the sensitivity (84%) and specificity (83%) estimates for 10\xa0g monofilament that were used in NICE's medical technologies guidance on VibraTip. The committee concluded, therefore, that the current evidence for Neuropad is insufficient to support its effectiveness as an alternative test to 10\xa0g monofilament for detecting DPN.\n\n# Pathway positioning\n\nThe clinical experts advised the committee that patients with diabetes are offered foot checks every year, during which physical examination, 10\xa0g monofilament testing and vibration testing are used to test for DPN and therefore the clinical risk of future complications. The clinical experts explained that patients who test positive for DPN at these foot checks (and who are therefore at moderate or high risk of foot complications) are referred to community podiatrists for ongoing foot care.\n\nThe clinical experts explained that Neuropad tests different nerve fibres and functions to a 10\xa0g monofilament test: Neuropad tests sudomotor dysfunction, which is a feature of small fibre, preclinical DPN, whereas 10\xa0g monofilaments are used to test for the loss of fine touch, which is a distinctive symptom of clinically apparent DPN. They explained that because it is uncertain how well autonomic testing (such as testing for sudomotor dysfunction) predicts progressive neuropathy or the development of complications, it is not included in current DPN scoring systems. This means that it would be difficult to understand, on the basis of current evidence, how Neuropad testing may affect diabetic foot risk assessment and referral practice. Specifically, the clinical experts advised that a positive Neuropad test alone would currently not lead to a change in management, because it would not alter the definition of risk status in a patient with diabetes. A patient diagnosed with preclinical DPN using Neuropad testing could be offered more attentive foot care, but it is unclear to what extent this would lead to beneficial clinical consequences.\n\n# Patient selection\n\nThe clinical experts explained that Neuropad has particular promise for patients who have difficulty in engaging with testing for DPN. Monofilament testing requires the patient to confirm when they feel a fine touch on their foot or toes, but for some people with cognitive impairment or communication difficulties, this may not be possible. The clinical experts estimated that between 5% and 10% of all patients with diabetes may have difficulty engaging with 10\xa0g monofilament testing for these reasons. The committee acknowledged that because Neuropad testing does not need patient feedback, it may be of particular value for patients with cognitive impairment or communication difficulties if future evidence supports its case for adoption in the NHS.\n\nThe committee also heard that some patients, such as older and frailer people, may not be able to easily access foot clinics. The clinical experts explained that type\xa02 diabetes, which accounts for 90% of all diabetes, is much more common in older people. Many of these patients do not always attend their yearly foot checks and so do not have the benefit of foot care programmes. The clinical experts also explained that DPN progression may be prevented if it is detected early and appropriate treatment is started. Consequently, limited access to regular testing may increase the risks of progressive DPN and its clinical complications in a vulnerable patient group. The committee acknowledged that a test such as Neuropad, which can be done easily in the community, may be of particular value to people with limited access to foot clinics but concluded that this has not been tested in clinical studies and cannot be inferred from the evidence available.\n\n# NHS considerations\n\nThe clinical experts stated that Neuropad might be considered as part of a community-delivered DPN detection and management service. However, they acknowledged that for this to be successful, changes would be needed to other important parts of the community package of care for people with diabetes. Having heard from the experts about the existing deficiencies in DPN detection and foot care services in the UK, the committee concluded that addressing these deficiencies in the current pathway would be needed before any potential benefits associated with detecting preclinical DPN could be realised.\n\nThe committee considered the importance of foot preparation before Neuropad testing in order to ensure a reliable result. It heard from the clinical experts that the foot needs to be completely dry and that the test strip should not be placed on calluses or dry skin for the result to be meaningful. It concluded that, were Neuropad introduced into the community, clear guidance on its use would be needed to avoid misleading results.\n\n# Cost savings\n\nThe committee noted the differences between the company's and EAC's revised cost models and their base-case estimates. It agreed with the EAC's changes and concluded that the revised model most accurately represented the cost consequences of adopting Neuropad.\n\nThe committee noted that Neuropad's low diagnostic specificity (based on the evidence presented and current diagnostic criteria) means that its use alone would increase the rate of false-positive results for DPN. Because of the current uncertainty about whether patients with diagnosed preclinical DPN would benefit from referral to a foot care service, the committee concluded that a positive result with Neuropad would probably lead to further 10\xa0g monofilament testing. The committee understood that the results of this dual-testing strategy in the EAC model should be treated with caution, because it assumed that the 2\xa0tests are done completely independently (that is, the sensitivity and specificity of the 10\xa0g monofilament test are not affected by the results of the Neuropad test). The committee was also aware there is no evidence to support the merits of such a dual-testing approach. It concluded that the cost modelling for Neuropad is uncertain, but that it is most likely that Neuropad testing alone would be cost incurring compared with conventional testing with a 10\xa0g monofilament.\n\n# Potential research\n\nIn its assessment report, the EAC identified a number of possible priorities for future research on the comparative effectiveness of Neuropad and 10\xa0g monofilament testing, and on the effectiveness of foot care programmes. The clinical experts also highlighted areas for future research that could be considered. They proposed a multicentre, longitudinal study with at least 5\xa0years' follow up, comparing point-of-care testing strategies (including Neuropad) in predicting future diabetic complications, including DPN, using a reference standard (such as the neuropathy disability score). The experts also proposed a community-based study to explore the benefits of using Neuropad to detect preclinical DPN in populations that include vulnerable people, in whom 10\xa0g monofilament testing is not possible. Such a study could also define the benefits to people with diabetes of improved access to DPN diagnostic and treatment services.\n\nThe committee considered that research into the wider benefits of detecting preclinical DPN and how to address the deficiencies in the current care pathway would be valuable but acknowledged that these are issues beyond the scope of this assessment. Such research would also help to clarify Neuropad's effectiveness in detecting preclinical DPN."}	https://www.nice.org.uk/guidance/mtg38	Evidence-based recommendations on Neuropad for detecting preclinical diabetic peripheral neuropathy.
7b98403ccc4cf5b3564f65c98bcf1474392edff7	nice	Avacopan for treating severe active granulomatosis with polyangiitis or microscopic polyangiitis	Avacopan for treating severe active granulomatosis with polyangiitis or microscopic polyangiitis Evidence-based recommendations on avacopan (Tavneos) for treating severe active granulomatosis with polyangiitis or microscopic polyangiitis in adults. # Recommendations Avacopan with a cyclophosphamide or rituximab regimen is recommended, within its marketing authorisation, as an option for treating severe active granulomatosis with polyangiitis or microscopic polyangiitis in adults. It is recommended only if the company provides it according to the commercial arrangement. Why the committee made these recommendations Standard care for granulomatosis with polyangiitis or microscopic polyangiitis usually starts with cyclophosphamide or rituximab, followed by maintenance treatment, usually with azathioprine or rituximab. Corticosteroids are also used throughout treatment. Avacopan is an option to be used alongside this standard care. Evidence from a clinical trial shows that, after a year, avacopan with standard care is more effective at stopping the conditions getting worse than standard care alone. It also suggests that using avacopan with standard care results in less toxicity from corticosteroids, possibly because of less use overall. The cost-effectiveness estimates for avacopan with standard care compared with standard care alone are within the range that NICE considers a cost-effective use of NHS resources. So, avacopan with a cyclophosphamide or rituximab regimen is recommended.# Information about avacopan # Marketing authorisation indication Avacopan (Tavneos, CSL Vifor), 'in combination with a rituximab or cyclophosphamide regimen, is indicated for the treatment of adult patients with severe, active granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for avacopan. # Price Avacopan costs £5,547.95 per pack of 180x10 mg capsules (company submission). The company has a commercial arrangement. This makes avacopan available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by CSL Vifor, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Population, treatment pathway and positioning ## People with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) can have severe symptoms Antineutrophil cytoplasmic antibody (ANCA)‑associated vasculitis is a group of rare autoimmune conditions characterised by blood vessel inflammation. The 2 most common types are GPA and MPA. Eosinophilic GPA is the rarest type of ANCA‑associated vasculitis and was not a proposed indication for this appraisal. The patient experts explained that people with GPA or MPA can have severe symptoms and the conditions can be life threatening. They explained that symptoms can include extreme pain, fatigue, night sweats and rashes. They added that ANCA‑associated vasculitis can affect the sinuses, kidneys, lungs, abdomen, skin and joints. They also explained that the condition can have a detrimental effect on everyday life, including people's ability to work and participate in family life. The clinical experts commented that, when the kidneys are involved, people can develop end-stage renal disease (ESRD), which can be life threatening. The committee recognised that people with severe active GPA or MPA can have severe symptoms. ## People with GPA or MPA, and clinicians, would welcome a new treatment option The clinical experts explained that GPA and MPA are usually treated in 2 phases. The first phase aims to control inflammation and reduce damage associated with the conditions by inducing disease remission (see section 3.4). The second phase of treatment (maintenance treatment) aims to prevent the conditions from relapsing and causing further damage (see section 3.5). Patient and professional organisations commented that quickly inducing and sustaining disease remission are important to reduce the risk of organ damage. The clinical experts agreed that the treatment pathway for people with severe active GPA or MPA is generally well defined. They explained that induction treatment usually includes cyclophosphamide or rituximab with high-dose corticosteroids (usually prednisolone, which is an active metabolite of prednisone). They added that maintenance treatment is usually azathioprine with a tapered dose of corticosteroids. The clinical experts also explained that disease relapses are treated by re-inducing remission in a similar way to initial inductions. Both patient and clinical experts commented on the side effects and toxicity of corticosteroids. The company also noted that relapses are associated with an increased risk of corticosteroid-mediated morbidity. The patient experts commented that mood swings, weight gain, diabetes, osteoporosis and cataracts are all potential side effects of corticosteroid treatment. They explained that weight gain can affect self-confidence and means that some people feel like they no longer recognise themselves. One patient organisation commented that regular monitoring for the side effects by several types of clinicians can be needed. For example, people having corticosteroids for a prolonged time may regularly visit a pain clinic, an ophthalmologist and a rheumatology and orthopaedic combined clinic to manage corticosteroid side effects. One clinical expert commented that infection and cardiovascular disease, which are the most common causes of death in this population, are both associated with corticosteroid use. The clinical experts also commented that the side effects of corticosteroids are generally dose related. So, they explained that a treatment which could sustain disease remission and reduce corticosteroid use would be beneficial. The committee concluded that people with GPA or MPA, and clinicians, would welcome such a new treatment option. ## The company's positioning of avacopan is appropriate The NICE scope did not specify which types of ANCA‑associated vasculitis would be considered in the appraisal. The company explained that only people with GPA or MPA were included in the clinical trial (see section 3.6). It also noted that the marketing authorisation only covered people with severe active GPA or MPA, and specified that avacopan would be used with a cyclophosphamide or rituximab regimen. The committee recognised that NICE's remit is to appraise a technology within its marketing authorisation, so agreed that the company's positioning was appropriate. ## The relevant induction treatment comparators are cyclophosphamide or rituximab with high-dose corticosteroids The clinical experts explained that people with severe disease are usually offered cyclophosphamide or rituximab with high-dose corticosteroids for induction treatment. They added that the decision to use rituximab instead of cyclophosphamide depends on many factors. They commented that people with more severe GPA or MPA may be offered cyclophosphamide because there is less evidence for rituximab for severe disease. The clinical experts also commented that anti‑CD20 antibody treatments (such as rituximab) can reduce response to vaccinations by depleting B‑cells. So, there is a general desire to avoid using these treatments in the context of the COVID‑19 pandemic. The committee concluded that the relevant induction treatment comparators were cyclophosphamide or rituximab with high-dose corticosteroids. ## The relevant maintenance treatment comparators are azathioprine or rituximab (for people who are eligible) with corticosteroids The committee recalled that, after the initial induction treatment, people will usually have maintenance treatment. The clinical experts explained that, after induction of remission with cyclophosphamide, most people would switch to azathioprine. The clinical experts also noted that, during the maintenance phase of treatment, corticosteroid dose is usually tapered. They explained that people who initially have rituximab induction would only have rituximab maintenance in specific circumstances, in accordance with the NHS Clinical Commissioning Policy on rituximab for treating ANCA-associated vasculitis in adults. This states that rituximab maintenance is only commissioned if the disease has relapsed and re-induction treatment is needed after rituximab-induced remission or if rituximab is needed to induce remission for cyclophosphamide-refractory disease. The clinical experts commented that, in clinical practice, around 30% to 40% of people who have had rituximab as induction treatment have rituximab maintenance treatment. People who are not eligible for rituximab maintenance treatment would have azathioprine instead. The committee concluded that the relevant maintenance comparators were azathioprine with tapered corticosteroids and rituximab with tapered corticosteroids. # Clinical effectiveness ## Avacopan with a cyclophosphamide or rituximab regimen is effective in sustaining disease remission and reducing corticosteroid toxicity The company provided clinical evidence for avacopan from several clinical trials including ADVOCATE, a phase 3 trial. ADVOCATE was a randomised, active-controlled trial comparing oral avacopan 30 mg twice daily with oral prednisone on a tapering schedule. Everyone also had either cyclophosphamide followed by azathioprine, or rituximab followed by nothing. The trial included people with a clinical diagnosis of GPA or MPA who had at least 1 major item, 3 minor items or 2 renal items of proteinuria and haematuria on the Birmingham Vasculitis Activity Score (BVAS). The primary endpoint was the proportion of people with disease remission at weeks 26 and 52. At week 26, disease remission was defined as a BVAS of 0, and no corticosteroids in the previous 4 weeks. Sustained remission was defined as disease remission at week 26, and a BVAS of 0 at week 52, no corticosteroids in the 4 weeks before week 52 and no disease relapse between weeks 26 and 52. In the intention-to-treat population, at week 26, 72% of people in the avacopan group compared with 70% in the prednisone group had disease remission (estimated common difference 3.4%, 95% confidence interval -6.0 to 12.8; p<0.001 for non-inferiority and p=0.240 for superiority). At week 52, 66% of people in the avacopan group compared with 55% in the prednisone group had sustained disease remission (estimated common difference 12.5%, 95% CI 2.6 to 22.3; p<0.001 for inferiority and p=0.007 for superiority). The trial also evaluated corticosteroid toxicity. At week 26, the mean Corticosteroid Toxicity Index Cumulative Worsening Score was 39.7 in the avacopan group compared with 56.6 in the prednisone group (a larger score represents worsening toxicity; p=0.0002). The committee concluded that avacopan with a cyclophosphamide or rituximab regimen was effective at sustaining disease remission and reducing corticosteroid-induced toxicity compared with a prednisone-based regimen in the intention-to-treat population of ADVOCATE. ## In ADVOCATE, non-study supplied corticosteroids in the intervention group reflect expected use in clinical practice In ADVOCATE, people in both the avacopan and prednisone groups could have non-study supplied corticosteroids as needed. This was, for example, to treat disease relapse or hypoadrenalism from previous use of high-dose corticosteroids. The company explained that this as-needed use of corticosteroids was in line with how they would be used in clinical practice if avacopan was available. The clinical experts agreed. The mean cumulative corticosteroid dose during the treatment period was 1,349 mg in the avacopan group compared with 3,655 mg in the prednisone group. The ERG noted that although total corticosteroid use was lower in the avacopan group, non-study supplied corticosteroid use was higher in the avacopan group. The mean non-study supplied corticosteroid use during the treatment period was 1,349 mg in the avacopan group compared with 1,265 mg in the prednisone group. The ERG also noted that a large proportion of people (87.3%) in the avacopan group had non-study supplied corticosteroids during the treatment period. It was concerned that the use of non-study supplied corticosteroids in the avacopan group could have biased the effect estimates from the trial. It was also concerned about the meaningfulness of the apparent comparison of avacopan with lower-dose corticosteroids compared with higher-dose corticosteroids. The company explained that non-study supplied corticosteroid use was reasonably well balanced between the avacopan and prednisone groups, so the benefits seen in ADVOCATE could be attributed to avacopan. The committee understood the ERG's concerns, and queried whether there were differences in the proportions of people who had pulsed high-dose corticosteroids. One clinical expert explained that most non-study supplied intravenous corticosteroids at 4 weeks were for prophylaxis for rituximab treatment rather than for treating relapse. The committee commented that, overall, people in the avacopan group had about one-third less corticosteroids than those in the prednisone group. The committee recalled that a reduction in corticosteroid use would be beneficial for people with GPA or MPA (see section 3.2). It concluded that the non-study supplied corticosteroids in the intervention group reflected expected use in clinical practice. # Cost effectiveness ## The company's economic model is appropriate for decision making The company provided a Markov model that was similar to the one used in NICE's technology appraisal guidance on rituximab in combination with glucocorticoids for treating anti-neutrophil cytoplasmic antibody-associated vasculitis. The model included 9 health states: active disease, 3 disease-remission states, 3 disease-relapse states, ESRD and death. The cohort's mean starting age (60 years), proportion of people having rituximab induction treatment (65%) and adherence to avacopan (86%) were from ADVOCATE. The clinical efficacy for avacopan was based on the results of ADVOCATE, and included disease remission at 26, 52 and 60 weeks, change in estimated glomerular filtration rate (eGFR) and health-related quality of life. In the company's base case, people were modelled to have standard care or standard care with avacopan. Standard care was defined as high-dose corticosteroids and either cyclophosphamide or rituximab followed by lower-dose corticosteroids with azathioprine. The company explained that modelling azathioprine maintenance treatment after rituximab induction was a deviation from ADVOCATE, but was based on an assumption explored in NICE's technology appraisal guidance on rituximab. At the first meeting, the committee was concerned about how maintenance treatment was modelled (see section 3.9). But it concluded that the company's overall model structure was appropriate for decision making. ## The cost-effectiveness analysis should include rituximab maintenance treatment for people who are eligible for it The committee recalled that some people are eligible to have rituximab in the maintenance phase if it was used in the induction phase and other criteria are met (see section 3.5). The company noted that there were no randomised controlled trials assessing maintenance treatment with avacopan plus rituximab. At clarification, the company provided a rituximab maintenance treatment option in the model. It explained that it had adjusted the baseline hazard ratio for relapse to reflect treatment with rituximab instead of azathioprine. It cautioned that the non-adjusted naive comparison should be treated as exploratory. The ERG commented that the rituximab maintenance scenario was uncertain. At the first meeting, the committee agreed that it would have preferred analyses in which 30% to 40% of people who had rituximab as induction treatment continued rituximab as maintenance treatment, with the remaining proportion having azathioprine. This was based on the clinical experts' comments (see section 3.5). In response to consultation, the company updated its base case to include rituximab maintenance treatment for 35% of people who had it as induction treatment. It also provided scenarios that assumed 30% and 40% of this population would continue to have rituximab. The company noted that there was no additional real-world evidence to inform the modelling. The ERG commented that, in the absence of real-world observational data, the company's naive approach was pragmatic. The committee concluded that the company's modelling of rituximab maintenance treatment was appropriate and considered all scenarios during decision making. ## Hazard ratios for ESRD from Gercik et al. and Brix et al. are relevant both individually and pooled In the company's model, people could transition to an ESRD state. The company considered it relevant to include a separate health state because ESRD is a significant complication of ANCA‑associated vasculitis. Disease progression to ESRD was modelled by a change in eGFR. The probability of ESRD in the active and remission health states was adjusted based on the improvement in eGFR in ADVOCATE. In the company's base case, the hazard rate, and probability of ESRD was adjusted based on the hazard ratio for ESRD per ml/min change in eGFR from Gercik et al. (2020; hazard ratio 0.90, 95% CI 0.86 to 0.95). However, the ERG noted that the company had provided several other options for the hazard ratio in the model. The ERG originally explored a pooled hazard ratio by combining estimates from Gercik et al., Ford et al. (2014) and Brix et al. (2018). The company disagreed with the ERG's pooled approach, explaining that estimates from Cox proportional hazards models were dependent on other covariates in the model. It explained that it would be inconsistent to pool coefficients from models that adjust for different covariates. During technical engagement, the ERG noted the company's concerns about pooling estimates. It re-evaluated the pooled studies and noted that the estimate from Ford et al. was for ESRD or death. The ERG did not consider it appropriate to include the Ford et al. hazard ratio in the pooled estimate. But the ERG reiterated that both the Gercik et al. and Brix et al. studies were relevant and preferred to pool them using an inverse variance approach (pooled HR 0.95, 95% CI 0.90 to 1.00). The committee understood the company's statistical concerns about pooling estimates. However, it agreed with the ERG that both the Gercik et al. and Brix et al. studies were relevant for consideration. The committee noted that the Gercik et al. study did not provide much detail and was published as a letter. It further noted comments from a clinical expert that the risk of ESRD is dependent on the population being studied. This meant that it may have been appropriate to pool estimates from studies that limited the inclusion criteria. The committee was concerned that the company's approach might have applied a hazard ratio from a single study with a narrower population to the broader, modelled population. The committee would have liked to see additional information from the company about why Brix et al. was not relevant. At the first meeting, the committee concluded that it was relevant to consider scenarios using the Gercik et al. and Brix et al. hazard ratios, both individually and pooled. In response to consultation, the company updated its base case to use the pooled hazard ratio estimated by the ERG (HR 0.95). The company commented that the pooled approach was conservative because evidence from the Gopaluni et al. (2019) paper suggested that the true hazard ratio could be less than 0.95 but was likely greater than 0.90. Consistent with the committee's preference from the first meeting, the company also provided results using the Gercik et al. and Brix et al. estimates individually. The committee noted that the incremental cost-effectiveness ratio (ICER) was sensitive to the individual and pooled hazard ratios. No evidence had been presented to suggest either Gercik et al. or Brix et al. estimates were not relevant. So, the committee concluded that the company's analyses using the individual and pooled estimates were relevant for decision making. ## The 2019/20 NHS reference costs are most appropriate to inform hospitalisation costs The company noted that the average length of hospital stay in ADVOCATE (13.8 days in the avacopan group and 19.6 days in the prednisone group) was longer than the mean length of stay reported in the 2019/20 NHS reference costs. The company explained that it adjusted hospital costs to account for the longer stays in ADVOCATE using excess bed day costs from 2017/18. It did this because the 2019/20 NHS reference costs no longer separately report excess bed day costs (as previous versions did). At technical engagement, the company updated its base case to use unit and excess bed day costs from 2017/18 inflated to 2020 prices. The ERG explained that it was uncertain whether the difference between mean length of stay in ADVOCATE compared with NHS reference costs implied excess bed days. Additionally, the ERG noted that NHS reference costs appeared to be calculated differently between 2017/18 and 2019/20 because the more recent version does not separately report excess bed day costs. NHS England confirmed that the 2019/20 reference costs included all hospitalisation costs, but no longer disaggregated costs into unit and excess bed days. At the first meeting, the committee noted a preference for hospitalisation costs using 2019/20 unit costs with no adjustment for excess bed days. This was because it was more reflective of costs in the NHS in England. In response to consultation, the company updated its base case to use 2019/20 unit costs with no adjustment for excess bed days. The company noted this approach was conservative because: the unit cost represents the average length of stay and does not reflect the long hospital stays seen in ADVOCATE the average length of stay from the NHS reference costs includes overall ANCA-associated vasculitis, rather than the narrower population with severe active GPA or MPA for which avacopan is indicated.The committee concluded that the company's revised approach to hospitalisation costs using 2019/20 unit costs with no adjustment for excess bed days was appropriate for decision making. ## The modelled healthcare costs may not fully represent costs in the NHS, but may be conservative The ERG noted the crude modelled annual healthcare costs for the standard care group were substantially lower than the costs in the Clinical Practice Research Datalink (CPRD) study. The CPRD study was a retrospective observational study using real-world evidence to evaluate resource use and adverse event rates for people with GPA or MPA in England. The company explained that the CPRD study costs were not appropriate for modelling because there is no information about change in resource use with avacopan. The company also noted that the CPRD included aggregate costs of all hospital episodes, including treatment of unrelated comorbidities, and the model did not account for these costs. The company added that costs for specific episodes were similar between the model and CPRD. It also explained that larger costs from worsening ANCA‑associated vasculitis would favour avacopan so the model was likely conservative. The ERG noted it was uncertain why the ICER increased when adverse event costs from CPRD were used. It explained that it was not possible to explore the CPRD data further because the database included limited detail on exact resource use and did not include people who had avacopan treatment. At the second committee meeting, the committee noted that the CPRD study may have underrepresented people with MPA. People with MPA are more likely to have renal involvement so there may be higher costs associated with their care because they have high-cost treatments such as dialysis. The committee recalled that higher costs for the standard care group would favour avacopan because it is effective at sustaining disease remission, reducing ESRD and reducing corticosteroid use and so toxicity. The committee concluded that although there was some uncertainty in the modelled healthcare costs, the company's base case was appropriate and likely conservative. # Cost-effectiveness estimate ## Avacopan with a cyclophosphamide or rituximab regimen compared with standard care is cost effective The committee recalled that its preferred assumptions were: that 30% to 40% of people who have rituximab induction treatment would have it as maintenance treatment (see section 3.9) that the Gercik et al. (2020) and Brix et al. (2018) estimates for the ESRD hazard ratio were relevant individually and pooled (see section 3.10) /20 NHS reference costs for hospitalisation costs with no adjustment for excess bed days (see section 3.11).The committee recognised that the company and ERG had the same base case. This included an assumption that 35% of people who had rituximab induction treatment continued it as maintenance treatment, and a pooled hazard ratio for ESRD that reflected its preferred assumptions. The committee also considered scenarios in which 30% and 40% of people had rituximab maintenance, and in which the individual hazard ratio estimates for ESRD were used. The committee recognised that, although there was inherent uncertainty associated with some assumptions, most were conservative. So, it thought that it was reasonable to assume that the ICER would decrease if it were possible to resolve these issues. The committee also recognised that the quality-adjusted life year (QALY) gains were relatively stable, and that GPA and MPA are rare, so considered the consequences of decision error to be relatively low. It concluded that the most plausible ICER was within the range NICE normally considers an acceptable use of NHS resources (that is, £20,000 to £30,000 per QALY gained). The exact ICER cannot be reported here because it includes confidential discounts for some of the comparator treatments. The committee concluded that avacopan with a cyclophosphamide or rituximab regimen is a cost-effective use of NHS resources compared with standard care alone. # Other factors ## There are no equality issues to address in this technology appraisal The committee understood a potential equality issue about the use of cyclophosphamide had been raised in NICE's related technology appraisal guidance on rituximab. In that appraisal, the committee considered that cyclophosphamide reduces fertility in everyone. But it was aware that the peak age of onset for ANCA‑associated vasculitis in England is between 60 and 70 years. The committee agreed that the number of people with ANCA‑associated vasculitis who have not completed their family is likely to be very small. The committee recalled that avacopan is proposed as an add-on to standard care. It considered that its recommendation for avacopan would not affect prescription rates for cyclophosphamide. So, it concluded that its recommendation for avacopan would not have a different effect on people protected by the equality legislation than on the wider population. ## There may be additional benefits of avacopan not captured in the cost-effectiveness analysis The committee recalled that, during the COVID‑19 pandemic, clinicians are being careful about using anti‑CD20 antibody treatments (like rituximab, see section 3.4). It also recalled that avacopan was proposed as an add-on to standard care so would not directly replace rituximab. But it also considered that a larger proportion in the avacopan group had sustained remission at week 52 than in the prednisone group. The clinical experts explained that a drug that could maintain disease remission may reduce future need for re-induction treatment with rituximab. The committee also recognised that the model mainly captured benefits of disease remission rather than the potential health benefits from a long-term reduction in corticosteroids. The committee concluded that there may be some benefits of avacopan not captured in the cost-effectiveness analysis. These included reducing the future need for rituximab and a long-term reduction in corticosteroid use. It took these factors into consideration when making its recommendation. # Conclusion ## Avacopan with a cyclophosphamide or rituximab regimen is recommended for treating severe active GPA or MPA in adults The committee recalled that GPA and MPA are rare, severe and potentially life-limiting conditions. It recognised that current treatment usually includes corticosteroids, which are associated with significant side effects. The committee understood that people with severe active GPA or MPA would welcome a treatment option that could reduce corticosteroid use and its associated toxicity. It recognised that avacopan with a cyclophosphamide or rituximab regimen compared with standard care sustained disease remission for a larger proportion of people, and reduced corticosteroid-induced toxicity. The committee noted that, after consultation, the company and ERG agreed on all assumptions. It also noted that these assumptions were consistent with the committee's preferences. These included: that 35% of people who had induction treatment with rituximab had it as maintenance treatment a pooled hazard ratio for ESRD hospitalisation costs based on 2019/20 NHS reference costs with no adjustment for excess bed days.It also acknowledged there may be additional benefits for avacopan that had not been captured in the cost-effectiveness analysis (see section 3.15). The committee considered the most plausible ICER was within the range that NICE normally considers a cost-effective use of NHS resources. So, avacopan is recommended for treating severe active GPA or MPA.	{'Recommendations': 'Avacopan with a cyclophosphamide or rituximab regimen is recommended, within its marketing authorisation, as an option for treating severe active granulomatosis with polyangiitis or microscopic polyangiitis in adults. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nStandard care for granulomatosis with polyangiitis or microscopic polyangiitis usually starts with cyclophosphamide or rituximab, followed by maintenance treatment, usually with azathioprine or rituximab. Corticosteroids are also used throughout treatment. Avacopan is an option to be used alongside this standard care.\n\nEvidence from a clinical trial shows that, after a year, avacopan with standard care is more effective at stopping the conditions getting worse than standard care alone. It also suggests that using avacopan with standard care results in less toxicity from corticosteroids, possibly because of less use overall.\n\nThe cost-effectiveness estimates for avacopan with standard care compared with standard care alone are within the range that NICE considers a cost-effective use of NHS resources. So, avacopan with a cyclophosphamide or rituximab regimen is recommended.', 'Information about avacopan': "# Marketing authorisation indication\n\nAvacopan (Tavneos, CSL Vifor), 'in combination with a rituximab or cyclophosphamide regimen, is indicated for the treatment of adult patients with severe, active granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for avacopan.\n\n# Price\n\nAvacopan costs £5,547.95 per pack of 180x10\xa0mg capsules (company submission). The company has a commercial arrangement. This makes avacopan available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by CSL Vifor, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Population, treatment pathway and positioning\n\n## People with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) can have severe symptoms\n\nAntineutrophil cytoplasmic antibody (ANCA)‑associated vasculitis is a group of rare autoimmune conditions characterised by blood vessel inflammation. The 2\xa0most common types are GPA and MPA. Eosinophilic GPA is the rarest type of ANCA‑associated vasculitis and was not a proposed indication for this appraisal. The patient experts explained that people with GPA or MPA can have severe symptoms and the conditions can be life threatening. They explained that symptoms can include extreme pain, fatigue, night sweats and rashes. They added that ANCA‑associated vasculitis can affect the sinuses, kidneys, lungs, abdomen, skin and joints. They also explained that the condition can have a detrimental effect on everyday life, including people's ability to work and participate in family life. The clinical experts commented that, when the kidneys are involved, people can develop end-stage renal disease (ESRD), which can be life threatening. The committee recognised that people with severe active GPA or MPA can have severe symptoms.\n\n## People with GPA or MPA, and clinicians, would welcome a new treatment option\n\nThe clinical experts explained that GPA and MPA are usually treated in 2\xa0phases. The first phase aims to control inflammation and reduce damage associated with the conditions by inducing disease remission (see section\xa03.4). The second phase of treatment (maintenance treatment) aims to prevent the conditions from relapsing and causing further damage (see section\xa03.5). Patient and professional organisations commented that quickly inducing and sustaining disease remission are important to reduce the risk of organ damage. The clinical experts agreed that the treatment pathway for people with severe active GPA or MPA is generally well defined. They explained that induction treatment usually includes cyclophosphamide or rituximab with high-dose corticosteroids (usually prednisolone, which is an active metabolite of prednisone). They added that maintenance treatment is usually azathioprine with a tapered dose of corticosteroids. The clinical experts also explained that disease relapses are treated by re-inducing remission in a similar way to initial inductions. Both patient and clinical experts commented on the side effects and toxicity of corticosteroids. The company also noted that relapses are associated with an increased risk of corticosteroid-mediated morbidity. The patient experts commented that mood swings, weight gain, diabetes, osteoporosis and cataracts are all potential side effects of corticosteroid treatment. They explained that weight gain can affect self-confidence and means that some people feel like they no longer recognise themselves. One patient organisation commented that regular monitoring for the side effects by several types of clinicians can be needed. For example, people having corticosteroids for a prolonged time may regularly visit a pain clinic, an ophthalmologist and a rheumatology and orthopaedic combined clinic to manage corticosteroid side effects. One clinical expert commented that infection and cardiovascular disease, which are the most common causes of death in this population, are both associated with corticosteroid use. The clinical experts also commented that the side effects of corticosteroids are generally dose related. So, they explained that a treatment which could sustain disease remission and reduce corticosteroid use would be beneficial. The committee concluded that people with GPA or MPA, and clinicians, would welcome such a new treatment option.\n\n## The company's positioning of avacopan is appropriate\n\nThe NICE scope did not specify which types of ANCA‑associated vasculitis would be considered in the appraisal. The company explained that only people with GPA or MPA were included in the clinical trial (see section\xa03.6). It also noted that the marketing authorisation only covered people with severe active GPA or MPA, and specified that avacopan would be used with a cyclophosphamide or rituximab regimen. The committee recognised that NICE's remit is to appraise a technology within its marketing authorisation, so agreed that the company's positioning was appropriate.\n\n## The relevant induction treatment comparators are cyclophosphamide or rituximab with high-dose corticosteroids\n\nThe clinical experts explained that people with severe disease are usually offered cyclophosphamide or rituximab with high-dose corticosteroids for induction treatment. They added that the decision to use rituximab instead of cyclophosphamide depends on many factors. They commented that people with more severe GPA or MPA may be offered cyclophosphamide because there is less evidence for rituximab for severe disease. The clinical experts also commented that anti‑CD20 antibody treatments (such as rituximab) can reduce response to vaccinations by depleting B‑cells. So, there is a general desire to avoid using these treatments in the context of the COVID‑19 pandemic. The committee concluded that the relevant induction treatment comparators were cyclophosphamide or rituximab with high-dose corticosteroids.\n\n## The relevant maintenance treatment comparators are azathioprine or rituximab (for people who are eligible) with corticosteroids\n\nThe committee recalled that, after the initial induction treatment, people will usually have maintenance treatment. The clinical experts explained that, after induction of remission with cyclophosphamide, most people would switch to azathioprine. The clinical experts also noted that, during the maintenance phase of treatment, corticosteroid dose is usually tapered. They explained that people who initially have rituximab induction would only have rituximab maintenance in specific circumstances, in accordance with the NHS Clinical Commissioning Policy on rituximab for treating ANCA-associated vasculitis in adults. This states that rituximab maintenance is only commissioned if the disease has relapsed and re-induction treatment is needed after rituximab-induced remission or if rituximab is needed to induce remission for cyclophosphamide-refractory disease. The clinical experts commented that, in clinical practice, around 30% to 40% of people who have had rituximab as induction treatment have rituximab maintenance treatment. People who are not eligible for rituximab maintenance treatment would have azathioprine instead. The committee concluded that the relevant maintenance comparators were azathioprine with tapered corticosteroids and rituximab with tapered corticosteroids.\n\n# Clinical effectiveness\n\n## Avacopan with a cyclophosphamide or rituximab regimen is effective in sustaining disease remission and reducing corticosteroid toxicity\n\nThe company provided clinical evidence for avacopan from several clinical trials including ADVOCATE, a phase\xa03 trial. ADVOCATE was a randomised, active-controlled trial comparing oral avacopan 30\xa0mg twice daily with oral prednisone on a tapering schedule. Everyone also had either cyclophosphamide followed by azathioprine, or rituximab followed by nothing. The trial included people with a clinical diagnosis of GPA or MPA who had at least 1\xa0major item, 3\xa0minor items or 2\xa0renal items of proteinuria and haematuria on the Birmingham Vasculitis Activity Score (BVAS). The primary endpoint was the proportion of people with disease remission at weeks\xa026 and\xa052. At week\xa026, disease remission was defined as a BVAS of\xa00, and no corticosteroids in the previous 4\xa0weeks. Sustained remission was defined as disease remission at week\xa026, and a BVAS of\xa00 at week\xa052, no corticosteroids in the 4\xa0weeks before week\xa052 and no disease relapse between weeks\xa026 and\xa052. In the intention-to-treat population, at week\xa026, 72% of people in the avacopan group compared with 70% in the prednisone group had disease remission (estimated common difference 3.4%, 95% confidence interval [CI] -6.0 to 12.8; p<0.001 for non-inferiority and p=0.240 for superiority). At week\xa052, 66% of people in the avacopan group compared with 55% in the prednisone group had sustained disease remission (estimated common difference 12.5%, 95%\xa0CI 2.6 to 22.3; p<0.001 for inferiority and p=0.007 for superiority). The trial also evaluated corticosteroid toxicity. At week\xa026, the mean Corticosteroid Toxicity Index Cumulative Worsening Score was 39.7 in the avacopan group compared with 56.6 in the prednisone group (a larger score represents worsening toxicity; p=0.0002). The committee concluded that avacopan with a cyclophosphamide or rituximab regimen was effective at sustaining disease remission and reducing corticosteroid-induced toxicity compared with a prednisone-based regimen in the intention-to-treat population of ADVOCATE.\n\n## In ADVOCATE, non-study supplied corticosteroids in the intervention group reflect expected use in clinical practice\n\nIn ADVOCATE, people in both the avacopan and prednisone groups could have non-study supplied corticosteroids as needed. This was, for example, to treat disease relapse or hypoadrenalism from previous use of high-dose corticosteroids. The company explained that this as-needed use of corticosteroids was in line with how they would be used in clinical practice if avacopan was available. The clinical experts agreed. The mean cumulative corticosteroid dose during the treatment period was 1,349\xa0mg in the avacopan group compared with 3,655\xa0mg in the prednisone group. The ERG noted that although total corticosteroid use was lower in the avacopan group, non-study supplied corticosteroid use was higher in the avacopan group. The mean non-study supplied corticosteroid use during the treatment period was 1,349\xa0mg in the avacopan group compared with 1,265\xa0mg in the prednisone group. The ERG also noted that a large proportion of people (87.3%) in the avacopan group had non-study supplied corticosteroids during the treatment period. It was concerned that the use of non-study supplied corticosteroids in the avacopan group could have biased the effect estimates from the trial. It was also concerned about the meaningfulness of the apparent comparison of avacopan with lower-dose corticosteroids compared with higher-dose corticosteroids. The company explained that non-study supplied corticosteroid use was reasonably well balanced between the avacopan and prednisone groups, so the benefits seen in ADVOCATE could be attributed to avacopan. The committee understood the ERG's concerns, and queried whether there were differences in the proportions of people who had pulsed high-dose corticosteroids. One clinical expert explained that most non-study supplied intravenous corticosteroids at 4\xa0weeks were for prophylaxis for rituximab treatment rather than for treating relapse. The committee commented that, overall, people in the avacopan group had about one-third less corticosteroids than those in the prednisone group. The committee recalled that a reduction in corticosteroid use would be beneficial for people with GPA or MPA (see section\xa03.2). It concluded that the non-study supplied corticosteroids in the intervention group reflected expected use in clinical practice.\n\n# Cost effectiveness\n\n## The company's economic model is appropriate for decision making\n\nThe company provided a Markov model that was similar to the one used in NICE's technology appraisal guidance on rituximab in combination with glucocorticoids for treating anti-neutrophil cytoplasmic antibody-associated vasculitis. The model included 9\xa0health states: active disease, 3\xa0disease-remission states, 3\xa0disease-relapse states, ESRD and death. The cohort's mean starting age (60\xa0years), proportion of people having rituximab induction treatment (65%) and adherence to avacopan (86%) were from ADVOCATE. The clinical efficacy for avacopan was based on the results of ADVOCATE, and included disease remission at\xa026, 52\xa0and 60\xa0weeks, change in estimated glomerular filtration rate (eGFR) and health-related quality of life. In the company's base case, people were modelled to have standard care or standard care with avacopan. Standard care was defined as high-dose corticosteroids and either cyclophosphamide or rituximab followed by lower-dose corticosteroids with azathioprine. The company explained that modelling azathioprine maintenance treatment after rituximab induction was a deviation from ADVOCATE, but was based on an assumption explored in NICE's technology appraisal guidance on rituximab. At the first meeting, the committee was concerned about how maintenance treatment was modelled (see section\xa03.9). But it concluded that the company's overall model structure was appropriate for decision making.\n\n## The cost-effectiveness analysis should include rituximab maintenance treatment for people who are eligible for it\n\nThe committee recalled that some people are eligible to have rituximab in the maintenance phase if it was used in the induction phase and other criteria are met (see section\xa03.5). The company noted that there were no randomised controlled trials assessing maintenance treatment with avacopan plus rituximab. At clarification, the company provided a rituximab maintenance treatment option in the model. It explained that it had adjusted the baseline hazard ratio for relapse to reflect treatment with rituximab instead of azathioprine. It cautioned that the non-adjusted naive comparison should be treated as exploratory. The ERG commented that the rituximab maintenance scenario was uncertain. At the first meeting, the committee agreed that it would have preferred analyses in which 30% to 40% of people who had rituximab as induction treatment continued rituximab as maintenance treatment, with the remaining proportion having azathioprine. This was based on the clinical experts' comments (see section\xa03.5). In response to consultation, the company updated its base case to include rituximab maintenance treatment for 35% of people who had it as induction treatment. It also provided scenarios that assumed 30% and 40% of this population would continue to have rituximab. The company noted that there was no additional real-world evidence to inform the modelling. The ERG commented that, in the absence of real-world observational data, the company's naive approach was pragmatic. The committee concluded that the company's modelling of rituximab maintenance treatment was appropriate and considered all scenarios during decision making.\n\n## Hazard ratios for ESRD from Gercik et al. and Brix et al. are relevant both individually and pooled\n\nIn the company's model, people could transition to an ESRD state. The company considered it relevant to include a separate health state because ESRD is a significant complication of ANCA‑associated vasculitis. Disease progression to ESRD was modelled by a change in eGFR. The probability of ESRD in the active and remission health states was adjusted based on the improvement in eGFR in ADVOCATE. In the company's base case, the hazard rate, and probability of ESRD was adjusted based on the hazard ratio for ESRD per\xa0ml/min change in eGFR from Gercik et al. (2020; hazard ratio [HR] 0.90, 95%\xa0CI 0.86 to 0.95). However, the ERG noted that the company had provided several other options for the hazard ratio in the model. The ERG originally explored a pooled hazard ratio by combining estimates from Gercik et al., Ford et al. (2014) and Brix et al. (2018). The company disagreed with the ERG's pooled approach, explaining that estimates from Cox proportional hazards models were dependent on other covariates in the model. It explained that it would be inconsistent to pool coefficients from models that adjust for different covariates. During technical engagement, the ERG noted the company's concerns about pooling estimates. It re-evaluated the pooled studies and noted that the estimate from Ford et al. was for ESRD or death. The ERG did not consider it appropriate to include the Ford et al. hazard ratio in the pooled estimate. But the ERG reiterated that both the Gercik et al. and Brix et al. studies were relevant and preferred to pool them using an inverse variance approach (pooled HR\xa00.95, 95%\xa0CI 0.90 to 1.00). The committee understood the company's statistical concerns about pooling estimates. However, it agreed with the ERG that both the Gercik et al. and Brix et al. studies were relevant for consideration. The committee noted that the Gercik et al. study did not provide much detail and was published as a letter. It further noted comments from a clinical expert that the risk of ESRD is dependent on the population being studied. This meant that it may have been appropriate to pool estimates from studies that limited the inclusion criteria. The committee was concerned that the company's approach might have applied a hazard ratio from a single study with a narrower population to the broader, modelled population. The committee would have liked to see additional information from the company about why Brix et al. was not relevant. At the first meeting, the committee concluded that it was relevant to consider scenarios using the Gercik et al. and Brix et al. hazard ratios, both individually and pooled. In response to consultation, the company updated its base case to use the pooled hazard ratio estimated by the ERG (HR\xa00.95). The company commented that the pooled approach was conservative because evidence from the Gopaluni et al. (2019) paper suggested that the true hazard ratio could be less than 0.95 but was likely greater than 0.90. Consistent with the committee's preference from the first meeting, the company also provided results using the Gercik et al. and Brix et al. estimates individually. The committee noted that the incremental cost-effectiveness ratio (ICER) was sensitive to the individual and pooled hazard ratios. No evidence had been presented to suggest either Gercik et al. or Brix et al. estimates were not relevant. So, the committee concluded that the company's analyses using the individual and pooled estimates were relevant for decision making.\n\n## The 2019/20 NHS reference costs are most appropriate to inform hospitalisation costs\n\nThe company noted that the average length of hospital stay in ADVOCATE (13.8\xa0days in the avacopan group and 19.6\xa0days in the prednisone group) was longer than the mean length of stay reported in the 2019/20 NHS reference costs. The company explained that it adjusted hospital costs to account for the longer stays in ADVOCATE using excess bed day costs from 2017/18. It did this because the 2019/20 NHS reference costs no longer separately report excess bed day costs (as previous versions did). At technical engagement, the company updated its base case to use unit and excess bed day costs from 2017/18 inflated to 2020 prices. The ERG explained that it was uncertain whether the difference between mean length of stay in ADVOCATE compared with NHS reference costs implied excess bed days. Additionally, the ERG noted that NHS reference costs appeared to be calculated differently between 2017/18 and 2019/20 because the more recent version does not separately report excess bed day costs. NHS England confirmed that the 2019/20 reference costs included all hospitalisation costs, but no longer disaggregated costs into unit and excess bed days. At the first meeting, the committee noted a preference for hospitalisation costs using 2019/20 unit costs with no adjustment for excess bed days. This was because it was more reflective of costs in the NHS in England. In response to consultation, the company updated its base case to use 2019/20 unit costs with no adjustment for excess bed days. The company noted this approach was conservative because:\n\nthe unit cost represents the average length of stay and does not reflect the long hospital stays seen in ADVOCATE\n\nthe average length of stay from the NHS reference costs includes overall ANCA-associated vasculitis, rather than the narrower population with severe active GPA or MPA for which avacopan is indicated.The committee concluded that the company's revised approach to hospitalisation costs using 2019/20 unit costs with no adjustment for excess bed days was appropriate for decision making.\n\n## The modelled healthcare costs may not fully represent costs in the NHS, but may be conservative\n\nThe ERG noted the crude modelled annual healthcare costs for the standard care group were substantially lower than the costs in the Clinical Practice Research Datalink (CPRD) study. The CPRD study was a retrospective observational study using real-world evidence to evaluate resource use and adverse event rates for people with GPA or MPA in England. The company explained that the CPRD study costs were not appropriate for modelling because there is no information about change in resource use with avacopan. The company also noted that the CPRD included aggregate costs of all hospital episodes, including treatment of unrelated comorbidities, and the model did not account for these costs. The company added that costs for specific episodes were similar between the model and CPRD. It also explained that larger costs from worsening ANCA‑associated vasculitis would favour avacopan so the model was likely conservative. The ERG noted it was uncertain why the ICER increased when adverse event costs from CPRD were used. It explained that it was not possible to explore the CPRD data further because the database included limited detail on exact resource use and did not include people who had avacopan treatment. At the second committee meeting, the committee noted that the CPRD study may have underrepresented people with MPA. People with MPA are more likely to have renal involvement so there may be higher costs associated with their care because they have high-cost treatments such as dialysis. The committee recalled that higher costs for the standard care group would favour avacopan because it is effective at sustaining disease remission, reducing ESRD and reducing corticosteroid use and so toxicity. The committee concluded that although there was some uncertainty in the modelled healthcare costs, the company's base case was appropriate and likely conservative.\n\n# Cost-effectiveness estimate\n\n## Avacopan with a cyclophosphamide or rituximab regimen compared with standard care is cost effective\n\nThe committee recalled that its preferred assumptions were:\n\nthat 30% to 40% of people who have rituximab induction treatment would have it as maintenance treatment (see section\xa03.9)\n\nthat the Gercik et al. (2020) and Brix et al. (2018) estimates for the ESRD hazard ratio were relevant individually and pooled (see section\xa03.10)\n\n/20 NHS reference costs for hospitalisation costs with no adjustment for excess bed days (see section\xa03.11).The committee recognised that the company and ERG had the same base case. This included an assumption that 35% of people who had rituximab induction treatment continued it as maintenance treatment, and a pooled hazard ratio for ESRD that reflected its preferred assumptions. The committee also considered scenarios in which 30% and 40% of people had rituximab maintenance, and in which the individual hazard ratio estimates for ESRD were used. The committee recognised that, although there was inherent uncertainty associated with some assumptions, most were conservative. So, it thought that it was reasonable to assume that the ICER would decrease if it were possible to resolve these issues. The committee also recognised that the quality-adjusted life year (QALY) gains were relatively stable, and that GPA and MPA are rare, so considered the consequences of decision error to be relatively low. It concluded that the most plausible ICER was within the range NICE normally considers an acceptable use of NHS resources (that is, £20,000 to £30,000 per QALY gained). The exact ICER cannot be reported here because it includes confidential discounts for some of the comparator treatments. The committee concluded that avacopan with a cyclophosphamide or rituximab regimen is a cost-effective use of NHS resources compared with standard care alone.\n\n# Other factors\n\n## There are no equality issues to address in this technology appraisal\n\nThe committee understood a potential equality issue about the use of cyclophosphamide had been raised in NICE's related technology appraisal guidance on rituximab. In that appraisal, the committee considered that cyclophosphamide reduces fertility in everyone. But it was aware that the peak age of onset for ANCA‑associated vasculitis in England is between 60\xa0and 70\xa0years. The committee agreed that the number of people with ANCA‑associated vasculitis who have not completed their family is likely to be very small. The committee recalled that avacopan is proposed as an add-on to standard care. It considered that its recommendation for avacopan would not affect prescription rates for cyclophosphamide. So, it concluded that its recommendation for avacopan would not have a different effect on people protected by the equality legislation than on the wider population.\n\n## There may be additional benefits of avacopan not captured in the cost-effectiveness analysis\n\nThe committee recalled that, during the COVID‑19 pandemic, clinicians are being careful about using anti‑CD20 antibody treatments (like rituximab, see section\xa03.4). It also recalled that avacopan was proposed as an add-on to standard care so would not directly replace rituximab. But it also considered that a larger proportion in the avacopan group had sustained remission at week\xa052 than in the prednisone group. The clinical experts explained that a drug that could maintain disease remission may reduce future need for re-induction treatment with rituximab. The committee also recognised that the model mainly captured benefits of disease remission rather than the potential health benefits from a long-term reduction in corticosteroids. The committee concluded that there may be some benefits of avacopan not captured in the cost-effectiveness analysis. These included reducing the future need for rituximab and a long-term reduction in corticosteroid use. It took these factors into consideration when making its recommendation.\n\n# Conclusion\n\n## Avacopan with a cyclophosphamide or rituximab regimen is recommended for treating severe active GPA or MPA in adults\n\nThe committee recalled that GPA and MPA are rare, severe and potentially life-limiting conditions. It recognised that current treatment usually includes corticosteroids, which are associated with significant side effects. The committee understood that people with severe active GPA or MPA would welcome a treatment option that could reduce corticosteroid use and its associated toxicity. It recognised that avacopan with a cyclophosphamide or rituximab regimen compared with standard care sustained disease remission for a larger proportion of people, and reduced corticosteroid-induced toxicity. The committee noted that, after consultation, the company and ERG agreed on all assumptions. It also noted that these assumptions were consistent with the committee's preferences. These included:\n\nthat 35% of people who had induction treatment with rituximab had it as maintenance treatment\n\na pooled hazard ratio for ESRD\n\nhospitalisation costs based on 2019/20 NHS reference costs with no adjustment for excess bed days.It also acknowledged there may be additional benefits for avacopan that had not been captured in the cost-effectiveness analysis (see section\xa03.15). The committee considered the most plausible ICER was within the range that NICE normally considers a cost-effective use of NHS resources. So, avacopan is recommended for treating severe active GPA or MPA."}	https://www.nice.org.uk/guidance/ta825	Evidence-based recommendations on avacopan (Tavneos) for treating severe active granulomatosis with polyangiitis or microscopic polyangiitis in adults.
b158065b7fcf574c5ad43bd28d31dd77f5e7f77f	nice	Colorectal cancer prevention: colonoscopic surveillance in adults with ulcerative colitis, Crohn's disease or adenomas	Colorectal cancer prevention: colonoscopic surveillance in adults with ulcerative colitis, Crohn's disease or adenomas This guideline covers using colonoscopy to check for signs of bowel cancer in people aged 18 and over with ulcerative colitis or Crohn’s disease (types of inflammatory bowel disease) or adenomas (also known as polyps). It aims to prevent cancer and prolong life by offering advice on identifying early bowel cancer in adults most at risk. # Introduction This guideline incorporates NICE'S interventional procedures guidance on computed tomographic colonography (virtual colonoscopy). Adults with inflammatory bowel disease (IBD, which covers ulcerative colitis and Crohn's disease) or with adenomas have a higher risk of developing colorectal cancer than the general population. Colorectal cancer is the third most common cancer in the UK, with approximately 32,300 new cases diagnosed and 14,000 deaths in England and Wales each year. Around half of the people diagnosed with colorectal cancer survive for at least 5 years after diagnosis. The prevalence of ulcerative colitis is approximately 100 to 200 per 100,000 and the annual incidence is 10 to 20 per 100,000. The risk of developing colorectal cancer for people with ulcerative colitis is estimated as 2% after 10 years, 8% after 20 years and 18% after 30 years of disease. The prevalence of Crohn's disease is approximately 50 to 100 per 100,000 and the annual incidence is 5 to 10 per 100,000. The risk of developing colorectal cancer for people with Crohn's disease is considered to be similar to that for people with ulcerative colitis with the same extent of colonic involvement. Colonoscopic surveillance in people with IBD or adenomas can detect any problems early and potentially prevent progression to colorectal cancer. For people who are not in these high-risk groups, the NHS Bowel Cancer Screening Programme offers screening using faecal occult blood testing every 2 years to all men and women aged 60 to 74 years. People undergoing colonoscopic surveillance are not generally offered screening as part of the Bowel Cancer Screening programme. The British Society of Gastroenterology (BSG) issued guidelines for colonoscopic surveillance for people who have had adenomas removed and for people with IBD (Atkin and Saunders 2002; Eaden and Mayberry 2002; updated by Cairns et al. 2010). NICE has developed this short clinical guideline on the use of colonoscopic surveillance because of variations in clinical practice. Some members of the NICE Guideline Development Group (GDG) were also members of the group that developed the BSG guidelines. The evidence-based recommendations and algorithms developed in the NICE guideline are broadly consistent with those in the 2010 BSG guidelines. Both guidelines used a similar evidence base, with the exception of health economics evidence, which was not considered for the BSG guidelines. However, there are some differences between the two guidelines because the processes and methods used to develop each guideline were different. Throughout this guideline, the term 'adenomas' is used. However, other terms have been used in the clinical studies included in the evidence review, for example 'polyps' or 'adenomatous polyps'.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. # People with inflammatory bowel disease Offer colonoscopic surveillance to people with inflammatory bowel disease (IBD) whose symptoms started 10 years ago and who have: ulcerative colitis (but not proctitis alone) or Crohn's colitis involving more than one segment of colon. Offer a baseline colonoscopy with chromoscopy and targeted biopsy of any abnormal areas to people with IBD who are being considered for colonoscopic surveillance to determine their risk of developing colorectal cancer (see box 1). Box 1 Risk of developing colorectal cancer in people with IBD Low risk: extensive but quiescent ulcerative colitis or extensive but quiescent Crohn's colitis or left-sided ulcerative colitis (but not proctitis alone) or Crohn's colitis of a similar extent. Intermediate risk: extensive ulcerative or Crohn's colitis with mild active inflammation that has been confirmed endoscopically or histologically or post-inflammatory polyps or family history of colorectal cancer in a first-degree relative aged 50 years or over. High risk: extensive ulcerative or Crohn's colitis with moderate or severe active inflammation that has been confirmed endoscopically or histologically or primary sclerosing cholangitis (including after liver transplant) or colonic stricture in the past 5 years or any grade of dysplasia in the past 5 years or family history of colorectal cancer in a first-degree relative aged under 50 years. Offer colonoscopic surveillance to people with IBD as defined in recommendation 1.1.1 based on their risk of developing colorectal cancer (see box 1), determined at the last complete colonoscopy: Low risk: offer colonoscopy at 5 years. Intermediate risk: offer colonoscopy at 3 years. High risk: offer colonoscopy at 1 year. For people with IBD who have been offered colonoscopic surveillance, continue to use colonoscopy with chromoscopy as the method of surveillance. Offer a repeat colonoscopy with chromoscopy if any colonoscopy is incomplete. Consider whether a more experienced colonoscopist is needed. # People with adenomas Recommendation deleted. See the British Society of Gastroenterology's guidelines on post-polypectomy and post-colorectal cancer resection surveillance. Recommendation deleted. Recommendation deleted. Recommendation deleted. Recommendation deleted. Recommendation deleted. Recommendation deleted. Recommendation deleted. # Providing information and support Discuss the potential benefits, limitations and risks with people who are considering colonoscopic surveillance including: early detection and prevention of colorectal cancer and quality of life and psychological outcomes. Inform people who have been offered colonoscopy, CTC, or barium enema about the procedure, including: bowel preparation impact on everyday activities sedation potential discomfort risk of perforation and bleeding. After receiving the results of each surveillance test, discuss the potential benefits, limitations and risks of ongoing surveillance. Base a decision to stop surveillance on potential benefits for the person, their preferences and any comorbidities. Make the decision jointly with the person, and if appropriate, their family or carers. If there are any findings at surveillance that need treatment or referral, discuss the options with the person, and if appropriate, their family or carers. Throughout the surveillance programme, give the person and their family or carers the opportunity to discuss any issues with a healthcare professional. Information should be provided in a variety of formats tailored to the person's needs and should include illustrations.# Recommendations for research We have made the following recommendations for research, based on our review of the evidence, to improve NICE guidance and patient care in the future. # Surveillance programmes for people at increased risk of colorectal cancer How effective are colonoscopic surveillance programmes in improving overall survival and cancer-related survival in people at increased risk of colorectal cancer? ## Why this is important There is no evidence from RCTs on the effectiveness of colonoscopic surveillance programmes in improving survival in people at increased risk of colorectal cancer. Although there is some observational evidence in people with IBD, there is no evidence in people after adenoma removal. RCTs should be undertaken to determine the comparative effect of different surveillance programmes on survival (preferably with a follow-up of 5 years and longer) and quality of life in people at increased risk of colorectal cancer because of IBD or adenomas. Such trials should also assess any differential effects associated with risk category (as defined in this guideline). # Natural history of progression to colorectal cancer in people at increased risk What is the natural history of progression to colorectal cancer in people with IBD or adenomas? ## Why this is important There is very limited evidence on the natural history of progression to colorectal cancer, and how factors such as extent of disease, grade of dysplasia and adenoma-related factors affect progression. Long-term studies (ideally with a follow-up of 20 years or longer) should be conducted to determine the natural history of colorectal cancer in people with IBD or adenomas. # Effectiveness of biomarkers for determining level of risk of colorectal cancer Which biomarkers, including epigenic and genetic markers, are predictors of colorectal cancer? How should these be used to improve risk stratification? ## Why this is important There is no high quality evidence on the predictive value of biomarkers, including epigenic and genetic markers, for colorectal cancer in people with IBD or adenomas. Research should be undertaken to identify the biomarkers that are predictive of colorectal cancer, if any can improve levels of early detection, and how they can be used to improve risk stratification. # Adenoma types and risk of colorectal cancer Does the risk of colorectal cancer depend on the type of adenoma? ## Why this is important There is no high quality evidence on the association between risk of colorectal cancer and some adenoma types (sessile, hyperplastic non-adenomatous). Research should be undertaken to determine if the level of risk of colorectal cancer depends on the adenoma type.	{'Introduction': "This guideline incorporates NICE'S interventional procedures guidance on computed tomographic colonography (virtual colonoscopy).\n\nAdults with inflammatory bowel disease (IBD, which covers ulcerative colitis and Crohn's disease) or with adenomas have a higher risk of developing colorectal cancer than the general population. Colorectal cancer is the third most common cancer in the UK, with approximately 32,300 new cases diagnosed and 14,000 deaths in England and Wales each year. Around half of the people diagnosed with colorectal cancer survive for at least 5 years after diagnosis.\n\nThe prevalence of ulcerative colitis is approximately 100\xa0to\xa0200 per 100,000 and the annual incidence is 10\xa0to\xa020 per 100,000. The risk of developing colorectal cancer for people with ulcerative colitis is estimated as 2% after 10 years, 8% after 20 years and 18% after 30 years of disease.\n\nThe prevalence of Crohn's disease is approximately 50\xa0to\xa0100 per 100,000 and the annual incidence is 5\xa0to\xa010 per 100,000. The risk of developing colorectal cancer for people with Crohn's disease is considered to be similar to that for people with ulcerative colitis with the same extent of colonic involvement.\n\nColonoscopic surveillance in people with IBD or adenomas can detect any problems early and potentially prevent progression to colorectal cancer. For people who are not in these high-risk groups, the NHS Bowel Cancer Screening Programme offers screening using faecal occult blood testing every 2 years to all men and women aged 60\xa0to\xa074 years. People undergoing colonoscopic surveillance are not generally offered screening as part of the Bowel Cancer Screening programme.\n\nThe British Society of Gastroenterology (BSG) issued guidelines for colonoscopic surveillance for people who have had adenomas removed and for people with IBD (Atkin and Saunders 2002; Eaden and Mayberry 2002; updated by Cairns et al. 2010). NICE has developed this short clinical guideline on the use of colonoscopic surveillance because of variations in clinical practice. Some members of the NICE Guideline Development Group (GDG) were also members of the group that developed the BSG guidelines. The evidence-based recommendations and algorithms developed in the NICE guideline are broadly consistent with those in the 2010 BSG guidelines. Both guidelines used a similar evidence base, with the exception of health economics evidence, which was not considered for the BSG guidelines. However, there are some differences between the two guidelines because the processes and methods used to develop each guideline were different.\n\nThroughout this guideline, the term 'adenomas' is used. However, other terms have been used in the clinical studies included in the evidence review, for example 'polyps' or 'adenomatous polyps'.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\n# People with inflammatory bowel disease\n\nOffer colonoscopic surveillance to people with inflammatory bowel disease (IBD) whose symptoms started 10\xa0years ago and who have:\n\nulcerative colitis (but not proctitis alone) or\n\nCrohn's colitis involving more than one segment of colon.\n\nOffer a baseline colonoscopy with chromoscopy and targeted biopsy of any abnormal areas to people with IBD who are being considered for colonoscopic surveillance to determine their risk of developing colorectal cancer (see box 1).\n\nBox 1 Risk of developing colorectal cancer in people with IBD\n\nLow risk:\n\nextensive but quiescent ulcerative colitis or\n\nextensive but quiescent Crohn's colitis or\n\nleft-sided ulcerative colitis (but not proctitis alone) or Crohn's colitis of a similar extent.\n\nIntermediate risk:\n\nextensive ulcerative or Crohn's colitis with mild active inflammation that has been confirmed endoscopically or histologically or\n\npost-inflammatory polyps or\n\nfamily history of colorectal cancer in a first-degree relative aged 50\xa0years or over.\n\nHigh risk:\n\nextensive ulcerative or Crohn's colitis with moderate or severe active inflammation that has been confirmed endoscopically or histologically or\n\nprimary sclerosing cholangitis (including after liver transplant) or\n\ncolonic stricture in the past 5\xa0years or\n\nany grade of dysplasia in the past 5\xa0years or\n\nfamily history of colorectal cancer in a first-degree relative aged under 50\xa0years.\n\nOffer colonoscopic surveillance to people with IBD as defined in recommendation 1.1.1 based on their risk of developing colorectal cancer (see box 1), determined at the last complete colonoscopy:\n\nLow risk: offer colonoscopy at 5\xa0years.\n\nIntermediate risk: offer colonoscopy at 3\xa0years.\n\nHigh risk: offer colonoscopy at 1\xa0year.\n\nFor people with IBD who have been offered colonoscopic surveillance, continue to use colonoscopy with chromoscopy as the method of surveillance.\n\nOffer a repeat colonoscopy with chromoscopy if any colonoscopy is incomplete. Consider whether a more experienced colonoscopist is needed.\n\n# People with adenomas\n\nRecommendation deleted. See the British Society of Gastroenterology's guidelines on post-polypectomy and post-colorectal cancer resection surveillance.\n\nRecommendation deleted.\n\nRecommendation deleted.\n\nRecommendation deleted.\n\nRecommendation deleted.\n\nRecommendation deleted.\n\nRecommendation deleted.\n\nRecommendation deleted.\n\n# Providing information and support\n\nDiscuss the potential benefits, limitations and risks with people who are considering colonoscopic surveillance including:\n\nearly detection and prevention of colorectal cancer and\n\nquality of life and psychological outcomes.\n\nInform people who have been offered colonoscopy, CTC, or barium enema about the procedure, including:\n\nbowel preparation\n\nimpact on everyday activities\n\nsedation\n\npotential discomfort\n\nrisk of perforation and bleeding.\n\nAfter receiving the results of each surveillance test, discuss the potential benefits, limitations and risks of ongoing surveillance. Base a decision to stop surveillance on potential benefits for the person, their preferences and any comorbidities. Make the decision jointly with the person, and if appropriate, their family or carers.\n\nIf there are any findings at surveillance that need treatment or referral, discuss the options with the person, and if appropriate, their family or carers.\n\nThroughout the surveillance programme, give the person and their family or carers the opportunity to discuss any issues with a healthcare professional. Information should be provided in a variety of formats tailored to the person's needs and should include illustrations.", 'Recommendations for research': 'We have made the following recommendations for research, based on our review of the evidence, to improve NICE guidance and patient care in the future.\n\n# Surveillance programmes for people at increased risk of colorectal cancer\n\nHow effective are colonoscopic surveillance programmes in improving overall survival and cancer-related survival in people at increased risk of colorectal cancer?\n\n## Why this is important\n\nThere is no evidence from RCTs on the effectiveness of colonoscopic surveillance programmes in improving survival in people at increased risk of colorectal cancer. Although there is some observational evidence in people with IBD, there is no evidence in people after adenoma removal. RCTs should be undertaken to determine the comparative effect of different surveillance programmes on survival (preferably with a follow-up of 5\xa0years and longer) and quality of life in people at increased risk of colorectal cancer because of IBD or adenomas. Such trials should also assess any differential effects associated with risk category (as defined in this guideline).\n\n# Natural history of progression to colorectal cancer in people at increased risk\n\nWhat is the natural history of progression to colorectal cancer in people with IBD or adenomas?\n\n## Why this is important\n\nThere is very limited evidence on the natural history of progression to colorectal cancer, and how factors such as extent of disease, grade of dysplasia and adenoma-related factors affect progression. Long-term studies (ideally with a follow-up of 20\xa0years or longer) should be conducted to determine the natural history of colorectal cancer in people with IBD or adenomas.\n\n# Effectiveness of biomarkers for determining level of risk of colorectal cancer\n\nWhich biomarkers, including epigenic and genetic markers, are predictors of colorectal cancer? How should these be used to improve risk stratification?\n\n## Why this is important\n\nThere is no high quality evidence on the predictive value of biomarkers, including epigenic and genetic markers, for colorectal cancer in people with IBD or adenomas. Research should be undertaken to identify the biomarkers that are predictive of colorectal cancer, if any can improve levels of early detection, and how they can be used to improve risk stratification.\n\n# Adenoma types and risk of colorectal cancer\n\nDoes the risk of colorectal cancer depend on the type of adenoma?\n\n## Why this is important\n\nThere is no high quality evidence on the association between risk of colorectal cancer and some adenoma types (sessile, hyperplastic non-adenomatous). Research should be undertaken to determine if the level of risk of colorectal cancer depends on the adenoma type.'}	https://www.nice.org.uk/guidance/cg118	This guideline covers using colonoscopy to check for signs of bowel cancer in people aged 18 and over with ulcerative colitis or Crohn’s disease (types of inflammatory bowel disease) or adenomas (also known as polyps). It aims to prevent cancer and prolong life by offering advice on identifying early bowel cancer in adults most at risk.
6260dc955b0cbce406d88367366521e0858b9773	nice	Dexamethasone intravitreal implant for treating diabetic macular oedema	Dexamethasone intravitreal implant for treating diabetic macular oedema Evidence-based recommendations on dexamethasone intravitreal implant (Ozurdex) for treating visual impairment caused by diabetic macular oedema in adults. # Recommendations Dexamethasone intravitreal implant is recommended as an option for treating visual impairment caused by diabetic macular oedema in adults only if their condition has not responded well enough to, or if they cannot have non-corticosteroid therapy. This recommendation is not intended to affect treatment with dexamethasone intravitreal implant that was started in the NHS before this guidance was published. Adults having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.This technology appraisal is a partial review of NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema (TA349) which recommended its use for people who have a pseudophakic (intraocular) lens and whose condition did not respond well enough to, or who could not have non-corticosteroid therapy. This partial review specifically considers people with diabetic macular oedema with a phakic (natural) lens and whose condition did not respond well enough to, or who could not have non-corticosteroid therapy. This final draft guidance from NICE means that dexamethasone intravitreal implant is recommended for treating visual impairment due to diabetic macular oedema only if the diabetic macular oedema has not responded well enough to non-corticosteroids, or non-corticosteroids are unsuitable, irrespective of whether they have a phakic or pseudophakic lens. TA349 has been updated and replaced by this guidance at publication. The considerations below refer only to evidence covered by the partial review. Why the committee made these recommendations Standard care for people with diabetic macular oedema who still have a natural lens (phakic) is anti-vascular endothelial growth factor (anti-VEGF) treatments (such as ranibizumab or aflibercept), or laser monotherapy. If non-corticosteroids do not work well enough, people can keep having anti-VEGFs or laser monotherapy. In people with a phakic lens and diabetic macular oedema who cannot have non-corticosteroid therapy, watch and wait is the only available treatment option. Clinical trial evidence shows that dexamethasone intravitreal implant is more effective than a sham (inactive) procedure. The sham procedure may be considered as a proxy for continued anti-VEGF therapies. The resulting cost-effectiveness estimates for dexamethasone intravitreal implant compared with anti-VEGF therapy are likely to be within what NICE normally considers an acceptable use of NHS resources. Although no cost-effectiveness evidence was presented for people for whom non-corticosteroids are unsuitable, the committee considered the equalities issues, the unmet need, and the size of the population, and agreed that the risk to the NHS was low, and therefore it is recommended.# Information about dexamethasone intravitreal implant # Marketing authorisation indication Dexamethasone 700 micrograms intravitreal implant (Ozurdex, AbbVie), is 'indicated for the treatment of adult patients with visual impairment due to diabetic macular oedema who are pseudophakic or who are considered insufficiently responsive to, or unsuitable for non-corticosteroid therapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for dexamethasone. # Price Dexamethasone intravitreal implant costs £870.00 per 700 micrograms (excluding VAT; BNF accessed online July 2022). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion This appraisal focuses only on the partial review for people who have a phakic (natural) lens. Considerations for people with a pseudophakic (intraocular) lens are still available in the evidence review for NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema (TA349). The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers (TA824) for full details of the evidence for people with a phakic (natural) lens. The appraisal committee was aware that several issues were resolved during the technical engagement stage. # The condition ## There is an unmet need for an effective treatment given less frequently The patient expert explained the nature of their experience with current treatment. They explained that the loss of vision has a significant impact on a person's independence and mental health. The patient expert highlighted that having frequent eye injections causes fear, but there is no alternative because laser therapy has not been very effective for them. They emphasised that reducing the number of times they need treatment, especially for an eye injection, would be of huge benefit for their quality of life. They also explained that for this population, there are no other effective treatment options if anti-vascular endothelial growth factor (anti-VEGF) treatments do not work. The patient expert highlighted that although treatments might not improve their diabetic macular oedema, they can stop it from getting worse, which is still very important to people with the condition. The company noted that for people for whom non-corticosteroids are unsuitable, there are no active pharmacological therapy options and watch and wait is the only available treatment option. Dexamethasone intravitreal implant would therefore provide a pharmacological treatment option for these people. They emphasised that the impact of dexamethasone intravitreal implant would mean less frequent hospital visits and injections compared with anti-VEGF treatments. The committee was aware that some people with diabetic macular oedema may require help from a carer to travel to appointments. The patient expert emphasised that people with diabetic macular oedema may be unsure about using steroids because it could affect their diabetes management. The clinical experts explained that because it is used in small quantities directly into the eye, using dexamethasone should not affect their diabetes management. The committee concluded that there is an unmet need for another treatment option for diabetic macular oedema in people who have a phakic lens. It added that people with diabetic macular oedema and clinicians would welcome an effective new treatment option that is used less frequently. ## Having a longer time between treatments will improve outcomes for people with diabetic macular oedema The clinical experts emphasised that having a longer time between treatments could benefit both people with diabetic macular oedema and clinicians. They highlighted that people with diabetes often have multiple hospital appointments in different departments. Using dexamethasone intravitreal implant would reduce the number of visits to the eye clinics for follow up or treatment. The clinical experts explained that a longer time between treatments will free up the capacity in the NHS as well as improve quality of life for people with diabetic macular oedema. The clinical experts agreed that the availability of dexamethasone intravitreal implant for this population would change practice. The other treatments do not work well for these people and are only used because clinicians prefer to offer some treatment rather than nothing at all. The clinical experts explained that people with diabetic macular oedema who still have their natural lens are at a significant disadvantage compared with people who have a pseudophakic lens because of the difference in access to dexamethasone. So, they would welcome it as an option to improve the quality of life for people with diabetic macular oedema and their carers. The committee heard from the clinical expert that having a longer time between treatments will free up the capacity in the NHS, but the committee noted that there was no evidence provided for this. The committee concluded that having a longer time between treatments will improve outcomes for people with diabetic macular oedema who have a natural (phakic) lens. # Treatment pathway and comparators ## Anti-VEGFs are the most relevant comparators for people for whom non-corticosteroids do not work well enough In its submission, the company compared dexamethasone intravitreal implant with the anti-VEGF therapies ranibizumab and aflibercept. It considered options such as laser photocoagulation alone and bevacizumab. It stated that anti-VEGF therapies would be the most relevant comparators for people for whom non-corticosteroids do not work well enough. It highlighted that bevacizumab does not have a marketing authorisation for this indication and therefore any use would be off-label. The company stated that based on UK clinical feedback, laser photocoagulation is only used in people when the macular oedema does not involve the centre (around 20% of the total diabetic macular oedema population) or in people with diabetic macular oedema with no associated visual impairment, because of concerns around safety and long-term clinical efficacy. For these reasons, laser photocoagulation and bevacizumab were excluded as comparators in the company submission. The committee accepted that anti-VEGFs were the most appropriate comparators for dexamethasone in people for whom non-corticosteroids did not work well enough. ## There is a small percentage of people for whom non-corticosteroids are unsuitable and this population can be easily defined in clinical practice The committee discussed the treatment pathway and the proposed position of dexamethasone intravitreal implant. The clinical experts highlighted that there is a low proportion of people for whom non-corticosteroids are unsuitable (5% to 10%) such as people who are pregnant, have established allergies to anti-VEGFs, or have had a cardiovascular event in the past 3 to 6 months (such as a stroke or myocardial infarction). The clinical experts added that people who are unable to have frequent injections because they cannot get to the hospital, their carers cannot bring them, or the hospital is too far would also be unable to have non-corticosteroids. The clinical experts emphasised that although this is a small group, it is important that they have access to treatment that is suitable for them as watch and wait is the only available treatment option. The committee agreed that there is a small percentage of people for whom non-corticosteroids are unsuitable and that this population could be easily defined in clinical practice. # Clinical evidence ## The results from the MEAD trials are generalisable to UK practice The ERG highlighted several differences in the baseline characteristics of people in the pooled MEAD trials compared with UK clinical practice. The previous use of laser, the previous use of anti-VEGF therapy, the proportion of people with baseline cataracts and the proportion of people with baseline best-corrected visual acuity (BCVA) differed from that expected in UK clinical practice. Additionally, in the company submission, the sham arm of MEAD was used as a proxy for continued anti-VEGF use. The committee acknowledged that the MEAD trials most closely represented the group for whom non-corticosteroids do not work well enough, and people for whom non-corticosteroids are unsuitable would not be part of this evidence base. The clinical expert explained that the population in the sham arm of the MEAD trials can be considered comparable to the population expected in clinical practice from a biological point of view, and that the sham arm of the MEAD is a good proxy for anti-VEGF use in the comparison. The company used a last observation carried forward (LOCF) approach to account for missing data. The ERG expressed concerns that a LOCF approach biases the sham and dexamethasone intravitreal implant arms and emphasised that it was not possible to predict the direction of bias. Despite the uncertainties, the committee considered that the MEAD trials represent the most appropriate source of evidence for dexamethasone intravitreal implant for people for whom non-corticosteroids do not work well enough. ## Data from MEAD-010 and MEAD-011 suggests that dexamethasone intravitreal implant is more effective than sham The clinical evidence for dexamethasone intravitreal implant came from 2 3‑year, phase 3, multicentre, masked, randomised, sham-controlled trials: MEAD‑010 and MEAD‑011. The trials compared dexamethasone 700 micrograms and dexamethasone 350 micrograms with sham procedure in adults with either pseudophakic or phakic diabetic macular oedema. MEAD‑010 included 494 people and took place at 59 study centres in 10 countries. MEAD‑011 included 554 people and took place at 72 study centres in 14 countries, with a maximum follow up of 39 months. For this appraisal, only the dexamethasone 700 microgram and sham arms from the phakic (natural lens) subgroups of the trials are relevant. The primary outcome was mean change in BCVA from baseline. BCVA was measured using the Early Treatment Diabetic Retinopathy Study method. The company submission pooled data from MEAD‑010 and MEAD‑011 for the phakic-only modified ITT (mITT) populations (262 dexamethasone intravitreal implant, 250 sham) and this analysis was used to inform the efficacy of dexamethasone intravitreal implant in the company's base case in their economic model. The sham arm of MEAD was used as a proxy for continued anti-VEGF use. The results from the pooled analysis of the phakic-only populations of the MEAD trials showed that at 39 months, a significantly greater number of people who had dexamethasone intravitreal implant achieved BCVA improvement of at least 10 letters and at least 15 letters from baseline compared with sham (the associated p values are academic in confidence and cannot be presented here). The results for at least a 10‑letter improvement in BCVA from baseline were also used in the company's economic model. The committee accepted that it is appropriate for the sham arm of the MEAD trial to be used as a proxy for continued anti-VEGF therapy. The committee concluded that the results from the pooled MEAD trials showed that dexamethasone intravitreal implant is more effective than sham in people with diabetic macular oedema who have a phakic lens. ## Dexamethasone intravitreal implant is likely to be clinically effective in people with phakic diabetic macular oedema for whom non-corticosteroids are unsuitable The company had not provided any clinical evidence for people with diabetic macular oedema and a phakic lens for whom non-corticosteroids are unsuitable. They explained that there is no relevant additional evidence available to model this specific population beyond the data that was presented in the evidence review for NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema (TA349). The company submission stated that this population has a high unmet need, and this group is likely to be a small number. The clinical experts explained that there was no biologically plausible reason why dexamethasone intravitreal implant would not be of similar clinical benefit in this group compared with those for whom non-corticosteroids do not work well enough. The committee agreed that although the company provided no evidence for this population, it is expected to be small and can be clearly defined in clinical practice. It concluded that dexamethasone intravitreal implant is likely to be clinically effective in people with diabetic macular oedema and a phakic lens that is unsuitable for non-corticosteroids. # The company's economic model ## The company's economic model structure is consistent with that used in NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema The company presented a Markov state transition model, with multiple discrete and independent health states used to capture the treatment of eyes affected with diabetic macular oedema and the progression of visual acuity over time. The ERG agreed that the model structure was consistent with that used in the evidence review for NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema (TA349). The committee agreed that the company's model structure was appropriate for decision making. # Time horizon ## Results do not affect the cost effectiveness when adopting a lifetime time horizon or 10-year time horizon The company adopted a lifetime time horizon (40 years), saying that this is consistent with that used in NICE's technology appraisal guidance on fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema in phakic eyes after an inadequate response to previous therapy and in the evidence review for NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema (TA349). The ERG considered that a shorter time horizon (10 years) should be used because the company's long-term modelling assumptions are too simplistic. The committee noted that the time horizon chosen by the company was the longest seen in eye appraisals to date. It also considered that a shorter time horizon may be more appropriate because it is also consistent with other technology appraisals in this clinical area. The committee considered both time horizons but concluded that the choice of time horizon made little difference to the cost effectiveness, so both were accepted for decision making. ## Assumptions about changes in BCVA in years 4 and 5 did not have a substantial effect on the cost-effectiveness results In the company's model, the 3‑monthly transition probabilities in years 4 and 5 were assumed to equal the last transition probability matrix estimated from MEAD (for both treatment options). The company emphasised that for dexamethasone intravitreal implant there is an upward trend in visual acuity outcomes from the end of MEAD (just over 3 years). The clinical experts highlighted that it is possible to see improvements in the long term in BCVA, although this might only be for a small number of people. The ERG highlighted that the changes in BCVA resulting from dexamethasone intravitreal implant treatment in years 4 and 5 are still a key area of uncertainty and preferred that dexamethasone intravitreal implant maintains vision (no net improvement) in years 4 and 5. The committee noted that this assumption did not have a big effect on the incremental cost-effectiveness ratio (ICER) or on the overall net monetary benefit. It agreed that it could be optimistic to assume an improvement in visual acuity in years 4 and 5 of the model without further data and if this might only be seen in a small number of people. However, it concluded that the use of different assumptions in the company's and ERG's analyses did not have a substantial effect on the cost-effectiveness results. ## Both the ERG and the company's preferred choice of source for the natural history of vision were considered for decision making and neither had a substantial effect on the cost-effectiveness results The company's economic model used a 3‑month probability of gaining or losing at least 10 letters of BCVA of 2.5% or 3.5% respectively, as reported in NICE's technology appraisal guidance on ranibizumab for treating diabetic macular oedema. The ERG preferred a 3‑month probability of gaining or losing at least 10 letters of BCVA of 0% or 3.5% respectively, based on NICE's technology appraisal guidance on fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema in phakic eyes after an inadequate response to previous therapy. The ERG highlighted that the choice of source for natural history of vision moved the ICER from the southeast to the southwest quadrant (southwest quadrant ICERs represent costs saved per quality-adjusted life year lost, whereas southeast quadrant ICERs represent costs saved per QALY gained). The committee noted that the choice did not have a substantial effect on the overall net monetary benefit result (the actual results are commercial in confidence and cannot be presented here). The committee concluded that without better data for the natural history of vision, both approaches were considered for decision making and neither had a substantial effect on the cost-effectiveness results. # Cost-effectiveness estimates ## Dexamethasone intravitreal implant is cost effective compared with anti-VEGFs for people for whom non-corticosteroids do not work well enough The company compared dexamethasone intravitreal implant with a composite comparator consisting of anti-VEGF treatments (aflibercept and ranibizumab). The company's base-case deterministic ICER for dexamethasone intravitreal implant dominates (that is, works better and costs less than) anti-VEGFs when the list price of anti-VEGFs is used (incremental costs ‑£6,969; incremental QALYs 0.114). The corresponding probabilistic ICER (generated by the ERG) for dexamethasone intravitreal implant also dominated anti-VEGFs when the list price of anti-VEGFs was used (incremental costs ‑£7,024; incremental QALYs 0.123). Additionally for the results using a 100% aflibercept comparator, the company's ICER for dexamethasone intravitreal implant dominated aflibercept when the list price of aflibercept was used (incremental costs ‑£9,549; incremental QALYs 0.114). When using a 100% ranibizumab comparator, the company's ICER for dexamethasone intravitreal implant also dominated ranibizumab when the list price of ranibizumab was used (incremental costs ‑£2,581; incremental QALYs 0.114). Taking into account confidential prices for anti-VEGFs, dexamethasone intravitreal implant still dominated anti-VEGFs (exact ICERs are confidential and cannot be reported here). The committee noted that the ERG's cost-effectiveness base case estimated that dexamethasone intravitreal implant was associated with a small loss in QALYs compared with anti-VEGFs. Therefore, the ERG's cost-effectiveness base-case ICER was in the southwest quadrant of the cost-effectiveness plane. It was noted that in situations in which an ICER is estimated for a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment becomes. The ERG's base-case cost-effectiveness analysis showed dexamethasone intravitreal implant was associated with cost savings per QALY lost compared with anti-VEGFs when the list price of anti-VEGFs was used. The ERG's deterministic ICER was £1,040,800 (southwest) per QALY lost (incremental costs ‑£6.333; incremental QALYs ‑0.006). The corresponding probabilistic ICER was £2,267,457 (southwest) per QALY lost (incremental costs ‑£6,322; incremental QALYs ‑0.0033). The ERG replicated the company analyses using the confidential discount for anti-VEGFs (exact ICERs are confidential and cannot be reported here). Dexamethasone intravitreal implant remained associated with cost savings per QALY lost in the ERG's base case and these ICERs were above £30,000 per QALY lost. Overall, the committee concluded that dexamethasone intravitreal implant was likely to be cost-effective compared with anti-VEGFs. ## Dexamethasone intravitreal implant is a cost-effective use of NHS resources when using the net monetary benefit approach compared with anti-VEGFs The committee also considered the incremental net monetary benefit to compare dexamethasone intravitreal implant with anti-VEGFs to support decision making. An advantage of the net monetary benefit is that it allows the cost of an error to be quantified. A positive net monetary benefit implies that the intervention is cost effective compared with the alternative at the given cost-effectiveness threshold. In analyses that included the confidential discount for anti-VEGFs, the net monetary benefit results were found to stay positive at thresholds of £20,000 and £30,000 per QALY gained for both the company base case and the ERG's base case. Given that any differences in QALYs between dexamethasone intravitreal implant and anti-VEGFs are small, the committee concluded that dexamethasone intravitreal implant is a cost-effective use of NHS resources when using the net monetary benefit approach compared with anti-VEGFs. ## Although no cost-effectiveness results were presented for people with phakic diabetic macular oedema that is unsuitable for non-corticosteroids, the risk to the NHS would be low The committee noted that the company provided no cost-effectiveness evidence for people for whom non-corticosteroids are unsuitable. The committee recalled the views of the company and the clinical experts that they expected that dexamethasone intravitreal implant would be of similar clinical benefit in this group compared with those for whom non-corticosteroids do not work well enough (see section 3.7). The committee noted that the comparator for people with diabetic macular oedema that is unsuitable for non-corticosteroids would be watch and wait rather than continued use of anti-VEGFs. The company submission highlighted that because this population is expected to be small, it would not have a substantial impact on the overall cost effectiveness. The committee noted that this group has no available pharmacotherapy treatment options. It was also mindful that it would need to consider relevant factors such as equalities issues in making its decision (see section 3.15). It agreed that dexamethasone was likely to be similarly effective in this population and since the population is expected to be small, the risk to the NHS would be low if approved. # Other factors ## Recommending dexamethasone intravitreal implant would address many of the important equalities issues identified The company submission noted that no equality considerations relating to using dexamethasone intravitreal implant were identified or anticipated. At scoping it was raised that if a person is registered as blind or partially sighted, it is considered a disability, as stated in the Equality Act 2010. Therefore, the committee noted the patient population addressed in this appraisal is a protected group under this act. The patient expert emphasised that there is a high prevalence of diabetes among people with a learning disability. They highlighted there are challenges in providing treatments and routine eye tests for people with a learning disability and that anything to help improve that access and reduce health inequality is worth considering. The committee noted that people with a learning disability could benefit from a treatment involving fewer injections and fewer visits to the clinic for treatment. The committee considered that a difference in prevalence between different groups was not considered an equalities issue that could be addressed through a technology appraisal. It was satisfied that these groups would have appropriate access to treatments such as dexamethasone intravitreal implant if it was recommended. The committee concluded that recommending dexamethasone intravitreal implant would address many of the important equalities issues identified. # Innovation ## Dexamethasone intravitreal implant will reduce the number of treatment visits and improve quality of life for people with diabetic macular oedema The company considered dexamethasone to be innovative. This is because it addresses a substantial unmet clinical need for people with phakic eyes for whom non-corticosteroids do not work well enough or are unsuitable. The company highlighted that dexamethasone intravitreal implant offers a treatment option that improves patient outcomes and decreases the burden on patients and healthcare systems. The clinical experts highlighted that dexamethasone needs less frequent injections compared with anti-VEGFs, and might address some of the capacity issues that they currently face in clinical practice. The committee noted that these benefits were likely to be captured in the QALY and concluded that dexamethasone intravitreal implant would reduce the number of treatment visits and improve quality of life for people with diabetic macular oedema. # Conclusion ## Dexamethasone intravitreal implant is recommended for treating diabetic macular oedema in people with a phakic lens Each of the plausible analyses for dexamethasone compared with anti-VEGFs in the population with phakic eyes when non-corticosteroids do not work well enough resulted in ICERs showing that dexamethasone dominated anti-VEGFs, or that dexamethasone was associated with cost savings per QALY lost in the range normally considered a cost-effective use of NHS resources. The committee noted that the company provided no evidence for people for whom non-corticosteroids are unsuitable. However, based on the feedback from the clinical experts, the committee added that they would expect clinical effectiveness to be similar in this group (see section 3.7). The committee was satisfied that this group can be clearly defined in clinical practice and that the group is very small meaning that the risk to the NHS would be low (see section 3.14). It agreed that recommending dexamethasone intravitreal implant in this group could address some important equalities issues (see section 3.15). Overall, the committee agreed that dexamethasone intravitreal implant is recommended for treating diabetic macular oedema in people with a phakic lens for whom non-corticosteroids do not work well enough or are unsuitable. This recommendation from NICE means that dexamethasone intravitreal implant is recommended for treating visual impairment due to diabetic macular oedema only if the diabetic macular oedema has not responded well enough to non-corticosteroids, or non-corticosteroids are unsuitable, irrespective of whether they have a phakic or pseudophakic lens. NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema (TA349) has been updated and replaced by this guidance at publication. Considerations for people with a pseudophakic (intraocular) lens are still available in the evidence review for NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema (TA349).	{'Recommendations': "Dexamethasone intravitreal implant is recommended as an option for treating visual impairment caused by diabetic macular oedema in adults only if their condition has not responded well enough to, or if they cannot have non-corticosteroid therapy.\n\nThis recommendation is not intended to affect treatment with dexamethasone intravitreal implant that was started in the NHS before this guidance was published. Adults having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.This technology appraisal is a partial review of NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema (TA349) which recommended its use for people who have a pseudophakic (intraocular) lens and whose condition did not respond well enough to, or who could not have non-corticosteroid therapy. This partial review specifically considers people with diabetic macular oedema with a phakic (natural) lens and whose condition did not respond well enough to, or who could not have non-corticosteroid therapy. This final draft guidance from NICE means that dexamethasone intravitreal implant is recommended for treating visual impairment due to diabetic macular oedema only if the diabetic macular oedema has not responded well enough to non-corticosteroids, or non-corticosteroids are unsuitable, irrespective of whether they have a phakic or pseudophakic lens. TA349 has been updated and replaced by this guidance at publication. The considerations below refer only to evidence covered by the partial review.\n\nWhy the committee made these recommendations\n\nStandard care for people with diabetic macular oedema who still have a natural lens (phakic) is anti-vascular endothelial growth factor (anti-VEGF) treatments (such as ranibizumab or aflibercept), or laser monotherapy. If non-corticosteroids do not work well enough, people can keep having anti-VEGFs or laser monotherapy. In people with a phakic lens and diabetic macular oedema who cannot have non-corticosteroid therapy, watch and wait is the only available treatment option.\n\nClinical trial evidence shows that dexamethasone intravitreal implant is more effective than a sham (inactive) procedure. The sham procedure may be considered as a proxy for continued anti-VEGF therapies. The resulting cost-effectiveness estimates for dexamethasone intravitreal implant compared with anti-VEGF therapy are likely to be within what NICE normally considers an acceptable use of NHS resources. Although no cost-effectiveness evidence was presented for people for whom non-corticosteroids are unsuitable, the committee considered the equalities issues, the unmet need, and the size of the population, and agreed that the risk to the NHS was low, and therefore it is recommended.", 'Information about dexamethasone intravitreal implant': "# Marketing authorisation indication\n\nDexamethasone 700\xa0micrograms intravitreal implant (Ozurdex, AbbVie), is 'indicated for the treatment of adult patients with visual impairment due to diabetic macular oedema who are pseudophakic or who are considered insufficiently responsive to, or unsuitable for non-corticosteroid therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for dexamethasone.\n\n# Price\n\nDexamethasone intravitreal implant costs £870.00 per 700\xa0micrograms (excluding VAT; BNF accessed online July\xa02022). Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "This appraisal focuses only on the partial review for people who have a phakic (natural) lens. Considerations for people with a pseudophakic (intraocular) lens are still available in the evidence review for NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema (TA349).\n\nThe appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers (TA824) for full details of the evidence for people with a phakic (natural) lens.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage.\n\n# The condition\n\n## There is an unmet need for an effective treatment given less frequently\n\nThe patient expert explained the nature of their experience with current treatment. They explained that the loss of vision has a significant impact on a person's independence and mental health. The patient expert highlighted that having frequent eye injections causes fear, but there is no alternative because laser therapy has not been very effective for them. They emphasised that reducing the number of times they need treatment, especially for an eye injection, would be of huge benefit for their quality of life. They also explained that for this population, there are no other effective treatment options if anti-vascular endothelial growth factor (anti-VEGF) treatments do not work. The patient expert highlighted that although treatments might not improve their diabetic macular oedema, they can stop it from getting worse, which is still very important to people with the condition. The company noted that for people for whom non-corticosteroids are unsuitable, there are no active pharmacological therapy options and watch and wait is the only available treatment option. Dexamethasone intravitreal implant would therefore provide a pharmacological treatment option for these people. They emphasised that the impact of dexamethasone intravitreal implant would mean less frequent hospital visits and injections compared with anti-VEGF treatments. The committee was aware that some people with diabetic macular oedema may require help from a carer to travel to appointments. The patient expert emphasised that people with diabetic macular oedema may be unsure about using steroids because it could affect their diabetes management. The clinical experts explained that because it is used in small quantities directly into the eye, using dexamethasone should not affect their diabetes management. The committee concluded that there is an unmet need for another treatment option for diabetic macular oedema in people who have a phakic lens. It added that people with diabetic macular oedema and clinicians would welcome an effective new treatment option that is used less frequently.\n\n## Having a longer time between treatments will improve outcomes for people with diabetic macular oedema\n\nThe clinical experts emphasised that having a longer time between treatments could benefit both people with diabetic macular oedema and clinicians. They highlighted that people with diabetes often have multiple hospital appointments in different departments. Using dexamethasone intravitreal implant would reduce the number of visits to the eye clinics for follow up or treatment. The clinical experts explained that a longer time between treatments will free up the capacity in the NHS as well as improve quality of life for people with diabetic macular oedema. The clinical experts agreed that the availability of dexamethasone intravitreal implant for this population would change practice. The other treatments do not work well for these people and are only used because clinicians prefer to offer some treatment rather than nothing at all. The clinical experts explained that people with diabetic macular oedema who still have their natural lens are at a significant disadvantage compared with people who have a pseudophakic lens because of the difference in access to dexamethasone. So, they would welcome it as an option to improve the quality of life for people with diabetic macular oedema and their carers. The committee heard from the clinical expert that having a longer time between treatments will free up the capacity in the NHS, but the committee noted that there was no evidence provided for this. The committee concluded that having a longer time between treatments will improve outcomes for people with diabetic macular oedema who have a natural (phakic) lens.\n\n# Treatment pathway and comparators\n\n## Anti-VEGFs are the most relevant comparators for people for whom non-corticosteroids do not work well enough\n\nIn its submission, the company compared dexamethasone intravitreal implant with the anti-VEGF therapies ranibizumab and aflibercept. It considered options such as laser photocoagulation alone and bevacizumab. It stated that anti-VEGF therapies would be the most relevant comparators for people for whom non-corticosteroids do not work well enough. It highlighted that bevacizumab does not have a marketing authorisation for this indication and therefore any use would be off-label. The company stated that based on UK clinical feedback, laser photocoagulation is only used in people when the macular oedema does not involve the centre (around 20% of the total diabetic macular oedema population) or in people with diabetic macular oedema with no associated visual impairment, because of concerns around safety and long-term clinical efficacy. For these reasons, laser photocoagulation and bevacizumab were excluded as comparators in the company submission. The committee accepted that anti-VEGFs were the most appropriate comparators for dexamethasone in people for whom non-corticosteroids did not work well enough.\n\n## There is a small percentage of people for whom non-corticosteroids are unsuitable and this population can be easily defined in clinical practice\n\nThe committee discussed the treatment pathway and the proposed position of dexamethasone intravitreal implant. The clinical experts highlighted that there is a low proportion of people for whom non-corticosteroids are unsuitable (5% to 10%) such as people who are pregnant, have established allergies to anti-VEGFs, or have had a cardiovascular event in the past 3\xa0to 6\xa0months (such as a stroke or myocardial infarction). The clinical experts added that people who are unable to have frequent injections because they cannot get to the hospital, their carers cannot bring them, or the hospital is too far would also be unable to have non-corticosteroids. The clinical experts emphasised that although this is a small group, it is important that they have access to treatment that is suitable for them as watch and wait is the only available treatment option. The committee agreed that there is a small percentage of people for whom non-corticosteroids are unsuitable and that this population could be easily defined in clinical practice.\n\n# Clinical evidence\n\n## The results from the MEAD trials are generalisable to UK practice\n\nThe ERG highlighted several differences in the baseline characteristics of people in the pooled MEAD trials compared with UK clinical practice. The previous use of laser, the previous use of anti-VEGF therapy, the proportion of people with baseline cataracts and the proportion of people with baseline best-corrected visual acuity (BCVA) differed from that expected in UK clinical practice. Additionally, in the company submission, the sham arm of MEAD was used as a proxy for continued anti-VEGF use. The committee acknowledged that the MEAD trials most closely represented the group for whom non-corticosteroids do not work well enough, and people for whom non-corticosteroids are unsuitable would not be part of this evidence base. The clinical expert explained that the population in the sham arm of the MEAD trials can be considered comparable to the population expected in clinical practice from a biological point of view, and that the sham arm of the MEAD is a good proxy for anti-VEGF use in the comparison. The company used a last observation carried forward (LOCF) approach to account for missing data. The ERG expressed concerns that a LOCF approach biases the sham and dexamethasone intravitreal implant arms and emphasised that it was not possible to predict the direction of bias. Despite the uncertainties, the committee considered that the MEAD trials represent the most appropriate source of evidence for dexamethasone intravitreal implant for people for whom non-corticosteroids do not work well enough.\n\n## Data from MEAD-010 and MEAD-011 suggests that dexamethasone intravitreal implant is more effective than sham\n\nThe clinical evidence for dexamethasone intravitreal implant came from 2 3‑year, phase\xa03, multicentre, masked, randomised, sham-controlled trials: MEAD‑010 and MEAD‑011. The trials compared dexamethasone 700\xa0micrograms and dexamethasone 350\xa0micrograms with sham procedure in adults with either pseudophakic or phakic diabetic macular oedema. MEAD‑010 included 494\xa0people and took place at 59\xa0study centres in 10\xa0countries. MEAD‑011 included 554\xa0people and took place at 72\xa0study centres in 14\xa0countries, with a maximum follow up of 39\xa0months. For this appraisal, only the dexamethasone 700\xa0microgram and sham arms from the phakic (natural lens) subgroups of the trials are relevant. The primary outcome was mean change in BCVA from baseline. BCVA was measured using the Early Treatment Diabetic Retinopathy Study method. The company submission pooled data from MEAD‑010 and MEAD‑011 for the phakic-only modified ITT (mITT) populations (262 dexamethasone intravitreal implant, 250 sham) and this analysis was used to inform the efficacy of dexamethasone intravitreal implant in the company's base case in their economic model. The sham arm of MEAD was used as a proxy for continued anti-VEGF use. The results from the pooled analysis of the phakic-only populations of the MEAD trials showed that at 39\xa0months, a significantly greater number of people who had dexamethasone intravitreal implant achieved BCVA improvement of at least 10\xa0letters and at least 15\xa0letters from baseline compared with sham (the associated p values are academic in confidence and cannot be presented here). The results for at least a 10‑letter improvement in BCVA from baseline were also used in the company's economic model. The committee accepted that it is appropriate for the sham arm of the MEAD trial to be used as a proxy for continued anti-VEGF therapy. The committee concluded that the results from the pooled MEAD trials showed that dexamethasone intravitreal implant is more effective than sham in people with diabetic macular oedema who have a phakic lens.\n\n## Dexamethasone intravitreal implant is likely to be clinically effective in people with phakic diabetic macular oedema for whom non-corticosteroids are unsuitable\n\nThe company had not provided any clinical evidence for people with diabetic macular oedema and a phakic lens for whom non-corticosteroids are unsuitable. They explained that there is no relevant additional evidence available to model this specific population beyond the data that was presented in the evidence review for NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema (TA349). The company submission stated that this population has a high unmet need, and this group is likely to be a small number. The clinical experts explained that there was no biologically plausible reason why dexamethasone intravitreal implant would not be of similar clinical benefit in this group compared with those for whom non-corticosteroids do not work well enough. The committee agreed that although the company provided no evidence for this population, it is expected to be small and can be clearly defined in clinical practice. It concluded that dexamethasone intravitreal implant is likely to be clinically effective in people with diabetic macular oedema and a phakic lens that is unsuitable for non-corticosteroids.\n\n# The company's economic model\n\n## The company's economic model structure is consistent with that used in NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema\n\nThe company presented a Markov state transition model, with multiple discrete and independent health states used to capture the treatment of eyes affected with diabetic macular oedema and the progression of visual acuity over time. The ERG agreed that the model structure was consistent with that used in the evidence review for NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema (TA349). The committee agreed that the company's model structure was appropriate for decision making.\n\n# Time horizon\n\n## Results do not affect the cost effectiveness when adopting a lifetime time horizon or 10-year time horizon\n\nThe company adopted a lifetime time horizon (40\xa0years), saying that this is consistent with that used in NICE's technology appraisal guidance on fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema in phakic eyes after an inadequate response to previous therapy and in the evidence review for NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema (TA349). The ERG considered that a shorter time horizon (10\xa0years) should be used because the company's long-term modelling assumptions are too simplistic. The committee noted that the time horizon chosen by the company was the longest seen in eye appraisals to date. It also considered that a shorter time horizon may be more appropriate because it is also consistent with other technology appraisals in this clinical area. The committee considered both time horizons but concluded that the choice of time horizon made little difference to the cost effectiveness, so both were accepted for decision making.\n\n## Assumptions about changes in BCVA in years\xa04 and 5 did not have a substantial effect on the cost-effectiveness results\n\nIn the company's model, the 3‑monthly transition probabilities in years\xa04 and 5 were assumed to equal the last transition probability matrix estimated from MEAD (for both treatment options). The company emphasised that for dexamethasone intravitreal implant there is an upward trend in visual acuity outcomes from the end of MEAD (just over 3\xa0years). The clinical experts highlighted that it is possible to see improvements in the long term in BCVA, although this might only be for a small number of people. The ERG highlighted that the changes in BCVA resulting from dexamethasone intravitreal implant treatment in years\xa04 and 5 are still a key area of uncertainty and preferred that dexamethasone intravitreal implant maintains vision (no net improvement) in years\xa04 and 5. The committee noted that this assumption did not have a big effect on the incremental cost-effectiveness ratio (ICER) or on the overall net monetary benefit. It agreed that it could be optimistic to assume an improvement in visual acuity in years\xa04 and 5 of the model without further data and if this might only be seen in a small number of people. However, it concluded that the use of different assumptions in the company's and ERG's analyses did not have a substantial effect on the cost-effectiveness results.\n\n## Both the ERG and the company's preferred choice of source for the natural history of vision were considered for decision making and neither had a substantial effect on the cost-effectiveness results\n\nThe company's economic model used a 3‑month probability of gaining or losing at least 10\xa0letters of BCVA of 2.5% or 3.5% respectively, as reported in NICE's technology appraisal guidance on ranibizumab for treating diabetic macular oedema. The ERG preferred a 3‑month probability of gaining or losing at least 10\xa0letters of BCVA of 0% or 3.5% respectively, based on NICE's technology appraisal guidance on fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema in phakic eyes after an inadequate response to previous therapy. The ERG highlighted that the choice of source for natural history of vision moved the ICER from the southeast to the southwest quadrant (southwest quadrant ICERs represent costs saved per quality-adjusted life year [QALY] lost, whereas southeast quadrant ICERs represent costs saved per QALY gained). The committee noted that the choice did not have a substantial effect on the overall net monetary benefit result (the actual results are commercial in confidence and cannot be presented here). The committee concluded that without better data for the natural history of vision, both approaches were considered for decision making and neither had a substantial effect on the cost-effectiveness results.\n\n# Cost-effectiveness estimates\n\n## Dexamethasone intravitreal implant is cost effective compared with anti-VEGFs for people for whom non-corticosteroids do not work well enough\n\nThe company compared dexamethasone intravitreal implant with a composite comparator consisting of anti-VEGF treatments (aflibercept and ranibizumab). The company's base-case deterministic ICER for dexamethasone intravitreal implant dominates (that is, works better and costs less than) anti-VEGFs when the list price of anti-VEGFs is used (incremental costs ‑£6,969; incremental QALYs 0.114). The corresponding probabilistic ICER (generated by the ERG) for dexamethasone intravitreal implant also dominated anti-VEGFs when the list price of anti-VEGFs was used (incremental costs ‑£7,024; incremental QALYs 0.123). Additionally for the results using a 100% aflibercept comparator, the company's ICER for dexamethasone intravitreal implant dominated aflibercept when the list price of aflibercept was used (incremental costs ‑£9,549; incremental QALYs 0.114). When using a 100% ranibizumab comparator, the company's ICER for dexamethasone intravitreal implant also dominated ranibizumab when the list price of ranibizumab was used (incremental costs ‑£2,581; incremental QALYs 0.114). Taking into account confidential prices for anti-VEGFs, dexamethasone intravitreal implant still dominated anti-VEGFs (exact ICERs are confidential and cannot be reported here). The committee noted that the ERG's cost-effectiveness base case estimated that dexamethasone intravitreal implant was associated with a small loss in QALYs compared with anti-VEGFs. Therefore, the ERG's cost-effectiveness base-case ICER was in the southwest quadrant of the cost-effectiveness plane. It was noted that in situations in which an ICER is estimated for a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment becomes. The ERG's base-case cost-effectiveness analysis showed dexamethasone intravitreal implant was associated with cost savings per QALY lost compared with anti-VEGFs when the list price of anti-VEGFs was used. The ERG's deterministic ICER was £1,040,800 (southwest) per QALY lost (incremental costs ‑£6.333; incremental QALYs ‑0.006). The corresponding probabilistic ICER was £2,267,457 (southwest) per QALY lost (incremental costs ‑£6,322; incremental QALYs ‑0.0033). The ERG replicated the company analyses using the confidential discount for anti-VEGFs (exact ICERs are confidential and cannot be reported here). Dexamethasone intravitreal implant remained associated with cost savings per QALY lost in the ERG's base case and these ICERs were above £30,000 per QALY lost. Overall, the committee concluded that dexamethasone intravitreal implant was likely to be cost-effective compared with anti-VEGFs.\n\n## Dexamethasone intravitreal implant is a cost-effective use of NHS resources when using the net monetary benefit approach compared with anti-VEGFs\n\nThe committee also considered the incremental net monetary benefit to compare dexamethasone intravitreal implant with anti-VEGFs to support decision making. An advantage of the net monetary benefit is that it allows the cost of an error to be quantified. A positive net monetary benefit implies that the intervention is cost effective compared with the alternative at the given cost-effectiveness threshold. In analyses that included the confidential discount for anti-VEGFs, the net monetary benefit results were found to stay positive at thresholds of £20,000 and £30,000 per QALY gained for both the company base case and the ERG's base case. Given that any differences in QALYs between dexamethasone intravitreal implant and anti-VEGFs are small, the committee concluded that dexamethasone intravitreal implant is a cost-effective use of NHS resources when using the net monetary benefit approach compared with anti-VEGFs.\n\n## Although no cost-effectiveness results were presented for people with phakic diabetic macular oedema that is unsuitable for non-corticosteroids, the risk to the NHS would be low\n\nThe committee noted that the company provided no cost-effectiveness evidence for people for whom non-corticosteroids are unsuitable. The committee recalled the views of the company and the clinical experts that they expected that dexamethasone intravitreal implant would be of similar clinical benefit in this group compared with those for whom non-corticosteroids do not work well enough (see section 3.7). The committee noted that the comparator for people with diabetic macular oedema that is unsuitable for non-corticosteroids would be watch and wait rather than continued use of anti-VEGFs. The company submission highlighted that because this population is expected to be small, it would not have a substantial impact on the overall cost effectiveness. The committee noted that this group has no available pharmacotherapy treatment options. It was also mindful that it would need to consider relevant factors such as equalities issues in making its decision (see section 3.15). It agreed that dexamethasone was likely to be similarly effective in this population and since the population is expected to be small, the risk to the NHS would be low if approved.\n\n# Other factors\n\n## Recommending dexamethasone intravitreal implant would address many of the important equalities issues identified\n\nThe company submission noted that no equality considerations relating to using dexamethasone intravitreal implant were identified or anticipated. At scoping it was raised that if a person is registered as blind or partially sighted, it is considered a disability, as stated in the Equality Act 2010. Therefore, the committee noted the patient population addressed in this appraisal is a protected group under this act. The patient expert emphasised that there is a high prevalence of diabetes among people with a learning disability. They highlighted there are challenges in providing treatments and routine eye tests for people with a learning disability and that anything to help improve that access and reduce health inequality is worth considering. The committee noted that people with a learning disability could benefit from a treatment involving fewer injections and fewer visits to the clinic for treatment. The committee considered that a difference in prevalence between different groups was not considered an equalities issue that could be addressed through a technology appraisal. It was satisfied that these groups would have appropriate access to treatments such as dexamethasone intravitreal implant if it was recommended. The committee concluded that recommending dexamethasone intravitreal implant would address many of the important equalities issues identified.\n\n# Innovation\n\n## Dexamethasone intravitreal implant will reduce the number of treatment visits and improve quality of life for people with diabetic macular oedema\n\nThe company considered dexamethasone to be innovative. This is because it addresses a substantial unmet clinical need for people with phakic eyes for whom non-corticosteroids do not work well enough or are unsuitable. The company highlighted that dexamethasone intravitreal implant offers a treatment option that improves patient outcomes and decreases the burden on patients and healthcare systems. The clinical experts highlighted that dexamethasone needs less frequent injections compared with anti-VEGFs, and might address some of the capacity issues that they currently face in clinical practice. The committee noted that these benefits were likely to be captured in the QALY and concluded that dexamethasone intravitreal implant would reduce the number of treatment visits and improve quality of life for people with diabetic macular oedema.\n\n# Conclusion\n\n## Dexamethasone intravitreal implant is recommended for treating diabetic macular oedema in people with a phakic lens\n\nEach of the plausible analyses for dexamethasone compared with anti-VEGFs in the population with phakic eyes when non-corticosteroids do not work well enough resulted in ICERs showing that dexamethasone dominated anti-VEGFs, or that dexamethasone was associated with cost savings per QALY lost in the range normally considered a cost-effective use of NHS resources. The committee noted that the company provided no evidence for people for whom non-corticosteroids are unsuitable. However, based on the feedback from the clinical experts, the committee added that they would expect clinical effectiveness to be similar in this group (see section 3.7). The committee was satisfied that this group can be clearly defined in clinical practice and that the group is very small meaning that the risk to the NHS would be low (see section 3.14). It agreed that recommending dexamethasone intravitreal implant in this group could address some important equalities issues (see section 3.15). Overall, the committee agreed that dexamethasone intravitreal implant is recommended for treating diabetic macular oedema in people with a phakic lens for whom non-corticosteroids do not work well enough or are unsuitable. This recommendation from NICE means that dexamethasone intravitreal implant is recommended for treating visual impairment due to diabetic macular oedema only if the diabetic macular oedema has not responded well enough to non-corticosteroids, or non-corticosteroids are unsuitable, irrespective of whether they have a phakic or pseudophakic lens. NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema (TA349) has been updated and replaced by this guidance at publication. Considerations for people with a pseudophakic (intraocular) lens are still available in the evidence review for NICE's technology appraisal guidance on dexamethasone intravitreal implant for treating diabetic macular oedema (TA349)."}	https://www.nice.org.uk/guidance/ta824	Evidence-based recommendations on dexamethasone intravitreal implant (Ozurdex) for treating visual impairment caused by diabetic macular oedema in adults.
79191f2276836f984a28a95e5de759cb5453cd74	nice	Obesity: identification, assessment and management	Obesity: identification, assessment and management This guideline covers identifying, assessing and managing obesity in children (aged 2 years and over), young people and adults. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Generic principles of care ## Adults Equip specialist settings for treating people who are living with severe obesity with, for example, special seating and adequate weighing and monitoring equipment. Ensure hospitals have access to specialist equipment – such as larger scanners and beds – when providing general care for people who are living with severe obesity. Discuss the choice of interventions for weight management with the person. The choice of intervention should be agreed with the person. Tailor the components of the planned weight management programme to the person's preferences, initial fitness, health status and lifestyle. ## Children Coordinate the care of children and young people around their individual and family needs. Comply with the approaches outlined in the Department of Health's A call to action on obesity in England. See also NICE's guideline on weight management: lifestyle services for overweight or obese children and young people. Aim to create a supportive environment that helps a child who is overweight or who has obesity, and their family, make lifestyle changes. (The committee noted that 'environment' could include settings other than the home, for example, schools.) Make decisions about the care of a child who is overweight or has obesity (including assessment and agreeing goals and actions) together with the child and family. Tailor interventions to the needs and preferences of the child and the family. Ensure that interventions for children who are living with overweight or obesity address lifestyle within the family and in social settings. Encourage parents (or carers) to take main responsibility for lifestyle changes in children who are living with overweight or obesity, especially if they are younger than 12 years. Take into account the age and maturity of the child, and the preferences of the child and the parents. ## Adults and children Offer regular, non-discriminatory long-term follow-up by a trained professional. Ensure continuity of care in the multidisciplinary team through good record keeping. # Identifying and assessing overweight, obesity and central adiposity ## Identification and assessment in adults Use clinical judgement to decide when to measure a person's height and weight. Opportunities include when registering with a GP, consultations for related conditions (such as type 2 diabetes and cardiovascular disease) and other routine health checks. Encourage adults with a body mass index (BMI) below 35 kg/m² to: measure their own waist-to-height ratio to assess central adiposity (the accumulation of excess fat in the abdominal area) seek advice and further clinical assessments (such as a cardiometabolic risk factor assessment) from a healthcare professional if the measurement indicates an increased health risk. Explain to people that to accurately measure their waist and calculate their own waist-to-height ratio, they should follow the advice in box 1. Direct people to resources that give advice on how to measure waist circumference, such as the NHS BMI healthy weight calculator. See recommendations 1.2.11 and 1.2.12 for how to interpret waist-to-height ratio. Measure Find the bottom of the ribs and the top of the hips. Wrap a tape measure around the waist midway between these points (this will be just above the belly button) and breathe out naturally before taking the measurement. Calculate Measure waist circumference and height in the same units (either both in centimetres, or both in inches). If you know your height in feet and inches, convert it to inches (for example, 5 feet 7 inches is 67 inches). Divide waist measurement by height measurement. For example: inches divided by 67 inches = waist-to-height ratio of 0.57 or cm divided by 170 cm = waist-to-height ratio of 0.57. Use BMI as a practical measure of overweight and obesity. Interpret it with caution because it is not a direct measure of central adiposity. In adults with BMI below 35 kg/m2, measure and use their waist-to-height ratio, as well as their BMI, as a practical estimate of central adiposity and use these measurements to help to assess and predict health risks (for example, type 2 diabetes, hypertension or cardiovascular disease). Do not use bioimpedance as a substitute for BMI as a measure of general adiposity in adults. Define the degree of overweight or obesity in adults as follows, if they are not in the groups covered by recommendation 1.2.8: healthy weight: BMI 18.5 kg/m2 to 24.9 kg/m2 -verweight: BMI 25 kg/m2 to 29.9 kg/m2 -besity class 1: BMI 30 kg/m2 to 34.9 kg/m2 -besity class 2: BMI 35 kg/m2 to 39.9 kg/m2 -besity class 3: BMI 40 kg/m2 or more. Use clinical judgement when interpreting the healthy weight category because a person in this category may nevertheless have central adiposity. See Public Health England's guidance on obesity and weight management for people with learning disabilities for information on reasonable adjustments that may need to be made. People with a South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family background are prone to central adiposity and their cardiometabolic risk occurs at lower BMI, so use lower BMI thresholds as a practical measure of overweight and obesity: -verweight: BMI 23 kg/m2 to 27.4 kg/m2 -besity: BMI 27.5 kg/m2 or above. For people in these groups, obesity classes 2 and 3 are usually identified by reducing the thresholds highlighted in recommendation 1.2.7 by 2.5 kg/m2. Interpret BMI with caution in adults with high muscle mass because it may be a less accurate measure of central adiposity in this group. Interpret BMI with caution in people aged 65 and over, taking into account comorbidities, conditions that may affect functional capacity and the possible protective effect of having a slightly higher BMI when older. Define the degree of central adiposity based on waist-to-height ratio as follows: healthy central adiposity: waist-to-height ratio 0.4 to 0.49, indicating no increased health risks increased central adiposity: waist-to-height ratio 0.5 to 0.59, indicating increased health risks high central adiposity: waist-to-height ratio 0.6 or more, indicating further increased health risks. These classifications can be used for people with a BMI under 35 kg/m2 of both sexes and all ethnicities, including adults with high muscle mass. The health risks associated with higher levels of central adiposity include type 2 diabetes, hypertension and cardiovascular disease. When talking to a person about their waist-to-height ratio, explain that they should try and keep their waist to half their height (so a waist-to-height ratio of under 0.5). Ask the person's permission before talking about the degree of overweight, obesity and central adiposity, and discuss it in a sensitive manner. Give adults information about the severity of their overweight or obesity and central adiposity and the impact this has on their risk of developing other long-term conditions (such as type 2 diabetes, cardiovascular disease, hypertension, dyslipidaemia, certain cancers and respiratory, musculoskeletal and other metabolic conditions such as non-alcoholic fatty liver disease). Discuss and agree the level of intervention with adults who: are living with overweight or obesity or have increased health risk based on their waist-to-height ratio.Take into account people's individual needs and preferences, and factors such as weight-related comorbidities, ethnicity, socioeconomic status, family medical history, and special educational needs and disabilities (SEND). See the recommendations on lifestyle interventions, behavioural interventions, physical activity, dietary approaches, pharmacological interventions and surgical interventions. Offer a higher level of intervention to people with weight-related comorbidities (see recommendation 1.3.6 for details of comorbidities). Adjust the approach depending on the person's clinical needs. For people with a BMI over 35 kg/m2 who have recently developed diabetes, see recommendation 1.11.1, and for people with a BMI of 50 and over, see recommendation 1.3.7 and recommendation 1.10.7. For a short explanation of why the committee made the 2022 recommendations and how they might affect practice, see the rationale and impact section on identifying and assessing overweight, obesity and central adiposity in adults . Full details of the evidence and the committee's discussion are in evidence review A: accuracy of anthropometric measures in assessing health risks associated with overweight and obesity in adults. Loading. Please wait. Ensure healthcare professionals are aware that people from Black, Asian and minority ethnic family backgrounds are at an increased risk of chronic health conditions at a lower BMI than people from a white family background (below BMI 25 kg/m2). Ensure people from Black, Asian and minority ethnic family backgrounds are aware that they face an increased risk of chronic health conditions at a lower BMI than people from a white family background (below BMI 25 kg/m2). Use existing local information networks for people of Black and minority ethnic family backgrounds to share information on the increased risks these groups face at a lower BMI. ## Identification and assessment in children and young people Use clinical judgement to decide when to measure a child or young person's height and weight. Opportunities include when registering with a GP, consultations for related conditions (such as type 2 diabetes and cardiovascular disease) and other routine health checks. Use BMI as a practical estimate of overweight and obesity, and ensure that charts used are: appropriate for children and young people and adjusted for age and sex. Interpret BMI with caution because it is not a direct measure of central adiposity. The Royal College of Paediatrics and Child Health UK-World Health Organization (WHO) growth charts and BMI charts should be used to plot and classify BMI centile. The childhood and puberty close monitoring (CPCM) form can also be used for continued BMI monitoring in children aged 2 and over, especially in instances where puberty is either premature or delayed. Refer to special BMI growth charts for children and young people with Down's syndrome, if needed. Consider using waist-to-height ratio in children and young people aged 5 and over to assess and predict health risks associated with central adiposity (such as type 2 diabetes, hypertension or cardiovascular disease). See box 1 for information on how the waist should be measured and how to calculate waist-to-height ratio. Do not use bioimpedance as a substitute for BMI as a measure of general adiposity in children and young people. Define the degree of overweight or obesity in children and young people using the following classifications: -verweight: BMI 91st centile + 1.34 standard deviations (SDs) clinical obesity: BMI 98th centile + 2.05 SDs severe obesity: BMI 99.6th centile + 2.68 SDs. Use clinical judgement when interpreting BMI below the 91st centile, especially the healthy weight category in BMI charts because a child or young person in this category may nevertheless have central adiposity. Define the degree of central adiposity based on waist-to-height ratio in children and young people as follows: healthy central adiposity: waist-to-height ratio 0.4 to 0.49, indicating no increased health risk increased central adiposity: waist-to-height ratio 0.5 to 0.59, indicating increased health risk high central adiposity: waist-to-height ratio 0.6 or more, indicating further increased health risk. These classifications can be used for children and young people of both sexes and all ethnicities. The health risks associated with higher central adiposity levels include type 2 diabetes, hypertension and cardiovascular disease. When talking to a child, young person, and their families and carers, explain that they should try and keep their waist to half their height (so a waist-to-height-ratio of under 0.5). Ask permission from children, young people, and their families and carers, before talking about the degree of overweight, obesity and central adiposity, and discuss it in a sensitive and age-appropriate manner. Consider tailored interventions for children and young people: who are living with overweight or obesity or have increased health risk based on their waist-to-height ratio. Take into account their individual needs and preferences, and factors such as weight-related comorbidities, ethnicity, socioeconomic status, social complexity (for example, looked-after children and young people), family medical history, mental and emotional health and wellbeing, developmental age, and special educational needs and disabilities (SEND). See the recommendations on lifestyle interventions, behavioural interventions, physical activity, dietary approaches, pharmacological interventions and surgical interventions. Offer a higher level of intervention to children with weight-related comorbidities (see recommendation 1.3.9 for details of comorbidities). Adjust the approach depending on the child's clinical needs. For pharmacological treatment in children with comorbidities, see recommendations 1.8.5 and 1.8.6 and for surgical interventions in young people with exceptional circumstances, see recommendations 1.10.12 and 1.10.13. For a short explanation of why the committee made the 2022 recommendations and how they might affect practice, see the rationale and impact section on identifying and assessing overweight, obesity and central adiposity in children and young people . Full details of the evidence and the committee's discussion are in evidence review B: accuracy of anthropometric measures in assessing health risks associated with overweight and obesity in children and young people. Loading. Please wait. # Assessment ## Adults and children Make an initial assessment (see recommendations 1.3.6 and 1.3.8), then use clinical judgement to investigate comorbidities and other factors to an appropriate level of detail, depending on the person, the timing of the assessment, the degree of overweight or obesity, and the results of previous assessments. Manage comorbidities when they are identified; do not wait until the person has lost weight. Offer people who are not yet ready to change the chance to return for further consultations when they are ready to discuss their weight again and willing or able to make lifestyle changes. Give them information on the benefits of losing weight, healthy eating and increased physical activity. Recognise that surprise, anger, denial or disbelief about their health situation may diminish people's ability or willingness to change. Stress that obesity is a clinical term with specific health implications, rather than a question of how people look; this may reduce any negative feelings.During the consultation: Assess the person's view of their weight and the diagnosis, and possible reasons for weight gain. Explore eating patterns and physical activity levels. Explore any beliefs about eating, physical activity and weight gain that are unhelpful if the person wants to lose weight. Be aware that people from certain ethnic and socioeconomic backgrounds may be at greater risk of obesity, and may have different beliefs about what is a healthy weight and different attitudes towards weight management. Find out what the person has already tried and how successful this has been, and what they learned from the experience. Assess the person's readiness to adopt changes. Assess the person's confidence in making changes. Give people and their families and/or carers information on the reasons for tests, how the tests are done, and their results and meaning. If necessary, offer another consultation to fully explore the options for treatment or discuss test results. ## Adults Take measurements (see section 1.2) to determine degree of overweight or obesity and discuss the implications of the person's weight. Then, assess: any presenting symptoms any underlying causes of overweight or obesity eating behaviours any comorbidities (for example type 2 diabetes, hypertension, cardiovascular disease, osteoarthritis, dyslipidaemia and sleep apnoea) any risk factors assessed using lipid profile (preferably done when fasting), blood pressure measurement and HbA1c measurement the person's lifestyle (diet and physical activity) any psychosocial distress any environmental, social and family factors, including family history of overweight and obesity and comorbidities the person's willingness and motivation to change lifestyle the potential of weight loss to improve health any psychological problems any medical problems and medication the role of family and care workers in supporting individuals with learning disabilities to make lifestyle changes.See also NICE's guideline on weight management: lifestyle services for overweight or obese children and young people. Consider referral to tier 3 services if: the underlying causes of overweight or obesity need to be assessed the person has complex disease states or needs that cannot be managed adequately in tier 2 (for example, the additional support needs of people with learning disabilities) conventional treatment has been unsuccessful drug treatment is being considered for a person with a BMI of more than 50 kg/m2 specialist interventions (such as a very-low-calorie diet) may be needed surgery is being considered. For more information on tier 3 services, see NHS England's report on joined up clinical pathways for obesity. ## Children Assessment of comorbidity should be considered for children with a BMI at or above the 98th centile. Take measurements to determine degree of overweight or obesity and raise the issue of weight with the child and family, then assess: presenting symptoms and underlying causes of overweight or obesity willingness and motivation to change comorbidities (such as hypertension, hyperinsulinaemia, dyslipidaemia, type 2 diabetes, psychosocial dysfunction and exacerbation of conditions such as asthma) any risk factors assessed using lipid profile (preferably done when fasting) blood pressure measurement and HbA1c measurement psychosocial distress, such as low self-esteem, teasing and bullying (See also NICE's guideline on weight management: lifestyle services for overweight or obese children and young people) family history of overweight or obesity and comorbidities the child and family's willingness and motivation to change lifestyle lifestyle (diet and physical activity) environmental, social and family factors that may contribute to overweight or obesity, and the success of treatment growth and pubertal status any medical problems and medication the role of family and care workers in supporting people with learning disabilities to make lifestyle changes. Consider referral to an appropriate specialist for children who are living with overweight or obesity and have significant comorbidities or complex needs (for example, learning disabilities or other additional support needs). In tier 3 services, assess associated comorbidities and possible causes for children and young people who are living with overweight or obesity. Use investigations such as: blood pressure measurement lipid profile, preferably while fasting fasting insulin fasting glucose levels and oral glucose tolerance test liver function endocrine function.Interpret the results of any tests used in the context of how the level of the child's overweight or obesity is, the child's age, history of comorbidities, possible genetic causes and any family history of metabolic disease related to overweight or obesity. Make arrangements for transitional care for children and young people who are moving from paediatric to adult services. # Lifestyle interventions ## Adults and children Multicomponent interventions are the treatment of choice. Ensure weight management programmes include behaviour change strategies (see recommendations 1.5.1 to 1.5.3) to increase people's physical activity levels or decrease inactivity, improve eating behaviour and the quality of the person's diet, and reduce energy intake. When choosing treatments, take into account: the person's individual preference and social circumstance and the experience and outcome of previous treatments (including whether there were any barriers) the person's degree of overweight and obesity or increased health risk based on their waist-to-height ratio (see recommendations 1.2.11 and 1.2.15) any comorbidities. Document the results of any discussion. Keep a copy of the agreed goals and actions (ensure the person also does this), or put this in the person's notes. Offer support depending on the person's needs, and be responsive to changes over time. Ensure any healthcare professionals who deliver interventions for weight management have relevant competencies and have had specific training. Provide information in formats and languages that are suited to the person. Use everyday, jargon‑free language and explain any technical terms when talking to the person and their family or carers. Take into account the person's: age and stage of life gender cultural needs and sensitivities ethnicity social and economic circumstances specific communication needs (for example because of learning disabilities, physical disabilities or cognitive impairments due to neurological conditions). Praise successes – however small – at every opportunity to encourage the person through the difficult process of changing established behaviour. Give people who are living with overweight or obesity, and their families and/or carers, relevant information on: being overweight and obesity in general, including related health risks realistic targets for weight loss; for adults, see NICE's guideline on managing overweight and obesity in adults the distinction between losing weight and maintaining weight loss, and the importance of developing skills for both; advise them that the change from losing weight to maintenance typically happens after 6 to 9 months of treatment realistic targets for outcomes other than weight loss, such as increased physical activity and healthier eating diagnosis and treatment options healthy eating in general (more information on healthy eating can be found on the eat well pages of the NHS website) medication and side effects surgical treatments self-care voluntary organisations and support groups and how to contact them.Ensure there is adequate time in the consultation to provide information and answer questions. If a person (or their family or carers) does not feel this is the right time for them to take action, explain that advice and support will be available in the future whenever they need it. Provide contact details so that the person can get in touch when they are ready. ## Adults Encourage the person's partner or spouse to support any weight management programme. Base the level of intensity of the intervention on the level of risk and the potential to gain health benefits (see recommendations 1.2.15 and 1.2.16). ## Children Be aware that the aim of weight management programmes for children and young people can vary. The focus may be on either weight maintenance or weight loss, depending on the person's age and stage of growth. Encourage parents of children and young people who are living with overweight or obesity to lose weight if they are also living with overweight or obesity. # Behavioural interventions ## Adults and children Deliver any behavioural intervention with the support of an appropriately trained professional. ## Adults Include the following strategies in behavioural interventions for adults, as appropriate: self-monitoring of behaviour and progress stimulus control goal setting slowing rate of eating ensuring social support problem solving assertiveness cognitive restructuring (modifying thoughts) reinforcement of changes relapse prevention strategies for dealing with weight regain. ## Children Include the following strategies in behavioural interventions for children, as appropriate: stimulus control self-monitoring goal setting rewards for reaching goals problem solving.Give praise to successes and encourage parents to role-model desired behaviours. # Physical activity ## Adults Encourage adults to increase their level of physical activity even if they do not lose weight as a result, because of the other health benefits it can bring (for example, reduced risk of type 2 diabetes and cardiovascular disease). Encourage adults to meet the recommendations in the UK Chief Medical Officers' physical activity guidelines for weekly activity. Advise that to prevent obesity, most people may need to do 45 to 60 minutes of moderate-intensity activity a day, particularly if they do not reduce their energy intake. Advise people who have been living with obesity and have lost weight that they may need to do 60 to 90 minutes of activity a day to avoid regaining weight. Encourage adults to build up to the recommended activity levels for weight maintenance, using a managed approach with agreed goals. Recommend types of physical activity, including: activities that can be incorporated into everyday life, such as brisk walking, gardening or cycling (see also NICE's guideline on walking and cycling) supervised exercise programmes -ther activities, such as swimming, aiming to walk a certain number of steps each day, or stair climbing.Take into account the person's current physical fitness and ability for all activities. Encourage people to also reduce the amount of time they spend inactive, such as watching television, using a computer or playing video games. ## Children Encourage children and young people to increase their level of physical activity, even if they do not lose weight as a result, because of the other health benefits exercise can bring (for example, reduced risk of type 2 diabetes and cardiovascular disease). Encourage children to meet the recommendations in the UK Chief Medical Officers' physical activity guidelines for daily activity. Be aware that children who are already living with overweight may need to do more than 60 minutes' activity. Encourage children to reduce inactive behaviours, such as sitting and watching television, using a computer or playing video games. Give children the opportunity and support to do more exercise in their daily lives (for example, walking, cycling, using the stairs and active play; see also NICE's guideline on walking and cycling). Make the choice of activity with the child, and ensure it is appropriate to the child's ability and confidence. Give children the opportunity and support to do more regular, structured physical activity (for example football, swimming or dancing). Make the choice of activity with the child, and ensure it is appropriate to the child's ability and confidence. # Dietary approaches ## Adults and children Tailor dietary changes to food preferences and allow for a flexible and individual approach to reducing calorie intake. Do not use unduly restrictive and nutritionally unbalanced diets, because they are ineffective in the long term and can be harmful. Encourage people to improve their diet even if they do not lose weight, because there can be other health benefits. ## Adults The main requirement of a dietary approach to weight loss is that total energy intake should be less than energy expenditure. Diets that have a 600 kcal/day deficit (that is, they contain 600 kcal less than the person needs to stay the same weight) or that reduce calories by lowering the fat content (low-fat diets), in combination with expert support and intensive follow‑up, are recommended for sustainable weight loss. Consider low-calorie diets (800 to 1600 kcal/day), but be aware these are less likely to be nutritionally complete. Do not routinely use very-low-calorie diets (800 kcal/day or less) to manage obesity. Only consider very-low-calorie diets, as part of a multicomponent weight management strategy, for people who are living with obesity and who have a clinically assessed need to rapidly lose weight (for example, people who need joint replacement surgery or who are seeking fertility services). Ensure that: the diet is nutritionally complete the diet is followed for a maximum of 12 weeks (continuously or intermittently) the person following the diet is given ongoing clinical support. Before starting someone on a very-low-calorie diet as part of a multicomponent weight management strategy: Consider counselling and assess for eating disorders or other psychopathology to make sure the diet is appropriate for them. Discuss the risks and benefits with them. Tell them that this is not a long-term weight management strategy, and that regaining weight may happen and is not because of their own or their clinician's failure. Discuss the reintroduction of food following a liquid diet with them. Provide a long-term multicomponent strategy to help the person maintain their weight after the use of a very-low-calorie diet. (See recommendation 1.4.1.) Encourage people to eat a balanced diet in the long term, consistent with other healthy eating advice.More information on healthy eating can be found on the eat well pages of the NHS website. ## Children A dietary approach alone is not recommended. It is essential that any dietary recommendations are part of a multicomponent intervention. Any dietary changes should be age appropriate and consistent with healthy eating advice. For children and young people living with overweight or obesity, total energy intake should be below their energy expenditure. Changes should be sustainable. # Pharmacological interventions ## Adults Consider pharmacological treatment (see table 1) only after dietary, exercise and behavioural approaches have been started and evaluated. NICE has not recommended naltrexone–bupropion, see NICE's technology appraisal guidance on naltrexone–bupropion for managing overweight and obesity. Consider drug treatment (see table 1) for people who have not reached their target weight loss or have reached a plateau on dietary, activity and behavioural changes. Make the decision to start drug treatments after discussing the potential benefits and limitations with the person, including the mode of action, adverse effects and monitoring requirements, and the potential impact on the person's motivation. Make arrangements for appropriate healthcare professionals to offer information, support and counselling on additional diet, physical activity and behavioural strategies when drug treatment is prescribed. Provide information on patient support programmes. Medicine Starting criteria Stopping criteria Liraglutide, see NICE's technology appraisal guidance on liraglutide for managing overweight and obesity BMI of: at least 35 kg/m2 or at least 32.5 kg/m2 for members of minority ethnic groups known to be at equivalent risk of the consequences of obesity at a lower BMI than the white populationandNon-diabetic hyperglycaemia (haemoglobin A1c level of 42 mmol/mol to 47 mmol/mol or a fasting plasma glucose level of 5.5 mmol/litre to 6.9 mmol/litre) andHigh risk of cardiovascular disease based on risk factors such as hypertension and dyslipidaemia andPrescribe in secondary care by a specialist weight management serviceandThe company provides it according to the commercial arrangement. Orlistat BMI of: kg/m2 or more or kg/m2 or more with associated risk factors.Use with other drugs aimed at weight reduction is not recommended. Continue beyond 3 months only if the person has lost at least 5% of their initial body weight since starting orlistat. (See also recommendation 1.9.6 for people with type 2 diabetes.) Semaglutide, see NICE's technology appraisal guidance on semaglutide for managing overweight and obesity BMI of: at least 35.0 kg/m2 or kg/m2 to 34.9 kg/m2 and meet the criteria for referral to specialist weight management services in recommendation 1.3.7.Use lower BMI thresholds (usually reduced by 2.5 kg/m2) for people from South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family backgroundsandAt least 1 weight-related comorbidityandUse within a specialist weight management service. Consider stopping if less than 5% of the initial weight has been lost after 6 months. Use for a maximum of 2 years. ## Children Drug treatment is not generally recommended for children younger than 12 years. In children younger than 12 years, drug treatment may be used only in exceptional circumstances, if severe comorbidities are present. Prescribing should be started and monitored only in specialist paediatric settings. In children aged 12 years and older, treatment with orlistat is recommended only if physical comorbidities (such as orthopaedic problems or sleep apnoea) or severe psychological comorbidities are present. Treatment should be started in a specialist paediatric setting, by multidisciplinary teams with experience of prescribing in this age group. In October 2014, this was an off-label use of orlistat. See NICE's information on prescribing medicines. Do not give orlistat to children for obesity unless prescribed by a multidisciplinary team with expertise in: drug monitoring psychological support behavioural interventions interventions to increase physical activity interventions to improve diet. Drug treatment may be continued in primary care for example with a shared care protocol if local circumstances and/or licensing allow. # Continued prescribing and withdrawal ## Adults and children Pharmacological treatment may be used to maintain weight loss rather than to continue to lose weight. If there is concern about micronutrient intake adequacy, a supplement providing the reference nutrient intake for all vitamins and minerals should be considered, particularly for vulnerable groups such as older people (who may be at risk of malnutrition) and young people (who need vitamins and minerals for growth and development). Offer support to help maintain weight loss to people whose drug treatment is being withdrawn; if they did not reach their target weight, their self-confidence and belief in their ability to make changes may be low. ## Adults Monitor the effect of drug treatment and reinforce lifestyle advice and adherence through regular review. Consider withdrawing drug treatment in people who have not reached weight loss targets (see recommendation 1.9.8 and table 1 for details). Rates of weight loss may be slower in people with type 2 diabetes, so less strict goals than those for people without diabetes may be appropriate. Agree the goals with the person and review them regularly. Only prescribe orlistat as part of an overall plan for managing obesity in adults who meet 1 of the following criteria: a BMI of 28 kg/m2 or more with associated risk factors a BMI of 30 kg/m2 or more. Continue orlistat therapy beyond 3 months only if the person has lost at least 5% of their initial body weight since starting drug treatment. (See also recommendation 1.9.6 for advice on targets for people with type 2 diabetes.) Make the decision to use drug treatment for longer than 12 months (usually for weight maintenance) after discussing potential benefits and limitations with the person. The co-prescribing of orlistat with other drugs aimed at weight reduction is not recommended. ## Children If orlistat is prescribed for children, a 6- to 12‑month trial is recommended, with regular review to assess effectiveness, adverse effects and adherence. In October 2014, this was an off-label use of orlistat. See NICE's information on prescribing medicines. # Surgical interventions Bariatric surgery is a treatment option for people living with obesity if all of the following criteria are fulfilled: They have a BMI of 40 kg/m2 or more, or between 35 kg/m2 and 40 kg/m2 and other significant disease (for example, type 2 diabetes or high blood pressure) that could be improved if they lost weight. All appropriate non-surgical measures have been tried but the person has not achieved or maintained adequate, clinically beneficial weight loss. The person has been receiving or will receive intensive management in a tier 3 service (for more information on tier 3 services, see NHS England's report on joined up clinical pathways for obesity). The person is generally fit for anaesthesia and surgery. The person commits to the need for long-term follow-up. See recommendations 1.10.12 and 1.10.13 for additional criteria to use when assessing children, and recommendation 1.10.7 for additional criteria for adults. See also recommendations 1.11.1 to 1.11.3 for additional criteria for people with type 2 diabetes. The hospital specialist and/or bariatric surgeon should discuss the following with people living with severe obesity if they are considering surgery to aid weight reduction: the potential benefits the longer-term implications of surgery associated risks complications perioperative mortality. The discussion should also include the person's family, as appropriate. Choose the surgical intervention jointly with the person, taking into account: the degree of obesity comorbidities the best available evidence on effectiveness and long-term effects the facilities and equipment available the experience of the surgeon who would perform the operation. Provide regular, specialist postoperative dietetic monitoring, including: information on the appropriate diet for the bariatric procedure monitoring of the person's micronutrient status information on patient support groups individualised nutritional supplementation, support and guidance to achieve long-term weight loss and weight maintenance. Arrange prospective audit so that the outcomes and complications of different procedures, the impact on quality of life and nutritional status, and the effect on comorbidities can be monitored in both the short and the long term. (The National Bariatric Surgery Registry is now available to conduct national audit for a number of agreed outcomes.) The surgeon in the multidisciplinary team should: have had a relevant supervised training programme have specialist experience in bariatric surgery submit data for a national clinical audit scheme (the National Bariatric Surgery Registry is now available to conduct national audit for a number of agreed outcomes). ## Adults In addition to the criteria listed in recommendation 1.10.1, bariatric surgery is the option of choice (instead of lifestyle interventions or drug treatment) for adults with a BMI of more than 50 kg/m2 when other interventions have not been effective. Orlistat may be used to maintain or reduce weight before surgery for people who have been recommended surgery as a first-line option, if it is considered that the waiting time for surgery is excessive. Surgery for obesity should be undertaken only by a multidisciplinary team that can provide: preoperative assessment, including a risk-benefit analysis that includes preventing complications of obesity, and specialist assessment for eating disorders information on the different procedures, including potential weight loss and associated risks regular postoperative assessment, including specialist dietetic and surgical follow up (see recommendation 1.12.1) management of comorbidities psychological support before and after surgery information on, or access to, plastic surgery (such as apronectomy) when appropriate access to suitable equipment, including scales, theatre tables, Zimmer frames, commodes, hoists, bed frames, pressure-relieving mattresses and seating suitable for people undergoing bariatric surgery, and staff trained to use them. Carry out a comprehensive preoperative assessment of any psychological or clinical factors that may affect adherence to postoperative care requirements (such as changes to diet) before performing surgery. Revisional surgery (if the original operation has failed) should be undertaken only in specialist centres by surgeons with extensive experience because of the high rate of complications and increased mortality. ## Children Surgical intervention is not generally recommended in children or young people. Bariatric surgery may be considered for young people only in exceptional circumstances, and if they have achieved or nearly achieved physiological maturity. Surgery for obesity should be undertaken only by a multidisciplinary team that can provide paediatric expertise in: preoperative assessment, including a risk-benefit analysis that includes preventing complications of obesity, and specialist assessment for eating disorders information on the different procedures, including potential weight loss and associated risks regular postoperative assessment, including specialist dietetic and surgical follow up management of comorbidities psychological support before and after surgery information on or access to plastic surgery (such as apronectomy) when appropriate access to suitable equipment, including scales, theatre tables, Zimmer frames, commodes, hoists, bed frames, pressure-relieving mattresses and seating suitable for children and young people undergoing bariatric surgery, and staff trained to use them. Coordinate surgical care and follow‑up around the child or young person and their family's needs. Comply with the approaches outlined in the Department of Heath's a call to action on obesity in England. Ensure all young people have had a comprehensive psychological, educational, family and social assessment before undergoing bariatric surgery. Perform a full medical evaluation, including genetic screening or assessment before surgery to exclude rare, treatable causes of obesity. # Bariatric surgery for people with recent-onset type 2 diabetes For the recommendations in this section, the committee considered that recent-onset type 2 diabetes would include those people whose diagnosis has been made within a 10-year time frame. Offer an expedited assessment for bariatric surgery to people with a BMI of 35 or over who have recent-onset type 2 diabetes as long as they are also receiving or will receive assessment in a tier 3 service (or equivalent). Consider an assessment for bariatric surgery for people with a BMI of 30 to 34.9 who have recent-onset type 2 diabetes as long as they are also receiving or will receive assessment in a tier 3 service (or equivalent). Consider an assessment for bariatric surgery for people of Asian family background who have recent-onset type 2 diabetes at a lower BMI than other populations (see recommendation 1.2.8) as long as they are also receiving or will receive assessment in a tier 3 service (or equivalent). # Follow-up care Offer people who have had bariatric surgery a follow-up care package for a minimum of 2 years within the bariatric service. This should include: monitoring nutritional intake (including protein and vitamins) and mineral deficiencies monitoring for comorbidities medication review dietary and nutritional assessment, advice and support physical activity advice and support psychological support tailored to the individual information about professionally led or peer-support groups. After discharge from bariatric surgery service follow-up, ensure that all people are offered at least annual monitoring of nutritional status and appropriate supplementation according to need following bariatric surgery, as part of a shared care model of chronic disease management. # Recommendations for research The guideline committee has made the following recommendations for research. # New recommendations for research ## Measurements for assessing health risks in adults What are the most accurate and suitable measurements and boundary values to assess the health risks associated with overweight, obesity and central adiposity in adults of different ethnicities, particularly those from Black, Asian and minority ethnic family backgrounds? For a short explanation of why the committee made the recommendation for research, see the rationale section on classifying overweight, obesity and central adiposity in adults . Full details of the evidence and the committee's discussion are in evidence review A: accuracy of anthropometric measures in assessing health risks associated with overweight and obesity in adults. Loading. Please wait. ## Measurements for assessing health risks in children and young people What are the most accurate and suitable measurements and boundary values to assess the health risk associated with overweight, obesity and central adiposity in children and young people of different ethnicities, particularly those from Black, Asian and minority ethnic family backgrounds? For a short explanation of why the committee made the recommendation for research, see the rationale section on measures of overweight, obesity and central adiposity in children and young people . Full details of the evidence and the committee's discussion are in evidence review B: accuracy of anthropometric measures in assessing health risks associated with overweight and obesity in children and young people. Loading. Please wait. # Other recommendations for research See the update information section for more details. ## Follow-up care after bariatric surgery Do post-operative lifestyle intervention programmes (exercise, behavioural or dietary) improve weight loss and weight-loss maintenance following bariatric surgery? ## Long-term outcomes of bariatric surgery on people with type 2 diabetes What is the long-term effect of bariatric surgery on diabetes-related complications and quality of life in people with type 2 diabetes compared with optimal medical treatment? ## Bariatric surgery in children and young people What are the long-term outcomes of bariatric surgery in children and young people living with obesity? ## Obesity management for people with a condition associated with an increased risk of obesity What is the best way to deliver obesity management interventions to people with particular conditions associated with increased risk of obesity (such as people with a physical disability that limits mobility, a learning disability or enduring mental health difficulties)? ## Long-term effect of very-low-calorie diets on people with a BMI of 40 kg/m2 or more What are the long-term effects of using very-low-calorie diets (VLCDs) versus low-calorie diets (LCDs) on weight and quality of life in patients with a body mass index (BMI) of 40 kg/m2 or more, including the impact on weight cycling? ## Comparative risks for different generations of immigrants Is the risk of ill health the same for first-, second- and third-generation immigrants from black, Asian and other minority ethnic groups at the same BMI and waist-to-height ratio thresholds? ## Single cut-off points What are the risks and benefits of developing single-figure cut-off points on BMI and waist-to-height ratio for black, Asian and other minority ethnic groups to help prevent diabetes and other conditions? ## Awareness of risk among black, Asian and other minority ethnic groups Are black, Asian and other minority ethnic groups aware that they are at the same risk of type 2 diabetes and mortality at a lower BMI, compared with the white population? ## Practitioners and providers' awareness of risk in black, Asian and other minority ethnic groups Are clinicians, practitioners and weight management service providers aware that black, Asian and other minority ethnic groups are at the same risk of type 2 diabetes and mortality at a lower BMI compared with the white population. If so, do they intervene at lower BMI and waist-to-height ratio thresholds? ## Lifestyle interventions for black, Asian and other minority ethnic groups How effective and cost effective are lifestyle interventions for people from black, Asian and other minority ethnic groups at different BMI and waist-to-height ratio thresholds, compared with the general population? # Rationale and impact These sections briefly explain why the committee made the 2022 recommendations and how they might affect practice. # Identifying and assessing overweight, obesity and central adiposity in adults Recommendations 1.2.2 to 1.2.5 and 1.2.7 to 1.2.16 ## Why the committee made the recommendations Based on their expertise, the committee agreed that a clear benefit of measuring the waist-to-height ratio is that people can easily do it themselves, interpret their results, and seek advice if they are at increased health risk. Self-measurement may reduce the sense of discomfort or stigma some people may feel from a healthcare professional doing the waist circumference measurement. People can also use resources to help them measure their waist accurately, such as the NHS BMI healthy weight calculator, and videos by Diabetes UK and the British Heart Foundation. When a person seeks advice because self-measurement indicates an increased health risk, they may need further assessment (such as for cardiometabolic risk factors) and their waist-to-height ratio may be measured again. The committee were aware that there may be situations when a professional taking a measurement may have a negative effect or be inappropriate, because of the stigma attached to it. And some people may not want to be measured because of their religious and cultural beliefs. The committee agreed on the importance of being sensitive to people's needs and recognising when it is not appropriate to measure. The committee noted that sensitivity and stigma will be addressed in a forthcoming update of the guideline. The committee looked at evidence from studies on the accuracy of different measures for predicting or identifying health conditions associated with overweight and obesity, including type 2 diabetes and cardiovascular disease. The quality of the evidence was mixed. Most studies included information on how accurate the measures were at predicting or diagnosing the health risks associated with overweight and obesity, in people of different ethnicities. Overall, the studies showed that body mass index (BMI), waist circumference, waist-to-hip ratio and waist-to-height ratio could all accurately predict or identify weight-related conditions. The committee noted that BMI is still a useful practical measure, particularly for defining overweight and obesity. But they emphasised that it needs to be interpreted with caution because it is not a direct measure of central adiposity. The committee highlighted that waist-to-height ratio offers a truer estimate of central adiposity by using waist circumference in the calculation. Based on evidence and their experience, they agreed that using waist-to-height ratio as well as BMI would help give a practical estimate of central adiposity in adults with BMI under 35 kg/m2. This would in turn help professionals assess and predict health risks. But because people with a BMI over 35 kg/m2 are always likely to have a high waist-to-height ratio, the committee recognised that it may not be a useful addition for predicting health risks in this group. BMI is the main measure for defining overweight and obesity, and the committee did not alter the BMI categories for the general population. But, based on their expertise, they agreed it was important to estimate central adiposity when assessing future health risks, including for people whose BMI is in the healthy weight category. The committee also highlighted the need for caution when interpreting BMI in adults with high muscle mass because it may be less accurate in this group. Age-related changes in the body are not well captured by BMI. The committee agreed that BMI should therefore be interpreted with caution in people aged 65 and over, because their functional capacity may be reduced due to conditions such as age-related spinal disorders or sarcopenia. They also recognised that slightly higher BMI in older people can have a protective effect (for example, reduced risk of all-cause mortality) because they are less likely to be experiencing undernutrition. So, it is important for professionals to evaluate the balance of these risks when interpreting BMI. The committee also highlighted that people from Black, Asian and minority ethnic family backgrounds are prone to central adiposity and have an increased cardiometabolic health risk at lower BMI thresholds. For example, studies in people of South Asian and Chinese family backgrounds showed an increased risk at a BMI of 21 kg/m2 to 26 kg/m2, whereas people from white family backgrounds showed increased risks at 25 kg/m2 to 29 kg/m2. There was also some evidence for using lower BMI thresholds for people from Middle Eastern (Arab and Iranian), Black African, Black Caribbean and other Asian (Japanese, Korean and Thai) family backgrounds. For these groups, studies identified an increase in risk at BMI values that ranged from 21 kg/m2 to 30 kg/m2 but most were below 25 kg/m2. The committee noted that these lower thresholds are in line with international guidance and are already used in practice to refer people from these family backgrounds to weight management services. Although NICE found no evidence on the thresholds for obesity classes 2 and 3 in people of these family backgrounds, the committee consensus was that it is generally good practice to reduce the thresholds used for the general population by about 2.5 kg/m2. This would mean that the threshold for obesity class 2 would be lowered to roughly 32.5 kg/m2, and for class 3 to 37.5 kg/m2 in these populations. Public Health England guidance on adult weight management and the British Obesity and Metabolic Surgery Society guidance on accessing tier 4 services also endorsed reducing the thresholds. In line with their recommendations for other populations, the committee used the terms overweight and obesity instead of risk levels to describe thresholds in people with a South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family background. They agreed that in their experience there was more stigma attached to talking about risk than overweight or obesity. They noted that terms such as 'high risk' could result in anxiety and overinterpretation of risk more than terms such as 'living with obesity'. The committee also discussed the accuracy of waist-to-height ratio boundary values in predicting and identifying health risks. The evidence showed that the cut-off from individual studies was generally around 0.5 for all ethnicities and sexes, which was in line with the wider evidence. They agreed that waist-to-height ratio could be used to define central adiposity in adults, and that a range of 0.5 to 0.59 corresponds to increased health risks. The committee noted that a waist-to-height ratio of 0.6 or more indicates a further increase in risk. The committee agreed that a key benefit of using waist-to-height ratio is that the classification is the same for all ethnicities and sexes. It can also be useful in adults with high muscle mass, for whom BMI may be less accurate. The committee also noted the boundary value of 0.5 could be communicated in a simple and memorable way with the message: 'Keep your waist to less than half your height'. Although there was a large evidence base, the committee noted a lack of evidence on the accuracy of methods for predicting future risks for people of some ethnicities. Few studies were based in the UK, so the evidence might not reflect how accurate different measures might be when used in a UK context. Therefore, the committee highlighted the need for more research on measurements and boundary values for different ethnicities and made a recommendation for research on measurements for assessing health risks in adults. The committee agreed that it is important for healthcare professionals to ask for permission before starting any discussions linked to overweight, obesity and central adiposity. Based on their experience, the committee stressed the importance of sensitive and positive discussions because the stigma associated with obesity can affect people's mental and physical health. This can lead to further weight gain and make them less likely to engage with healthcare professionals. It is especially important to be sensitive when talking to people with conditions such as eating disorders (such as anorexia nervosa, bulimia and binge eating disorder), or disordered eating (such as restrictive dieting, compulsive eating or skipping meals). The committee noted existing resources and advice that could help conduct sensitive, person-centred conversations. These include Health Education England's healthier weight competency framework, Obesity UK's language matters, and training courses by the Royal College of General Practitioners (RCGBP), World Obesity Federation and European Association for the Study of Obesity (EASO). The committee did not make specific recommendations on sensitive language and measures to prevent stigma because a forthcoming update of this guideline will address these. The committee noted it is important for adults to know the long-term health risks and conditions associated with overweight, obesity and central adiposity. These include type 2 diabetes, cardiovascular disease, hypertension, dyslipidaemia, certain cancers, and respiratory, musculoskeletal or other metabolic conditions (such as non-alcoholic fatty liver disease). Knowledge about these may encourage the person to stick to a weight loss strategy. Based on their understanding of practice, the committee stressed the importance of an all-round discussion of the person's individual needs and preferences to reach a shared decision about what level and types of intervention would suit them. This includes taking into account factors such as ethnicity, weight-related comorbidities, socioeconomic status, family medical history and special educational needs and disabilities (SEND). These discussions can also involve giving information about local weight management services and other support services. Based on their expertise, the committee agreed people with weight-related comorbidities may benefit from a higher level of intervention. They also highlighted groups of people, such as those newly diagnosed with type 2 diabetes and those with BMI over 50, who would benefit more from immediate weight management interventions. Based on their expertise, the committee noted that these groups are often not offered appropriate interventions early enough. ## How the recommendations might affect practice The committee highlighted that encouraging self-measurement is in line with changes in practice over the past 2 years, particularly the increase in carrying out initial assessments by phone. It has already become standard practice to use self-reported measurements such as weight, blood pressure readings and blood sugar levels for conditions like diabetes. Using waist-to-height ratio as well as BMI would be likely to have minimal cost impact because tape measures are already routinely available in NHS settings for measuring waist circumference. The committee noted that community pharmacies have been involved in taking measurements as well as it being done in general practice. Public Health England's Healthier weight competency framework highlights that healthcare professionals involved in identification of overweight and obesity should be able to accurately measure and classify weight status. With the addition of waist-to-height ratio, it is important that training is available so that measurements can be conducted by trained personnel. Currently, there are no established resources for calculating waist-to-height ratio. But resources such as the NHS BMI healthy weight calculator can be used to explain how to take waist measurements. Additional training programmes may need to be developed to help healthcare professionals understand central adiposity and conduct waist measurement in a sensitive manner and with care, especially in people with specific conditions such as eating disorders. This will lead to additional training costs. There may also be a cost increase associated with the extra staff time needed to teach people how to measure themselves and calculate waist-to-height ratio. But the committee agreed that these additional costs are unlikely to result in a significant resource impact and will be balanced out by the long-term health improvements such as decreased risk of developing diabetes or cardiovascular disease. Using lower BMI thresholds in people from Black, Asian and minority ethnic family backgrounds will increase the number of people who are eligible for weight management services. However, this could reduce levels of overweight and obesity, and thereby reduce the costs of treating obesity-related conditions for the NHS and wider system, such as social care systems. There may be challenges in using BMI or waist-to-height ratio in people who have a physical disability, some physical conditions (such as scoliosis) or learning difficulties because people may be unable to get on scales independently or be lifted safely. In such circumstances, reasonable adjustments would be needed for adults, for example using seated or hoist scales, or scales that can used for wheelchairs (including moulded wheelchairs). Measurements may also need to be modified, for example using sitting height or demi-span (the distance between the mid-point of the sternal notch and the finger roots with the arms outstretched laterally) instead of overall height, meaning specialist assessment may be needed. It may also be challenging to take measurements in people who are housebound because it may not be possible to access equipment such as specialist scales during home visits. Return to recommendations # Identifying and assessing overweight, obesity and central adiposity in children and young people Recommendations 1.2.21 and 1.2.22 and 1.2.24 to 1.2.29 ## Why the committee made the recommendations The committee were aware of the need to update advice on sensitivity when taking measurements, remaining mindful and sensitive to children and young people's needs (including cultural and religious beliefs) as well as the needs of their parents and carers, and recognising when it is not appropriate to measure. They did not make any recommendations because this section will be reviewed as part of a forthcoming update of the guideline. The committee looked at evidence on the accuracy of different measures for predicting or identifying health conditions associated with overweight and obesity, including type 2 diabetes and cardiovascular disease. The quality of the evidence was mixed. Some studies included information on how accurate measures were at predicting or diagnosing the health risks associated with overweight and obesity in children and young people of different ethnicities. Overall, the committee agreed that the studies showed that BMI, waist circumference and waist-to-height ratio could all be used to accurately predict or identify weight-related conditions when they were adjusted for age and sex. The same was true of waist-to-height ratio when it was not adjusted for age and sex. They discussed that BMI z-score adjusted for sex and age tended to be the most accurate measure for identifying different health conditions, but waist-to-height ratio was often equally accurate and, in some studies, more accurate. (BMI z-score is also known as BMI standard deviations , which indicate how many units a child's BMI is above or below the average BMI value for their age group and sex.) Based on the evidence and their clinical expertise, the committee agreed that BMI is a useful practical measure for estimating and defining overweight and obesity. However, they noted that BMI should not be interpreted in the same way for children and young people as for adults. Healthcare professionals should use charts that are specific to children and young people and adjusted for age and sex. The committee also noted that waist-to-height ratio is a truer estimate of central adiposity, which is related to health risks. The committee agreed that special growth charts may be needed when assessing children and young people with cognitive and physical disabilities, including those with learning disabilities. They noted that growth charts for children and young people with Down's syndrome are available from the Centres for Disease Control and the Royal College of Paediatrics and Child Health. The committee agreed that the evidence for using waist-to-height ratio as a practical estimate for central adiposity to assess and predict health risk in children and young people was not as good as the evidence for adults. They agreed that it could still be useful as an indication of future health risks. But they stated that more research was needed on the accuracy of different measures and made a recommendation for research on measurements for assessing health risks in children and young people. The committee looked at evidence for different boundary values for BMI and BMI z-scores but these focused on identifying current health conditions rather than defining the degree of overweight and obesity. Based on their expertise, they provided clinical definitions of overweight and obesity using BMI centiles and BMI SDs. These values correspond with those in the Royal College of Paediatrics (RCPCH) and Child Health UK-World Health Organization (WHO) growth charts. The committee agreed that it was important to use clinical judgement when interpreting BMI below the 91st centile, especially because children and young people in the healthy weight category may still have central adiposity. The committee also noted that there are resources that can help professionals understand how to measure, plot and assess BMI in children and young people. These include educational resources from the RCPCH and the National Child Measurement Programme Operational Guidance, which both give information on how the clinical definitions of BMI link to BMI centiles and SDs. There was a lack of evidence identified on BMI boundary values for children and young people from different ethnicities. The committee agreed this was an important area for research to investigate whether there are variations in thresholds, as there are in adults, and made a recommendation for research on measurements for assessing health risks in children and young people. The committee noted that although they could not provide different thresholds for BMI, waist-to-height ratio could be used as an indicator of central adiposity regardless of ethnicity and sex. Studies also suggested that the optimal waist-to-height ratio cut-offs for children and young people ranged from 0.42 to 0.57, with most studies averaging around 0.5. Based on the evidence and their clinical knowledge, the committee agreed the waist-to-height ratio boundary value of 0.5 should be the same for children and young people as for adults. The committee agreed that it is important to ask for permission from children, young people, and their parents or carers (if appropriate), before starting any discussions linked to overweight, obesity or central adiposity. They agreed that professional judgement is needed to ensure discussions are age appropriate and decide whether the child or young person should be involved. They also noted that it was standard practice for healthcare professionals to use Gillick competency to determine the capacity of a child or young person under 16 to consent. Based on their expertise, the committee stressed the importance of sensitive and positive discussions because the stigma associated with obesity can affect a child or young person's mental and physical health. It is especially important to be sensitive when talking to children and young people with conditions such as eating disorders (such as anorexia nervosa, bulimia and binge eating disorder), or disordered eating (such as restrictive dieting, compulsive eating or skipping meals). The committee noted existing resources and advice that could help conduct conversations with children and young people in a sensitive and positive way. These include Health Education England's healthier weight competency framework, Public Health England's let's talk about weight (which highlights a focus on weight maintenance and growing into a healthier weight, rather than weight loss) and Obesity UK's language matters guidance. There are also training courses by the Royal College of General Practitioners (RCGBP), World Obesity Federation and European Association for the Study of Obesity (EASO). The committee did not make specific recommendations on sensitive language and measures to prevent stigma because a forthcoming update of this guideline will address these. Based on their clinical expertise, the committee agreed that tailored interventions were useful for children who are living with overweight or obesity or have increased health risk based on waist-to-height ratio. They agreed that weight-related comorbidities, ethnicity, socioeconomic status, social complexity (for example, looked-after children and young people), family medical history, mental and emotional health and wellbeing, developmental age, and special educational needs and disabilities (SEND) need to be taken into account when tailoring interventions. The committee were particularly aware that children and young people with weight-related comorbidities, such as type 2 diabetes, may benefit from a higher level of intervention regardless of their waist-to-height ratio. The committee stressed the importance of working with the child or young person, and their families and carers (if appropriate), to make an informed decision about the treatment or care option that is best for them. As highlighted in resources such as the step-by-step guide produced by Public Health England on conversations about weight, healthcare professionals can also give information about local weight management services and other support services during these discussions. ## How the recommendations might affect practice Waist-to-height ratio is not routinely measured in practice, so there may be additional costs for the extra staff time involved. But the cost impact should be small because waist measurements are already widely used in primary care so it would not need much extra time to calculate the ratio. The committee noted that health visitors and school nurses, as well as general practice, are involved in taking measurements. The healthier weight competency framework does highlight that healthcare professionals involved in identification of overweight and obesity should be able to accurately measure and classify weight status in children and young people. With the addition of waist-to-height ratio, it is important that training is available so that measurements can be conducted by trained personnel. There are no established resources for measuring waist-to-height ratio, but healthcare professionals can use the NHS BMI healthy weight calculator, and videos by organisations such as Diabetes UK and the British Heart Foundation. These are for adults but can also be useful for older children and young people, families and carers. There are a few training programmes specifically for managing overweight and obesity in children and young people, such as the ones by the World Obesity Federation, European Childhood Obesity Group, the Department of Health and Social Care's obesity team and Health Education England. Some of these need to be updated to include measuring waist circumference and interpreting waist-to-height ratio, which might lead to additional training costs. Healthcare professionals may need extra time to teach older children and young people, and their families and carers, how to measure the waist accurately and calculate waist-to-height ratio. However, the committee agreed that additional costs of training and staff time are unlikely to result in a significant resource impact and are justified by the long-term health benefits associated with a reduction in obesity-related conditions. There may be challenges in using BMI or waist-to-height ratio in children and young people with physical disabilities, some physical conditions (such as scoliosis) or learning difficulties. Reasonable adjustments would also be needed for children and young people using wheelchairs (including moulded wheelchairs) such as using seated or hoist scales, or scales that are suitable for wheelchairs. And although there is published guidance on supporting people with learning disabilities in obesity and weight management, there are no validated proxy measurements for height in children and young people (for example, using their sitting height or demi-span to estimate their height). This makes taking measurements difficult in children and young people with physical disabilities or learning difficulties. Return to recommendations# Context The 2019 Health Survey for England estimated the prevalence of obesity in adults in England to be 28%, with overweight affecting a further 36%. It estimated the prevalence of obesity in children aged 2 to 15 to be 20% in boys and 13% in girls, with overweight affecting a further 12% of boys and 15% of girls. Government estimates indicate that the current costs of obesity in the UK are £6.1 billion to the NHS and £27 billion to wider society. Currently, people who would benefit from weight management interventions are identified opportunistically. The lack of active case finding may mean that conditions such as type 2 diabetes are likely to be under-diagnosed in people of Black, Asian and other minority ethnic backgrounds whose risk is increased at a lower body mass index (BMI) and waist circumference. New evidence identified since this guideline was first published may help to refine weight management programmes that address diet, physical activity and behaviour change, and inform implementation of interventions in specific settings. This guideline update covers identifying and assessing overweight, obesity and central adiposity in children aged 2 years and older, young people and adults. It updates NICE's guideline on obesity: identification, assessment and management (NICE guideline CG189) and replaces NICE's guideline on BMI: preventing ill health and premature death in Black, Asian and other minority ethnic groups (NICE guideline PH46). Forthcoming updates will cover preventing and managing these conditions. They will produce a single guideline that will partially replace NICE's guideline on weight management before, during and after pregnancy (NICE guideline PH27; only the recommendations that apply before and after pregnancy) and will fully update and replace this guideline and NICE's guidelines on: preventing excess weight gain (NICE guideline NG7) weight management: lifestyle services for overweight or obese adults (NICE guideline PH53) weight management: lifestyle services for overweight or obese children and young people (NICE guideline PH47) -besity: working with local communities (NICE guideline PH42) -besity prevention (NICE guideline CG43).	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Generic principles of care\n\n## Adults\n\nEquip specialist settings for treating people who are living with severe obesity with, for example, special seating and adequate weighing and monitoring equipment. Ensure hospitals have access to specialist equipment – such as larger scanners and beds – when providing general care for people who are living with severe obesity. [2006, amended 2014]\n\nDiscuss the choice of interventions for weight management with the person. The choice of intervention should be agreed with the person. [2006, amended 2014]\n\nTailor the components of the planned weight management programme to the person's preferences, initial fitness, health status and lifestyle. \n\n## Children\n\nCoordinate the care of children and young people around their individual and family needs. Comply with the approaches outlined in the Department of Health's A call to action on obesity in England. See also NICE's guideline on weight management: lifestyle services for overweight or obese children and young people. [2006, amended 2014]\n\nAim to create a supportive environment that helps a child who is overweight or who has obesity, and their family, make lifestyle changes. (The committee noted that 'environment' could include settings other than the home, for example, schools.) [2006, amended 2014]\n\nMake decisions about the care of a child who is overweight or has obesity (including assessment and agreeing goals and actions) together with the child and family. Tailor interventions to the needs and preferences of the child and the family. \n\nEnsure that interventions for children who are living with overweight or obesity address lifestyle within the family and in social settings. [2006, amended 2014]\n\nEncourage parents (or carers) to take main responsibility for lifestyle changes in children who are living with overweight or obesity, especially if they are younger than 12\xa0years. Take into account the age and maturity of the child, and the preferences of the child and the parents. \n\n## Adults and children\n\nOffer regular, non-discriminatory long-term follow-up by a trained professional. Ensure continuity of care in the multidisciplinary team through good record keeping. \n\n# Identifying and assessing overweight, obesity and central adiposity\n\n## Identification and assessment in adults\n\nUse clinical judgement to decide when to measure a person's height and weight. Opportunities include when registering with a GP, consultations for related conditions (such as type\xa02 diabetes and cardiovascular disease) and other routine health checks. \n\nEncourage adults with a body mass index (BMI) below 35\xa0kg/m² to:\n\nmeasure their own waist-to-height ratio to assess central adiposity (the accumulation of excess fat in the abdominal area)\n\nseek advice and further clinical assessments (such as a cardiometabolic risk factor assessment) from a healthcare professional if the measurement indicates an increased health risk. Explain to people that to accurately measure their waist and calculate their own waist-to-height ratio, they should follow the advice in box 1. \n\nDirect people to resources that give advice on how to measure waist circumference, such as the NHS BMI healthy weight calculator. See recommendations 1.2.11 and 1.2.12 for how to interpret waist-to-height ratio. \n\nMeasure\n\nFind the bottom of the ribs and the top of the hips.\n\nWrap a tape measure around the waist midway between these points (this will be just above the belly button) and breathe out naturally before taking the measurement.\n\nCalculate\n\nMeasure waist circumference and height in the same units (either both in centimetres, or both in inches). If you know your height in feet and inches, convert it to inches (for example, 5\xa0feet 7\xa0inches is 67\xa0inches).\n\nDivide waist measurement by height measurement. For example:\n\ninches divided by 67\xa0inches = waist-to-height ratio of 0.57 or\n\ncm divided by 170\xa0cm = waist-to-height ratio of 0.57.\n\nUse BMI as a practical measure of overweight and obesity. Interpret it with caution because it is not a direct measure of central adiposity. \n\nIn adults with BMI below 35\xa0kg/m2, measure and use their waist-to-height ratio, as well as their BMI, as a practical estimate of central adiposity and use these measurements to help to assess and predict health risks (for example, type\xa02 diabetes, hypertension or cardiovascular disease). \n\nDo not use bioimpedance as a substitute for BMI as a measure of general adiposity in adults. [2006, amended 2014]\n\nDefine the degree of overweight or obesity in adults as follows, if they are not in the groups covered by recommendation 1.2.8:\n\nhealthy weight: BMI 18.5\xa0kg/m2 to 24.9\xa0kg/m2\n\noverweight: BMI 25\xa0kg/m2 to 29.9\xa0kg/m2\n\nobesity class 1: BMI 30\xa0kg/m2 to 34.9\xa0kg/m2\n\nobesity class 2: BMI 35\xa0kg/m2 to 39.9\xa0kg/m2\n\nobesity class 3: BMI 40\xa0kg/m2 or more. Use clinical judgement when interpreting the healthy weight category because a person in this category may nevertheless have central adiposity. See Public Health England's guidance on obesity and weight management for people with learning disabilities for information on reasonable adjustments that may need to be made. \n\nPeople with a South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family background are prone to central adiposity and their cardiometabolic risk occurs at lower BMI, so use lower BMI thresholds as a practical measure of overweight and obesity:\n\noverweight: BMI 23\xa0kg/m2 to 27.4\xa0kg/m2\n\nobesity: BMI 27.5\xa0kg/m2 or above. For people in these groups, obesity classes 2 and 3 are usually identified by reducing the thresholds highlighted in recommendation 1.2.7 by 2.5\xa0kg/m2. \n\nInterpret BMI with caution in adults with high muscle mass because it may be a less accurate measure of central adiposity in this group. \n\nInterpret BMI with caution in people aged 65 and over, taking into account comorbidities, conditions that may affect functional capacity and the possible protective effect of having a slightly higher BMI when older. \n\nDefine the degree of central adiposity based on waist-to-height ratio as follows:\n\nhealthy central adiposity: waist-to-height ratio 0.4 to 0.49, indicating no increased health risks\n\nincreased central adiposity: waist-to-height ratio 0.5 to 0.59, indicating increased health risks\n\nhigh central adiposity: waist-to-height ratio 0.6 or more, indicating further increased health risks. These classifications can be used for people with a BMI under 35\xa0kg/m2 of both sexes and all ethnicities, including adults with high muscle mass. The health risks associated with higher levels of central adiposity include type\xa02 diabetes, hypertension and cardiovascular disease. \n\nWhen talking to a person about their waist-to-height ratio, explain that they should try and keep their waist to half their height (so a waist-to-height ratio of under 0.5). \n\nAsk the person's permission before talking about the degree of overweight, obesity and central adiposity, and discuss it in a sensitive manner. \n\nGive adults information about the severity of their overweight or obesity and central adiposity and the impact this has on their risk of developing other long-term conditions (such as type\xa02 diabetes, cardiovascular disease, hypertension, dyslipidaemia, certain cancers and respiratory, musculoskeletal and other metabolic conditions such as non-alcoholic fatty liver disease). [2006, amended 2022]\n\nDiscuss and agree the level of intervention with adults who:\n\nare living with overweight or obesity or\n\nhave increased health risk based on their waist-to-height ratio.Take into account people's individual needs and preferences, and factors such as weight-related comorbidities, ethnicity, socioeconomic status, family medical history, and special educational needs and disabilities (SEND). See the recommendations on lifestyle interventions, behavioural interventions, physical activity, dietary approaches, pharmacological interventions and surgical interventions. \n\nOffer a higher level of intervention to people with weight-related comorbidities (see recommendation 1.3.6 for details of comorbidities). Adjust the approach depending on the person's clinical needs. For people with a BMI over 35\xa0kg/m2 who have recently developed diabetes, see recommendation 1.11.1, and for people with a BMI of 50 and over, see recommendation 1.3.7 and recommendation 1.10.7. \n\nFor a short explanation of why the committee made the 2022 recommendations and how they might affect practice, see the rationale and impact section on identifying and assessing overweight, obesity and central adiposity in adults\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: accuracy of anthropometric measures in assessing health risks associated with overweight and obesity in adults.\n\nLoading. Please wait.\n\nEnsure healthcare professionals are aware that people from Black, Asian and minority ethnic family backgrounds are at an increased risk of chronic health conditions at a lower BMI than people from a white family background (below BMI 25\xa0kg/m2). \n\nEnsure people from Black, Asian and minority ethnic family backgrounds are aware that they face an increased risk of chronic health conditions at a lower BMI than people from a white family background (below BMI 25\xa0kg/m2). \n\nUse existing local information networks for people of Black and minority ethnic family backgrounds to share information on the increased risks these groups face at a lower BMI. \n\n## Identification and assessment in children and young people\n\nUse clinical judgement to decide when to measure a child or young person's height and weight. Opportunities include when registering with a GP, consultations for related conditions (such as type\xa02 diabetes and cardiovascular disease) and other routine health checks. \n\nUse BMI as a practical estimate of overweight and obesity, and ensure that charts used are:\n\nappropriate for children and young people and\n\nadjusted for age and sex. Interpret BMI with caution because it is not a direct measure of central adiposity. The Royal College of Paediatrics and Child Health UK-World Health Organization (WHO) growth charts and BMI charts should be used to plot and classify BMI centile. The childhood and puberty close monitoring (CPCM) form can also be used for continued BMI monitoring in children aged\xa02 and over, especially in instances where puberty is either premature or delayed. Refer to special BMI growth charts for children and young people with Down's syndrome, if needed. \n\nConsider using waist-to-height ratio in children and young people aged 5 and over to assess and predict health risks associated with central adiposity (such as type\xa02 diabetes, hypertension or cardiovascular disease). See box 1 for information on how the waist should be measured and how to calculate waist-to-height ratio. \n\nDo not use bioimpedance as a substitute for BMI as a measure of general adiposity in children and young people. [2006, amended 2014]\n\nDefine the degree of overweight or obesity in children and young people using the following classifications:\n\noverweight: BMI 91st centile + 1.34 standard deviations (SDs)\n\nclinical obesity: BMI 98th centile + 2.05 SDs\n\nsevere obesity: BMI 99.6th centile + 2.68 SDs. Use clinical judgement when interpreting BMI below the 91st centile, especially the healthy weight category in BMI charts because a child or young person in this category may nevertheless have central adiposity. \n\nDefine the degree of central adiposity based on waist-to-height ratio in children and young people as follows:\n\nhealthy central adiposity: waist-to-height ratio 0.4 to 0.49, indicating no increased health risk\n\nincreased central adiposity: waist-to-height ratio 0.5 to 0.59, indicating increased health risk\n\nhigh central adiposity: waist-to-height ratio 0.6 or more, indicating further increased health risk. These classifications can be used for children and young people of both sexes and all ethnicities. The health risks associated with higher central adiposity levels include type 2 diabetes, hypertension and cardiovascular disease. \n\nWhen talking to a child, young person, and their families and carers, explain that they should try and keep their waist to half their height (so a waist-to-height-ratio of under 0.5). \n\nAsk permission from children, young people, and their families and carers, before talking about the degree of overweight, obesity and central adiposity, and discuss it in a sensitive and age-appropriate manner. \n\nConsider tailored interventions for children and young people:\n\nwho are living with overweight or obesity or\n\nhave increased health risk based on their waist-to-height ratio. Take into account their individual needs and preferences, and factors such as weight-related comorbidities, ethnicity, socioeconomic status, social complexity (for example, looked-after children and young people), family medical history, mental and emotional health and wellbeing, developmental age, and special educational needs and disabilities (SEND). See the recommendations on lifestyle interventions, behavioural interventions, physical activity, dietary approaches, pharmacological interventions and surgical interventions. \n\nOffer a higher level of intervention to children with weight-related comorbidities (see recommendation 1.3.9 for details of comorbidities). Adjust the approach depending on the child's clinical needs. For pharmacological treatment in children with comorbidities, see recommendations 1.8.5 and 1.8.6 and for surgical interventions in young people with exceptional circumstances, see recommendations 1.10.12 and 1.10.13. \n\nFor a short explanation of why the committee made the 2022 recommendations and how they might affect practice, see the rationale and impact section on identifying and assessing overweight, obesity and central adiposity in children and young people\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: accuracy of anthropometric measures in assessing health risks associated with overweight and obesity in children and young people.\n\nLoading. Please wait.\n\n# Assessment\n\n## Adults and children\n\nMake an initial assessment (see recommendations 1.3.6 and 1.3.8), then use clinical judgement to investigate comorbidities and other factors to an appropriate level of detail, depending on the person, the timing of the assessment, the degree of overweight or obesity, and the results of previous assessments. \n\nManage comorbidities when they are identified; do not wait until the person has lost weight. \n\nOffer people who are not yet ready to change the chance to return for further consultations when they are ready to discuss their weight again and willing or able to make lifestyle changes. Give them information on the benefits of losing weight, healthy eating and increased physical activity. \n\nRecognise that surprise, anger, denial or disbelief about their health situation may diminish people's ability or willingness to change. Stress that obesity is a clinical term with specific health implications, rather than a question of how people look; this may reduce any negative feelings.During the consultation:\n\nAssess the person's view of their weight and the diagnosis, and possible reasons for weight gain.\n\nExplore eating patterns and physical activity levels.\n\nExplore any beliefs about eating, physical activity and weight gain that are unhelpful if the person wants to lose weight.\n\nBe aware that people from certain ethnic and socioeconomic backgrounds may be at greater risk of obesity, and may have different beliefs about what is a healthy weight and different attitudes towards weight management.\n\nFind out what the person has already tried and how successful this has been, and what they learned from the experience.\n\nAssess the person's readiness to adopt changes.\n\nAssess the person's confidence in making changes. [2006, amended 2014]\n\nGive people and their families and/or carers information on the reasons for tests, how the tests are done, and their results and meaning. If necessary, offer another consultation to fully explore the options for treatment or discuss test results. [2006, amended 2014]\n\n## Adults\n\nTake measurements (see section 1.2) to determine degree of overweight or obesity and discuss the implications of the person's weight. Then, assess:\n\nany presenting symptoms\n\nany underlying causes of overweight or obesity\n\neating behaviours\n\nany comorbidities (for example type\xa02 diabetes, hypertension, cardiovascular disease, osteoarthritis, dyslipidaemia and sleep apnoea)\n\nany risk factors assessed using lipid profile (preferably done when fasting), blood pressure measurement and HbA1c measurement\n\nthe person's lifestyle (diet and physical activity)\n\nany psychosocial distress\n\nany environmental, social and family factors, including family history of overweight and obesity and comorbidities\n\nthe person's willingness and motivation to change lifestyle\n\nthe potential of weight loss to improve health\n\nany psychological problems\n\nany medical problems and medication\n\nthe role of family and care workers in supporting individuals with learning disabilities to make lifestyle changes.See also NICE's guideline on weight management: lifestyle services for overweight or obese children and young people. [2006, amended 2014]\n\nConsider referral to tier\xa03 services if:\n\nthe underlying causes of overweight or obesity need to be assessed\n\nthe person has complex disease states or needs that cannot be managed adequately in tier\xa02 (for example, the additional support needs of people with learning disabilities)\n\nconventional treatment has been unsuccessful\n\ndrug treatment is being considered for a person with a BMI of more than 50\xa0kg/m2\n\nspecialist interventions (such as a very-low-calorie diet) may be needed\n\nsurgery is being considered. For more information on tier\xa03 services, see NHS England's report on joined up clinical pathways for obesity. [2006, amended 2014]\n\n## Children\n\nAssessment of comorbidity should be considered for children with a BMI at or above the 98th centile. \n\nTake measurements to determine degree of overweight or obesity and raise the issue of weight with the child and family, then assess:\n\npresenting symptoms and underlying causes of overweight or obesity\n\nwillingness and motivation to change\n\ncomorbidities (such as hypertension, hyperinsulinaemia, dyslipidaemia, type\xa02 diabetes, psychosocial dysfunction and exacerbation of conditions such as asthma)\n\nany risk factors assessed using lipid profile (preferably done when fasting) blood pressure measurement and HbA1c measurement\n\npsychosocial distress, such as low self-esteem, teasing and bullying (See also NICE's guideline on weight management: lifestyle services for overweight or obese children and young people)\n\nfamily history of overweight or obesity and comorbidities\n\nthe child and family's willingness and motivation to change lifestyle\n\nlifestyle (diet and physical activity)\n\nenvironmental, social and family factors that may contribute to overweight or obesity, and the success of treatment\n\ngrowth and pubertal status\n\nany medical problems and medication\n\nthe role of family and care workers in supporting people with learning disabilities to make lifestyle changes. [2006, amended 2014]\n\nConsider referral to an appropriate specialist for children who are living with overweight or obesity and have significant comorbidities or complex needs (for example, learning disabilities or other additional support needs). [2006, amended 2014]\n\nIn tier\xa03 services, assess associated comorbidities and possible causes for children and young people who are living with overweight or obesity. Use investigations such as:\n\nblood pressure measurement\n\nlipid profile, preferably while fasting\n\nfasting insulin\n\nfasting glucose levels and oral glucose tolerance test\n\nliver function\n\nendocrine function.Interpret the results of any tests used in the context of how the level of the child's overweight or obesity is, the child's age, history of comorbidities, possible genetic causes and any family history of metabolic disease related to overweight or obesity. [2006, amended 2014]\n\nMake arrangements for transitional care for children and young people who are moving from paediatric to adult services. \n\n# Lifestyle interventions\n\n## Adults and children\n\nMulticomponent interventions are the treatment of choice. Ensure weight management programmes include behaviour change strategies (see recommendations 1.5.1 to 1.5.3) to increase people's physical activity levels or decrease inactivity, improve eating behaviour and the quality of the person's diet, and reduce energy intake. [2006, amended 2014]\n\nWhen choosing treatments, take into account:\n\nthe person's individual preference and social circumstance and the experience and outcome of previous treatments (including whether there were any barriers)\n\nthe person's degree of overweight and obesity or increased health risk based on their waist-to-height ratio (see recommendations 1.2.11 and 1.2.15)\n\nany comorbidities. [2006, amended 2022]\n\nDocument the results of any discussion. Keep a copy of the agreed goals and actions (ensure the person also does this), or put this in the person's notes. [2006, amended 2014]\n\nOffer support depending on the person's needs, and be responsive to changes over time. \n\nEnsure any healthcare professionals who deliver interventions for weight management have relevant competencies and have had specific training. [2006, amended 2014]\n\nProvide information in formats and languages that are suited to the person. Use everyday, jargon‑free language and explain any technical terms when talking to the person and their family or carers. Take into account the person's:\n\nage and stage of life\n\ngender\n\ncultural needs and sensitivities\n\nethnicity\n\nsocial and economic circumstances\n\nspecific communication needs (for example because of learning disabilities, physical disabilities or cognitive impairments due to neurological conditions). [2006, amended 2014]\n\nPraise successes – however small – at every opportunity to encourage the person through the difficult process of changing established behaviour. \n\nGive people who are living with overweight or obesity, and their families and/or carers, relevant information on:\n\nbeing overweight and obesity in general, including related health risks\n\nrealistic targets for weight loss; for adults, see NICE's guideline on managing overweight and obesity in adults\n\nthe distinction between losing weight and maintaining weight loss, and the importance of developing skills for both; advise them that the change from losing weight to maintenance typically happens after 6 to 9\xa0months of treatment\n\nrealistic targets for outcomes other than weight loss, such as increased physical activity and healthier eating\n\ndiagnosis and treatment options\n\nhealthy eating in general (more information on healthy eating can be found on the eat well pages of the NHS website)\n\nmedication and side effects\n\nsurgical treatments\n\nself-care\n\nvoluntary organisations and support groups and how to contact them.Ensure there is adequate time in the consultation to provide information and answer questions. [2006, amended 2014]\n\nIf a person (or their family or carers) does not feel this is the right time for them to take action, explain that advice and support will be available in the future whenever they need it. Provide contact details so that the person can get in touch when they are ready. [2006, amended 2014]\n\n## Adults\n\nEncourage the person's partner or spouse to support any weight management programme. \n\nBase the level of intensity of the intervention on the level of risk and the potential to gain health benefits (see recommendations 1.2.15 and 1.2.16). \n\n## Children\n\nBe aware that the aim of weight management programmes for children and young people can vary. The focus may be on either weight maintenance or weight loss, depending on the person's age and stage of growth. [2006, amended 2014]\n\nEncourage parents of children and young people who are living with overweight or obesity to lose weight if they are also living with overweight or obesity. \n\n# Behavioural interventions\n\n## Adults and children\n\nDeliver any behavioural intervention with the support of an appropriately trained professional. \n\n## Adults\n\nInclude the following strategies in behavioural interventions for adults, as appropriate:\n\nself-monitoring of behaviour and progress\n\nstimulus control\n\ngoal setting\n\nslowing rate of eating\n\nensuring social support\n\nproblem solving\n\nassertiveness\n\ncognitive restructuring (modifying thoughts)\n\nreinforcement of changes\n\nrelapse prevention\n\nstrategies for dealing with weight regain. \n\n## Children\n\nInclude the following strategies in behavioural interventions for children, as appropriate:\n\nstimulus control\n\nself-monitoring\n\ngoal setting\n\nrewards for reaching goals\n\nproblem solving.Give praise to successes and encourage parents to role-model desired behaviours. [2006, amended 2014]\n\n# Physical activity\n\n## Adults\n\nEncourage adults to increase their level of physical activity even if they do not lose weight as a result, because of the other health benefits it can bring (for example, reduced risk of type\xa02 diabetes and cardiovascular disease). Encourage adults to meet the recommendations in the UK Chief Medical Officers' physical activity guidelines for weekly activity. \n\nAdvise that to prevent obesity, most people may need to do 45 to 60\xa0minutes of moderate-intensity activity a day, particularly if they do not reduce their energy intake. Advise people who have been living with obesity and have lost weight that they may need to do 60 to 90\xa0minutes of activity a day to avoid regaining weight. \n\nEncourage adults to build up to the recommended activity levels for weight maintenance, using a managed approach with agreed goals. Recommend types of physical activity, including:\n\nactivities that can be incorporated into everyday life, such as brisk walking, gardening or cycling (see also NICE's guideline on walking and cycling)\n\nsupervised exercise programmes\n\nother activities, such as swimming, aiming to walk a certain number of steps each day, or stair climbing.Take into account the person's current physical fitness and ability for all activities. Encourage people to also reduce the amount of time they spend inactive, such as watching television, using a computer or playing video games. \n\n## Children\n\nEncourage children and young people to increase their level of physical activity, even if they do not lose weight as a result, because of the other health benefits exercise can bring (for example, reduced risk of type 2\xa0diabetes and cardiovascular disease). Encourage children to meet the recommendations in the UK Chief Medical Officers' physical activity guidelines for daily activity. \n\nBe aware that children who are already living with overweight may need to do more than 60\xa0minutes' activity. [2006, amended 2014]\n\nEncourage children to reduce inactive behaviours, such as sitting and watching television, using a computer or playing video games. \n\nGive children the opportunity and support to do more exercise in their daily lives (for example, walking, cycling, using the stairs and active play; see also NICE's guideline on walking and cycling). Make the choice of activity with the child, and ensure it is appropriate to the child's ability and confidence. \n\nGive children the opportunity and support to do more regular, structured physical activity (for example football, swimming or dancing). Make the choice of activity with the child, and ensure it is appropriate to the child's ability and confidence. \n\n# Dietary approaches\n\n## Adults and children\n\nTailor dietary changes to food preferences and allow for a flexible and individual approach to reducing calorie intake. \n\nDo not use unduly restrictive and nutritionally unbalanced diets, because they are ineffective in the long term and can be harmful. [2006, amended 2014]\n\nEncourage people to improve their diet even if they do not lose weight, because there can be other health benefits. \n\n## Adults\n\nThe main requirement of a dietary approach to weight loss is that total energy intake should be less than energy expenditure. \n\nDiets that have a 600\xa0kcal/day deficit (that is, they contain 600\xa0kcal less than the person needs to stay the same weight) or that reduce calories by lowering the fat content (low-fat diets), in combination with expert support and intensive follow‑up, are recommended for sustainable weight loss. \n\nConsider low-calorie diets (800 to 1600\xa0kcal/day), but be aware these are less likely to be nutritionally complete. [2006, amended 2014]\n\nDo not routinely use very-low-calorie diets (800\xa0kcal/day or less) to manage obesity. \n\nOnly consider very-low-calorie diets, as part of a multicomponent weight management strategy, for people who are living with obesity and who have a clinically assessed need to rapidly lose weight (for example, people who need joint replacement surgery or who are seeking fertility services). Ensure that:\n\nthe diet is nutritionally complete\n\nthe diet is followed for a maximum of 12\xa0weeks (continuously or intermittently)\n\nthe person following the diet is given ongoing clinical support. \n\nBefore starting someone on a very-low-calorie diet as part of a multicomponent weight management strategy:\n\nConsider counselling and assess for eating disorders or other psychopathology to make sure the diet is appropriate for them.\n\nDiscuss the risks and benefits with them.\n\nTell them that this is not a long-term weight management strategy, and that regaining weight may happen and is not because of their own or their clinician's failure.\n\nDiscuss the reintroduction of food following a liquid diet with them. \n\nProvide a long-term multicomponent strategy to help the person maintain their weight after the use of a very-low-calorie diet. (See recommendation 1.4.1.) \n\nEncourage people to eat a balanced diet in the long term, consistent with other healthy eating advice.More information on healthy eating can be found on the eat well pages of the NHS website. [2006, amended 2014]\n\n## Children\n\nA dietary approach alone is not recommended. It is essential that any dietary recommendations are part of a multicomponent intervention. \n\nAny dietary changes should be age appropriate and consistent with healthy eating advice. \n\nFor children and young people living with overweight or obesity, total energy intake should be below their energy expenditure. Changes should be sustainable. [2006, amended 2014]\n\n# Pharmacological interventions\n\n## Adults\n\nConsider pharmacological treatment (see table 1) only after dietary, exercise and behavioural approaches have been started and evaluated. NICE has not recommended naltrexone–bupropion, see NICE's technology appraisal guidance on naltrexone–bupropion for managing overweight and obesity. [2006, amended 2023]\n\nConsider drug treatment (see table 1) for people who have not reached their target weight loss or have reached a plateau on dietary, activity and behavioural changes. \n\nMake the decision to start drug treatments after discussing the potential benefits and limitations with the person, including the mode of action, adverse effects and monitoring requirements, and the potential impact on the person's motivation. Make arrangements for appropriate healthcare professionals to offer information, support and counselling on additional diet, physical activity and behavioural strategies when drug treatment is prescribed. Provide information on patient support programmes. [2006, amended 2014]\n\nMedicine\n\nStarting criteria\n\nStopping criteria\n\nLiraglutide, see NICE's technology appraisal guidance on liraglutide for managing overweight and obesity\n\nBMI of:\n\nat least 35\xa0kg/m2\xa0or\n\nat least 32.5\xa0kg/m2\xa0for members of minority ethnic groups known to be at equivalent risk of the consequences of obesity at a lower BMI than the white populationandNon-diabetic hyperglycaemia (haemoglobin\xa0A1c level of 42\xa0mmol/mol to 47\xa0mmol/mol [6.0% to 6.4%] or a fasting plasma glucose level of 5.5\xa0mmol/litre to 6.9\xa0mmol/litre) andHigh risk of cardiovascular disease based on risk factors such as hypertension and dyslipidaemia andPrescribe in secondary care by a specialist weight management serviceandThe company provides it according to the commercial arrangement.\n\n–\n\nOrlistat\n\nBMI of:\n\nkg/m2 or more or\n\nkg/m2 or more with associated risk factors.Use with other drugs aimed at weight reduction is not recommended.\n\nContinue beyond 3 months only if the person has lost at least 5% of their initial body weight since starting orlistat. (See also recommendation 1.9.6 for people with type 2 diabetes.)\n\nSemaglutide, see NICE's technology appraisal guidance on semaglutide for managing overweight and obesity\n\nBMI of:\n\nat least 35.0\xa0kg/m2\xa0or\n\nkg/m2\xa0to 34.9\xa0kg/m2\xa0and meet the criteria for referral to specialist weight management services in recommendation 1.3.7.Use lower BMI thresholds (usually reduced by 2.5\xa0kg/m2) for people from South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family backgroundsandAt least 1\xa0weight-related comorbidityandUse within a specialist weight management service.\n\nConsider stopping if less than 5% of the initial weight has been lost after 6 months.\n\nUse for a maximum of 2 years.\n\n## Children\n\nDrug treatment is not generally recommended for children younger than 12\xa0years. \n\nIn children younger than 12\xa0years, drug treatment may be used only in exceptional circumstances, if severe comorbidities are present. Prescribing should be started and monitored only in specialist paediatric settings. [2006, amended 2014]\n\nIn children aged 12\xa0years and older, treatment with orlistat is recommended only if physical comorbidities (such as orthopaedic problems or sleep apnoea) or severe psychological comorbidities are present. Treatment should be started in a specialist paediatric setting, by multidisciplinary teams with experience of prescribing in this age group. In October 2014, this was an off-label use of orlistat. See NICE's information on prescribing medicines. [2006, amended 2014]\n\nDo not give orlistat to children for obesity unless prescribed by a multidisciplinary team with expertise in:\n\ndrug monitoring\n\npsychological support\n\nbehavioural interventions\n\ninterventions to increase physical activity\n\ninterventions to improve diet. [2006, amended 2014]\n\nDrug treatment may be continued in primary care for example with a shared care protocol if local circumstances and/or licensing allow. [2006, amended 2014]\n\n# Continued prescribing and withdrawal\n\n## Adults and children\n\nPharmacological treatment may be used to maintain weight loss rather than to continue to lose weight. \n\nIf there is concern about micronutrient intake adequacy, a supplement providing the reference nutrient intake for all vitamins and minerals should be considered, particularly for vulnerable groups such as older people (who may be at risk of malnutrition) and young people (who need vitamins and minerals for growth and development). \n\nOffer support to help maintain weight loss to people whose drug treatment is being withdrawn; if they did not reach their target weight, their self-confidence and belief in their ability to make changes may be low. \n\n## Adults\n\nMonitor the effect of drug treatment and reinforce lifestyle advice and adherence through regular review. [2006, amended 2014]\n\nConsider withdrawing drug treatment in people who have not reached weight loss targets (see recommendation 1.9.8 and table 1 for details). \n\nRates of weight loss may be slower in people with type\xa02 diabetes, so less strict goals than those for people without diabetes may be appropriate. Agree the goals with the person and review them regularly. \n\nOnly prescribe orlistat as part of an overall plan for managing obesity in adults who meet 1 of the following criteria:\n\na BMI of 28\xa0kg/m2 or more with associated risk factors\n\na BMI of 30\xa0kg/m2 or more. \n\nContinue orlistat therapy beyond 3\xa0months only if the person has lost at least 5% of their initial body weight since starting drug treatment. (See also recommendation 1.9.6 for advice on targets for people with type\xa02 diabetes.) \n\nMake the decision to use drug treatment for longer than 12\xa0months (usually for weight maintenance) after discussing potential benefits and limitations with the person. \n\nThe co-prescribing of orlistat with other drugs aimed at weight reduction is not recommended. \n\n## Children\n\nIf orlistat is prescribed for children, a 6- to 12‑month trial is recommended, with regular review to assess effectiveness, adverse effects and adherence. In October 2014, this was an off-label use of orlistat. See NICE's information on prescribing medicines. [2006, amended 2014]\n\n# Surgical interventions\n\nBariatric surgery is a treatment option for people living with obesity if all of the following criteria are fulfilled:\n\nThey have a BMI of 40\xa0kg/m2 or more, or between 35\xa0kg/m2 and 40\xa0kg/m2 and other significant disease (for example, type\xa02 diabetes or high blood pressure) that could be improved if they lost weight.\n\nAll appropriate non-surgical measures have been tried but the person has not achieved or maintained adequate, clinically beneficial weight loss.\n\nThe person has been receiving or will receive intensive management in a tier 3\xa0service (for more information on tier\xa03 services, see NHS England's report on joined up clinical pathways for obesity).\n\nThe person is generally fit for anaesthesia and surgery.\n\nThe person commits to the need for long-term follow-up. See recommendations 1.10.12 and 1.10.13 for additional criteria to use when assessing children, and recommendation 1.10.7 for additional criteria for adults. See also recommendations 1.11.1 to 1.11.3 for additional criteria for people with type\xa02 diabetes. [2006, amended 2014]\n\nThe hospital specialist and/or bariatric surgeon should discuss the following with people living with severe obesity if they are considering surgery to aid weight reduction:\n\nthe potential benefits\n\nthe longer-term implications of surgery\n\nassociated risks\n\ncomplications\n\nperioperative mortality. The discussion should also include the person's family, as appropriate. [2006, amended 2014]\n\nChoose the surgical intervention jointly with the person, taking into account:\n\nthe degree of obesity\n\ncomorbidities\n\nthe best available evidence on effectiveness and long-term effects\n\nthe facilities and equipment available\n\nthe experience of the surgeon who would perform the operation. \n\nProvide regular, specialist postoperative dietetic monitoring, including:\n\ninformation on the appropriate diet for the bariatric procedure\n\nmonitoring of the person's micronutrient status\n\ninformation on patient support groups\n\nindividualised nutritional supplementation, support and guidance to achieve long-term weight loss and weight maintenance. \n\nArrange prospective audit so that the outcomes and complications of different procedures, the impact on quality of life and nutritional status, and the effect on comorbidities can be monitored in both the short and the long term. (The National Bariatric Surgery Registry is now available to conduct national audit for a number of agreed outcomes.) [2006, amended 2014]\n\nThe surgeon in the multidisciplinary team should:\n\nhave had a relevant supervised training programme\n\nhave specialist experience in bariatric surgery\n\nsubmit data for a national clinical audit scheme (the National Bariatric Surgery Registry is now available to conduct national audit for a number of agreed outcomes). [2006, amended 2014]\n\n## Adults\n\nIn addition to the criteria listed in recommendation 1.10.1, bariatric surgery is the option of choice (instead of lifestyle interventions or drug treatment) for adults with a BMI of more than 50\xa0kg/m2 when other interventions have not been effective. [2006, amended 2014]\n\nOrlistat may be used to maintain or reduce weight before surgery for people who have been recommended surgery as a first-line option, if it is considered that the waiting time for surgery is excessive. [2006, amended 2014]\n\nSurgery for obesity should be undertaken only by a multidisciplinary team that can provide:\n\npreoperative assessment, including a risk-benefit analysis that includes preventing complications of obesity, and specialist assessment for eating disorders\n\ninformation on the different procedures, including potential weight loss and associated risks\n\nregular postoperative assessment, including specialist dietetic and surgical follow up (see recommendation 1.12.1)\n\nmanagement of comorbidities\n\npsychological support before and after surgery\n\ninformation on, or access to, plastic surgery (such as apronectomy) when appropriate\n\naccess to suitable equipment, including scales, theatre tables, Zimmer frames, commodes, hoists, bed frames, pressure-relieving mattresses and seating suitable for people undergoing bariatric surgery, and staff trained to use them. \n\nCarry out a comprehensive preoperative assessment of any psychological or clinical factors that may affect adherence to postoperative care requirements (such as changes to diet) before performing surgery. [2006, amended 2014]\n\nRevisional surgery (if the original operation has failed) should be undertaken only in specialist centres by surgeons with extensive experience because of the high rate of complications and increased mortality. \n\n## Children\n\nSurgical intervention is not generally recommended in children or young people. \n\nBariatric surgery may be considered for young people only in exceptional circumstances, and if they have achieved or nearly achieved physiological maturity. \n\nSurgery for obesity should be undertaken only by a multidisciplinary team that can provide paediatric expertise in:\n\npreoperative assessment, including a risk-benefit analysis that includes preventing complications of obesity, and specialist assessment for eating disorders\n\ninformation on the different procedures, including potential weight loss and associated risks\n\nregular postoperative assessment, including specialist dietetic and surgical follow up\n\nmanagement of comorbidities\n\npsychological support before and after surgery\n\ninformation on or access to plastic surgery (such as apronectomy) when appropriate\n\naccess to suitable equipment, including scales, theatre tables, Zimmer frames, commodes, hoists, bed frames, pressure-relieving mattresses and seating suitable for children and young people undergoing bariatric surgery, and staff trained to use them. \n\nCoordinate surgical care and follow‑up around the child or young person and their family's needs. Comply with the approaches outlined in the Department of Heath's a call to action on obesity in England. [2006, amended 2014]\n\nEnsure all young people have had a comprehensive psychological, educational, family and social assessment before undergoing bariatric surgery. [2006, amended 2014]\n\nPerform a full medical evaluation, including genetic screening or assessment before surgery to exclude rare, treatable causes of obesity. \n\n# Bariatric surgery for people with recent-onset type\xa02 diabetes\n\nFor the recommendations in this section, the committee considered that recent-onset type\xa02 diabetes would include those people whose diagnosis has been made within a 10-year time frame.\n\nOffer an expedited assessment for bariatric surgery to people with a BMI of 35 or over who have recent-onset type 2\xa0diabetes as long as they are also receiving or will receive assessment in a tier\xa03 service (or equivalent). \n\nConsider an assessment for bariatric surgery for people with a BMI of 30 to 34.9 who have recent-onset type 2\xa0diabetes as long as they are also receiving or will receive assessment in a tier\xa03 service (or equivalent). \n\nConsider an assessment for bariatric surgery for people of Asian family background who have recent-onset type\xa02 diabetes at a lower BMI than other populations (see recommendation 1.2.8) as long as they are also receiving or will receive assessment in a tier\xa03 service (or equivalent). \n\n# Follow-up care\n\nOffer people who have had bariatric surgery a follow-up care package for a minimum of 2\xa0years within the bariatric service. This should include:\n\nmonitoring nutritional intake (including protein and vitamins) and mineral deficiencies\n\nmonitoring for comorbidities\n\nmedication review\n\ndietary and nutritional assessment, advice and support\n\nphysical activity advice and support\n\npsychological support tailored to the individual\n\ninformation about professionally led or peer-support groups. \n\nAfter discharge from bariatric surgery service follow-up, ensure that all people are offered at least annual monitoring of nutritional status and appropriate supplementation according to need following bariatric surgery, as part of a shared care model of chronic disease management. ", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# New recommendations for research\n\n## Measurements for assessing health risks in adults\n\nWhat are the most accurate and suitable measurements and boundary values to assess the health risks associated with overweight, obesity and central adiposity in adults of different ethnicities, particularly those from Black, Asian and minority ethnic family backgrounds? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on classifying overweight, obesity and central adiposity in adults\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: accuracy of anthropometric measures in assessing health risks associated with overweight and obesity in adults.\n\nLoading. Please wait.\n\n## Measurements for assessing health risks in children and young people\n\nWhat are the most accurate and suitable measurements and boundary values to assess the health risk associated with overweight, obesity and central adiposity in children and young people of different ethnicities, particularly those from Black, Asian and minority ethnic family backgrounds? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on measures of overweight, obesity and central adiposity in children and young people\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: accuracy of anthropometric measures in assessing health risks associated with overweight and obesity in children and young people.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\nSee the update information section for more details.\n\n## Follow-up care after bariatric surgery\n\nDo post-operative lifestyle intervention programmes (exercise, behavioural or dietary) improve weight loss and weight-loss maintenance following bariatric surgery? \n\n## Long-term outcomes of bariatric surgery on people with type\xa02 diabetes\n\nWhat is the long-term effect of bariatric surgery on diabetes-related complications and quality of life in people with type\xa02 diabetes compared with optimal medical treatment? \n\n## Bariatric surgery in children and young people\n\nWhat are the long-term outcomes of bariatric surgery in children and young people living with obesity? \n\n## Obesity management for people with a condition associated with an increased risk of obesity\n\nWhat is the best way to deliver obesity management interventions to people with particular conditions associated with increased risk of obesity (such as people with a physical disability that limits mobility, a learning disability or enduring mental health difficulties)? \n\n## Long-term effect of very-low-calorie diets on people with a BMI of 40\xa0kg/m2 or more\n\nWhat are the long-term effects of using very-low-calorie diets (VLCDs) versus low-calorie diets (LCDs) on weight and quality of life in patients with a body mass index (BMI) of 40\xa0kg/m2 or more, including the impact on weight cycling? \n\n## Comparative risks for different generations of immigrants\n\nIs the risk of ill health the same for first-, second- and third-generation immigrants from black, Asian and other minority ethnic groups at the same BMI and waist-to-height ratio thresholds? \n\n## Single cut-off points\n\nWhat are the risks and benefits of developing single-figure cut-off points on BMI and waist-to-height ratio for black, Asian and other minority ethnic groups to help prevent diabetes and other conditions? \n\n## Awareness of risk among black, Asian and other minority ethnic groups\n\nAre black, Asian and other minority ethnic groups aware that they are at the same risk of type 2 diabetes and mortality at a lower BMI, compared with the white population? \n\n## Practitioners and providers' awareness of risk in black, Asian and other minority ethnic groups\n\nAre clinicians, practitioners and weight management service providers aware that black, Asian and other minority ethnic groups are at the same risk of type 2 diabetes and mortality at a lower BMI compared with the white population. If so, do they intervene at lower BMI and waist-to-height ratio thresholds? \n\n## Lifestyle interventions for black, Asian and other minority ethnic groups\n\nHow effective and cost effective are lifestyle interventions for people from black, Asian and other minority ethnic groups at different BMI and waist-to-height ratio thresholds, compared with the general population? ", 'Rationale and impact': "These sections briefly explain why the committee made the 2022 recommendations and how they might affect practice.\n\n# Identifying and assessing overweight, obesity and central adiposity in adults\n\nRecommendations 1.2.2 to 1.2.5 and 1.2.7 to 1.2.16\n\n## Why the committee made the recommendations\n\nBased on their expertise, the committee agreed that a clear benefit of measuring the waist-to-height ratio is that people can easily do it themselves, interpret their results, and seek advice if they are at increased health risk.\n\nSelf-measurement may reduce the sense of discomfort or stigma some people may feel from a healthcare professional doing the waist circumference measurement. People can also use resources to help them measure their waist accurately, such as the NHS BMI healthy weight calculator, and videos by Diabetes UK and the British Heart Foundation.\n\nWhen a person seeks advice because self-measurement indicates an increased health risk, they may need further assessment (such as for cardiometabolic risk factors) and their waist-to-height ratio may be measured again. The committee were aware that there may be situations when a professional taking a measurement may have a negative effect or be inappropriate, because of the stigma attached to it. And some people may not want to be measured because of their religious and cultural beliefs. The committee agreed on the importance of being sensitive to people's needs and recognising when it is not appropriate to measure. The committee noted that sensitivity and stigma will be addressed in a forthcoming update of the guideline.\n\nThe committee looked at evidence from studies on the accuracy of different measures for predicting or identifying health conditions associated with overweight and obesity, including type\xa02 diabetes and cardiovascular disease. The quality of the evidence was mixed. Most studies included information on how accurate the measures were at predicting or diagnosing the health risks associated with overweight and obesity, in people of different ethnicities. Overall, the studies showed that body mass index (BMI), waist circumference, waist-to-hip ratio and waist-to-height ratio could all accurately predict or identify weight-related conditions. The committee noted that BMI is still a useful practical measure, particularly for defining overweight and obesity. But they emphasised that it needs to be interpreted with caution because it is not a direct measure of central adiposity. The committee highlighted that waist-to-height ratio offers a truer estimate of central adiposity by using waist circumference in the calculation. Based on evidence and their experience, they agreed that using waist-to-height ratio as well as BMI would help give a practical estimate of central adiposity in adults with BMI under 35\xa0kg/m2. This would in turn help professionals assess and predict health risks. But because people with a BMI over 35\xa0kg/m2 are always likely to have a high waist-to-height ratio, the committee recognised that it may not be a useful addition for predicting health risks in this group.\n\nBMI is the main measure for defining overweight and obesity, and the committee did not alter the BMI categories for the general population. But, based on their expertise, they agreed it was important to estimate central adiposity when assessing future health risks, including for people whose BMI is in the healthy weight category. The committee also highlighted the need for caution when interpreting BMI in adults with high muscle mass because it may be less accurate in this group.\n\nAge-related changes in the body are not well captured by BMI. The committee agreed that BMI should therefore be interpreted with caution in people aged 65 and over, because their functional capacity may be reduced due to conditions such as age-related spinal disorders or sarcopenia. They also recognised that slightly higher BMI in older people can have a protective effect (for example, reduced risk of all-cause mortality) because they are less likely to be experiencing undernutrition. So, it is important for professionals to evaluate the balance of these risks when interpreting BMI.\n\nThe committee also highlighted that people from Black, Asian and minority ethnic family backgrounds are prone to central adiposity and have an increased cardiometabolic health risk at lower BMI thresholds. For example, studies in people of South Asian and Chinese family backgrounds showed an increased risk at a BMI of 21\xa0kg/m2 to 26\xa0kg/m2, whereas people from white family backgrounds showed increased risks at 25\xa0kg/m2 to 29\xa0kg/m2.\n\nThere was also some evidence for using lower BMI thresholds for people from Middle Eastern (Arab and Iranian), Black African, Black Caribbean and other Asian (Japanese, Korean and Thai) family backgrounds. For these groups, studies identified an increase in risk at BMI values that ranged from 21\xa0kg/m2 to 30\xa0kg/m2 but most were below 25\xa0kg/m2. The committee noted that these lower thresholds are in line with international guidance and are already used in practice to refer people from these family backgrounds to weight management services.\n\nAlthough NICE found no evidence on the thresholds for obesity classes 2 and 3 in people of these family backgrounds, the committee consensus was that it is generally good practice to reduce the thresholds used for the general population by about 2.5\xa0kg/m2. This would mean that the threshold for obesity class 2 would be lowered to roughly 32.5\xa0kg/m2, and for class 3 to 37.5\xa0kg/m2 in these populations. Public Health England guidance on adult weight management and the British Obesity and Metabolic Surgery Society guidance on accessing tier 4 services also endorsed reducing the thresholds.\n\nIn line with their recommendations for other populations, the committee used the terms overweight and obesity instead of risk levels to describe thresholds in people with a South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family background. They agreed that in their experience there was more stigma attached to talking about risk than overweight or obesity. They noted that terms such as 'high risk' could result in anxiety and overinterpretation of risk more than terms such as 'living with obesity'.\n\nThe committee also discussed the accuracy of waist-to-height ratio boundary values in predicting and identifying health risks. The evidence showed that the cut-off from individual studies was generally around 0.5 for all ethnicities and sexes, which was in line with the wider evidence. They agreed that waist-to-height ratio could be used to define central adiposity in adults, and that a range of 0.5 to 0.59 corresponds to increased health risks. The committee noted that a waist-to-height ratio of 0.6 or more indicates a further increase in risk.\n\nThe committee agreed that a key benefit of using waist-to-height ratio is that the classification is the same for all ethnicities and sexes. It can also be useful in adults with high muscle mass, for whom BMI may be less accurate.\n\nThe committee also noted the boundary value of 0.5 could be communicated in a simple and memorable way with the message: 'Keep your waist to less than half your height'.\n\nAlthough there was a large evidence base, the committee noted a lack of evidence on the accuracy of methods for predicting future risks for people of some ethnicities. Few studies were based in the UK, so the evidence might not reflect how accurate different measures might be when used in a UK context. Therefore, the committee highlighted the need for more research on measurements and boundary values for different ethnicities and made a recommendation for research on measurements for assessing health risks in adults.\n\nThe committee agreed that it is important for healthcare professionals to ask for permission before starting any discussions linked to overweight, obesity and central adiposity.\n\nBased on their experience, the committee stressed the importance of sensitive and positive discussions because the stigma associated with obesity can affect people's mental and physical health. This can lead to further weight gain and make them less likely to engage with healthcare professionals. It is especially important to be sensitive when talking to people with conditions such as eating disorders (such as anorexia nervosa, bulimia and binge eating disorder), or disordered eating (such as restrictive dieting, compulsive eating or skipping meals).\n\nThe committee noted existing resources and advice that could help conduct sensitive, person-centred conversations. These include Health Education England's healthier weight competency framework, Obesity UK's language matters, and training courses by the Royal College of General Practitioners (RCGBP), World Obesity Federation and European Association for the Study of Obesity (EASO).\n\nThe committee did not make specific recommendations on sensitive language and measures to prevent stigma because a forthcoming update of this guideline will address these.\n\nThe committee noted it is important for adults to know the long-term health risks and conditions associated with overweight, obesity and central adiposity. These include type\xa02 diabetes, cardiovascular disease, hypertension, dyslipidaemia, certain cancers, and respiratory, musculoskeletal or other metabolic conditions (such as non-alcoholic fatty liver disease). Knowledge about these may encourage the person to stick to a weight loss strategy. Based on their understanding of practice, the committee stressed the importance of an all-round discussion of the person's individual needs and preferences to reach a shared decision about what level and types of intervention would suit them. This includes taking into account factors such as ethnicity, weight-related comorbidities, socioeconomic status, family medical history and special educational needs and disabilities (SEND). These discussions can also involve giving information about local weight management services and other support services.\n\nBased on their expertise, the committee agreed people with weight-related comorbidities may benefit from a higher level of intervention. They also highlighted groups of people, such as those newly diagnosed with type\xa02 diabetes and those with BMI over 50, who would benefit more from immediate weight management interventions. Based on their expertise, the committee noted that these groups are often not offered appropriate interventions early enough.\n\n## How the recommendations might affect practice\n\nThe committee highlighted that encouraging self-measurement is in line with changes in practice over the past 2\xa0years, particularly the increase in carrying out initial assessments by phone. It has already become standard practice to use self-reported measurements such as weight, blood pressure readings and blood sugar levels for conditions like diabetes.\n\nUsing waist-to-height ratio as well as BMI would be likely to have minimal cost impact because tape measures are already routinely available in NHS settings for measuring waist circumference.\n\nThe committee noted that community pharmacies have been involved in taking measurements as well as it being done in general practice. Public Health England's Healthier weight competency framework highlights that healthcare professionals involved in identification of overweight and obesity should be able to accurately measure and classify weight status. With the addition of waist-to-height ratio, it is important that training is available so that measurements can be conducted by trained personnel.\n\nCurrently, there are no established resources for calculating waist-to-height ratio. But resources such as the NHS BMI healthy weight calculator can be used to explain how to take waist measurements. Additional training programmes may need to be developed to help healthcare professionals understand central adiposity and conduct waist measurement in a sensitive manner and with care, especially in people with specific conditions such as eating disorders. This will lead to additional training costs. There may also be a cost increase associated with the extra staff time needed to teach people how to measure themselves and calculate waist-to-height ratio. But the committee agreed that these additional costs are unlikely to result in a significant resource impact and will be balanced out by the long-term health improvements such as decreased risk of developing diabetes or cardiovascular disease.\n\nUsing lower BMI thresholds in people from Black, Asian and minority ethnic family backgrounds will increase the number of people who are eligible for weight management services. However, this could reduce levels of overweight and obesity, and thereby reduce the costs of treating obesity-related conditions for the NHS and wider system, such as social care systems.\n\nThere may be challenges in using BMI or waist-to-height ratio in people who have a physical disability, some physical conditions (such as scoliosis) or learning difficulties because people may be unable to get on scales independently or be lifted safely. In such circumstances, reasonable adjustments would be needed for adults, for example using seated or hoist scales, or scales that can used for wheelchairs (including moulded wheelchairs). Measurements may also need to be modified, for example using sitting height or demi-span (the distance between the mid-point of the sternal notch and the finger roots with the arms outstretched laterally) instead of overall height, meaning specialist assessment may be needed. It may also be challenging to take measurements in people who are housebound because it may not be possible to access equipment such as specialist scales during home visits.\n\nReturn to recommendations\n\n# Identifying and assessing overweight, obesity and central adiposity in children and young people\n\nRecommendations 1.2.21 and 1.2.22 and 1.2.24 to 1.2.29\n\n## Why the committee made the recommendations\n\nThe committee were aware of the need to update advice on sensitivity when taking measurements, remaining mindful and sensitive to children and young people's needs (including cultural and religious beliefs) as well as the needs of their parents and carers, and recognising when it is not appropriate to measure. They did not make any recommendations because this section will be reviewed as part of a forthcoming update of the guideline.\n\nThe committee looked at evidence on the accuracy of different measures for predicting or identifying health conditions associated with overweight and obesity, including type\xa02 diabetes and cardiovascular disease. The quality of the evidence was mixed. Some studies included information on how accurate measures were at predicting or diagnosing the health risks associated with overweight and obesity in children and young people of different ethnicities.\n\nOverall, the committee agreed that the studies showed that BMI, waist circumference and waist-to-height ratio could all be used to accurately predict or identify weight-related conditions when they were adjusted for age and sex. The same was true of waist-to-height ratio when it was not adjusted for age and sex. They discussed that BMI z-score adjusted for sex and age tended to be the most accurate measure for identifying different health conditions, but waist-to-height ratio was often equally accurate and, in some studies, more accurate. (BMI z-score is also known as BMI standard deviations [SDs], which indicate how many units a child's BMI is above or below the average BMI value for their age group and sex.)\n\nBased on the evidence and their clinical expertise, the committee agreed that BMI is a useful practical measure for estimating and defining overweight and obesity. However, they noted that BMI should not be interpreted in the same way for children and young people as for adults. Healthcare professionals should use charts that are specific to children and young people and adjusted for age and sex. The committee also noted that waist-to-height ratio is a truer estimate of central adiposity, which is related to health risks.\n\nThe committee agreed that special growth charts may be needed when assessing children and young people with cognitive and physical disabilities, including those with learning disabilities. They noted that growth charts for children and young people with Down's syndrome are available from the Centres for Disease Control and the Royal College of Paediatrics and Child Health.\n\nThe committee agreed that the evidence for using waist-to-height ratio as a practical estimate for central adiposity to assess and predict health risk in children and young people was not as good as the evidence for adults. They agreed that it could still be useful as an indication of future health risks. But they stated that more research was needed on the accuracy of different measures and made a recommendation for research on measurements for assessing health risks in children and young people.\n\nThe committee looked at evidence for different boundary values for BMI and BMI z-scores but these focused on identifying current health conditions rather than defining the degree of overweight and obesity. Based on their expertise, they provided clinical definitions of overweight and obesity using BMI centiles and BMI SDs. These values correspond with those in the Royal College of Paediatrics (RCPCH) and Child Health UK-World Health Organization (WHO) growth charts. The committee agreed that it was important to use clinical judgement when interpreting BMI below the 91st centile, especially because children and young people in the healthy weight category may still have central adiposity.\n\nThe committee also noted that there are resources that can help professionals understand how to measure, plot and assess BMI in children and young people. These include educational resources from the RCPCH and the National Child Measurement Programme Operational Guidance, which both give information on how the clinical definitions of BMI link to BMI centiles and SDs.\n\nThere was a lack of evidence identified on BMI boundary values for children and young people from different ethnicities. The committee agreed this was an important area for research to investigate whether there are variations in thresholds, as there are in adults, and made a recommendation for research on measurements for assessing health risks in children and young people. The committee noted that although they could not provide different thresholds for BMI, waist-to-height ratio could be used as an indicator of central adiposity regardless of ethnicity and sex.\n\nStudies also suggested that the optimal waist-to-height ratio cut-offs for children and young people ranged from 0.42 to 0.57, with most studies averaging around 0.5. Based on the evidence and their clinical knowledge, the committee agreed the waist-to-height ratio boundary value of 0.5 should be the same for children and young people as for adults.\n\nThe committee agreed that it is important to ask for permission from children, young people, and their parents or carers (if appropriate), before starting any discussions linked to overweight, obesity or central adiposity. They agreed that professional judgement is needed to ensure discussions are age appropriate and decide whether the child or young person should be involved. They also noted that it was standard practice for healthcare professionals to use Gillick competency to determine the capacity of a child or young person under 16 to consent.\n\nBased on their expertise, the committee stressed the importance of sensitive and positive discussions because the stigma associated with obesity can affect a child or young person's mental and physical health. It is especially important to be sensitive when talking to children and young people with conditions such as eating disorders (such as anorexia nervosa, bulimia and binge eating disorder), or disordered eating (such as restrictive dieting, compulsive eating or skipping meals).\n\nThe committee noted existing resources and advice that could help conduct conversations with children and young people in a sensitive and positive way. These include Health Education England's healthier weight competency framework, Public Health England's let's talk about weight (which highlights a focus on weight maintenance and growing into a healthier weight, rather than weight loss) and Obesity UK's language matters guidance. There are also training courses by the Royal College of General Practitioners (RCGBP), World Obesity Federation and European Association for the Study of Obesity (EASO).\n\nThe committee did not make specific recommendations on sensitive language and measures to prevent stigma because a forthcoming update of this guideline will address these.\n\nBased on their clinical expertise, the committee agreed that tailored interventions were useful for children who are living with overweight or obesity or have increased health risk based on waist-to-height ratio. They agreed that weight-related comorbidities, ethnicity, socioeconomic status, social complexity (for example, looked-after children and young people), family medical history, mental and emotional health and wellbeing, developmental age, and special educational needs and disabilities (SEND) need to be taken into account when tailoring interventions.\n\nThe committee were particularly aware that children and young people with weight-related comorbidities, such as type\xa02 diabetes, may benefit from a higher level of intervention regardless of their waist-to-height ratio. The committee stressed the importance of working with the child or young person, and their families and carers (if appropriate), to make an informed decision about the treatment or care option that is best for them. As highlighted in resources such as the step-by-step guide produced by Public Health England on conversations about weight, healthcare professionals can also give information about local weight management services and other support services during these discussions.\n\n## How the recommendations might affect practice\n\nWaist-to-height ratio is not routinely measured in practice, so there may be additional costs for the extra staff time involved. But the cost impact should be small because waist measurements are already widely used in primary care so it would not need much extra time to calculate the ratio.\n\nThe committee noted that health visitors and school nurses, as well as general practice, are involved in taking measurements. The healthier weight competency framework does highlight that healthcare professionals involved in identification of overweight and obesity should be able to accurately measure and classify weight status in children and young people. With the addition of waist-to-height ratio, it is important that training is available so that measurements can be conducted by trained personnel.\n\nThere are no established resources for measuring waist-to-height ratio, but healthcare professionals can use the NHS BMI healthy weight calculator, and videos by organisations such as Diabetes UK and the British Heart Foundation. These are for adults but can also be useful for older children and young people, families and carers.\n\nThere are a few training programmes specifically for managing overweight and obesity in children and young people, such as the ones by the World Obesity Federation, European Childhood Obesity Group, the Department of Health and Social Care's obesity team and Health Education England. Some of these need to be updated to include measuring waist circumference and interpreting waist-to-height ratio, which might lead to additional training costs. Healthcare professionals may need extra time to teach older children and young people, and their families and carers, how to measure the waist accurately and calculate waist-to-height ratio. However, the committee agreed that additional costs of training and staff time are unlikely to result in a significant resource impact and are justified by the long-term health benefits associated with a reduction in obesity-related conditions.\n\nThere may be challenges in using BMI or waist-to-height ratio in children and young people with physical disabilities, some physical conditions (such as scoliosis) or learning difficulties. Reasonable adjustments would also be needed for children and young people using wheelchairs (including moulded wheelchairs) such as using seated or hoist scales, or scales that are suitable for wheelchairs. And although there is published guidance on supporting people with learning disabilities in obesity and weight management, there are no validated proxy measurements for height in children and young people (for example, using their sitting height or demi-span to estimate their height). This makes taking measurements difficult in children and young people with physical disabilities or learning difficulties.\n\nReturn to recommendations", 'Context': "The 2019 Health Survey for England estimated the prevalence of obesity in adults in England to be 28%, with overweight affecting a further 36%. It estimated the prevalence of obesity in children aged 2 to 15 to be 20% in boys and 13% in girls, with overweight affecting a further 12% of boys and 15% of girls. Government estimates indicate that the current costs of obesity in the UK are £6.1\xa0billion to the NHS and £27\xa0billion to wider society.\n\nCurrently, people who would benefit from weight management interventions are identified opportunistically. The lack of active case finding may mean that conditions such as type\xa02 diabetes are likely to be under-diagnosed in people of Black, Asian and other minority ethnic backgrounds whose risk is increased at a lower body mass index (BMI) and waist circumference.\n\nNew evidence identified since this guideline was first published may help to refine weight management programmes that address diet, physical activity and behaviour change, and inform implementation of interventions in specific settings.\n\nThis guideline update covers identifying and assessing overweight, obesity and central adiposity in children aged 2\xa0years and older, young people and adults. It updates NICE's guideline on obesity: identification, assessment and management (NICE guideline CG189) and replaces NICE's guideline on BMI: preventing ill health and premature death in Black, Asian and other minority ethnic groups (NICE guideline PH46).\n\nForthcoming updates will cover preventing and managing these conditions. They will produce a single guideline that will partially replace NICE's guideline on weight management before, during and after pregnancy (NICE guideline PH27; only the recommendations that apply before and after pregnancy) and will fully update and replace this guideline and NICE's guidelines on:\n\npreventing excess weight gain (NICE guideline NG7)\n\nweight management: lifestyle services for overweight or obese adults (NICE guideline PH53)\n\nweight management: lifestyle services for overweight or obese children and young people (NICE guideline PH47)\n\nobesity: working with local communities (NICE guideline PH42)\n\nobesity prevention (NICE guideline CG43)."}	https://www.nice.org.uk/guidance/cg189	This guideline covers identifying, assessing and managing obesity in children (aged 2 years and over), young people and adults.
20d83c400b031feead37471826c783d7065b7abb	nice	Self-harm: assessment, management and preventing recurrence	Self-harm: assessment, management and preventing recurrence This guideline covers assessment, management and preventing recurrence for children, young people and adults who have self-harmed. It includes those with a mental health problem, neurodevelopmental disorder or learning disability and applies to all sectors that work with people who have self-harmed. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The recommendations apply to staff from all sectors that work with people who have self-harmed, unless a recommendation or section specifically states that it is for a certain group. Because of the wide variety of criminal justice system settings that exist and the need to take other relevant national guidance into account, the recommendations in the guideline may need to be tailored for certain criminal justice system settings during implementation. Putting recommendations into practice can take time depending on how much change in practice or services is needed. Most of the recommendations in this guideline reinforce best practice and will not need additional resources to implement if previous guidance has been followed. If changes to current local practice are needed to implement the recommendations, they may take time and significant additional resources. The recommendations apply to all people who have self-harmed, unless a recommendation specifically states that it is for adults or children and young people only. # Information and support Provide information and support for people who have self-harmed. Share information with family members or carers (as appropriate). Topics to discuss include: what self-harm is why people self-harm and, where possible, the specific circumstances of the person support and treatments available self-care (also see recommendation 1.11.12 in the section on harm minimisation), including when to seek help how to deal with injuries how to manage scars care plans and safety plans, and what they involve the impact of encountering stigma around self-harm who will be involved in their care and how to get in touch with them where appointments will take place what to do if they have any concerns what do to in an emergency local services and how to get in touch with them, including out-of-hours local peer support groups, online forums, local and national charities, and how to get in touch with them. Provide information and support for the family members or carers (as appropriate) of the person who has self-harmed. Topics to discuss include: the emotional impact on the person and their family members or carers advice on how to cope when supporting someone who self-harms what to do if the person self-harms again how to seek help for the physical consequences of self-harm how to assist and support the person how to recognise signs that the person may self-harm steps to reduce the likelihood of self-harm in the future support for families and carers and how to access it the impact of encountering stigma around self-harm local services and how to get in touch with them, including out-of-hours local peer support groups, online forums, local and national charities, and how to get in touch with them their right to a formal assessment of their own needs including their physical and mental health (known as a 'carer's assessment'), and how to access this (see the NICE guideline on supporting adult carers). Information for people who have self-harmed and their family members or carers should be: tailored to their individual needs and circumstances, taking into account, for example, whether this is a first presentation or repeat self‑harm, the severity and type of self-harm, and if the person has any coexisting health conditions, neurodevelopmental conditions or a learning disability provided throughout their care sensitive and empathetic supportive and respectful consistent with their care plan, if there is one in place conveyed in the spirit of hope and optimism.For more guidance on communication, providing information (including different formats) and shared decision making, see the NICE guidelines on shared decision making, service user experience in adult mental health, patient experience in adult NHS services and babies, children and young people's experience of healthcare. Recognise that support and information may need to be adapted for people who may be subject to discrimination, for example, people who are physically disabled, people with neurodevelopmental conditions or a learning disability, people from underserved groups, people from Black, Asian and minority ethnic backgrounds and people who are LGBTQ+. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support . Full details of the evidence and the committee's discussion are in: evidence review A: information and support needs of people who have self-harmed evidence review B: information and support needs of families and carers of people who have self-harmed. Loading. Please wait. # Consent and confidentiality Healthcare professionals and social care practitioners who have contact with people who self-harm should be able to: understand when and how to apply the principles of the Mental Capacity Act 2005 and its Code of Practice, the Mental Health Act 2007 and its Code of Practice, and the Care Act 2014 and the Care Act 2014 statutory guidance assess mental capacity make decisions about when treatment and care can be given without consent understand when and how to seek further guidance about consent to care direct people to independent mental capacity advocates (IMCAs).Also see the NICE guidelines on decision making and mental capacity, service user experience in adult mental health, and babies, children and young people's experience of healthcare, and the Department of Health and Social Care's consensus statement on information sharing and suicide prevention. Healthcare professionals and social care practitioners who have contact with children and young people who self-harm should also be able to: understand how to apply the principles of the Children Act 1989 and the Children and Families Act 2014 in relation to competence, capacity and confidentiality and the scope of parental responsibility understand how to apply the principles of the Mental Health Act 2007 to young people understand how issues of capacity and competence to consent apply to children and young people of different ages assess the young person's capacity to consent (including Gillick competence). If staff working with people who self-harm need to discuss issues relating to capacity and consent, they should have access to: specialist advice (for example, liaison psychiatry) at all times and legal advice as needed. Staff working with people who self-harm should be familiar with the limits of confidentiality with regard to information about a person's treatment and care. Staff working with people who self-harm should be aware of the benefits of involving the person's family and carers and sharing information, and should recognise the need to seek consent from the person as early as possible. Also see the Department of Health and Social Care's consensus statement on information sharing and suicide prevention. Staff working with people who self-harm should recognise that if it is necessary to breach confidentiality, they should ensure that the person who has self-harmed is still involved in decisions about their care and, where possible, is informed about the breach of confidentiality. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on consent and confidentiality . Full details of the evidence and the committee's discussion are in evidence review C: consent, confidentiality and safeguarding. Loading. Please wait. # Safeguarding All staff who have contact with people who self-harm should: understand when and how to apply the safeguarding principles of the Care Act 2014, the Children Act 1989, and the Children and Families Act 2014 ask about safeguarding concerns, for example, domestic abuse, violence or exploitation at the earliest opportunity and, if appropriate, when the person is alone explore whether the person's needs should be assessed and documented according to local safeguarding procedures be aware of local safeguarding procedures for vulnerable adults and children in their care, and seek advice from the local named lead on safeguarding if needed.Also see the NICE guidelines on domestic violence and abuse, looked-after children and young people, child abuse and neglect and child maltreatment. If people who self-harm are referred to local health and social care services under local safeguarding procedures, use a multi-agency approach, including education and/or third sector services, to ensure that different areas of the person's life are taken into account when assessing and planning for their needs. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on safeguarding . Full details of the evidence and the committee's discussion are in evidence review C: consent, confidentiality and safeguarding. Loading. Please wait. # Involving family members and carers The recommendations in this section should be read alongside the recommendations on consent and confidentiality. Ask the person who has self-harmed whether and how they would like their family or carers to be involved in their care, taking into account the factors in recommendation 1.4.2, and review this regularly. If the person agrees, share information with family members or carers (as appropriate), and encourage them to be involved. When thinking about involving family members or carers in supporting a person who has self-harmed, take into account issues such as: whether the person has consented for information to be shared and, if so, if the consent is limited to certain aspects of their care any safeguarding concerns the person's mental capacity, age and competence to make decisions the person's right to confidentiality and autonomy in decision making the balance between autonomy (in children and young people, their developing independence and maturity) and the need to involve family members or carers the balance between the possible benefits and risks of involving family members of carers and the rights of the person. Also see the NICE guidelines on decision making and mental capacity, service user experience in adult mental health, and babies, children and young people's experience of healthcare. When involving family members or carers in supporting a person who has self-harmed: encourage a collaborative approach to: empower and support the person who has self-harmed minimise the person's self-harm behaviours and support the person's recovery to prevent recurrence give them opportunities to be involved in decision making, care planning and developing safety plans to support the person beyond the initial self-harm episode, and through their care pathway ensure that there is ongoing and timely communication with the family or carers regularly review whether the person who has self-harmed still wants their family or carers to be involved in their care, and ensure that they know they can withdraw consent to share information at any time. Be aware that even if the person has not consented to involving their family or carers in their care, family members or carers can still provide information about the person. If the person who has self-harmed finds it difficult to vocalise their distress when they are in need of care, support the person and their family members or carers (as appropriate) in trying alternative methods of communication (such as non-verbal language, letters, emotional wellbeing passports, and using agreed safe words, phrases or emojis). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on involving family members and carers . Full details of the evidence and the committee's discussion are in evidence review D: involving family and carers in the management of people who have self-harmed. Loading. Please wait. # Psychosocial assessment and care by mental health professionals At the earliest opportunity after an episode of self-harm, a mental health professional should carry out a psychosocial assessment to: develop a collaborative therapeutic relationship with the person begin to develop a shared understanding of why the person has self‑harmed ensure that the person receives the care they need give the person and their family members or carers (as appropriate) information about their condition and diagnosis. Do not delay the psychosocial assessment until after medical treatment is completed. If the person who has self-harmed is intoxicated by drugs or alcohol, agree with the person and colleagues what immediate assistance is needed, for example, support and advice about medical assessment and treatment. Do not use breath or blood alcohol levels to delay the psychosocial assessment. If the person is not able to participate in the psychosocial assessment, ensure that they have regular reviews, and complete a psychosocial assessment as soon as possible. If the person who has self-harmed has agreed a care plan, check this with them and follow it as much as possible. Carry out the psychosocial assessment in a private, designated area where it is possible to speak in confidence without being overheard. Take into account the needs and preferences of the person who has self‑harmed as much as possible when carrying out the psychosocial assessment, for example, by: making appropriate adaptations for any learning disability or physical, mental health or neurodevelopmental condition the person may have and providing the option to have a healthcare professional of the same sex carry out the psychosocial assessment when the person has requested this. During the psychosocial assessment, explore the functions of self-harm for the person. Take into account: the person's values, wishes and what matters to them the need for psychological interventions, social care and support, or occupational or vocational rehabilitation any learning disability, neurodevelopmental conditions or mental health problems the person's treatment preferences that each person who self-harms does so for their own reasons that each episode of self-harm should be treated in its own right, and a person's reasons for self-harm may vary from episode to episode whether it is appropriate to involve their family and carers; see the section on involving family members and carers. During the psychosocial assessment, explore the following to identify the person's strengths, vulnerabilities and needs: historic factors changeable and current factors future factors, including specific upcoming events or circumstances protective or mitigating factors. For children and young people who have self-harmed, ensure that a mental health professional experienced in assessing children and young people who self-harm carries out the psychosocial assessment. They should ask about: their social, peer group, education and home situations any caring responsibilities the use of social media and the internet to connect with others and the effects of these on mental health and wellbeing any child protection or safeguarding issues (also see the section on safeguarding). For older people who have self-harmed, ensure that a mental health professional experienced in assessing older people who self-harm carries out the psychosocial assessment. They should: pay particular attention to the potential presence of depression, cognitive impairment, physical ill health and frailty include an assessment of the person's social and home situation, including any role they have as a carer recognise the increased potential for loneliness and isolation recognise that there are higher rates of suicide after an episode of self‑harm for older people. For people with a learning disability who have self-harmed, ensure that a mental health professional experienced in assessing people with a learning disability who self-harm carries out the psychosocial assessment. If a person has self-harmed and presents to services but wants to leave before a full psychosocial assessment has taken place, assess the person's safety and any mental health problems before they leave. Together with the person who self-harms and their family and carers (if appropriate), develop or review a care plan using the key areas of needs and safety considerations identified in the psychosocial assessment (see recommendations 1.5.8 to 1.5.14). Give the person a copy of their care plan, and share the plan as soon as possible with relevant healthcare professionals and social care practitioners involved in the person's care. If a person presents with frequent episodes of self-harm or if treatment has not been effective, carry out a multidisciplinary review with the person and those involved in their care and support, and others who may need to be involved, to agree a joint plan and approach. This should involve: identifying an appropriately trained professional or practitioner to coordinate the person's care and act as a point of contact reviewing the person's existing care and support, and arranging referral to any necessary services developing a care plan developing a safety plan for future episodes of self-harm, which should be written with and agreed by the person who self-harms. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychosocial assessment and care by mental health professionals . Full details of the evidence and the committee's discussion are in: evidence review F: assessment in specialist settings evidence review G: risk assessment and formulation. Loading. Please wait. # Risk assessment tools and scales Do not use risk assessment tools and scales to predict future suicide or repetition of self-harm. Do not use risk assessment tools and scales to determine who should and should not be offered treatment or who should be discharged. Do not use global risk stratification into low, medium or high risk to predict future suicide or repetition of self-harm. Do not use global risk stratification into low, medium or high risk to determine who should be offered treatment or who should be discharged. Focus the assessment (see the section on principles for assessment and care by healthcare professionals and social care practitioners) on the person's needs and how to support their immediate and long-term psychological and physical safety. Mental health professionals should undertake a risk formulation as part of every psychosocial assessment. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk assessment tools and scales . Full details of the evidence and the committee's discussion are in evidence review G: risk assessment and formulation. Loading. Please wait. # Assessment and care by healthcare professionals and social care practitioners ## Principles for assessment and care by healthcare professionals and social care practitioners When a person presents to a healthcare professional or social care practitioner following an episode of self-harm, the professional should: treat the person with respect, dignity and compassion, with an awareness of cultural sensitivity establish the means of self-harm and, if accessible to the person, discuss removing this with therapeutic collaboration or negotiation, to keep the person safe assess whether there are concerns about capacity, competence, consent or duty of care, and seek advice from a senior colleague or appropriate clinical support if necessary; be aware and accept that the person may have a different view and this needs to be taken into account seek consent to liaise with those involved in the person's care (including family members and carers, as appropriate) to gather information to understand the context of and reasons for the self-harm discuss with the person and their families or carers (as appropriate), their current support network, any safety plan or coping strategies. When a person presents to a healthcare professional or social care practitioner following an episode of self-harm, the professional should establish the following as soon as possible: the severity of the injury and how urgently medical treatment is needed the person's emotional and mental state, and level of distress whether there is immediate concern about the person's safety whether there are any safeguarding concerns whether the person has a care plan if there is a need to refer the person to a specialist mental health service for assessment. Carry out concurrent physical healthcare and the psychosocial assessment as soon as possible after a self-harm episode. For immediate first aid for self-poisoning, see the BNF's guidance on poisoning, emergency treatment, TOXBASE and the National Poisons Information Service. Do not use aversive treatment, punitive approaches or criminal justice approaches such as community protection notices, criminal behaviour orders or prosecution for high service use as an intervention for frequent self-harm episodes. ## Assessment and care in primary care When a person presents in primary care after an episode of self-harm, consider referring them to mental health or social care services for a psychosocial assessment or informing their existing mental health team, with consent from the person and their family members or carers (as appropriate). Make referral to mental health professionals a priority when: the person's levels of concern or distress are rising, high or sustained the frequency or degree of self-harm or suicidal intent is increasing the person providing assessment in primary care is concerned the person asks for further support from mental health services levels of distress in family members or carers of children, young people and adults are rising, high or sustained, despite attempts to help. If the person who has self-harmed is being supported and given care in primary care, their GP should ensure that the person has: regular appointments with their GP for review of self-harm a medicines review information about available social care, voluntary and non-NHS sector support and self-help resources care for any coexisting mental health problems, including referral to mental health services as appropriate. ## Assessment and care by ambulance staff and paramedics When attending a person who has self-harmed but who does not need urgent physical care, ambulance staff and paramedics should: discuss with the person the best way that the ambulance service can help them follow the person's care plan and safety plan if available seek advice from mental health professionals, where necessary record relevant information about the following, and pass this information to staff if the person is conveyed, or share it with other relevant people involved in the person's ongoing care if the person is not being conveyed: home environment social and family support network history leading to self-harm initial emotional state and level of distress any medicines found at their home. When attending a person who has self-harmed but who does not need urgent physical care, ambulance staff and paramedics should discuss with the person (and any relevant services) if it is possible for the person to be assessed by or receive treatment from an appropriate alternative service, such as a specialist mental health service or their GP. When deciding whether the person can receive treatment from an appropriate alternative service, ambulance staff and paramedics should assess immediate safety concerns, as well as the availability and accessibility of alternative services at that time. ## Assessment and care by non-mental health emergency department professionals When a person attends the emergency department or minor injury unit following an episode of self-harm, emergency department staff responsible for initial assessment or triage should establish the following as soon as possible: the severity of the injury and how urgently physical treatment is needed the person's emotional and mental state, and level of distress whether there is immediate concern about the person's safety whether there are any safeguarding concerns the person's willingness to accept medical treatment and mental healthcare the appropriate nursing observation level whether the person has a care plan. When a person attends the emergency department or minor injury unit following an episode of self-harm, offer referral to age-appropriate liaison psychiatry services, or for children and young people, crisis response service (or an equivalent specialist mental health service or a suitably skilled mental health professional) as soon as possible after arrival, for a psychosocial assessment (see the section on psychosocial assessment and care by mental health professionals and the section on risk assessment tools and scales), and support and assistance alongside physical healthcare. An age-appropriate liaison psychiatry professional or a suitably skilled mental health professional should see and speak to the person at every attendance after an episode of self-harm. Ensure that the emergency department has a private, designated area for psychosocial assessments to take place, where it is possible to speak in confidence without being overheard. Ensure that the waiting area in the emergency department for people who have self-harmed is close to staff who can provide care, support and observation. Ensure that appropriate joint governance arrangements are in place so that physical and mental healthcare can be delivered together in emergency departments. This should include: access to electronic record systems for both mental health services and medical treatment at the point of care jointly agreed referral pathways for concurrent physical and mental healthcare jointly agreed approaches to initial assessment and triage monitoring of the use of mental health law and mental capacity law joint safeguarding procedures jointly agreed nursing observation policies referral pathways to appropriate community services. Do not use mechanical restraint in emergency departments to prevent self-harm or to prevent a person from leaving the emergency department. Also see the NICE guideline on violence and aggression for recommendations about mechanical restraint. Ensure that policies and procedures are in place for people who have self‑harmed who wish to leave, or have left, the emergency department before physical healthcare and mental health assessment and care is complete. Ensure that policies and procedures are in place to identify people who frequently attend the emergency department or minor injury unit following an episode of self-harm so that a multidisciplinary review can be arranged in collaboration with mental health services (see recommendation 1.5.17 in the section on psychosocial assessment and care by mental health professionals). ## Assessment and care in general hospital settings When a person is admitted to hospital following an episode of self-harm, offer referral to age-appropriate liaison psychiatry services (or an equivalent specialist mental health service or a suitably skilled mental health professional) as soon as possible after admission for a psychosocial assessment (see the section on psychosocial assessment and care by mental health professionals and the section on risk assessment tools and scales), and support and assistance alongside physical healthcare. An age-appropriate liaison psychiatry professional or a suitably skilled mental health professional should see and speak to the person at every admission after an episode of self-harm. Mental health and acute ward staff should jointly decide the need for close observation on a case-by-case basis, taking into account the person's views and ensuring that observation is: by appropriately skilled and trained healthcare staff with the informed consent of the person or within an appropriate legal framework reviewed regularly. Children and young people who have been admitted to a paediatric ward following an episode of self-harm should have: access to a specialist child and adolescent mental health service (CAMHS or children and young people's mental health services ) or age-appropriate liaison psychiatry 24 hours a day a joint daily review by both the paediatric team and children and young people's mental health team daily access to their family members or carers regular multidisciplinary meetings between the general paediatric team and mental health services. ## Assessment and care in social care When working with people who have self-harmed, social care practitioners should foster a collaborative approach with all agencies involved in the care of the person, as well as their family members and carers, as appropriate. If self-harm has been identified during a social care assessment or through ongoing work, seek advice from, or refer the person to, the local urgent and emergency mental health service. Continue to offer social care support and involvement to a person who has self-harmed, particularly if the person may be looked after or have ongoing social care needs.Also see the NICE guidelines on domestic violence and abuse, looked-after children and young people, child abuse and neglect and child maltreatment. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment and care by healthcare professionals and social care practitioners . Full details of the evidence and the committee's discussion are in: evidence review E: assessment in non-specialist settings evidence review T: models of care for people who have self-harmed. Loading. Please wait. # Assessment and care by professionals from other sectors The recommendations in this section apply to all staff in non-healthcare and social care settings. Because of the wide variety of criminal justice system settings that exist and the need to take other relevant national guidance into account, staff working in the criminal justice system may need to tailor the recommendations for certain criminal justice system settings during implementation. ## Principles for assessment and care by professionals from other sectors When a person who has self-harmed presents to a non-health professional, for example, a teacher or a member of staff in the criminal justice system, the non-health professional should: treat the person with respect, dignity and compassion, with an awareness of cultural sensitivity work collaboratively with the person to ensure that their views are taken into account when making decisions address any immediate physical health needs resulting from the self‑harm, in line with locally agreed policies; if necessary, call 111 or 999 or other external medical support seek advice from a healthcare professional or social care practitioners, which may include referral to a healthcare or mental health service ensure that the person is aware of sources of support such as local NHS urgent mental health helplines, local authority social care services, Samaritans, Combat Stress helpline, NHS111 and Childline, and that people know how to seek help promptly address any safeguarding issues, or refer the person to the correct team for safeguarding. When a person presents to a non-health professional, for example, a teacher or a member of staff in the criminal justice system, the non-health professional should establish the following as soon as possible: the severity of the injury and how urgently medical treatment is needed the person's emotional and mental state, and level of distress whether there is immediate concern about the person's safety whether there are any safeguarding concerns whether the person has a care plan if there is a need to refer the person to a specialist mental health service for assessment. ## Assessment in schools and educational settings Educational settings should have policies and procedures for staff to support students who self-harm. These should include: how to identify self-harm behaviours how to assess the needs of students what do to if they suspect a student is self-harming how to support the student's close friends and peer group. Educational settings should have a designated lead responsible for: ensuring that self-harm policies and procedures are implemented ensuring that self-harm policies and procedures are regularly reviewed and kept up-to-date in line with current national guidance ensuring that staff are aware of the self-harm policies and procedures and understand how to implement them supporting staff with implementation if there are any uncertainties. All educational staff should: be aware of the policies and procedures for identifying and assessing the needs of students who self-harm know how to implement the policies and procedures within their roles and responsibilities know who to go to for support and supervision. For students who have self-harmed, the designated lead should seek the advice of mental health professionals to develop a support plan with the student and their family members and carers (as appropriate) for when they are in the educational setting. This should include guidance from other agencies involved in the person's care, as appropriate. Educational staff should take into account how the student's self-harm may affect their close friends and peer groups, and provide appropriate support to reduce distress to them and the person. ## Assessment and care in the criminal justice system and other secure settings Staff in criminal justice settings and other secure settings such as immigration removal centres should be aware that those in their care have higher rates of self-harm and suicide. Staff in criminal justice settings and other secure settings such as immigration removal centres should be aware of support services available to them to support their own wellbeing. Staff in criminal justice settings and other secure settings such as immigration removal centres should be aware of arrangements for: transferring people to a healthcare setting when necessary in-reach or onsite support their responsibilities for information sharing how to access health services. Staff in criminal justice settings and other secure settings such as immigration removal centres should follow local guidance on assessing people who have self-harmed, and healthcare professionals and social care practitioners in these settings should also follow the NICE guideline on mental health of adults in contact with the criminal justice system. Staff in criminal justice settings and other secure settings such as immigration removal centres should ensure that people who have self‑harmed have a safe location to await assessment or treatment following an episode of self-harm. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment and care by professionals from other sectors . Full details of the evidence and the committee's discussion are in evidence review E: assessment in non-specialist settings. Loading. Please wait. # Admission to and discharge from hospital The recommendations in this section apply to all healthcare professionals and social care practitioners. Consider admission to a general hospital after an episode of self-harm if: there are concerns about the safety of the person (for example, the person is at risk of violence, abuse or exploitation) and psychiatric admission is not indicated safeguarding planning needs to be completed and psychiatric admission is not indicated the person is unable to engage in a psychosocial assessment (for example, because they are too distressed or intoxicated). If a 16- or 17-year-old is admitted to a general hospital, ensure that it is to a ward that can meet the needs of young people. For arrangements for initial aftercare for people who have been admitted to a general hospital after they have self-harmed, see the section on initial aftercare after an episode of self-harm. Do not delay carrying out a psychosocial assessment or offering mental health treatment if the person is admitted to hospital or needs treatment for physical injuries. If a person self-harms during a hospital admission, follow the local hospital policy for investigating untoward incidents and undertake a full investigation. Local areas should be aware of the NHS Patient Safety Incident Response Framework. Before discharging a person who has self-harmed from a general hospital, ensure that: a psychosocial assessment has taken place a plan for further management has been drawn up with all appropriate agencies and people a discharge planning meeting with all appropriate agencies and people has taken place and arrangements for aftercare have been specified, including clear written communication with the primary care team. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on admission to and discharge from hospital . Full details of the evidence and the committee's discussion are in evidence review H: admission to hospital. Loading. Please wait. # Initial aftercare after an episode of self-harm The recommendations in this section apply to all healthcare professionals and social care practitioners. After an episode of self-harm, discuss and agree with the person, and their family members and carers (as appropriate), the purpose, format and frequency of initial aftercare and which services will be involved in their care. Record this in the person's care plan and ensure that the person and their family members and carers have a copy of the plan and contact details for the team providing the aftercare. If there are ongoing safety concerns for the person after an episode of self-harm, the mental health team, GP, team who carried out the psychosocial assessment or the team responsible for their care should provide initial aftercare within 48 hours of the psychosocial assessment. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on initial aftercare after an episode of self-harm . Full details of the evidence and the committee's discussion are in: evidence review I: initial aftercare evidence review T: models of care for people who have self-harmed. Loading. Please wait. # Interventions for self-harm The recommendations in this section apply to all healthcare professionals unless otherwise stated. When planning treatment following self-harm, take into account any associated coexisting conditions and the psychosocial assessment. For guidance on how to treat coexisting conditions that may be related to self-harm, also see the NICE guidelines on: Alcohol-use disorders Autism spectrum disorder in adults Autism spectrum disorder in under 19s Bipolar disorder Borderline personality disorder Care and support of people growing older with learning disabilities Challenging behaviour and learning disabilities Depression in adults Depression in children and young people Drug misuse in over 16s: opioid detoxification Drug misuse in over 16s: psychosocial interventions Eating disorders Generalised anxiety disorder and panic disorder in adults Learning disabilities and behaviour that challenges Mental health problems in people with learning disabilities Obsessive-compulsive disorder and body dysmorphic disorder Psychosis and schizophrenia in adults Post-traumatic stress disorder. Offer a structured, person-centred, cognitive behavioural therapy (CBT)-informed psychological intervention (for example, CBT or problem-solving therapy) that is specifically tailored for adults who self-harm. Ensure that the intervention: starts as soon as possible is typically between 4 and 10 sessions; more sessions may be needed depending on individual needs is tailored to the person's needs and preferences. For children and young people with significant emotional dysregulation difficulties who have frequent episodes of self-harm, consider dialectical behaviour therapy adapted for adolescents (DBT-A). Take into account the age of the child or young person and any planned transition between services. Healthcare staff should be appropriately trained and supervised in the therapy they are offering to people who self-harm. Work collaboratively with the person, using a strengths-based approach to identify solutions to reduce their distress that leads to self-harm. Consider developing a safety plan in partnership with people who have self-harmed. Safety plans should be used to: establish the means of self-harm recognise the triggers and warning signs of increased distress, further self-harm or a suicidal crisis identify individualised coping strategies, including problem solving any factors that may act as a barrier identify social contacts and social settings as a means of distraction from suicidal thoughts or escalating crisis identify family members or friends to provide support and/or help resolve the crisis include contact details for the mental health service, including out‑of‑hours services and emergency contact details keep the environment safe by working collaboratively to remove or restrict lethal means of suicide. The safety plan should be in an accessible format and: be developed collaboratively and compassionately between the person who has self-harmed and the professional involved in their care using shared decision making (see the NICE guideline on shared decision making) be developed in collaboration with family and carers, as appropriate use a problem-solving approach be held by the person be shared with the family, carers and relevant professionals and practitioners as decided by the person be accessible to the person and the professionals and practitioners involved in their care at times of crisis. Do not use diagnosis, age, substance misuse or coexisting conditions as reasons to withhold psychological interventions for self-harm. Do not offer drug treatment as a specific intervention to reduce self-harm. ## Harm minimisation Although ways to self-harm safely are often considered a harm minimisation strategy, this guideline does not make any recommendations about the use of safer self-harm. If a person is engaged in ongoing care and treatment but is not yet in a position to resist the urge to self-harm, only consider harm minimisation strategies: in the spirit of hope and optimism, and to reduce the severity and/or recurrence of injury as part of an overall approach to the person's ongoing recovery‑focused care and support, and not as a standalone intervention and after being discussed and agreed in a collaborative way with the person and their family members or carers (as appropriate), and the wider multidisciplinary team. Mental health professionals should discuss with the person harm minimisation strategies that could help to avoid, delay or reduce further episodes of self-harm and reduce complications, for example: distraction techniques or coping strategies approaches to self-care wound hygiene and aftercare providing factual information on the potential complications of self-harm the impact of alcohol and recreational drugs on the urge to self-harm. Be aware that harm minimisation strategies may not be appropriate for all people who self-harm. ## Therapeutic risk taking Therapeutic risk taking should only be used after a psychosocial assessment (see the section on psychosocial assessment and care by mental health professionals), and should: use shared decision making, to ensure that the person is able to make an informed choice at all stages, and include family and carers, as appropriate include other relevant professionals involved in the care of the person who has self-harmed draw on the person's strengths and coping strategies and what matters to them focus on positive outcomes be part of an ongoing assessment to revisit the decision be concurrent with psychiatric care if necessary. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on interventions for self-harm . Full details of the evidence and the committee's discussion are in: evidence review J: psychological and psychosocial interventions evidence review K: pharmacological interventions evidence review L: harm minimisation strategies evidence review M: therapeutic risk taking strategies evidence review P: skills required by staff in specialist settings evidence review R: skills required by staff in non-specialist settings evidence review T: models of care for people who have self-harmed. Loading. Please wait. # Supporting people to be safe after self-harm Ensure continuity of care, wherever possible, in the staff caring for people who have self-harmed by minimising the number of different staff they see. For guidance on ensuring continuity of care, see the section on continuity of care and relationships in the NICE guideline on patient experience in adult NHS services and the section on continuity and coordination of care in the NICE guideline on babies, children and young people's experience of healthcare. Do not use staff who are untrained in clinical observation (for example, security staff or trainee health and social care staff) to undertake such observations in a person who has self-harmed. Ensure that the care plans of people who have self-harmed can be accessed by primary and secondary care plus other professionals and practitioners involved in their care. Ensure that staff working with people who have self-harmed are visible and accessible to the people they are caring for, to encourage interaction, particularly during handovers and busy periods. Assess the safety of the environment, balancing respect for the person's autonomy against the need for restrictions. Use the least restrictive measures. Consider removing items that may be used to self-harm and involve the person who has self-harmed in this decision. At the earliest opportunity, healthcare staff should help people who have self-harmed to become familiar with the clinical setting in which they are being cared for, and tell them how to get support. Staff should know how to raise concerns without delay about a person who has self-harmed. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting people to be safe after self-harm . Full details of the evidence and the committee's discussion are in evidence review N: supporting people to be safe after self-harm. Loading. Please wait. # Safer prescribing and dispensing The recommendations in this section apply to all healthcare professionals. When prescribing medicines to someone who has previously self-harmed or who may self-harm in the future, healthcare professionals should take into account: the toxicity of the prescribed medicines for people at risk of overdose (for example, opiate-containing painkillers and tricyclic antidepressants) their recreational drug and alcohol consumption, the risk of misuse, and possible interaction with prescribed medicines the person's wider access to medicines prescribed for themselves or others the need for effective communication where multiple prescribers are involved. Also see the section on reducing access to methods of suicide in the NICE guideline on preventing suicide in community and custodial settings. Use shared decision making to discuss limiting the quantity of medicines supplied to people with a history of self-harm (for example, weekly prescriptions), and ask them to return unwanted medicines for safe disposal. Also see the NICE guideline on shared decision making. Consider carrying out a medicines review after an episode of self-harm. Take into account the pharmacokinetic properties of medicines, for example, half-life, risk of toxicity and the concurrent use of medicines such as benzodiazepines and opiates. If necessary, contact the National Poisons Information Service for further advice. Also see the NICE guideline on medicines optimisation. For people with learning disabilities or autism or both, the NHS England STOMP-STAMP principles may be useful. Community pharmacy staff should be aware of warning signs relating to self-harm, such as identifying people who are in acute distress, buying large amounts of over-the-counter medicines or who have access to large amounts of medicines. Healthcare professionals, including GPs and community pharmacy staff, should use consultations and medicines reviews as an opportunity to assess self-harm if appropriate, for example, asking about thoughts of self-harm or suicide, actual self-harm, and access to substances that might be taken in overdose (including prescribed, over-the-counter medicines, herbal remedies and recreational drugs). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on safer prescribing and dispensing . Full details of the evidence and the committee's discussion are in evidence review O: safer prescribing. Loading. Please wait. # Training Training for all staff who work with people of any age who self-harm should: involve people who self-harm and, where appropriate, their families or carers, and staff in the planning, delivery and evaluation of training be available in a range of formats, including interactive role play, online, face-to-face and through provision of resources explore staff attitudes (including non-healthcare staff), values, beliefs and biases be appropriate to the level of responsibility of the staff member be provided on a regular and ongoing basis. All staff who work with people of any age who self-harm should have training specific to their role so that they can provide care and treatment outlined in this guideline. Training should cover: the range of different behaviours that can be considered self-harm treating and managing episodes of self-harm, including de‑escalation using the least restrictive measures discussing self-harm with the person in an open way to explore the reasons for each episode of self-harm involving people who self-harm in all discussions and allowing sufficient time for decision making about their treatment and subsequent care communicating compassionately and facilitating engagement with people who have self-harmed, including using active listening skills being culturally competent through respecting and appreciating the cultural contexts of people's lives education about the underlying factors, triggers or motives that may lead people to self-harm education about the stigma and discrimination usually associated with self-harm and the need to avoid judgemental attitudes recognising the impact of other diagnoses and comorbidities, and how they interact with self-harm balancing patient autonomy and safety when providing care for people who have self-harmed assessing the needs and safety of the person who has self-harmed (relevant to their role and environment) the formal processes involved in treatment after self-harm, including: treatment and referral options relevant care pathways relevant legislation procedures specific to the setting, including layout, policies and protocols. In addition to the training in recommendation 1.14.2, mental health professionals who work with people of any age who self-harm should have training on conducting psychosocial assessments and risk formulation. All staff observing people who have self-harmed should also be trained in therapeutic observation methods, including engagement and rapport building. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on training . Full details of the evidence and the committee's discussion are in: evidence review P: skills required by staff in specialist settings evidence review R: skills required by staff in non-specialist settings evidence review N: supporting people to be safe after self-harm. Loading. Please wait. # Supervision All staff who work with people of any age who self-harm should have the opportunity for regular, high-quality formal supervision from senior staff with relevant skills, training and experience. Supervision should: take into account the emotional impact of self-harm on staff and how best to support them promote the delivery of compassionate care focus on ongoing skill development include reflective practice promote confidence and competence in staff working with people who have self-harmed. Ensure that all staff working with people who self-harm have easily accessible ongoing support from senior staff with relevant skills, training and experience. Support should include: clear lines of responsibility around decision making, particularly for situations where there are challenges around the balance between autonomy and safety for a person who has self-harmed emotional support or signposting to emotional support services, as preferred by the member of staff. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supervision . Full details of the evidence and the committee's discussion are in: evidence review Q: supervision required for staff in specialist mental health settings evidence review S: supervision required for staff in non-specialist settings. Loading. Please wait.# Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. # Care plan The plan of treatment or healthcare to be provided to the service user. It typically documents the needs and safety considerations of the service user, the interventions that will support their recovery, as well as the key professionals and practitioners involved in their care. # Cognitive behavioural therapy-informed psychological intervention Cognitive behavioural therapy (CBT)-informed psychotherapy helps people identify and critically evaluate their thoughts about emotional experiences and events, and aims to help them change the ways in which they deal with problems. The Cochrane review that NICE drew on to evaluate research evidence for this guideline used a broad conceptualisation that included treatments focused on modifying thoughts, behaviours, and problem-solving skills. # Clinical observation A therapeutic intervention most commonly used in hospital settings, which allows staff to monitor and assess the mental and physical health of people who might harm themselves and/or others. It should be seen as an opportunity for active engagement as well as sensitive supervision. # Designated lead A senior member of staff within an educational setting who takes lead responsibility for the mental health and wellbeing of students who is given appropriate resources such as funding, time and training to do so. Their role is to provide advice and support to other members of staff, participate in the assessment of students, and take part in developing strategies and policies within the education setting for the care of students with mental health problems, including self-harm. The designated lead liaises with external agencies and parents to work collaboratively in supporting students' needs with an awareness of local provisions. # Dialectic behavioural therapy for adolescents Dialectic behavioural therapy for adolescents (DBT-A) is a manualised, typically 16‑week behavioural treatment, comprising weekly concurrent individual therapy, a multifamily skills training group, between-session skills coaching for young people and their families, family therapy as needed and a peer-consultation group for therapists. DBT-A aims to equip young people and their parents and carers with the skills to reduce or stop self-harm and suicidal behaviours, effectively manage their emotions and improve their relationships. # Harm minimisation Harm minimisation is an approach to self-harm that accepts the person's continued urge to self-harm while aiming to keep long-term damage and frequency of injury to a minimum. It can include suggestions to avoid, delay or reduce self-harm. # Mechanical restraint A method of physical intervention involving the use of authorised equipment, for example, handcuffs or restraining belts, applied in a skilled manner by designated healthcare professionals. # Psychosocial assessment A comprehensive assessment including an evaluation of the person's needs, safety considerations and vulnerabilities that is designed to identify those personal psychological and environmental (social) factors that might explain an act of self‑harm. # Risk formulation A collaborative process between the person who has self-harmed and a mental health professional that aims to summarise the person's current risks and difficulties and understand why they are happening in order to inform a treatment plan. Formulation typically includes taking into consideration historical factors and experiences, more recent problems, and existing strengths and resources. # Safety plan A written, prioritised list of coping strategies and/or sources of support that the person who has self-harmed can use to help alleviate a crisis. Components can include recognising warning signs, listing coping strategies, involving friends and family members, contacting mental health services, and limiting access to self-harm methods. # Self-harm Intentional self-poisoning or injury irrespective of the apparent purpose of the act. The treatment and care of repetitive, stereotypical, self-injurious behaviour (such as head banging) is not covered by this guideline. # Therapeutic risk taking A process that aims to empower people who self-harm to make decisions about their own safety and to take risks to enable recovery. Key principles include joint decision making, clear information sharing, drawing on existing strengths, collaborative planning, and an understanding that risk taking may result in positive as well as negative outcomes. Inappropriately withholding or withdrawing care (such as treatment or assessment) without adequate assessment or collaboration cannot be considered therapeutic risk taking.# Recommendations for research The guideline committee has made the following recommendations for research. # Models of care What is the effectiveness of different models of care for children and young people who self-harm? For a short explanation of why the committee made this recommendation for research, see the rationale section on assessment and care by healthcare professionals and social care practitioners . Full details of the evidence and the committee's discussion are in evidence review T: models of care for people who have self-harmed. Loading. Please wait. # Assessment in non-specialist settings What are the most effective approaches to assessment in non-specialist settings? Healthcare professionals and social care practitioners For a short explanation of why the committee made this recommendation for research, see the rationale section on assessment and care by .healthcare professionals and social care practitioners . Full details of the evidence and the committee's discussion are in evidence review E: assessment in non-specialist settings. Loading. Please wait. Professionals from other sectors For a short explanation of why the committee made this recommendation for research, see the rationale section on assessment and care by professionals from other sectors . Full details of the evidence and the committee's discussion are in evidence review E: assessment in non-specialist settings. Loading. Please wait. # Routine admission to hospital Is routine or automatic admission effective for young people or older adults who have self-harmed? For a short explanation of why the committee made this recommendation for research, see the rationale section on admission to and discharge from hospital . Full details of the evidence and the committee's discussion are in evidence review H: admission to hospital. Loading. Please wait. # Psychological interventions What is the effectiveness of specific psychological interventions including digital compared with face-to-face (technology use) in different populations and settings? For a short explanation of why the committee made this recommendation for research, see the rationale section on interventions for self-harm . Full details of the evidence and the committee's discussion are in evidence review J: psychological and psychosocial interventions. Loading. Please wait. # Harm minimisation What is the experience, feasibility, acceptability and effectiveness of harm minimisation strategies for people who self-harm? For a short explanation of why the committee made this recommendation for research, see the rationale section on interventions for self-harm . Full details of the evidence and the committee's discussion are in evidence review L: harm minimisation strategies. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Information and support Recommendations 1.1.1 to 1.1.4 ## Why the committee made the recommendations There was evidence on the information that people who had self-harmed and their family members and carers want to receive, and how they want to receive it. The committee based the recommendations on the evidence, their knowledge and experience, and the NICE guidelines on patient experience in adult NHS mental health services, and patient experience in adult NHS services. Much of the evidence on the information needs of people who had self-harmed was consistent with that of family and carers, who want information about self-harm to be shared with them. However, there was conflicting evidence about whether people want information to be shared with family members. The committee agreed that information should be available to the person's family and carers where appropriate and in agreement with the person. There was evidence that family members and carers have additional information and support needs specific to their experience that are often unmet. The committee agreed that further information and support should be provided to family members and carers as appropriate. There was evidence that people who had self-harmed and their family and carers perceived support (or a lack of it) based on how they had been communicated with, and that they value support from a range of sources. There was also evidence that people who had self-harmed value information that is specific to their circumstances, and the committee agreed that information should be tailored to the individual. The evidence also suggested that people and their family and carers find it difficult to get the information or support they need. The committee discussed existing NICE guidelines that have important information about how to appropriately provide information and support to people and agreed that the guidelines are relevant for people who have self-harmed. The recommendation that people from protected groups should have additional support was based on the committee's experience and knowledge that forms of discrimination are often causal factors for self-harm. ## How the recommendations might affect practice The recommendations should make it easier for people who have self-harmed and their family members and carers to get support and information after an episode of self-harm, and reduce the variation in the information provided. It should also lead to a higher quality of care. The impact for providers will vary according to what information and support they currently offer. The recommendations may mean that providers need to change the information they give, but the cost should be minimal and will result in people who self-harm and their family and carers being better informed about self-harm and their care options. The recommendations may mean that family members seek further care for themselves more frequently than they currently do, but it is difficult to estimate the effect this will have on practice. Return to recommendations # Consent and confidentiality Recommendations 1.2.1 to 1.2.6 ## Why the committee made the recommendations There was no evidence so the committee based the recommendations on their knowledge of current best practice as well as existing guidance and protocols. Without evidence, the committee could not be more specific about how consent and confidentiality should be considered specifically for people who have self-harmed. The committee agreed that existing guidance covers any issues that might arise about consent and assessing capacity to consent in children and young people of different ages. Staff should be aware of these principles while still feeling empowered to seek additional advice, and to feel confident in situations when consent to care may not be given. The committee also agreed that access to independent mental capacity advocates (IMCAs) would allow the person who has self-harmed to feel confident about decisions about their care. The committee discussed the risk of legal repercussions for staff either when making decisions about a person's care without their consent or when breaching confidentiality. They recommended that staff have access to experienced colleagues for advice at all times, and to legal advice as needed to allow them to provide care with confidence. The recommendation about the limitations of confidentiality was based on the consensus statement from the National Suicide Prevention Strategy Advisory Group, which states that confidentiality can often be a barrier to information sharing, to the detriment of other staff members and family members and carers. The committee agreed that confidentiality could also limit collaboration between staff across different clinical settings. The committee agreed that sharing information about a person's care with family members and carers has multiple benefits that often improve outcomes, such as allowing the person to receive appropriate care outside of clinical settings. The committee discussed the risks attached to information sharing and agreed it is still necessary to seek consent from the person, especially before sharing information with family members and carers. This was supported by qualitative evidence from review for involving family members and carers, that family members and carers want to be more involved in the management of self-harm, whereas people who have self-harmed find information sharing without their consent to be a breach of trust. The committee discussed the risks of breaching confidentiality and agreed that it can lead to feelings of disempowerment and further distress for the person who has self‑harmed. The committee therefore agreed that the person should still be included in decisions after confidentiality has been breached, and if possible, be informed about this decision to promote autonomy. ## How the recommendations might affect practice These recommendations are in line with existing recommended practice, and should result in easier access to legal advice and better awareness of the benefits of information sharing. Return to recommendations # Safeguarding Recommendations 1.3.1 and 1.3.2 ## Why the committee made the recommendations The recommendations are based on the committee's knowledge of current best practice, as well as existing guidance on safeguarding in healthcare. The committee agreed that staff should always consider whether such concerns exist for children and adults who have self-harmed, and be prepared to follow safeguarding procedures when necessary. This will enable staff to intervene in situations where safeguarding is a concern to reduce the risk of further harm to the person. The committee agree that a multi-agency approach to safeguarding would promote collaborative working between different sectors, allowing for information sharing and therefore improving the service provided to the person. ## How the recommendations might affect practice These recommendations are in line with existing recommended practice, but may also enable better communication and transitions across services through multi‑agency approaches. Return to recommendations # Involving family members and carers Recommendations 1.4.1 to 1.4.5 ## Why the committee made the recommendations There was conflicting evidence on if and how family members and carers should be involved in the support and treatment of people who have self-harmed. The evidence showed both potential harms and benefits, so the committee based the recommendations on the evidence and their own knowledge and experience. The committee agreed that because involving family members and carers is linked to issues around consent and confidentiality, the recommendations should be read in conjunction with the recommendations on consent and confidentiality. There was good evidence that involving family members and carers can have a positive effect on care and that a collaborative approach to care is helpful as long as the person continues to consent to their family and carers' involvement. The committee recognised that there may be circumstances where involving family members or carers is not appropriate, so agreed that involvement should be encouraged and accommodated where appropriate, after taking into account the person's preferences and capacity, and the potential harms and benefits. There was also evidence that family members, school staff and healthcare professionals value two-way communication to enable information sharing about any changes in the life or treatment of the person who has self-harmed. The committee highlighted if the person has not given consent, family and carers can still share information with healthcare professionals, which can provide helpful insights to make a holistic assessment of, and base their professional judgements on, the needs of the person who has self-harmed. There was evidence that people who had self-harmed and their family and carers value being able to communicate using non-verbal means. The committee agreed that this can encourage positive communication because it can often be difficult for the person to express their needs when they are very distressed. The use of non‑verbal forms of communication can reduce the need for the person to explain how they are feeling, and help to build the initial therapeutic rapport and understanding of the person's needs. ## How the recommendations might affect practice These recommendations should make it easier for healthcare professionals to recognise when it is appropriate to involve family members and carers in the care of people who have self-harmed, and allow people who have self-harmed to make decisions about the involvement of family and carers. They should also enable family members and carers to be involved in care in a way that is collaborative and helpful for the person who has self-harmed. Providers may need to change how they involve family members and carers, but the costs are expected to be small and will result in a higher quality of care for people who self-harm. Return to recommendations # Psychosocial assessment and care by mental health professionals Recommendations 1.5.1 to 1.5.17 ## Why the committee made the recommendations The recommendations are based on the available evidence, but because of concerns over the quality and scarcity of evidence, most are based on the committee's knowledge and experience. There was evidence that an assessment model incorporating therapeutic elements such as identification of the target problem has a positive effect on satisfaction. The committee agreed the factors to take into account in the psychosocial assessment, and what it should include. The committee agreed that delaying a psychosocial assessment could result in the person receiving inappropriate treatment. They discussed that if the person is not able to meaningfully engage in the assessment (for example, if the person is unconscious or has very high levels of intoxication), they should be regularly reviewed so that it can take place as soon as appropriate, and that any care plan should always be followed to optimise the psychosocial assessment. The committee agreed that breathalysers and blood alcohol tests do not accurately assess the ability of a person to meaningfully engage with an assessment, and could be used to wrongly deny someone an assessment. The committee agreed that care plans should be followed where possible to ensure a higher standard of care and inform the assessment, including whether certain questions should be prioritised. There was evidence that people value privacy and having a safe and trusted environment when discussing self-harm. The committee agreed the self-harm functions and factors to explore. The committee agreed these would allow coexisting conditions to be taken into account and enable staff to provide a higher quality of care. The committee also agreed that using the psychosocial assessment to develop a care plan could have a positive impact on the person's engagement with follow-up. Qualitative evidence was consistent with the committee's agreement that including family and carers in the person's care has a positive impact. The committee agreed that children, young people, older adults and people with learning disabilities should be assessed by staff with appropriate experience to ensure a higher standard of care. They also agreed that there are additional factors to consider for children, young people and older adults, which would enable the assessment to be more individualised. The committee discussed that briefly assessing the person if they chose to leave before a full assessment had taken place could prevent repeat self-harm or attempted suicide. The committee agreed that providing the person with a copy of their care plan would increase transparency and improve trust. Additionally, the committee agreed that providing any other relevant healthcare professionals and social care practitioners with the care plan would ensure that all staff are up-to-date about the person's preferences, improving the quality of their care and their transition between services. There was insufficient evidence for the committee to define how frequent attendance for self-harm would have to be to trigger a multidisciplinary review. However, the committee agreed that this recommendation was still important based on their knowledge that the individual circumstances of the person, including whether they are continuing to self-harm, should be assessed to evaluate whether a multidisciplinary review is necessary. The committee agreed that a multidisciplinary review should enable staff to reconsider current care, finding the most suitable care approach for the person and therefore preventing further repeat self-harm. ## How the recommendations might affect practice The recommendations should change how psychosocial assessments are conducted, to reduce the potential for distress during assessment and improve the person's satisfaction and engagement with services. The recommendations should also allow for more involvement of family members and carers when appropriate, which could result in better quality care. Most of the recommendations are based on existing recommended practice with some additional considerations that should have a minimal effect on costs, depending on how services currently assess people who have self-harmed. Return to recommendations # Risk assessment tools and scales Recommendations 1.6.1 to 1.6.6 ## Why the committee made the recommendations The committee agreed that risk assessment tools and scales cannot accurately predict risk of self-harm or suicide, and that determining access to treatment or hospital admission based on inaccurate risk assessment tools could lead to repeat self-harm, distress and lower patient satisfaction. The committee agreed that the potential harms of risk stratification, including the implication that risk is static instead of dynamic, outweigh any benefits it has as a clinical communication tool or an adjunct to clinical assessment, so agreed that risk stratification should not be used. The committee agreed that assessment of a person's needs, vulnerabilities, and safety should be a part of every assessment and that 'risk' should not be used to determine care management in isolation of other factors. They agreed that all staff should use their clinical judgement when assessing someone who has self-harmed and they should refer to the non-specialist assessment recommendations for what to do in the event they are concerned about the person and their safety. Additionally, mental health staff should conduct a risk formulation to place the person's safety considerations in context with their strengths and difficulties. ## How the recommendations might affect practice The recommendations should change how assessments are conducted to take into account the person's needs and safety as standard and reduce reliance on assessment of a person's 'risk' in isolation of other factors. This should result in a reduction in the occurrence of arbitrary thresholds being used to determine access to care. Risk assessment tools and scales are still used in some settings to determine access to treatment and care. The recommendations might have an initial effect on costs, depending on how services currently assess people who have self-harmed; however, service provision should already be determined by a person's needs rather than risk thresholds. Additionally, the change in practice should result in lower costs over time because people will receive the care they need rather than have it determined by unreliable risk tools and scales, potentially reducing repeat self-harm. Return to recommendations # Assessment and care by healthcare professionals and social care practitioners Recommendations 1.7.1 to 1.7.27 ## Why the committee made the recommendations There was no evidence, so the committee made recommendations mostly based on their knowledge and experience, supplemented by qualitative evidence from the reviews on information and support needs, and staff skills. They agreed it is important to give advice about assessment and care in different settings, but the lack of evidence meant they were unable to be more specific. The committee made a recommendation for research on the most effective approaches to assessment in non-specialist settings to better inform future guideline development. Because of a lack of evidence, the committee also made a recommendation for research on models of care for children and young people who self-harm. Recommendations 1.7.1 to 1.7.5 The committee agreed that assessment for people who have self-harmed should be collaborative and prioritise preserving the person's dignity to minimise distress, while maintaining physical safety. Evidence showed that people who had self-harmed value positive, compassionate support after an episode of self-harm. The committee agreed that the person carrying out the assessment should gather information from other sources, such as professionals, practitioners and family members, in order for the assessment to be as accurate as possible, and ask about potential coping strategies to inform any future safety plan. The committee agreed that healthcare professionals and social care practitioners should establish a number of specific presenting factors to inform their assessment and care. Healthcare professionals and social care practitioners should also be involved in the care of people who have self-harmed as much as possible but know when to refer them to mental health services (as set out in the sections on assessment and care in different health and social care settings), to ensure that the care is appropriate. The committee agreed that physical healthcare and mental healthcare should always be delivered concurrently so neither is prioritised at the expense of the other, and to prevent treatment delays. Non-specialist healthcare professionals and social care practitioners should seek appropriate advice about care for people who have self‑poisoned. The committee agreed that punitive or aversive approaches should not be used, based on their knowledge that such approaches are considered malpractice and often have harmful effects on people who have self-harmed, potentially leading to increased distress and repeat self-harm or suicide. Recommendations 1.7.6 to 1.7.8 The committee agreed that referring people to mental health services would be reassuring and ensure that people are in the most appropriate setting, and that referral should be prioritised in certain situations to prevent further distress. The committee agreed that if people are being cared for in primary care following an episode of self-harm, there should be continuity of care and regular reviews of factors relating to their self-harm to ensure that the person who has self-harmed feels supported and engaged with services. Recommendations 1.7.9 to 1.7.11 The committee agreed that information about the person's situation should be recorded because it is invaluable for mental health staff when they carry out the psychosocial assessment. The committee agreed that collaboration between ambulance staff and the person who has self-harmed about their care would allow these preferences to be accommodated by ambulance staff and in other settings. The committee agreed that ambulance staff should discuss whether assessment should be carried out by alternative services based on qualitative evidence from the review on skills for non-specialist staff. This showed that ambulance staff often felt that the emergency department was not the preferred place that the person who had self-harmed wanted to be taken. They agreed that referral to alternative services when the situation is appropriate could facilitate the person's engagement with services. The committee also discussed factors that should be considered when deciding whether alternative services should be used, to ensure that the person receives the best possible care without delay. Recommendations 1.7.12 to 1.7.20 The committee agreed that an initial rapid assessment of the person's mental and physical care needs is important to quickly establish the best course of action and accommodate the person's needs and safety considerations. The recommendations about liaison psychiatry are based on the committee's knowledge that such services have a positive influence on care. The recommendations are also based on evidence from the review on models of care, which showed that specialist psychosocial assessment by mental health staff has an important benefit in terms of self-harm repetition over 12 months. Evidence from the qualitative review on the information and support needs of people who have self-harmed showed that people value privacy and a safe and trusted environment when discussing self-harm. The committee agreed that people who have self-harmed may feel neglected when asked to wait in isolated areas of the emergency department, and that people who have self-harmed may need support during a time of potential distress. The committee based the governance recommendations on the Healthcare Safety Information Branch (HSIB) report on investigation into the provision of mental health care to patients presenting at the emergency department (2018), which found that clarity about service pathways and good communication between teams can result in successful safeguarding, de‑escalation of mental health crises, and prevent immediate repeat self-harm or suicide. The HSIB report also informed the recommendation that there should be an agreed policy or procedure in place for people who wish to leave before treatment is complete. The committee agreed this would ensure that people who leave and who have ongoing safety concerns are identified so appropriate follow-up contact can be made. The committee also agreed it is important that mechanical restraint is not used on people to prevent them from leaving the emergency department or from self-harming, because in their experience, this results in increased distress and a loss of autonomy and dignity for the person, potentially resulting in a loss of trust in services and an unwillingness to seek help in the future. The committee agreed that policies and procedures for identifying people who frequently self-harm would allow non-specialist staff in emergency departments to facilitate a multidisciplinary review to ensure that people get the right treatment and support. Recommendations 1.7.21 to 1.7.24 The recommendations about liaison psychiatry are based on the committee's knowledge that such services have a positive influence on care. The recommendations are also based on evidence from the review on models of care, which showed that specialist psychosocial assessment by mental health staff had an important benefit in terms of self-harm repetition over 12 months. The recommendation about observation was based on the committee's experience that observation can be intimidating and unnecessary, especially when carried out by security guards. The committee agreed that observation should be discussed with people to reduce distress, and carried out by healthcare staff. The committee agreed that children and young people in hospital have specific needs and should therefore have access to age-appropriate specialist care. Recommendations 1.7.25 to 1.7.27 The committee agreed that a shared approach between healthcare professionals and social care practitioners is important to promote holistic care for people who self‑harm to ensure that different areas of the person's life are taken into account. The committee discussed their experience that social care services can be withdrawn from people after an episode of self-harm, and agreed that this practice should be strongly discouraged despite the lack of evidence, based on their knowledge that this often results in people not receiving the care that they need, potentially leading to repeat self-harm and suicide. The committee agreed that in many circumstances, self-harm is identified by social care practitioners through a safeguarding concern. They agreed that when this occurs, social care practitioners should refer the person to local mental health services to ensure they start on a care pathway and receive appropriate care. The committee agreed that social care services should be provided in conjunction with mental health care, to ensure that the person continues to receive social care support as needed. ## How the recommendations might affect practice The recommendations should change the way in which assessments are conducted in a range of settings, to reduce the potential for distress after self-harm and improve the person's satisfaction and engagement with services. Most of the recommendations are based on existing best practice with some additional considerations that should have a minimal effect on costs, depending on how services currently assess people who have self-harmed. The recommendation that people who have self-harmed should have access to age-appropriate liaison psychiatry in emergency departments and general hospital settings should not have a cost or resource impact because this should already be standard practice. Return to recommendations # Assessment and care by professionals from other sectors Recommendations 1.8.1 to 1.8.12 ## Why the committee made the recommendations There was no evidence, so the committee based the recommendations on their knowledge and experience. They agreed it is important to give advice about assessment and care in different settings, but the lack of evidence meant they were unable to be more specific. The committee made a recommendation for research on the most effective approaches to psychosocial assessment in non-specialist settings to better inform future guideline development. Recommendations 1.8.1 and 1.8.2 The committee agreed that people who have self-harmed can often initially present to non-health professionals, and agreed principles on compassion and preserving the dignity of the person who has self-harmed, regardless of whether the professional has healthcare training. The committee also agreed that non-health professionals should address immediate physical health needs if necessary to prevent further potential harm, but should also seek appropriate clinical support or refer to healthcare services to ensure that the care is appropriate. There was also qualitative evidence from the review on information and support needs of parents and carers, which showed that carers often urgently seek information from qualified healthcare professionals or social care practitioners on discovery of self-harm. The committee agreed there were factors of a person's presentation that professionals should establish to inform how they care for the person who has self‑harmed. Non-health professionals should also be involved in the care of people who have self-harmed as much as possible but know when to refer them to mental health services, to ensure that the care is appropriate. Recommendations 1.8.3 to 1.8.7 The recommendations are based on the committee's knowledge that both non‑specialist staff and specialist mental health staff can work in educational settings with children and young people who have self-harmed, and therefore all staff in educational settings need policies and procedures for how to identify and respond to students who have self-harmed. The recommendations are also based on qualitative evidence from the review on skills for specialist staff, which showed that school mental health staff want policies for how to respond to people who have self-harmed because they often feel unsupported and unsure whether they are acting in the best interest of the student. The committee agreed that formal policies and procedures and a designated lead on self-harm would ensure educational staff would be equipped with appropriate means to respond to self-harm and be supported in their decision making, boosting staff confidence and competence, and improving the quality of care of children and young adults who have self-harmed. The committee agreed that collaboration with other mental health staff would support the person's access to services and help prevent repeat self-harm, while taking into account the effect on the person's friends and peers would allow support to be provided. Recommendations 1.8.8 to 1.8.12 The committee based the recommendations on the NICE guideline on mental health of adults in contact with the criminal justice system and their knowledge and experience. They agreed that staff awareness of the high rates of self-harm would allow them to be better prepared to assess and care for people who self-harm. They also agreed staff should be aware of support services that are available to them to ensure that their own support needs are met. The committee agreed that people who have self-harmed in secure settings need onsite support or, where that is not possible, transfer to healthcare settings. As a result, the committee agreed that staff in these settings should be aware of the arrangements in place, so they can facilitate appropriate care and support if a person self-harms. The committee also agreed that the NICE guideline on the mental health of adults in contact with the criminal justice system contained a lot of detail about assessment, especially in prisons, and that staff knowledge of this guideline would ensure staff in these settings followed best practice. The committee discussed the benefits of providing a safe place to people who had self-harmed and agreed that this could reduce the person's distress and their access to means to self-harm, as well as reducing the risk for people to be subject to punitive measures such as isolation after self-harm. ## How the recommendations might affect practice The recommendations should change the way in which assessments are conducted in a range of settings to reduce the potential for distress after self-harm and improve the person's satisfaction and engagement with services. The recommendations should also allow for better communication between services, including between non-health and healthcare settings. Most of the recommendations are based on existing best practice with some additional considerations that should have a minimal effect on costs, depending on how services currently assess people who have self-harmed. Return to recommendations # Admission to and discharge from hospital Recommendations 1.9.1 to 1.9.6 ## Why the committee made the recommendations The evidence showed that there were no significant short- or long-term differences in repeat self-harm by poisoning, regardless of whether people were admitted to hospital or discharged home. There was no evidence for other types of self-harm or other outcomes. The recommendations are based on the available evidence and the committee's experience and knowledge that admission to hospital carries a greater risk of distress to people of all ages than any potential benefit. The committee agreed that despite the lack of evidence for the benefit of admitting people to hospital, in some cases it can be helpful to give the person time to recover or if there are safeguarding concerns. If it is necessary to admit a young person who has self-harmed into hospital, the committee agreed that it can be distressing for them to be admitted to a ward that is not equipped to meet the needs of young people. The committee agreed that treatment for physical injuries should never be used as a reason to delay or deny a psychosocial assessment because this would be considered malpractice, potentially resulting in heightened distress or neglect of the person's other healthcare needs. The committee discussed current practice about what happens when a person self‑harms while in hospital, and agreed that full investigations should continue to be recommended when an incident occurs to consistently improve services and ensure that further incidents are prevented. The committee also agreed that discharging a person before they had been assessed and a plan for further management drawn up could be detrimental because people who have self-harmed are likely to need further care and support. A lack of a plan could result in repeat self-harm or suicide, and would create a barrier to care for the person. The committee made a recommendation for research on routine or automatic hospital admission for young people or adults to better inform future guideline development. ## How the recommendations might affect practice The recommendations should reduce variation in practice, and reduce the potential for distress because of any unnecessary admissions. The recommendations could increase the number of beds available in hospitals and reduce overall costs related to overnight admissions to hospital for people who have self-harmed. Return to recommendations # Initial aftercare after an episode of self-harm Recommendations 1.10.1 and 1.10.2 ## Why the committee made the recommendations There was evidence that discharge protocols with enhanced initial aftercare provide important benefits such as increased engagement with services and treatment, and reduced rates of repeat self-harm compared with usual discharge. The committee based the recommendations on the evidence and their knowledge and experience that prioritising person-centred care and empowering people who have self-harmed to make decisions about their own care could improve service-user satisfaction and reduce distress or hopelessness. The committee agreed that any aftercare arrangements should be shared with the person, based on their knowledge that this is an important facet of collaborative care, and that providing contact details encourages engagement with care. The committee discussed that people who have self-harmed are most likely to repeat self-harm within 2 to 3 days of their previous episode of self-harm. They discussed current best practice in line with the existing NICE guideline on transition between inpatient mental health settings and community or care home settings, which includes follow‑up within 48 hours of presentation. Quantitative evidence was consistent with this, because it showed that telephone contact within 48 hours after discharge had a positive effect on service engagement. The evidence also found a possible important reduction in the number of suicide attempts for those receiving initial contact 3 days after discharge compared with those receiving initial contact within 7 days of discharge, although the different settings in which follow‑up was conducted may also have affected the outcomes. Qualitative evidence from the review on information and support needs for people who have self-harmed also showed that people value proactive, prompt follow‑up and find long waiting times frustrating. However, there were concerns about resourcing and capacity to provide initial aftercare to all patients within this timeframe. The committee agreed that, although follow-up within 48 hours would be ideal for everyone, not all people who have self-harmed will need immediate aftercare. To ensure priority is given to those who need it most, aftercare within 48 hours should be provided to people with ongoing safety concerns to reduce rates of repeat self-harm. There was limited evidence that continuity of personnel has a positive effect on service engagement and repeat self-harm. The committee agreed, based on their experience, that continuity of personnel from initial assessment to aftercare allows people to gain familiarity with particular professionals, improving satisfaction and service engagement, and reducing the risk of distress or hopelessness. Evidence from the review on models of care showed that a continuity chain protocol has a possible important benefit in terms of engagement with services compared with usual care. The committee agreed that this is most important for people who have received treatment from a mental health service, based on their knowledge that the person who had self-harmed would have spent more time with mental health staff and may have built up trust with particular staff members, as well as evidence from the review on models of care, which showed that specialist community mental health follow‑up has an important benefit in terms of self-harm repetition over 12 months. ## How the recommendations might affect practice The recommendations are mostly in line with current practice. They should lead to a reduction in people waiting for up to 72 hours for aftercare following presentation for self-harm. Providing initial aftercare within 48 hours for people if there are ongoing safety concerns should reduce repeat self-harm and suicide, and improve satisfaction and engagement with services. Any resource impact associated with this would be a worthwhile use of resources. The recommendations for continuity of personnel may have a resource impact depending on how often the same staff members who have carried out an assessment or mental healthcare also carry out aftercare. Where this is not the case, there will be an increased workload for these healthcare professionals. Return to recommendations # Interventions for self-harm Recommendations 1.11.1 to 1.11.14 ## Why the committee made the recommendations The committee agreed that the psychosocial assessment should be used to develop a meaningful narrative that would inform the care plan. They agreed this would ensure that treatment for any coexisting conditions that could be linked to self-harm are prioritised, enabling healthcare professionals to provide the most appropriate intervention for the individual, and resulting in more person-centred, higher-quality care. The committee referred to a number of other NICE guidelines for conditions that can be linked to self-harm, and agreed it is important that healthcare professionals plan treatment for people who have self-harmed in line with the guidance for any underlying or coexisting conditions before other interventions are considered. The evidence showed that psychotherapies informed by cognitive behavioural therapy (CBT) have positive effects on repetition of self-harm at long-term follow‑up and on depression, hopelessness and suicidal ideation over time for adults. However, the evidence did not show an effect on repeat self-harm at other follow-up times. Additionally, the evidence was limited by the wide interpretation of 'CBT-based psychotherapies' as being inclusive of other types of therapies in addition to CBT, and the indistinct categorisation of all interventions throughout the evidence review. The committee agreed other therapies might be effective for adults who have self-harmed as long as they are informed by CBT, as indicated by the evidence. The evidence also showed that dialectic behavioural therapy for adolescents (DBT‑A) has a positive effect on repetition of self-harm at post-intervention for adolescents. However, the evidence was limited by the fact that participants in studies had all self-harmed more than once, were all older than 12 years and most were female, and there was no evidence of effect of DBT-A on repeat self-harm by 12‑month follow‑up. The committee extrapolated the evidence based on their confidence that DBT-A is likely to be similarly effective in younger children and boys as it is in over-12s and girls; however, the committee agreed they could not be sure that DBT-A would be similarly effective for children and young people who did not frequently self-harm. The evidence for other therapies was uncertain, and the evidence for the effects of pharmacological interventions was limited. The pharmacological evidence showed an uncertain effect of newer-generation antidepressants or antipsychotics on repetition of self-harm for adults, and no evidence of effect for mood stabilisers or natural products on repetition of self-harm for adults. The recommendations are based on the available evidence and the committee's knowledge and experience of the current practice of offering psychological or psychosocial interventions. The committee agreed that any therapy offered should be delivered by staff with training in the relevant therapy and who are receiving appropriate supervision. This is to ensure the competence of the professional delivering the training allows for the needs of the person to be met and for the treatment to be tailored for people who self-harm. The committee agreed that further limitations on which staff could deliver therapies were unnecessary and could result in implementation difficulties and delays in treatment provision. The recommendation that treatment should be offered without delay was based on the committee's knowledge that delaying treatment could lead to further self-harm or suicide, and on evidence from the review on involving families and carers in the management of self-harm, which showed that long waiting times for treatment is often a barrier to seeking help. The safety planning recommendations were based on the committee's knowledge and experience that safety plans equip people who have self-harmed with the ability to identify and use their strengths and sources of support to overcome crisis moments and prevent repeat self-harm. This was supplemented by qualitative evidence from both staff skills reviews, which showed that individualised coping strategies are important to people who have self-harmed, and that specialist staff identified safety planning as an important technique to help manage self-harm. The committee considered the components of safety planning interventions from 3 studies included in the Cochrane review on psychosocial interventions, and used this evidence to recommend important aspects of safety plans that the committee agreed would prevent further self-harm. The recommendations about how the safety plan should be implemented were based on the committee's knowledge and experience that collaborative decision making improves engagement with services, and that ensuring a copy is available to the person emphasises this collaborative aspect. The committee agreed that sharing the care plan with family and friends when appropriate could provide the benefit of social connectedness between the person and their sources of support, which is a protective factor against self-harm. The committee agreed that safety plans should always be accessible to ensure that people receive the most appropriate care, especially if they are too distressed to remember their plan. The committee agreed that psychological or psychosocial interventions should always be available for those who may need them, based on their knowledge and experience that exclusion from these services even when they are appropriate for the individual increases the potential for repeat self-harm or suicide. The committee agreed, based on the uncertain evidence on pharmacological interventions and their knowledge and experience, that drug treatment is usually offered for other comorbidities such as depression, and should not be offered specifically for self-harm. The committee made a recommendation for research on specific psychological interventions (digital and/or face-to-face) to better inform future guideline development. Recommendations 1.11.11 to 1.11.13 There was no evidence, so the recommendations are based on the committee's knowledge and experience. They agreed there are benefits to providing advice on coping strategies. However, the lack of evidence meant they were unable to make any recommendations about the use of safer self-harm strategies, or to be more specific in the recommendations. The committee agreed that harm minimisation strategies can be helpful when a person is working towards stopping self-harm but has not yet managed to do so. In these circumstances, it may be possible to discuss harm minimisation strategies with the person who has self-harmed; however, this should only be done as part of a therapeutic partnership where treatment is ongoing. The aim of these strategies should be to work towards stopping the self-harm, while minimising the harm before this is possible for the person. The committee also agreed that some harm minimisation strategies are not appropriate for all people who self-harm, depending on the person's care and support needs. The committee made a recommendation for research on the experience, feasibility, acceptability and effectiveness of harm minimisation strategies for people who self-harm to better inform future guideline development. Recommendation 1.11.14 There was no evidence, so the committee based the recommendation on their knowledge and experience. They agreed that there are benefits to taking therapeutic risks when working with people who have self-harmed. However, the lack of evidence meant they were unable to be more specific about when therapeutic risk taking should be considered. The committee agreed that therapeutic risk taking could promote autonomy, problem-solving skills and positive thinking, leading to improved patient satisfaction and reduced rates of self-harm. However, the committee discussed the fact that a misunderstanding of therapeutic risk taking resulting in assessment or care being withheld could potentially lead to significant increased rates of repeat self-harm or suicide, and agreed it is important to recommend that risk-taking strategies should only follow a psychosocial assessment and be used concurrently with any other psychiatric care. They also agreed that risk‑taking strategies should be a part of ongoing assessments to determine the efficacy of the approach for the person. The committee also agreed that other relevant professionals and practitioners would need to be involved to help with implementing the therapeutic risk-taking approach and to ensure that the approach has been communicated to the relevant teams. ## How the recommendations might affect practice The recommendations should increase the number of people receiving psychological interventions after an episode of self-harm, and reduce the number of people denied appropriate interventions because of limited or no availability. In turn, this should reduce repeat self-harm and suicide, and improve satisfaction and engagement with services. The recommendations should also ensure that a therapeutic risk-taking approach will not lead to the withholding of assessment or treatment for people who have self-harmed, potentially improving the quality of care provided, service user satisfaction, and reducing the rates of repeat self-harm or suicide. The recommendations for specific therapies are likely to increase overall costs related to the provision of psychological interventions to people who self-harm, if CBT-informed psychological interventions and DBT‑A are offered to more service users. The recommendation that psychological interventions should be available could also have a resource impact depending on how many centres do not currently offer these therapies. For those that do not, training and additional staffing may be needed for these interventions to be available to all service users. Using therapeutic risk-taking approaches is unlikely to increase overall costs; instead, approaches such as discharging patients from hospital where appropriate may have a positive resource impact on, for example, the availability of hospital beds. Return to recommendations # Supporting people to be safe after self-harm Recommendations 1.12.1 to 1.12.9 ## Why the committee made the recommendations Where possible, the recommendations are based on evidence, but because of concerns over the quality and scarcity of evidence, the committee also used their knowledge and experience. The committee discussed the evidence on the consistency and continuity of staffing, and agreed that this is a fundamental aspect of supporting people to be safe after self-harm because minimising the number of staff that people who have self-harmed see minimises distress and reduces the rates of repeat episodes of self-harm. The committee discussed the limited evidence on observation for people who have self-harmed. They highlighted that observation could cause harm to people who have self-harmed if carried out by untrained clinical staff and if a therapeutic interaction is not established or maintained. The committee discussed safety considerations when transferring between settings and agreed the importance of care plans being available to staff involved in their care in primary and secondary care and other settings to promote continuity of care. There was limited evidence on the benefits of ensuring staff presence during periods in inpatient settings when rates of self-harm are higher. Using this and their knowledge and experience, the committee agreed that it is particularly important for staff to remain visible and accessible during handovers and busy periods to maintain continuity of care and ensure patient safety. By being visible, it minimises barriers between staff and patients, making it more likely that both parties can help and ask for help if needed. Although it is important to ensure a safe physical environment for all mental health inpatients, the committee noted that a particular focus on safety is needed for people who have self-harmed. However, the committee agreed that safety considerations should not be prioritised over the person's autonomy and dignity, and therefore the least restrictive measures should always be used, dependant on the safety of the person. The committee agreed that staff should consider removing certain items from the environment, according to the individual's specific needs and vulnerabilities. This could include sharp objects, potential ligatures and possible ligature points and things that might cause harm when ingested. However, the committee agreed that the need for this should be reviewed and only done when necessary to avoid excessive restrictions. Although there was no evidence on the benefits of familiarising the patient with the procedures and physical environment of inpatient settings, the committee agreed that this is an important component of person-centred care, which should be carried out at the earliest opportunity to help reduce distress and the rate of repeat self-harm. Although there was limited evidence, the committee highlighted the importance of all staff working in care settings knowing how to promptly raise concerns about people who have self-harmed. The committee agreed that open communication channels are important to ensure prompt responses to any signs of repeat self-harm. ## How the recommendations might affect practice These recommendations are in line with existing recommended practice, but they emphasise the importance of consistency and continuity of care and the therapeutic role of clinical observation. The recommendations may lead to trust-specific staff training in caring for people who have self-harmed. Return to recommendations # Safer prescribing and dispensing Recommendations 1.13.1 to 1.13.5 ## Why the committee made the recommendations There was no evidence, so the committee based the recommendations on their knowledge and experience. The committee agreed that when prescribing medicines to people after an episode of self-harm, it is important to take into account the toxicity of the prescribed medicines, the likelihood of drug or alcohol misuse and interactions with prescribed treatment, and the person's wider access to medicines prescribed for themselves or others, to limit the risk of overdose. They also agreed the need for effective communication when there are multiple prescribers. The committee acknowledged the importance of shared decision making with people who have self-harmed when prescribing medicines in order to balance the risk of the person stockpiling medicines with their autonomy to improve patient satisfaction and adherence to medicines, and referred to the existing NICE guideline on shared decision making. The committee agreed that a review of all current and any new medicines should be considered after an episode of self-harm. The committee identified that healthcare professionals could consider contacting the National Poisons Information Service for further advice and referred to the existing NICE guideline on medicines optimisation and STOMP-STAMP principles for people with learning disabilities or autism or both. The committee agreed that when pharmacy staff are aware of warning signs and when healthcare professionals are prepared to use consultations to discuss self-harm, the opportunities for people to self-poison or overdose are reduced. The committee also agreed that the recommendations provide the chance for staff to enact safe prescribing principles. The committee agreed that consultations and medicines reviews provide an opportunity for healthcare staff to assess self-harm, and therefore whether any existing or new medicines might be taken in overdose. This would allow for staff to amend any prescriptions as appropriate to reduce the potential for future self-poisoning. ## How the recommendations might affect practice These recommendations should improve safety for people after an episode of self-harm and improve person-centred care by involving people in decisions about safer prescribing practices. For prescribers, these recommendations may mean that they review current prescriptions more routinely after an episode of self-harm with respect to the person's risks of toxicity from overdose. For primary healthcare professionals, these recommendations may increase communication with healthcare professionals from other settings, such as specialist mental health centres and specialist pharmacies when prescribing and reviewing medications. Improved communication between healthcare professionals should limit variations in prescribing practices and improve continuity of care. Return to recommendations # Training Recommendations 1.14.1 to 1.14.4 ## Why the committee made the recommendations The recommendations are based on the evidence from specialist and non-specialist staff, people who have self-harmed who have had care provided by specialist and non-specialist staff, and their parents and carers, which showed that there is a significant overlap between the kind of training considered important for both mental health and non-specialist professionals when working with people who have self-harmed. Both reviews found that formal training on how to work with people who have self-harmed was considered important by all participants, so the committee agreed that all staff who work with people who self-harm should receive regular, ongoing training to address the areas where people felt their skills needed developing. The committee discussed the overlap between the specialist and non-specialist skills reviews and agreed that, although the evidence showed that similar skills are required by all staff, there would be different levels of skill required for each group of people. The committee agreed that the list of topics should be considered by those running the training to ensure the training would be appropriate to each professional's level of responsibility, because it would be unreasonable and impractical to expect specialist and non-specialist staff to receive the same level of training. The recommendation listing topics to cover in training was based on the evidence for the skills that both specialist and non-specialist staff need. The committee agreed that specialist staff should also receive additional training about how to conduct a psychosocial assessment and risk formulation. The committee discussed using security staff for observation of people who have self-harmed, and agreed that this is not appropriate and usually results in people feeling intimidated and distressed. They agreed, based on their knowledge and experience, that training in observation methods that promote therapeutic engagement and rapport building would allow staff to undertake therapeutic observation in a way that is least distressing for patients. ## How the recommendations might affect practice These recommendations should increase the frequency of formal self-harm specific training for all staff. There may be cost implications associated with the provision of high-quality training depending on the current frequency of formal training deemed necessary within different settings. Return to recommendations # Supervision Recommendations 1.15.1 and 1.15.2 ## Why the committee made the recommendations There was evidence that staff value different types of supervision for specific purposes, and the committee agreed recommendations on regular formal supervision and accessible 'on-the-job' support. The committee agreed that all staff should have the opportunity to access supervision that is distinct from general clinical supervision and case load management, but that staff who work with people who self-harm have a particular need for high-quality formal supervision and support. There was limited evidence to determine the regularity of formal self-harm supervision, and the committee agreed this would be decided on setting-specific factors, such as rates of self-harm, the acuteness of self-harm and available resources. The committee highlighted that supervision should focus on ongoing skills development, because there was evidence that staff feel that they are not suitably trained or confident in caring for people who had self-harmed, especially in crisis situations. There was evidence that staff view reflective practice as an invaluable means to learn and improve their clinical practice; however, often this was not prioritised because of time and resource constraints. The committee agreed that formal self-harm supervision should aim to promote confidence and competence in staff when caring for people who self-harm, and this is particularly important for non-specialist staff who may feel less capable of managing difficult situations. In addition to formal supervision, there was evidence that staff value having accessible and immediate support from senior colleagues. The committee were concerned that anxiety around fear of litigation in difficult situations could impact quality of care, and agreed that support for staff working with people who self-harm should reinforce lines of responsibility and provide advice to facilitate staff in making the most appropriate decisions. There was evidence of the value placed on professional emotional support after an episode of self-harm or suicide, with staff describing how it helped them to process their experience and normalise their feelings and reactions and return to practice. The committee agreed that in their experience and expertise, it is often more appropriate for the member of staff to speak to someone removed from the situation and not necessarily their clinical supervisor, and agreed that all staff should have access to emotional support or emotional support services, as preferred by the member of staff, when requested. ## How the recommendations might affect practice These recommendations should increase the frequency of formal self-harm specific supervision for all staff. There may be cost implications associated with the provision of high-quality supervision depending on the frequency of formal supervision deemed necessary within different settings. The recommendations on everyday supervision and support are in line with recommended practice but should help to foster a culture of supervision within all settings for staff working with people who self-harm. The committee discussed the cost implications of providing accessible emotional support or emotional support services to all staff and concluded that in most clinical settings, 24‑hour support was already available. Return to recommendations# Context Self-harm is defined as intentional self-poisoning or self-injury irrespective of the apparent purpose of the act. Prevalence statistics are unreliable because it is a problem that is sometimes hidden, but a recent national study reported that 7.3% of girls aged 11 to 16, and 3.6% of boys aged 11 to 16, had self-harmed or attempted suicide at some point. The figures for 17‑ to 19‑year‑olds were 21.5% for girls and 9.7% for boys. Self-harm can occur at any age, but there is evidence that there has been a recent increase in self-harm among young people in England. Only a minority of people who have self-harmed present to hospital services, but it remains one of the commonest reasons for hospital attendance. Some estimates suggest upwards of 200,000 presentations in England every year, mostly for self‑poisoning. For some people, self-harm is a one-off episode but repetition is also common, with 20% of people repeating self‑harm within a year. People who have self-harmed are at greatly increased risk of suicide, with a 30‑ to 50‑fold increase in risk in the year after hospital presentation. Self-harm can present in a variety of locations including community, home, educational, custodial, social care and healthcare settings. However, much of the evidence on management comes from hospitals. Despite the potential seriousness, only about half of the people who present to emergency departments after an episode of self-harm are assessed by a mental health professional. Treatments include psychosocial and pharmacological interventions, and harm minimisation strategies. People who have self-harmed have often had contact with primary care. About half of the people who attend an emergency department after an episode of self-harm will have visited their GP in the previous month.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe recommendations apply to staff from all sectors that work with people who have self-harmed, unless a recommendation or section specifically states that it is for a certain group. Because of the wide variety of criminal justice system settings that exist and the need to take other relevant national guidance into account, the recommendations in the guideline may need to be tailored for certain criminal justice system settings during implementation.\n\nPutting recommendations into practice can take time depending on how much change in practice or services is needed. Most of the recommendations in this guideline reinforce best practice and will not need additional resources to implement if previous guidance has been followed. If changes to current local practice are needed to implement the recommendations, they may take time and significant additional resources.\n\nThe recommendations apply to all people who have self-harmed, unless a recommendation specifically states that it is for adults or children and young people only.\n\n# Information and support\n\nProvide information and support for people who have self-harmed. Share information with family members or carers (as appropriate). Topics to discuss include:\n\nwhat self-harm is\n\nwhy people self-harm and, where possible, the specific circumstances of the person\n\nsupport and treatments available\n\nself-care (also see recommendation 1.11.12 in the section on harm minimisation), including when to seek help\n\nhow to deal with injuries\n\nhow to manage scars\n\ncare plans and safety plans, and what they involve\n\nthe impact of encountering stigma around self-harm\n\nwho will be involved in their care and how to get in touch with them\n\nwhere appointments will take place\n\nwhat to do if they have any concerns\n\nwhat do to in an emergency\n\nlocal services and how to get in touch with them, including out-of-hours\n\nlocal peer support groups, online forums, local and national charities, and how to get in touch with them.\n\nProvide information and support for the family members or carers (as appropriate) of the person who has self-harmed. Topics to discuss include:\n\nthe emotional impact on the person and their family members or carers\n\nadvice on how to cope when supporting someone who self-harms\n\nwhat to do if the person self-harms again\n\nhow to seek help for the physical consequences of self-harm\n\nhow to assist and support the person\n\nhow to recognise signs that the person may self-harm\n\nsteps to reduce the likelihood of self-harm in the future\n\nsupport for families and carers and how to access it\n\nthe impact of encountering stigma around self-harm\n\nlocal services and how to get in touch with them, including out-of-hours\n\nlocal peer support groups, online forums, local and national charities, and how to get in touch with them\n\ntheir right to a formal assessment of their own needs including their physical and mental health (known as a 'carer's assessment'), and how to access this (see the NICE guideline on supporting adult carers).\n\nInformation for people who have self-harmed and their family members or carers should be:\n\ntailored to their individual needs and circumstances, taking into account, for example, whether this is a first presentation or repeat self‑harm, the severity and type of self-harm, and if the person has any coexisting health conditions, neurodevelopmental conditions or a learning disability\n\nprovided throughout their care\n\nsensitive and empathetic\n\nsupportive and respectful\n\nconsistent with their care plan, if there is one in place\n\nconveyed in the spirit of hope and optimism.For more guidance on communication, providing information (including different formats) and shared decision making, see the NICE guidelines on shared decision making, service user experience in adult mental health, patient experience in adult NHS services and babies, children and young people's experience of healthcare.\n\nRecognise that support and information may need to be adapted for people who may be subject to discrimination, for example, people who are physically disabled, people with neurodevelopmental conditions or a learning disability, people from underserved groups, people from Black, Asian and minority ethnic backgrounds and people who are LGBTQ+.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: information and support needs of people who have self-harmed\n\nevidence review\xa0B: information and support needs of families and carers of people who have self-harmed.\n\nLoading. Please wait.\n\n# Consent and confidentiality\n\nHealthcare professionals and social care practitioners who have contact with people who self-harm should be able to:\n\nunderstand when and how to apply the principles of the Mental Capacity Act 2005 and its Code of Practice, the Mental Health Act 2007 and its Code of Practice, and the Care Act 2014 and the Care Act 2014 statutory guidance\n\nassess mental capacity\n\nmake decisions about when treatment and care can be given without consent\n\nunderstand when and how to seek further guidance about consent to care\n\ndirect people to independent mental capacity advocates (IMCAs).Also see the NICE guidelines on decision making and mental capacity, service user experience in adult mental health, and babies, children and young people's experience of healthcare, and the Department of Health and Social Care's consensus statement on information sharing and suicide prevention.\n\nHealthcare professionals and social care practitioners who have contact with children and young people who self-harm should also be able to:\n\nunderstand how to apply the principles of the Children Act 1989 and the Children and Families Act 2014 in relation to competence, capacity and confidentiality and the scope of parental responsibility\n\nunderstand how to apply the principles of the Mental Health Act 2007 to young people\n\nunderstand how issues of capacity and competence to consent apply to children and young people of different ages\n\nassess the young person's capacity to consent (including Gillick competence).\n\nIf staff working with people who self-harm need to discuss issues relating to capacity and consent, they should have access to:\n\nspecialist advice (for example, liaison psychiatry) at all times and\n\nlegal advice as needed.\n\nStaff working with people who self-harm should be familiar with the limits of confidentiality with regard to information about a person's treatment and care.\n\nStaff working with people who self-harm should be aware of the benefits of involving the person's family and carers and sharing information, and should recognise the need to seek consent from the person as early as possible. Also see the Department of Health and Social Care's consensus statement on information sharing and suicide prevention.\n\nStaff working with people who self-harm should recognise that if it is necessary to breach confidentiality, they should ensure that the person who has self-harmed is still involved in decisions about their care and, where possible, is informed about the breach of confidentiality.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on consent and confidentiality\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: consent, confidentiality and safeguarding.\n\nLoading. Please wait.\n\n# Safeguarding\n\nAll staff who have contact with people who self-harm should:\n\nunderstand when and how to apply the safeguarding principles of the Care Act 2014, the Children Act 1989, and the Children and Families Act 2014\n\nask about safeguarding concerns, for example, domestic abuse, violence or exploitation at the earliest opportunity and, if appropriate, when the person is alone\n\nexplore whether the person's needs should be assessed and documented according to local safeguarding procedures\n\nbe aware of local safeguarding procedures for vulnerable adults and children in their care, and seek advice from the local named lead on safeguarding if needed.Also see the NICE guidelines on domestic violence and abuse, looked-after children and young people, child abuse and neglect and child maltreatment.\n\nIf people who self-harm are referred to local health and social care services under local safeguarding procedures, use a multi-agency approach, including education and/or third sector services, to ensure that different areas of the person's life are taken into account when assessing and planning for their needs.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on safeguarding\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: consent, confidentiality and safeguarding.\n\nLoading. Please wait.\n\n# Involving family members and carers\n\nThe recommendations in this section should be read alongside the recommendations on consent and confidentiality.\n\nAsk the person who has self-harmed whether and how they would like their family or carers to be involved in their care, taking into account the factors in recommendation 1.4.2, and review this regularly. If the person agrees, share information with family members or carers (as appropriate), and encourage them to be involved.\n\nWhen thinking about involving family members or carers in supporting a person who has self-harmed, take into account issues such as:\n\nwhether the person has consented for information to be shared and, if so, if the consent is limited to certain aspects of their care\n\nany safeguarding concerns\n\nthe person's mental capacity, age and competence to make decisions\n\nthe person's right to confidentiality and autonomy in decision making\n\nthe balance between autonomy (in children and young people, their developing independence and maturity) and the need to involve family members or carers\n\nthe balance between the possible benefits and risks of involving family members of carers and the rights of the person. Also see the NICE guidelines on decision making and mental capacity, service user experience in adult mental health, and babies, children and young people's experience of healthcare.\n\nWhen involving family members or carers in supporting a person who has self-harmed:\n\nencourage a collaborative approach to:\n\n\n\nempower and support the person who has self-harmed\n\nminimise the person's self-harm behaviours and\n\nsupport the person's recovery to prevent recurrence\n\n\n\ngive them opportunities to be involved in decision making, care planning and developing safety plans to support the person beyond the initial self-harm episode, and through their care pathway\n\nensure that there is ongoing and timely communication with the family or carers\n\nregularly review whether the person who has self-harmed still wants their family or carers to be involved in their care, and ensure that they know they can withdraw consent to share information at any time.\n\nBe aware that even if the person has not consented to involving their family or carers in their care, family members or carers can still provide information about the person.\n\nIf the person who has self-harmed finds it difficult to vocalise their distress when they are in need of care, support the person and their family members or carers (as appropriate) in trying alternative methods of communication (such as non-verbal language, letters, emotional wellbeing passports, and using agreed safe words, phrases or emojis).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on involving family members and carers\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: involving family and carers in the management of people who have self-harmed.\n\nLoading. Please wait.\n\n# Psychosocial assessment and care by mental health professionals\n\nAt the earliest opportunity after an episode of self-harm, a mental health professional should carry out a psychosocial assessment to:\n\ndevelop a collaborative therapeutic relationship with the person\n\nbegin to develop a shared understanding of why the person has self‑harmed\n\nensure that the person receives the care they need\n\ngive the person and their family members or carers (as appropriate) information about their condition and diagnosis.\n\nDo not delay the psychosocial assessment until after medical treatment is completed.\n\nIf the person who has self-harmed is intoxicated by drugs or alcohol, agree with the person and colleagues what immediate assistance is needed, for example, support and advice about medical assessment and treatment.\n\nDo not use breath or blood alcohol levels to delay the psychosocial assessment.\n\nIf the person is not able to participate in the psychosocial assessment, ensure that they have regular reviews, and complete a psychosocial assessment as soon as possible.\n\nIf the person who has self-harmed has agreed a care plan, check this with them and follow it as much as possible.\n\nCarry out the psychosocial assessment in a private, designated area where it is possible to speak in confidence without being overheard.\n\nTake into account the needs and preferences of the person who has self‑harmed as much as possible when carrying out the psychosocial assessment, for example, by:\n\nmaking appropriate adaptations for any learning disability or physical, mental health or neurodevelopmental condition the person may have and\n\nproviding the option to have a healthcare professional of the same sex carry out the psychosocial assessment when the person has requested this.\n\nDuring the psychosocial assessment, explore the functions of self-harm for the person. Take into account:\n\nthe person's values, wishes and what matters to them\n\nthe need for psychological interventions, social care and support, or occupational or vocational rehabilitation\n\nany learning disability, neurodevelopmental conditions or mental health problems\n\nthe person's treatment preferences\n\nthat each person who self-harms does so for their own reasons\n\nthat each episode of self-harm should be treated in its own right, and a person's reasons for self-harm may vary from episode to episode\n\nwhether it is appropriate to involve their family and carers; see the section on involving family members and carers.\n\nDuring the psychosocial assessment, explore the following to identify the person's strengths, vulnerabilities and needs:\n\nhistoric factors\n\nchangeable and current factors\n\nfuture factors, including specific upcoming events or circumstances\n\nprotective or mitigating factors.\n\nFor children and young people who have self-harmed, ensure that a mental health professional experienced in assessing children and young people who self-harm carries out the psychosocial assessment. They should ask about:\n\ntheir social, peer group, education and home situations\n\nany caring responsibilities\n\nthe use of social media and the internet to connect with others and the effects of these on mental health and wellbeing\n\nany child protection or safeguarding issues (also see the section on safeguarding).\n\nFor older people who have self-harmed, ensure that a mental health professional experienced in assessing older people who self-harm carries out the psychosocial assessment. They should:\n\npay particular attention to the potential presence of depression, cognitive impairment, physical ill health and frailty\n\ninclude an assessment of the person's social and home situation, including any role they have as a carer\n\nrecognise the increased potential for loneliness and isolation\n\nrecognise that there are higher rates of suicide after an episode of self‑harm for older people.\n\nFor people with a learning disability who have self-harmed, ensure that a mental health professional experienced in assessing people with a learning disability who self-harm carries out the psychosocial assessment.\n\nIf a person has self-harmed and presents to services but wants to leave before a full psychosocial assessment has taken place, assess the person's safety and any mental health problems before they leave.\n\nTogether with the person who self-harms and their family and carers (if appropriate), develop or review a care plan using the key areas of needs and safety considerations identified in the psychosocial assessment (see recommendations 1.5.8 to 1.5.14).\n\nGive the person a copy of their care plan, and share the plan as soon as possible with relevant healthcare professionals and social care practitioners involved in the person's care.\n\nIf a person presents with frequent episodes of self-harm or if treatment has not been effective, carry out a multidisciplinary review with the person and those involved in their care and support, and others who may need to be involved, to agree a joint plan and approach. This should involve:\n\nidentifying an appropriately trained professional or practitioner to coordinate the person's care and act as a point of contact\n\nreviewing the person's existing care and support, and arranging referral to any necessary services\n\ndeveloping a care plan\n\ndeveloping a safety plan for future episodes of self-harm, which should be written with and agreed by the person who self-harms.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychosocial assessment and care by mental health professionals\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0F: assessment in specialist settings\n\nevidence review G: risk assessment and formulation.\n\nLoading. Please wait.\n\n# Risk assessment tools and scales\n\nDo not use risk assessment tools and scales to predict future suicide or repetition of self-harm.\n\nDo not use risk assessment tools and scales to determine who should and should not be offered treatment or who should be discharged.\n\nDo not use global risk stratification into low, medium or high risk to predict future suicide or repetition of self-harm.\n\nDo not use global risk stratification into low, medium or high risk to determine who should be offered treatment or who should be discharged.\n\nFocus the assessment (see the section on principles for assessment and care by healthcare professionals and social care practitioners) on the person's needs and how to support their immediate and long-term psychological and physical safety.\n\nMental health professionals should undertake a risk formulation as part of every psychosocial assessment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk assessment tools and scales\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: risk assessment and formulation.\n\nLoading. Please wait.\n\n# Assessment and care by healthcare professionals and social care practitioners\n\n## Principles for assessment and care by healthcare professionals and social care practitioners\n\nWhen a person presents to a healthcare professional or social care practitioner following an episode of self-harm, the professional should:\n\ntreat the person with respect, dignity and compassion, with an awareness of cultural sensitivity\n\nestablish the means of self-harm and, if accessible to the person, discuss removing this with therapeutic collaboration or negotiation, to keep the person safe\n\nassess whether there are concerns about capacity, competence, consent or duty of care, and seek advice from a senior colleague or appropriate clinical support if necessary; be aware and accept that the person may have a different view and this needs to be taken into account\n\nseek consent to liaise with those involved in the person's care (including family members and carers, as appropriate) to gather information to understand the context of and reasons for the self-harm\n\ndiscuss with the person and their families or carers (as appropriate), their current support network, any safety plan or coping strategies.\n\nWhen a person presents to a healthcare professional or social care practitioner following an episode of self-harm, the professional should establish the following as soon as possible:\n\nthe severity of the injury and how urgently medical treatment is needed\n\nthe person's emotional and mental state, and level of distress\n\nwhether there is immediate concern about the person's safety\n\nwhether there are any safeguarding concerns\n\nwhether the person has a care plan\n\nif there is a need to refer the person to a specialist mental health service for assessment.\n\nCarry out concurrent physical healthcare and the psychosocial assessment as soon as possible after a self-harm episode.\n\nFor immediate first aid for self-poisoning, see the BNF's guidance on poisoning, emergency treatment, TOXBASE and the National Poisons Information Service.\n\nDo not use aversive treatment, punitive approaches or criminal justice approaches such as community protection notices, criminal behaviour orders or prosecution for high service use as an intervention for frequent self-harm episodes.\n\n## Assessment and care in primary care\n\nWhen a person presents in primary care after an episode of self-harm, consider referring them to mental health or social care services for a psychosocial assessment or informing their existing mental health team, with consent from the person and their family members or carers (as appropriate).\n\nMake referral to mental health professionals a priority when:\n\nthe person's levels of concern or distress are rising, high or sustained\n\nthe frequency or degree of self-harm or suicidal intent is increasing\n\nthe person providing assessment in primary care is concerned\n\nthe person asks for further support from mental health services\n\nlevels of distress in family members or carers of children, young people and adults are rising, high or sustained, despite attempts to help.\n\nIf the person who has self-harmed is being supported and given care in primary care, their GP should ensure that the person has:\n\nregular appointments with their GP for review of self-harm\n\na medicines review\n\ninformation about available social care, voluntary and non-NHS sector support and self-help resources\n\ncare for any coexisting mental health problems, including referral to mental health services as appropriate.\n\n## Assessment and care by ambulance staff and paramedics\n\nWhen attending a person who has self-harmed but who does not need urgent physical care, ambulance staff and paramedics should:\n\ndiscuss with the person the best way that the ambulance service can help them\n\nfollow the person's care plan and safety plan if available\n\nseek advice from mental health professionals, where necessary\n\nrecord relevant information about the following, and pass this information to staff if the person is conveyed, or share it with other relevant people involved in the person's ongoing care if the person is not being conveyed:\n\n\n\nhome environment\n\nsocial and family support network\n\nhistory leading to self-harm\n\ninitial emotional state and level of distress\n\nany medicines found at their home.\n\n\n\nWhen attending a person who has self-harmed but who does not need urgent physical care, ambulance staff and paramedics should discuss with the person (and any relevant services) if it is possible for the person to be assessed by or receive treatment from an appropriate alternative service, such as a specialist mental health service or their GP.\n\nWhen deciding whether the person can receive treatment from an appropriate alternative service, ambulance staff and paramedics should assess immediate safety concerns, as well as the availability and accessibility of alternative services at that time.\n\n## Assessment and care by non-mental health emergency department professionals\n\nWhen a person attends the emergency department or minor injury unit following an episode of self-harm, emergency department staff responsible for initial assessment or triage should establish the following as soon as possible:\n\nthe severity of the injury and how urgently physical treatment is needed\n\nthe person's emotional and mental state, and level of distress\n\nwhether there is immediate concern about the person's safety\n\nwhether there are any safeguarding concerns\n\nthe person's willingness to accept medical treatment and mental healthcare\n\nthe appropriate nursing observation level\n\nwhether the person has a care plan.\n\nWhen a person attends the emergency department or minor injury unit following an episode of self-harm, offer referral to age-appropriate liaison psychiatry services, or for children and young people, crisis response service (or an equivalent specialist mental health service or a suitably skilled mental health professional) as soon as possible after arrival, for a psychosocial assessment (see the section on psychosocial assessment and care by mental health professionals and the section on risk assessment tools and scales), and support and assistance alongside physical healthcare.\n\nAn age-appropriate liaison psychiatry professional or a suitably skilled mental health professional should see and speak to the person at every attendance after an episode of self-harm.\n\nEnsure that the emergency department has a private, designated area for psychosocial assessments to take place, where it is possible to speak in confidence without being overheard.\n\nEnsure that the waiting area in the emergency department for people who have self-harmed is close to staff who can provide care, support and observation.\n\nEnsure that appropriate joint governance arrangements are in place so that physical and mental healthcare can be delivered together in emergency departments. This should include:\n\naccess to electronic record systems for both mental health services and medical treatment at the point of care\n\njointly agreed referral pathways for concurrent physical and mental healthcare\n\njointly agreed approaches to initial assessment and triage\n\nmonitoring of the use of mental health law and mental capacity law\n\njoint safeguarding procedures\n\njointly agreed nursing observation policies\n\nreferral pathways to appropriate community services.\n\nDo not use mechanical restraint in emergency departments to prevent self-harm or to prevent a person from leaving the emergency department. Also see the NICE guideline on violence and aggression for recommendations about mechanical restraint.\n\nEnsure that policies and procedures are in place for people who have self‑harmed who wish to leave, or have left, the emergency department before physical healthcare and mental health assessment and care is complete.\n\nEnsure that policies and procedures are in place to identify people who frequently attend the emergency department or minor injury unit following an episode of self-harm so that a multidisciplinary review can be arranged in collaboration with mental health services (see recommendation\xa01.5.17 in the section on psychosocial assessment and care by mental health professionals).\n\n## Assessment and care in general hospital settings\n\nWhen a person is admitted to hospital following an episode of self-harm, offer referral to age-appropriate liaison psychiatry services (or an equivalent specialist mental health service or a suitably skilled mental health professional) as soon as possible after admission for a psychosocial assessment (see the section on psychosocial assessment and care by mental health professionals and the section on risk assessment tools and scales), and support and assistance alongside physical healthcare.\n\nAn age-appropriate liaison psychiatry professional or a suitably skilled mental health professional should see and speak to the person at every admission after an episode of self-harm.\n\nMental health and acute ward staff should jointly decide the need for close observation on a case-by-case basis, taking into account the person's views and ensuring that observation is:\n\nby appropriately skilled and trained healthcare staff\n\nwith the informed consent of the person or within an appropriate legal framework\n\nreviewed regularly.\n\nChildren and young people who have been admitted to a paediatric ward following an episode of self-harm should have:\n\naccess to a specialist child and adolescent mental health service (CAMHS or children and young people's mental health services [CYPMHS]) or age-appropriate liaison psychiatry 24\xa0hours a day\n\na joint daily review by both the paediatric team and children and young people's mental health team\n\ndaily access to their family members or carers\n\nregular multidisciplinary meetings between the general paediatric team and mental health services.\n\n## Assessment and care in social care\n\nWhen working with people who have self-harmed, social care practitioners should foster a collaborative approach with all agencies involved in the care of the person, as well as their family members and carers, as appropriate.\n\nIf self-harm has been identified during a social care assessment or through ongoing work, seek advice from, or refer the person to, the local urgent and emergency mental health service.\n\nContinue to offer social care support and involvement to a person who has self-harmed, particularly if the person may be looked after or have ongoing social care needs.Also see the NICE guidelines on domestic violence and abuse, looked-after children and young people, child abuse and neglect and child maltreatment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment and care by healthcare professionals and social care practitioners\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0E: assessment in non-specialist settings\n\nevidence review\xa0T: models of care for people who have self-harmed.\n\nLoading. Please wait.\n\n# Assessment and care by professionals from other sectors\n\nThe recommendations in this section apply to all staff in non-healthcare and social care settings. Because of the wide variety of criminal justice system settings that exist and the need to take other relevant national guidance into account, staff working in the criminal justice system may need to tailor the recommendations for certain criminal justice system settings during implementation.\n\n## Principles for assessment and care by professionals from other sectors\n\nWhen a person who has self-harmed presents to a non-health professional, for example, a teacher or a member of staff in the criminal justice system, the non-health professional should:\n\ntreat the person with respect, dignity and compassion, with an awareness of cultural sensitivity\n\nwork collaboratively with the person to ensure that their views are taken into account when making decisions\n\naddress any immediate physical health needs resulting from the self‑harm, in line with locally agreed policies; if necessary, call 111 or 999 or other external medical support\n\nseek advice from a healthcare professional or social care practitioners, which may include referral to a healthcare or mental health service\n\nensure that the person is aware of sources of support such as local NHS urgent mental health helplines, local authority social care services, Samaritans, Combat Stress helpline, NHS111 and Childline, and that people know how to seek help promptly\n\naddress any safeguarding issues, or refer the person to the correct team for safeguarding.\n\nWhen a person presents to a non-health professional, for example, a teacher or a member of staff in the criminal justice system, the non-health professional should establish the following as soon as possible:\n\nthe severity of the injury and how urgently medical treatment is needed\n\nthe person's emotional and mental state, and level of distress\n\nwhether there is immediate concern about the person's safety\n\nwhether there are any safeguarding concerns\n\nwhether the person has a care plan\n\nif there is a need to refer the person to a specialist mental health service for assessment.\n\n## Assessment in schools and educational settings\n\nEducational settings should have policies and procedures for staff to support students who self-harm. These should include:\n\nhow to identify self-harm behaviours\n\nhow to assess the needs of students\n\nwhat do to if they suspect a student is self-harming\n\nhow to support the student's close friends and peer group.\n\nEducational settings should have a designated lead responsible for:\n\nensuring that self-harm policies and procedures are implemented\n\nensuring that self-harm policies and procedures are regularly reviewed and kept up-to-date in line with current national guidance\n\nensuring that staff are aware of the self-harm policies and procedures and understand how to implement them\n\nsupporting staff with implementation if there are any uncertainties.\n\nAll educational staff should:\n\nbe aware of the policies and procedures for identifying and assessing the needs of students who self-harm\n\nknow how to implement the policies and procedures within their roles and responsibilities\n\nknow who to go to for support and supervision.\n\nFor students who have self-harmed, the designated lead should seek the advice of mental health professionals to develop a support plan with the student and their family members and carers (as appropriate) for when they are in the educational setting. This should include guidance from other agencies involved in the person's care, as appropriate.\n\nEducational staff should take into account how the student's self-harm may affect their close friends and peer groups, and provide appropriate support to reduce distress to them and the person.\n\n## Assessment and care in the criminal justice system and other secure settings\n\nStaff in criminal justice settings and other secure settings such as immigration removal centres should be aware that those in their care have higher rates of self-harm and suicide.\n\nStaff in criminal justice settings and other secure settings such as immigration removal centres should be aware of support services available to them to support their own wellbeing.\n\nStaff in criminal justice settings and other secure settings such as immigration removal centres should be aware of arrangements for:\n\ntransferring people to a healthcare setting when necessary\n\nin-reach or onsite support\n\ntheir responsibilities for information sharing\n\nhow to access health services.\n\nStaff in criminal justice settings and other secure settings such as immigration removal centres should follow local guidance on assessing people who have self-harmed, and healthcare professionals and social care practitioners in these settings should also follow the NICE guideline on mental health of adults in contact with the criminal justice system.\n\nStaff in criminal justice settings and other secure settings such as immigration removal centres should ensure that people who have self‑harmed have a safe location to await assessment or treatment following an episode of self-harm.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment and care by professionals from other sectors\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: assessment in non-specialist settings.\n\nLoading. Please wait.\n\n# Admission to and discharge from hospital\n\nThe recommendations in this section apply to all healthcare professionals and social care practitioners.\n\nConsider admission to a general hospital after an episode of self-harm if:\n\nthere are concerns about the safety of the person (for example, the person is at risk of violence, abuse or exploitation) and psychiatric admission is not indicated\n\nsafeguarding planning needs to be completed and psychiatric admission is not indicated\n\nthe person is unable to engage in a psychosocial assessment (for example, because they are too distressed or intoxicated).\n\nIf a 16- or 17-year-old is admitted to a general hospital, ensure that it is to a ward that can meet the needs of young people.\n\nFor arrangements for initial aftercare for people who have been admitted to a general hospital after they have self-harmed, see the section on initial aftercare after an episode of self-harm.\n\nDo not delay carrying out a psychosocial assessment or offering mental health treatment if the person is admitted to hospital or needs treatment for physical injuries.\n\nIf a person self-harms during a hospital admission, follow the local hospital policy for investigating untoward incidents and undertake a full investigation. Local areas should be aware of the NHS Patient Safety Incident Response Framework.\n\nBefore discharging a person who has self-harmed from a general hospital, ensure that:\n\na psychosocial assessment has taken place\n\na plan for further management has been drawn up with all appropriate agencies and people\n\na discharge planning meeting with all appropriate agencies and people has taken place and\n\narrangements for aftercare have been specified, including clear written communication with the primary care team.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on admission to and discharge from hospital\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: admission to hospital.\n\nLoading. Please wait.\n\n# Initial aftercare after an episode of self-harm\n\nThe recommendations in this section apply to all healthcare professionals and social care practitioners.\n\nAfter an episode of self-harm, discuss and agree with the person, and their family members and carers (as appropriate), the purpose, format and frequency of initial aftercare and which services will be involved in their care. Record this in the person's care plan and ensure that the person and their family members and carers have a copy of the plan and contact details for the team providing the aftercare.\n\nIf there are ongoing safety concerns for the person after an episode of self-harm, the mental health team, GP, team who carried out the psychosocial assessment or the team responsible for their care should provide initial aftercare within 48\xa0hours of the psychosocial assessment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on initial aftercare after an episode of self-harm\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0I: initial aftercare\n\nevidence review\xa0T: models of care for people who have self-harmed.\n\nLoading. Please wait.\n\n# Interventions for self-harm\n\nThe recommendations in this section apply to all healthcare professionals unless otherwise stated.\n\nWhen planning treatment following self-harm, take into account any associated coexisting conditions and the psychosocial assessment.\n\nFor guidance on how to treat coexisting conditions that may be related to self-harm, also see the NICE guidelines on:\n\nAlcohol-use disorders\n\nAutism spectrum disorder in adults\n\nAutism spectrum disorder in under 19s\n\nBipolar disorder\n\nBorderline personality disorder\n\nCare and support of people growing older with learning disabilities\n\nChallenging behaviour and learning disabilities\n\nDepression in adults\n\nDepression in children and young people\n\nDrug misuse in over 16s: opioid detoxification\n\nDrug misuse in over 16s: psychosocial interventions\n\nEating disorders\n\nGeneralised anxiety disorder and panic disorder in adults\n\nLearning disabilities and behaviour that challenges\n\nMental health problems in people with learning disabilities\n\nObsessive-compulsive disorder and body dysmorphic disorder\n\nPsychosis and schizophrenia in adults\n\nPost-traumatic stress disorder.\n\nOffer a structured, person-centred, cognitive behavioural therapy (CBT)-informed psychological intervention (for example, CBT or problem-solving therapy) that is specifically tailored for adults who self-harm. Ensure that the intervention:\n\nstarts as soon as possible\n\nis typically between 4\xa0and 10\xa0sessions; more sessions may be needed depending on individual needs\n\nis tailored to the person's needs and preferences.\n\nFor children and young people with significant emotional dysregulation difficulties who have frequent episodes of self-harm, consider dialectical behaviour therapy adapted for adolescents (DBT-A). Take into account the age of the child or young person and any planned transition between services.\n\nHealthcare staff should be appropriately trained and supervised in the therapy they are offering to people who self-harm.\n\nWork collaboratively with the person, using a strengths-based approach to identify solutions to reduce their distress that leads to self-harm.\n\nConsider developing a safety plan in partnership with people who have self-harmed. Safety plans should be used to:\n\nestablish the means of self-harm\n\nrecognise the triggers and warning signs of increased distress, further self-harm or a suicidal crisis\n\nidentify individualised coping strategies, including problem solving any factors that may act as a barrier\n\nidentify social contacts and social settings as a means of distraction from suicidal thoughts or escalating crisis\n\nidentify family members or friends to provide support and/or help resolve the crisis\n\ninclude contact details for the mental health service, including out‑of‑hours services and emergency contact details\n\nkeep the environment safe by working collaboratively to remove or restrict lethal means of suicide.\n\nThe safety plan should be in an accessible format and:\n\nbe developed collaboratively and compassionately between the person who has self-harmed and the professional involved in their care using shared decision making (see the NICE guideline on shared decision making)\n\nbe developed in collaboration with family and carers, as appropriate\n\nuse a problem-solving approach\n\nbe held by the person\n\nbe shared with the family, carers and relevant professionals and practitioners as decided by the person\n\nbe accessible to the person and the professionals and practitioners involved in their care at times of crisis.\n\nDo not use diagnosis, age, substance misuse or coexisting conditions as reasons to withhold psychological interventions for self-harm.\n\nDo not offer drug treatment as a specific intervention to reduce self-harm.\n\n## Harm minimisation\n\nAlthough ways to self-harm safely are often considered a harm minimisation strategy, this guideline does not make any recommendations about the use of safer self-harm.\n\nIf a person is engaged in ongoing care and treatment but is not yet in a position to resist the urge to self-harm, only consider harm minimisation strategies:\n\nin the spirit of hope and optimism, and to reduce the severity and/or recurrence of injury\n\nas part of an overall approach to the person's ongoing recovery‑focused care and support, and not as a standalone intervention and\n\nafter being discussed and agreed in a collaborative way with the person and their family members or carers (as appropriate), and the wider multidisciplinary team.\n\nMental health professionals should discuss with the person harm minimisation strategies that could help to avoid, delay or reduce further episodes of self-harm and reduce complications, for example:\n\ndistraction techniques or coping strategies\n\napproaches to self-care\n\nwound hygiene and aftercare\n\nproviding factual information on the potential complications of self-harm\n\nthe impact of alcohol and recreational drugs on the urge to self-harm.\n\nBe aware that harm minimisation strategies may not be appropriate for all people who self-harm.\n\n## Therapeutic risk taking\n\nTherapeutic risk taking should only be used after a psychosocial assessment (see the section on psychosocial assessment and care by mental health professionals), and should:\n\nuse shared decision making, to ensure that the person is able to make an informed choice at all stages, and include family and carers, as appropriate\n\ninclude other relevant professionals involved in the care of the person who has self-harmed\n\ndraw on the person's strengths and coping strategies and what matters to them\n\nfocus on positive outcomes\n\nbe part of an ongoing assessment to revisit the decision\n\nbe concurrent with psychiatric care if necessary.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on interventions for self-harm\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0J: psychological and psychosocial interventions\n\nevidence review\xa0K: pharmacological interventions\n\nevidence review\xa0L: harm minimisation strategies\n\nevidence review\xa0M: therapeutic risk taking strategies\n\nevidence review\xa0P: skills required by staff in specialist settings\n\nevidence review\xa0R: skills required by staff in non-specialist settings\n\nevidence review\xa0T: models of care for people who have self-harmed.\n\nLoading. Please wait.\n\n# Supporting people to be safe after self-harm\n\nEnsure continuity of care, wherever possible, in the staff caring for people who have self-harmed by minimising the number of different staff they see.\n\nFor guidance on ensuring continuity of care, see the section on continuity of care and relationships in the NICE guideline on patient experience in adult NHS services and the section on continuity and coordination of care in the NICE guideline on babies, children and young people's experience of healthcare.\n\nDo not use staff who are untrained in clinical observation (for example, security staff or trainee health and social care staff) to undertake such observations in a person who has self-harmed.\n\nEnsure that the care plans of people who have self-harmed can be accessed by primary and secondary care plus other professionals and practitioners involved in their care.\n\nEnsure that staff working with people who have self-harmed are visible and accessible to the people they are caring for, to encourage interaction, particularly during handovers and busy periods.\n\nAssess the safety of the environment, balancing respect for the person's autonomy against the need for restrictions. Use the least restrictive measures.\n\nConsider removing items that may be used to self-harm and involve the person who has self-harmed in this decision.\n\nAt the earliest opportunity, healthcare staff should help people who have self-harmed to become familiar with the clinical setting in which they are being cared for, and tell them how to get support.\n\nStaff should know how to raise concerns without delay about a person who has self-harmed.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting people to be safe after self-harm\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: supporting people to be safe after self-harm.\n\nLoading. Please wait.\n\n# Safer prescribing and dispensing\n\nThe recommendations in this section apply to all healthcare professionals.\n\nWhen prescribing medicines to someone who has previously self-harmed or who may self-harm in the future, healthcare professionals should take into account:\n\nthe toxicity of the prescribed medicines for people at risk of overdose (for example, opiate-containing painkillers and tricyclic antidepressants)\n\ntheir recreational drug and alcohol consumption, the risk of misuse, and possible interaction with prescribed medicines\n\nthe person's wider access to medicines prescribed for themselves or others\n\nthe need for effective communication where multiple prescribers are involved. Also see the section on reducing access to methods of suicide in the NICE guideline on preventing suicide in community and custodial settings.\n\nUse shared decision making to discuss limiting the quantity of medicines supplied to people with a history of self-harm (for example, weekly prescriptions), and ask them to return unwanted medicines for safe disposal. Also see the NICE guideline on shared decision making.\n\nConsider carrying out a medicines review after an episode of self-harm. Take into account the pharmacokinetic properties of medicines, for example, half-life, risk of toxicity and the concurrent use of medicines such as benzodiazepines and opiates. If necessary, contact the National Poisons Information Service for further advice. Also see the NICE guideline on medicines optimisation. For people with learning disabilities or autism or both, the NHS England STOMP-STAMP principles may be useful.\n\nCommunity pharmacy staff should be aware of warning signs relating to self-harm, such as identifying people who are in acute distress, buying large amounts of over-the-counter medicines or who have access to large amounts of medicines.\n\nHealthcare professionals, including GPs and community pharmacy staff, should use consultations and medicines reviews as an opportunity to assess self-harm if appropriate, for example, asking about thoughts of self-harm or suicide, actual self-harm, and access to substances that might be taken in overdose (including prescribed, over-the-counter medicines, herbal remedies and recreational drugs).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on safer prescribing and dispensing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0O: safer prescribing.\n\nLoading. Please wait.\n\n# Training\n\nTraining for all staff who work with people of any age who self-harm should:\n\ninvolve people who self-harm and, where appropriate, their families or carers, and staff in the planning, delivery and evaluation of training\n\nbe available in a range of formats, including interactive role play, online, face-to-face and through provision of resources\n\nexplore staff attitudes (including non-healthcare staff), values, beliefs and biases\n\nbe appropriate to the level of responsibility of the staff member\n\nbe provided on a regular and ongoing basis.\n\nAll staff who work with people of any age who self-harm should have training specific to their role so that they can provide care and treatment outlined in this guideline. Training should cover:\n\nthe range of different behaviours that can be considered self-harm\n\ntreating and managing episodes of self-harm, including de‑escalation using the least restrictive measures\n\ndiscussing self-harm with the person in an open way to explore the reasons for each episode of self-harm\n\ninvolving people who self-harm in all discussions and allowing sufficient time for decision making about their treatment and subsequent care\n\ncommunicating compassionately and facilitating engagement with people who have self-harmed, including using active listening skills\n\nbeing culturally competent through respecting and appreciating the cultural contexts of people's lives\n\neducation about the underlying factors, triggers or motives that may lead people to self-harm\n\neducation about the stigma and discrimination usually associated with self-harm and the need to avoid judgemental attitudes\n\nrecognising the impact of other diagnoses and comorbidities, and how they interact with self-harm\n\nbalancing patient autonomy and safety when providing care for people who have self-harmed\n\nassessing the needs and safety of the person who has self-harmed (relevant to their role and environment)\n\nthe formal processes involved in treatment after self-harm, including:\n\n\n\ntreatment and referral options\n\nrelevant care pathways\n\nrelevant legislation\n\nprocedures specific to the setting, including layout, policies and protocols.\n\n\n\nIn addition to the training in recommendation 1.14.2, mental health professionals who work with people of any age who self-harm should have training on conducting psychosocial assessments and risk formulation.\n\nAll staff observing people who have self-harmed should also be trained in therapeutic observation methods, including engagement and rapport building.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on training\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0P: skills required by staff in specialist settings\n\nevidence review\xa0R: skills required by staff in non-specialist settings\n\nevidence review\xa0N: supporting people to be safe after self-harm.\n\nLoading. Please wait.\n\n# Supervision\n\nAll staff who work with people of any age who self-harm should have the opportunity for regular, high-quality formal supervision from senior staff with relevant skills, training and experience. Supervision should:\n\ntake into account the emotional impact of self-harm on staff and how best to support them\n\npromote the delivery of compassionate care\n\nfocus on ongoing skill development\n\ninclude reflective practice\n\npromote confidence and competence in staff working with people who have self-harmed.\n\nEnsure that all staff working with people who self-harm have easily accessible ongoing support from senior staff with relevant skills, training and experience. Support should include:\n\nclear lines of responsibility around decision making, particularly for situations where there are challenges around the balance between autonomy and safety for a person who has self-harmed\n\nemotional support or signposting to emotional support services, as preferred by the member of staff.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supervision\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0Q: supervision required for staff in specialist mental health settings\n\nevidence review\xa0S: supervision required for staff in non-specialist settings.\n\nLoading. Please wait.", 'Terms used in this guideline': "This section defines terms that have been used in a particular way for this guideline.\n\n# Care plan\n\nThe plan of treatment or healthcare to be provided to the service user. It typically documents the needs and safety considerations of the service user, the interventions that will support their recovery, as well as the key professionals and practitioners involved in their care.\n\n# Cognitive behavioural therapy-informed psychological intervention\n\nCognitive behavioural therapy (CBT)-informed psychotherapy helps people identify and critically evaluate their thoughts about emotional experiences and events, and aims to help them change the ways in which they deal with problems. The Cochrane review that NICE drew on to evaluate research evidence for this guideline used a broad conceptualisation that included treatments focused on modifying thoughts, behaviours, and problem-solving skills.\n\n# Clinical observation\n\nA therapeutic intervention most commonly used in hospital settings, which allows staff to monitor and assess the mental and physical health of people who might harm themselves and/or others. It should be seen as an opportunity for active engagement as well as sensitive supervision.\n\n# Designated lead\n\nA senior member of staff within an educational setting who takes lead responsibility for the mental health and wellbeing of students who is given appropriate resources such as funding, time and training to do so. Their role is to provide advice and support to other members of staff, participate in the assessment of students, and take part in developing strategies and policies within the education setting for the care of students with mental health problems, including self-harm. The designated lead liaises with external agencies and parents to work collaboratively in supporting students' needs with an awareness of local provisions.\n\n# Dialectic behavioural therapy for adolescents\n\nDialectic behavioural therapy for adolescents (DBT-A) is a manualised, typically 16‑week behavioural treatment, comprising weekly concurrent individual therapy, a multifamily skills training group, between-session skills coaching for young people and their families, family therapy as needed and a peer-consultation group for therapists. DBT-A aims to equip young people and their parents and carers with the skills to reduce or stop self-harm and suicidal behaviours, effectively manage their emotions and improve their relationships.\n\n# Harm minimisation\n\nHarm minimisation is an approach to self-harm that accepts the person's continued urge to self-harm while aiming to keep long-term damage and frequency of injury to a minimum. It can include suggestions to avoid, delay or reduce self-harm.\n\n# Mechanical restraint\n\nA method of physical intervention involving the use of authorised equipment, for example, handcuffs or restraining belts, applied in a skilled manner by designated healthcare professionals.\n\n# Psychosocial assessment\n\nA comprehensive assessment including an evaluation of the person's needs, safety considerations and vulnerabilities that is designed to identify those personal psychological and environmental (social) factors that might explain an act of self‑harm.\n\n# Risk formulation\n\nA collaborative process between the person who has self-harmed and a mental health professional that aims to summarise the person's current risks and difficulties and understand why they are happening in order to inform a treatment plan. Formulation typically includes taking into consideration historical factors and experiences, more recent problems, and existing strengths and resources.\n\n# Safety plan\n\nA written, prioritised list of coping strategies and/or sources of support that the person who has self-harmed can use to help alleviate a crisis. Components can include recognising warning signs, listing coping strategies, involving friends and family members, contacting mental health services, and limiting access to self-harm methods.\n\n# Self-harm\n\nIntentional self-poisoning or injury irrespective of the apparent purpose of the act. The treatment and care of repetitive, stereotypical, self-injurious behaviour (such as head banging) is not covered by this guideline.\n\n# Therapeutic risk taking\n\nA process that aims to empower people who self-harm to make decisions about their own safety and to take risks to enable recovery. Key principles include joint decision making, clear information sharing, drawing on existing strengths, collaborative planning, and an understanding that risk taking may result in positive as well as negative outcomes. Inappropriately withholding or withdrawing care (such as treatment or assessment) without adequate assessment or collaboration cannot be considered therapeutic risk taking.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Models of care\n\nWhat is the effectiveness of different models of care for children and young people who self-harm?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on assessment and care by healthcare professionals and social care practitioners\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0T: models of care for people who have self-harmed.\n\nLoading. Please wait.\n\n# Assessment in non-specialist settings\n\nWhat are the most effective approaches to assessment in non-specialist settings?\n\nHealthcare professionals and social care practitioners\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on assessment and care by .healthcare professionals and social care practitioners\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: assessment in non-specialist settings.\n\nLoading. Please wait.\n\nProfessionals from other sectors\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on assessment and care by professionals from other sectors\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: assessment in non-specialist settings.\n\nLoading. Please wait.\n\n# Routine admission to hospital\n\nIs routine or automatic admission effective for young people or older adults who have self-harmed?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on admission to and discharge from hospital\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: admission to hospital.\n\nLoading. Please wait.\n\n# Psychological interventions\n\nWhat is the effectiveness of specific psychological interventions including digital compared with face-to-face (technology use) in different populations and settings?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on interventions for self-harm\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: psychological and psychosocial interventions.\n\nLoading. Please wait.\n\n# Harm minimisation\n\nWhat is the experience, feasibility, acceptability and effectiveness of harm minimisation strategies for people who self-harm?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on interventions for self-harm\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: harm minimisation strategies.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Information and support\n\nRecommendations 1.1.1 to 1.1.4\n\n## Why the committee made the recommendations\n\nThere was evidence on the information that people who had self-harmed and their family members and carers want to receive, and how they want to receive it. The committee based the recommendations on the evidence, their knowledge and experience, and the NICE guidelines on patient experience in adult NHS mental health services, and patient experience in adult NHS services.\n\nMuch of the evidence on the information needs of people who had self-harmed was consistent with that of family and carers, who want information about self-harm to be shared with them. However, there was conflicting evidence about whether people want information to be shared with family members. The committee agreed that information should be available to the person's family and carers where appropriate and in agreement with the person.\n\nThere was evidence that family members and carers have additional information and support needs specific to their experience that are often unmet. The committee agreed that further information and support should be provided to family members and carers as appropriate.\n\nThere was evidence that people who had self-harmed and their family and carers perceived support (or a lack of it) based on how they had been communicated with, and that they value support from a range of sources. There was also evidence that people who had self-harmed value information that is specific to their circumstances, and the committee agreed that information should be tailored to the individual. The evidence also suggested that people and their family and carers find it difficult to get the information or support they need.\n\nThe committee discussed existing NICE guidelines that have important information about how to appropriately provide information and support to people and agreed that the guidelines are relevant for people who have self-harmed.\n\nThe recommendation that people from protected groups should have additional support was based on the committee's experience and knowledge that forms of discrimination are often causal factors for self-harm.\n\n## How the recommendations might affect practice\n\nThe recommendations should make it easier for people who have self-harmed and their family members and carers to get support and information after an episode of self-harm, and reduce the variation in the information provided. It should also lead to a higher quality of care.\n\nThe impact for providers will vary according to what information and support they currently offer. The recommendations may mean that providers need to change the information they give, but the cost should be minimal and will result in people who self-harm and their family and carers being better informed about self-harm and their care options. The recommendations may mean that family members seek further care for themselves more frequently than they currently do, but it is difficult to estimate the effect this will have on practice.\n\nReturn to recommendations\n\n# Consent and confidentiality\n\nRecommendations 1.2.1 to 1.2.6\n\n## Why the committee made the recommendations\n\nThere was no evidence so the committee based the recommendations on their knowledge of current best practice as well as existing guidance and protocols. Without evidence, the committee could not be more specific about how consent and confidentiality should be considered specifically for people who have self-harmed.\n\nThe committee agreed that existing guidance covers any issues that might arise about consent and assessing capacity to consent in children and young people of different ages. Staff should be aware of these principles while still feeling empowered to seek additional advice, and to feel confident in situations when consent to care may not be given. The committee also agreed that access to independent mental capacity advocates (IMCAs) would allow the person who has self-harmed to feel confident about decisions about their care.\n\nThe committee discussed the risk of legal repercussions for staff either when making decisions about a person's care without their consent or when breaching confidentiality. They recommended that staff have access to experienced colleagues for advice at all times, and to legal advice as needed to allow them to provide care with confidence.\n\nThe recommendation about the limitations of confidentiality was based on the consensus statement from the National Suicide Prevention Strategy Advisory Group, which states that confidentiality can often be a barrier to information sharing, to the detriment of other staff members and family members and carers. The committee agreed that confidentiality could also limit collaboration between staff across different clinical settings.\n\nThe committee agreed that sharing information about a person's care with family members and carers has multiple benefits that often improve outcomes, such as allowing the person to receive appropriate care outside of clinical settings. The committee discussed the risks attached to information sharing and agreed it is still necessary to seek consent from the person, especially before sharing information with family members and carers. This was supported by qualitative evidence from review for involving family members and carers, that family members and carers want to be more involved in the management of self-harm, whereas people who have self-harmed find information sharing without their consent to be a breach of trust.\n\nThe committee discussed the risks of breaching confidentiality and agreed that it can lead to feelings of disempowerment and further distress for the person who has self‑harmed. The committee therefore agreed that the person should still be included in decisions after confidentiality has been breached, and if possible, be informed about this decision to promote autonomy.\n\n## How the recommendations might affect practice\n\nThese recommendations are in line with existing recommended practice, and should result in easier access to legal advice and better awareness of the benefits of information sharing.\n\nReturn to recommendations\n\n# Safeguarding\n\nRecommendations 1.3.1 and 1.3.2\n\n## Why the committee made the recommendations\n\nThe recommendations are based on the committee's knowledge of current best practice, as well as existing guidance on safeguarding in healthcare. The committee agreed that staff should always consider whether such concerns exist for children and adults who have self-harmed, and be prepared to follow safeguarding procedures when necessary. This will enable staff to intervene in situations where safeguarding is a concern to reduce the risk of further harm to the person.\n\nThe committee agree that a multi-agency approach to safeguarding would promote collaborative working between different sectors, allowing for information sharing and therefore improving the service provided to the person.\n\n## How the recommendations might affect practice\n\nThese recommendations are in line with existing recommended practice, but may also enable better communication and transitions across services through multi‑agency approaches.\n\nReturn to recommendations\n\n# Involving family members and carers\n\nRecommendations 1.4.1 to 1.4.5\n\n## Why the committee made the recommendations\n\nThere was conflicting evidence on if and how family members and carers should be involved in the support and treatment of people who have self-harmed. The evidence showed both potential harms and benefits, so the committee based the recommendations on the evidence and their own knowledge and experience. The committee agreed that because involving family members and carers is linked to issues around consent and confidentiality, the recommendations should be read in conjunction with the recommendations on consent and confidentiality.\n\nThere was good evidence that involving family members and carers can have a positive effect on care and that a collaborative approach to care is helpful as long as the person continues to consent to their family and carers' involvement. The committee recognised that there may be circumstances where involving family members or carers is not appropriate, so agreed that involvement should be encouraged and accommodated where appropriate, after taking into account the person's preferences and capacity, and the potential harms and benefits.\n\nThere was also evidence that family members, school staff and healthcare professionals value two-way communication to enable information sharing about any changes in the life or treatment of the person who has self-harmed.\n\nThe committee highlighted if the person has not given consent, family and carers can still share information with healthcare professionals, which can provide helpful insights to make a holistic assessment of, and base their professional judgements on, the needs of the person who has self-harmed.\n\nThere was evidence that people who had self-harmed and their family and carers value being able to communicate using non-verbal means. The committee agreed that this can encourage positive communication because it can often be difficult for the person to express their needs when they are very distressed. The use of non‑verbal forms of communication can reduce the need for the person to explain how they are feeling, and help to build the initial therapeutic rapport and understanding of the person's needs.\n\n## How the recommendations might affect practice\n\nThese recommendations should make it easier for healthcare professionals to recognise when it is appropriate to involve family members and carers in the care of people who have self-harmed, and allow people who have self-harmed to make decisions about the involvement of family and carers. They should also enable family members and carers to be involved in care in a way that is collaborative and helpful for the person who has self-harmed.\n\nProviders may need to change how they involve family members and carers, but the costs are expected to be small and will result in a higher quality of care for people who self-harm.\n\nReturn to recommendations\n\n# Psychosocial assessment and care by mental health professionals\n\nRecommendations 1.5.1 to 1.5.17\n\n## Why the committee made the recommendations\n\nThe recommendations are based on the available evidence, but because of concerns over the quality and scarcity of evidence, most are based on the committee's knowledge and experience.\n\nThere was evidence that an assessment model incorporating therapeutic elements such as identification of the target problem has a positive effect on satisfaction. The committee agreed the factors to take into account in the psychosocial assessment, and what it should include.\n\nThe committee agreed that delaying a psychosocial assessment could result in the person receiving inappropriate treatment. They discussed that if the person is not able to meaningfully engage in the assessment (for example, if the person is unconscious or has very high levels of intoxication), they should be regularly reviewed so that it can take place as soon as appropriate, and that any care plan should always be followed to optimise the psychosocial assessment.\n\nThe committee agreed that breathalysers and blood alcohol tests do not accurately assess the ability of a person to meaningfully engage with an assessment, and could be used to wrongly deny someone an assessment.\n\nThe committee agreed that care plans should be followed where possible to ensure a higher standard of care and inform the assessment, including whether certain questions should be prioritised.\n\nThere was evidence that people value privacy and having a safe and trusted environment when discussing self-harm.\n\nThe committee agreed the self-harm functions and factors to explore. The committee agreed these would allow coexisting conditions to be taken into account and enable staff to provide a higher quality of care. The committee also agreed that using the psychosocial assessment to develop a care plan could have a positive impact on the person's engagement with follow-up. Qualitative evidence was consistent with the committee's agreement that including family and carers in the person's care has a positive impact.\n\nThe committee agreed that children, young people, older adults and people with learning disabilities should be assessed by staff with appropriate experience to ensure a higher standard of care. They also agreed that there are additional factors to consider for children, young people and older adults, which would enable the assessment to be more individualised.\n\nThe committee discussed that briefly assessing the person if they chose to leave before a full assessment had taken place could prevent repeat self-harm or attempted suicide.\n\nThe committee agreed that providing the person with a copy of their care plan would increase transparency and improve trust. Additionally, the committee agreed that providing any other relevant healthcare professionals and social care practitioners with the care plan would ensure that all staff are up-to-date about the person's preferences, improving the quality of their care and their transition between services.\n\nThere was insufficient evidence for the committee to define how frequent attendance for self-harm would have to be to trigger a multidisciplinary review. However, the committee agreed that this recommendation was still important based on their knowledge that the individual circumstances of the person, including whether they are continuing to self-harm, should be assessed to evaluate whether a multidisciplinary review is necessary. The committee agreed that a multidisciplinary review should enable staff to reconsider current care, finding the most suitable care approach for the person and therefore preventing further repeat self-harm.\n\n## How the recommendations might affect practice\n\nThe recommendations should change how psychosocial assessments are conducted, to reduce the potential for distress during assessment and improve the person's satisfaction and engagement with services. The recommendations should also allow for more involvement of family members and carers when appropriate, which could result in better quality care.\n\nMost of the recommendations are based on existing recommended practice with some additional considerations that should have a minimal effect on costs, depending on how services currently assess people who have self-harmed.\n\nReturn to recommendations\n\n# Risk assessment tools and scales\n\nRecommendations 1.6.1 to 1.6.6\n\n## Why the committee made the recommendations\n\nThe committee agreed that risk assessment tools and scales cannot accurately predict risk of self-harm or suicide, and that determining access to treatment or hospital admission based on inaccurate risk assessment tools could lead to repeat self-harm, distress and lower patient satisfaction.\n\nThe committee agreed that the potential harms of risk stratification, including the implication that risk is static instead of dynamic, outweigh any benefits it has as a clinical communication tool or an adjunct to clinical assessment, so agreed that risk stratification should not be used.\n\nThe committee agreed that assessment of a person's needs, vulnerabilities, and safety should be a part of every assessment and that 'risk' should not be used to determine care management in isolation of other factors. They agreed that all staff should use their clinical judgement when assessing someone who has self-harmed and they should refer to the non-specialist assessment recommendations for what to do in the event they are concerned about the person and their safety. Additionally, mental health staff should conduct a risk formulation to place the person's safety considerations in context with their strengths and difficulties.\n\n## How the recommendations might affect practice\n\nThe recommendations should change how assessments are conducted to take into account the person's needs and safety as standard and reduce reliance on assessment of a person's 'risk' in isolation of other factors. This should result in a reduction in the occurrence of arbitrary thresholds being used to determine access to care.\n\nRisk assessment tools and scales are still used in some settings to determine access to treatment and care. The recommendations might have an initial effect on costs, depending on how services currently assess people who have self-harmed; however, service provision should already be determined by a person's needs rather than risk thresholds. Additionally, the change in practice should result in lower costs over time because people will receive the care they need rather than have it determined by unreliable risk tools and scales, potentially reducing repeat self-harm.\n\nReturn to recommendations\n\n# Assessment and care by healthcare professionals and social care practitioners\n\nRecommendations 1.7.1 to 1.7.27\n\n## Why the committee made the recommendations\n\nThere was no evidence, so the committee made recommendations mostly based on their knowledge and experience, supplemented by qualitative evidence from the reviews on information and support needs, and staff skills. They agreed it is important to give advice about assessment and care in different settings, but the lack of evidence meant they were unable to be more specific.\n\nThe committee made a recommendation for research on the most effective approaches to assessment in non-specialist settings to better inform future guideline development. Because of a lack of evidence, the committee also made a recommendation for research on models of care for children and young people who self-harm.\n\nRecommendations 1.7.1 to 1.7.5\n\nThe committee agreed that assessment for people who have self-harmed should be collaborative and prioritise preserving the person's dignity to minimise distress, while maintaining physical safety. Evidence showed that people who had self-harmed value positive, compassionate support after an episode of self-harm. The committee agreed that the person carrying out the assessment should gather information from other sources, such as professionals, practitioners and family members, in order for the assessment to be as accurate as possible, and ask about potential coping strategies to inform any future safety plan.\n\nThe committee agreed that healthcare professionals and social care practitioners should establish a number of specific presenting factors to inform their assessment and care. Healthcare professionals and social care practitioners should also be involved in the care of people who have self-harmed as much as possible but know when to refer them to mental health services (as set out in the sections on assessment and care in different health and social care settings), to ensure that the care is appropriate.\n\nThe committee agreed that physical healthcare and mental healthcare should always be delivered concurrently so neither is prioritised at the expense of the other, and to prevent treatment delays. Non-specialist healthcare professionals and social care practitioners should seek appropriate advice about care for people who have self‑poisoned.\n\nThe committee agreed that punitive or aversive approaches should not be used, based on their knowledge that such approaches are considered malpractice and often have harmful effects on people who have self-harmed, potentially leading to increased distress and repeat self-harm or suicide.\n\nRecommendations 1.7.6 to 1.7.8\n\nThe committee agreed that referring people to mental health services would be reassuring and ensure that people are in the most appropriate setting, and that referral should be prioritised in certain situations to prevent further distress.\n\nThe committee agreed that if people are being cared for in primary care following an episode of self-harm, there should be continuity of care and regular reviews of factors relating to their self-harm to ensure that the person who has self-harmed feels supported and engaged with services.\n\nRecommendations 1.7.9 to 1.7.11\n\nThe committee agreed that information about the person's situation should be recorded because it is invaluable for mental health staff when they carry out the psychosocial assessment. The committee agreed that collaboration between ambulance staff and the person who has self-harmed about their care would allow these preferences to be accommodated by ambulance staff and in other settings.\n\nThe committee agreed that ambulance staff should discuss whether assessment should be carried out by alternative services based on qualitative evidence from the review on skills for non-specialist staff. This showed that ambulance staff often felt that the emergency department was not the preferred place that the person who had self-harmed wanted to be taken. They agreed that referral to alternative services when the situation is appropriate could facilitate the person's engagement with services. The committee also discussed factors that should be considered when deciding whether alternative services should be used, to ensure that the person receives the best possible care without delay.\n\nRecommendations 1.7.12 to 1.7.20\n\nThe committee agreed that an initial rapid assessment of the person's mental and physical care needs is important to quickly establish the best course of action and accommodate the person's needs and safety considerations.\n\nThe recommendations about liaison psychiatry are based on the committee's knowledge that such services have a positive influence on care. The recommendations are also based on evidence from the review on models of care, which showed that specialist psychosocial assessment by mental health staff has an important benefit in terms of self-harm repetition over 12\xa0months.\n\nEvidence from the qualitative review on the information and support needs of people who have self-harmed showed that people value privacy and a safe and trusted environment when discussing self-harm.\n\nThe committee agreed that people who have self-harmed may feel neglected when asked to wait in isolated areas of the emergency department, and that people who have self-harmed may need support during a time of potential distress.\n\nThe committee based the governance recommendations on the Healthcare Safety Information Branch (HSIB) report on investigation into the provision of mental health care to patients presenting at the emergency department (2018), which found that clarity about service pathways and good communication between teams can result in successful safeguarding, de‑escalation of mental health crises, and prevent immediate repeat self-harm or suicide.\n\nThe HSIB report also informed the recommendation that there should be an agreed policy or procedure in place for people who wish to leave before treatment is complete. The committee agreed this would ensure that people who leave and who have ongoing safety concerns are identified so appropriate follow-up contact can be made. The committee also agreed it is important that mechanical restraint is not used on people to prevent them from leaving the emergency department or from self-harming, because in their experience, this results in increased distress and a loss of autonomy and dignity for the person, potentially resulting in a loss of trust in services and an unwillingness to seek help in the future.\n\nThe committee agreed that policies and procedures for identifying people who frequently self-harm would allow non-specialist staff in emergency departments to facilitate a multidisciplinary review to ensure that people get the right treatment and support.\n\nRecommendations 1.7.21 to 1.7.24\n\nThe recommendations about liaison psychiatry are based on the committee's knowledge that such services have a positive influence on care. The recommendations are also based on evidence from the review on models of care, which showed that specialist psychosocial assessment by mental health staff had an important benefit in terms of self-harm repetition over 12\xa0months.\n\nThe recommendation about observation was based on the committee's experience that observation can be intimidating and unnecessary, especially when carried out by security guards. The committee agreed that observation should be discussed with people to reduce distress, and carried out by healthcare staff.\n\nThe committee agreed that children and young people in hospital have specific needs and should therefore have access to age-appropriate specialist care.\n\nRecommendations 1.7.25 to 1.7.27\n\nThe committee agreed that a shared approach between healthcare professionals and social care practitioners is important to promote holistic care for people who self‑harm to ensure that different areas of the person's life are taken into account. The committee discussed their experience that social care services can be withdrawn from people after an episode of self-harm, and agreed that this practice should be strongly discouraged despite the lack of evidence, based on their knowledge that this often results in people not receiving the care that they need, potentially leading to repeat self-harm and suicide.\n\nThe committee agreed that in many circumstances, self-harm is identified by social care practitioners through a safeguarding concern. They agreed that when this occurs, social care practitioners should refer the person to local mental health services to ensure they start on a care pathway and receive appropriate care. The committee agreed that social care services should be provided in conjunction with mental health care, to ensure that the person continues to receive social care support as needed.\n\n## How the recommendations might affect practice\n\nThe recommendations should change the way in which assessments are conducted in a range of settings, to reduce the potential for distress after self-harm and improve the person's satisfaction and engagement with services.\n\nMost of the recommendations are based on existing best practice with some additional considerations that should have a minimal effect on costs, depending on how services currently assess people who have self-harmed. The recommendation that people who have self-harmed should have access to age-appropriate liaison psychiatry in emergency departments and general hospital settings should not have a cost or resource impact because this should already be standard practice.\n\nReturn to recommendations\n\n# Assessment and care by professionals from other sectors\n\nRecommendations 1.8.1 to 1.8.12\n\n## Why the committee made the recommendations\n\nThere was no evidence, so the committee based the recommendations on their knowledge and experience. They agreed it is important to give advice about assessment and care in different settings, but the lack of evidence meant they were unable to be more specific.\n\nThe committee made a recommendation for research on the most effective approaches to psychosocial assessment in non-specialist settings to better inform future guideline development.\n\nRecommendations 1.8.1 and 1.8.2\n\nThe committee agreed that people who have self-harmed can often initially present to non-health professionals, and agreed principles on compassion and preserving the dignity of the person who has self-harmed, regardless of whether the professional has healthcare training. The committee also agreed that non-health professionals should address immediate physical health needs if necessary to prevent further potential harm, but should also seek appropriate clinical support or refer to healthcare services to ensure that the care is appropriate. There was also qualitative evidence from the review on information and support needs of parents and carers, which showed that carers often urgently seek information from qualified healthcare professionals or social care practitioners on discovery of self-harm.\n\nThe committee agreed there were factors of a person's presentation that professionals should establish to inform how they care for the person who has self‑harmed. Non-health professionals should also be involved in the care of people who have self-harmed as much as possible but know when to refer them to mental health services, to ensure that the care is appropriate.\n\nRecommendations 1.8.3 to 1.8.7\n\nThe recommendations are based on the committee's knowledge that both non‑specialist staff and specialist mental health staff can work in educational settings with children and young people who have self-harmed, and therefore all staff in educational settings need policies and procedures for how to identify and respond to students who have self-harmed. The recommendations are also based on qualitative evidence from the review on skills for specialist staff, which showed that school mental health staff want policies for how to respond to people who have self-harmed because they often feel unsupported and unsure whether they are acting in the best interest of the student.\n\nThe committee agreed that formal policies and procedures and a designated lead on self-harm would ensure educational staff would be equipped with appropriate means to respond to self-harm and be supported in their decision making, boosting staff confidence and competence, and improving the quality of care of children and young adults who have self-harmed.\n\nThe committee agreed that collaboration with other mental health staff would support the person's access to services and help prevent repeat self-harm, while taking into account the effect on the person's friends and peers would allow support to be provided.\n\nRecommendations 1.8.8 to 1.8.12\n\nThe committee based the recommendations on the NICE guideline on mental health of adults in contact with the criminal justice system and their knowledge and experience. They agreed that staff awareness of the high rates of self-harm would allow them to be better prepared to assess and care for people who self-harm. They also agreed staff should be aware of support services that are available to them to ensure that their own support needs are met.\n\nThe committee agreed that people who have self-harmed in secure settings need onsite support or, where that is not possible, transfer to healthcare settings. As a result, the committee agreed that staff in these settings should be aware of the arrangements in place, so they can facilitate appropriate care and support if a person self-harms.\n\nThe committee also agreed that the NICE guideline on the mental health of adults in contact with the criminal justice system contained a lot of detail about assessment, especially in prisons, and that staff knowledge of this guideline would ensure staff in these settings followed best practice.\n\nThe committee discussed the benefits of providing a safe place to people who had self-harmed and agreed that this could reduce the person's distress and their access to means to self-harm, as well as reducing the risk for people to be subject to punitive measures such as isolation after self-harm.\n\n## How the recommendations might affect practice\n\nThe recommendations should change the way in which assessments are conducted in a range of settings to reduce the potential for distress after self-harm and improve the person's satisfaction and engagement with services. The recommendations should also allow for better communication between services, including between non-health and healthcare settings.\n\nMost of the recommendations are based on existing best practice with some additional considerations that should have a minimal effect on costs, depending on how services currently assess people who have self-harmed.\n\nReturn to recommendations\n\n# Admission to and discharge from hospital\n\nRecommendations 1.9.1 to 1.9.6\n\n## Why the committee made the recommendations\n\nThe evidence showed that there were no significant short- or long-term differences in repeat self-harm by poisoning, regardless of whether people were admitted to hospital or discharged home. There was no evidence for other types of self-harm or other outcomes. The recommendations are based on the available evidence and the committee's experience and knowledge that admission to hospital carries a greater risk of distress to people of all ages than any potential benefit.\n\nThe committee agreed that despite the lack of evidence for the benefit of admitting people to hospital, in some cases it can be helpful to give the person time to recover or if there are safeguarding concerns.\n\nIf it is necessary to admit a young person who has self-harmed into hospital, the committee agreed that it can be distressing for them to be admitted to a ward that is not equipped to meet the needs of young people.\n\nThe committee agreed that treatment for physical injuries should never be used as a reason to delay or deny a psychosocial assessment because this would be considered malpractice, potentially resulting in heightened distress or neglect of the person's other healthcare needs.\n\nThe committee discussed current practice about what happens when a person self‑harms while in hospital, and agreed that full investigations should continue to be recommended when an incident occurs to consistently improve services and ensure that further incidents are prevented.\n\nThe committee also agreed that discharging a person before they had been assessed and a plan for further management drawn up could be detrimental because people who have self-harmed are likely to need further care and support. A lack of a plan could result in repeat self-harm or suicide, and would create a barrier to care for the person.\n\nThe committee made a recommendation for research on routine or automatic hospital admission for young people or adults to better inform future guideline development.\n\n## How the recommendations might affect practice\n\nThe recommendations should reduce variation in practice, and reduce the potential for distress because of any unnecessary admissions.\n\nThe recommendations could increase the number of beds available in hospitals and reduce overall costs related to overnight admissions to hospital for people who have self-harmed.\n\nReturn to recommendations\n\n# Initial aftercare after an episode of self-harm\n\nRecommendations 1.10.1 and 1.10.2\n\n## Why the committee made the recommendations\n\nThere was evidence that discharge protocols with enhanced initial aftercare provide important benefits such as increased engagement with services and treatment, and reduced rates of repeat self-harm compared with usual discharge. The committee based the recommendations on the evidence and their knowledge and experience that prioritising person-centred care and empowering people who have self-harmed to make decisions about their own care could improve service-user satisfaction and reduce distress or hopelessness. The committee agreed that any aftercare arrangements should be shared with the person, based on their knowledge that this is an important facet of collaborative care, and that providing contact details encourages engagement with care.\n\nThe committee discussed that people who have self-harmed are most likely to repeat self-harm within 2\xa0to 3\xa0days of their previous episode of self-harm. They discussed current best practice in line with the existing NICE guideline on transition between inpatient mental health settings and community or care home settings, which includes follow‑up within 48\xa0hours of presentation. Quantitative evidence was consistent with this, because it showed that telephone contact within 48\xa0hours after discharge had a positive effect on service engagement. The evidence also found a possible important reduction in the number of suicide attempts for those receiving initial contact 3\xa0days after discharge compared with those receiving initial contact within 7\xa0days of discharge, although the different settings in which follow‑up was conducted may also have affected the outcomes. Qualitative evidence from the review on information and support needs for people who have self-harmed also showed that people value proactive, prompt follow‑up and find long waiting times frustrating. However, there were concerns about resourcing and capacity to provide initial aftercare to all patients within this timeframe. The committee agreed that, although follow-up within 48\xa0hours would be ideal for everyone, not all people who have self-harmed will need immediate aftercare. To ensure priority is given to those who need it most, aftercare within 48\xa0hours should be provided to people with ongoing safety concerns to reduce rates of repeat self-harm.\n\nThere was limited evidence that continuity of personnel has a positive effect on service engagement and repeat self-harm. The committee agreed, based on their experience, that continuity of personnel from initial assessment to aftercare allows people to gain familiarity with particular professionals, improving satisfaction and service engagement, and reducing the risk of distress or hopelessness. Evidence from the review on models of care showed that a continuity chain protocol has a possible important benefit in terms of engagement with services compared with usual care. The committee agreed that this is most important for people who have received treatment from a mental health service, based on their knowledge that the person who had self-harmed would have spent more time with mental health staff and may have built up trust with particular staff members, as well as evidence from the review on models of care, which showed that specialist community mental health follow‑up has an important benefit in terms of self-harm repetition over 12\xa0months.\n\n## How the recommendations might affect practice\n\nThe recommendations are mostly in line with current practice. They should lead to a reduction in people waiting for up to 72\xa0hours for aftercare following presentation for self-harm. Providing initial aftercare within 48\xa0hours for people if there are ongoing safety concerns should reduce repeat self-harm and suicide, and improve satisfaction and engagement with services. Any resource impact associated with this would be a worthwhile use of resources.\n\nThe recommendations for continuity of personnel may have a resource impact depending on how often the same staff members who have carried out an assessment or mental healthcare also carry out aftercare. Where this is not the case, there will be an increased workload for these healthcare professionals.\n\nReturn to recommendations\n\n# Interventions for self-harm\n\nRecommendations 1.11.1 to 1.11.14\n\n## Why the committee made the recommendations\n\nThe committee agreed that the psychosocial assessment should be used to develop a meaningful narrative that would inform the care plan. They agreed this would ensure that treatment for any coexisting conditions that could be linked to self-harm are prioritised, enabling healthcare professionals to provide the most appropriate intervention for the individual, and resulting in more person-centred, higher-quality care. The committee referred to a number of other NICE guidelines for conditions that can be linked to self-harm, and agreed it is important that healthcare professionals plan treatment for people who have self-harmed in line with the guidance for any underlying or coexisting conditions before other interventions are considered.\n\nThe evidence showed that psychotherapies informed by cognitive behavioural therapy (CBT) have positive effects on repetition of self-harm at long-term follow‑up and on depression, hopelessness and suicidal ideation over time for adults. However, the evidence did not show an effect on repeat self-harm at other follow-up times. Additionally, the evidence was limited by the wide interpretation of 'CBT-based psychotherapies' as being inclusive of other types of therapies in addition to CBT, and the indistinct categorisation of all interventions throughout the evidence review. The committee agreed other therapies might be effective for adults who have self-harmed as long as they are informed by CBT, as indicated by the evidence.\n\nThe evidence also showed that dialectic behavioural therapy for adolescents (DBT‑A) has a positive effect on repetition of self-harm at post-intervention for adolescents. However, the evidence was limited by the fact that participants in studies had all self-harmed more than once, were all older than 12\xa0years and most were female, and there was no evidence of effect of DBT-A on repeat self-harm by 12‑month follow‑up. The committee extrapolated the evidence based on their confidence that DBT-A is likely to be similarly effective in younger children and boys as it is in over-12s and girls; however, the committee agreed they could not be sure that DBT-A would be similarly effective for children and young people who did not frequently self-harm.\n\nThe evidence for other therapies was uncertain, and the evidence for the effects of pharmacological interventions was limited. The pharmacological evidence showed an uncertain effect of newer-generation antidepressants or antipsychotics on repetition of self-harm for adults, and no evidence of effect for mood stabilisers or natural products on repetition of self-harm for adults. The recommendations are based on the available evidence and the committee's knowledge and experience of the current practice of offering psychological or psychosocial interventions.\n\nThe committee agreed that any therapy offered should be delivered by staff with training in the relevant therapy and who are receiving appropriate supervision. This is to ensure the competence of the professional delivering the training allows for the needs of the person to be met and for the treatment to be tailored for people who self-harm. The committee agreed that further limitations on which staff could deliver therapies were unnecessary and could result in implementation difficulties and delays in treatment provision.\n\nThe recommendation that treatment should be offered without delay was based on the committee's knowledge that delaying treatment could lead to further self-harm or suicide, and on evidence from the review on involving families and carers in the management of self-harm, which showed that long waiting times for treatment is often a barrier to seeking help.\n\nThe safety planning recommendations were based on the committee's knowledge and experience that safety plans equip people who have self-harmed with the ability to identify and use their strengths and sources of support to overcome crisis moments and prevent repeat self-harm. This was supplemented by qualitative evidence from both staff skills reviews, which showed that individualised coping strategies are important to people who have self-harmed, and that specialist staff identified safety planning as an important technique to help manage self-harm. The committee considered the components of safety planning interventions from 3\xa0studies included in the Cochrane review on psychosocial interventions, and used this evidence to recommend important aspects of safety plans that the committee agreed would prevent further self-harm.\n\nThe recommendations about how the safety plan should be implemented were based on the committee's knowledge and experience that collaborative decision making improves engagement with services, and that ensuring a copy is available to the person emphasises this collaborative aspect. The committee agreed that sharing the care plan with family and friends when appropriate could provide the benefit of social connectedness between the person and their sources of support, which is a protective factor against self-harm. The committee agreed that safety plans should always be accessible to ensure that people receive the most appropriate care, especially if they are too distressed to remember their plan.\n\nThe committee agreed that psychological or psychosocial interventions should always be available for those who may need them, based on their knowledge and experience that exclusion from these services even when they are appropriate for the individual increases the potential for repeat self-harm or suicide.\n\nThe committee agreed, based on the uncertain evidence on pharmacological interventions and their knowledge and experience, that drug treatment is usually offered for other comorbidities such as depression, and should not be offered specifically for self-harm.\n\nThe committee made a recommendation for research on specific psychological interventions (digital and/or face-to-face) to better inform future guideline development.\n\nRecommendations 1.11.11 to 1.11.13\n\nThere was no evidence, so the recommendations are based on the committee's knowledge and experience. They agreed there are benefits to providing advice on coping strategies. However, the lack of evidence meant they were unable to make any recommendations about the use of safer self-harm strategies, or to be more specific in the recommendations.\n\nThe committee agreed that harm minimisation strategies can be helpful when a person is working towards stopping self-harm but has not yet managed to do so. In these circumstances, it may be possible to discuss harm minimisation strategies with the person who has self-harmed; however, this should only be done as part of a therapeutic partnership where treatment is ongoing. The aim of these strategies should be to work towards stopping the self-harm, while minimising the harm before this is possible for the person. The committee also agreed that some harm minimisation strategies are not appropriate for all people who self-harm, depending on the person's care and support needs.\n\nThe committee made a recommendation for research on the experience, feasibility, acceptability and effectiveness of harm minimisation strategies for people who self-harm to better inform future guideline development.\n\nRecommendation 1.11.14\n\nThere was no evidence, so the committee based the recommendation on their knowledge and experience. They agreed that there are benefits to taking therapeutic risks when working with people who have self-harmed. However, the lack of evidence meant they were unable to be more specific about when therapeutic risk taking should be considered. The committee agreed that therapeutic risk taking could promote autonomy, problem-solving skills and positive thinking, leading to improved patient satisfaction and reduced rates of self-harm. However, the committee discussed the fact that a misunderstanding of therapeutic risk taking resulting in assessment or care being withheld could potentially lead to significant increased rates of repeat self-harm or suicide, and agreed it is important to recommend that risk-taking strategies should only follow a psychosocial assessment and be used concurrently with any other psychiatric care. They also agreed that risk‑taking strategies should be a part of ongoing assessments to determine the efficacy of the approach for the person. The committee also agreed that other relevant professionals and practitioners would need to be involved to help with implementing the therapeutic risk-taking approach and to ensure that the approach has been communicated to the relevant teams.\n\n## How the recommendations might affect practice\n\nThe recommendations should increase the number of people receiving psychological interventions after an episode of self-harm, and reduce the number of people denied appropriate interventions because of limited or no availability. In turn, this should reduce repeat self-harm and suicide, and improve satisfaction and engagement with services. The recommendations should also ensure that a therapeutic risk-taking approach will not lead to the withholding of assessment or treatment for people who have self-harmed, potentially improving the quality of care provided, service user satisfaction, and reducing the rates of repeat self-harm or suicide.\n\nThe recommendations for specific therapies are likely to increase overall costs related to the provision of psychological interventions to people who self-harm, if CBT-informed psychological interventions and DBT‑A are offered to more service users. The recommendation that psychological interventions should be available could also have a resource impact depending on how many centres do not currently offer these therapies. For those that do not, training and additional staffing may be needed for these interventions to be available to all service users. Using therapeutic risk-taking approaches is unlikely to increase overall costs; instead, approaches such as discharging patients from hospital where appropriate may have a positive resource impact on, for example, the availability of hospital beds.\n\nReturn to recommendations\n\n# Supporting people to be safe after self-harm\n\nRecommendations 1.12.1 to 1.12.9\n\n## Why the committee made the recommendations\n\nWhere possible, the recommendations are based on evidence, but because of concerns over the quality and scarcity of evidence, the committee also used their knowledge and experience.\n\nThe committee discussed the evidence on the consistency and continuity of staffing, and agreed that this is a fundamental aspect of supporting people to be safe after self-harm because minimising the number of staff that people who have self-harmed see minimises distress and reduces the rates of repeat episodes of self-harm.\n\nThe committee discussed the limited evidence on observation for people who have self-harmed. They highlighted that observation could cause harm to people who have self-harmed if carried out by untrained clinical staff and if a therapeutic interaction is not established or maintained.\n\nThe committee discussed safety considerations when transferring between settings and agreed the importance of care plans being available to staff involved in their care in primary and secondary care and other settings to promote continuity of care.\n\nThere was limited evidence on the benefits of ensuring staff presence during periods in inpatient settings when rates of self-harm are higher. Using this and their knowledge and experience, the committee agreed that it is particularly important for staff to remain visible and accessible during handovers and busy periods to maintain continuity of care and ensure patient safety. By being visible, it minimises barriers between staff and patients, making it more likely that both parties can help and ask for help if needed.\n\nAlthough it is important to ensure a safe physical environment for all mental health inpatients, the committee noted that a particular focus on safety is needed for people who have self-harmed. However, the committee agreed that safety considerations should not be prioritised over the person's autonomy and dignity, and therefore the least restrictive measures should always be used, dependant on the safety of the person.\n\nThe committee agreed that staff should consider removing certain items from the environment, according to the individual's specific needs and vulnerabilities. This could include sharp objects, potential ligatures and possible ligature points and things that might cause harm when ingested. However, the committee agreed that the need for this should be reviewed and only done when necessary to avoid excessive restrictions.\n\nAlthough there was no evidence on the benefits of familiarising the patient with the procedures and physical environment of inpatient settings, the committee agreed that this is an important component of person-centred care, which should be carried out at the earliest opportunity to help reduce distress and the rate of repeat self-harm.\n\nAlthough there was limited evidence, the committee highlighted the importance of all staff working in care settings knowing how to promptly raise concerns about people who have self-harmed. The committee agreed that open communication channels are important to ensure prompt responses to any signs of repeat self-harm.\n\n## How the recommendations might affect practice\n\nThese recommendations are in line with existing recommended practice, but they emphasise the importance of consistency and continuity of care and the therapeutic role of clinical observation. The recommendations may lead to trust-specific staff training in caring for people who have self-harmed.\n\nReturn to recommendations\n\n# Safer prescribing and dispensing\n\nRecommendations 1.13.1 to 1.13.5\n\n## Why the committee made the recommendations\n\nThere was no evidence, so the committee based the recommendations on their knowledge and experience. The committee agreed that when prescribing medicines to people after an episode of self-harm, it is important to take into account the toxicity of the prescribed medicines, the likelihood of drug or alcohol misuse and interactions with prescribed treatment, and the person's wider access to medicines prescribed for themselves or others, to limit the risk of overdose. They also agreed the need for effective communication when there are multiple prescribers.\n\nThe committee acknowledged the importance of shared decision making with people who have self-harmed when prescribing medicines in order to balance the risk of the person stockpiling medicines with their autonomy to improve patient satisfaction and adherence to medicines, and referred to the existing NICE guideline on shared decision making.\n\nThe committee agreed that a review of all current and any new medicines should be considered after an episode of self-harm. The committee identified that healthcare professionals could consider contacting the National Poisons Information Service for further advice and referred to the existing NICE guideline on medicines optimisation and STOMP-STAMP principles for people with learning disabilities or autism or both.\n\nThe committee agreed that when pharmacy staff are aware of warning signs and when healthcare professionals are prepared to use consultations to discuss self-harm, the opportunities for people to self-poison or overdose are reduced. The committee also agreed that the recommendations provide the chance for staff to enact safe prescribing principles.\n\nThe committee agreed that consultations and medicines reviews provide an opportunity for healthcare staff to assess self-harm, and therefore whether any existing or new medicines might be taken in overdose. This would allow for staff to amend any prescriptions as appropriate to reduce the potential for future self-poisoning.\n\n## How the recommendations might affect practice\n\nThese recommendations should improve safety for people after an episode of self-harm and improve person-centred care by involving people in decisions about safer prescribing practices.\n\nFor prescribers, these recommendations may mean that they review current prescriptions more routinely after an episode of self-harm with respect to the person's risks of toxicity from overdose. For primary healthcare professionals, these recommendations may increase communication with healthcare professionals from other settings, such as specialist mental health centres and specialist pharmacies when prescribing and reviewing medications. Improved communication between healthcare professionals should limit variations in prescribing practices and improve continuity of care.\n\nReturn to recommendations\n\n# Training\n\nRecommendations 1.14.1 to 1.14.4\n\n## Why the committee made the recommendations\n\nThe recommendations are based on the evidence from specialist and non-specialist staff, people who have self-harmed who have had care provided by specialist and non-specialist staff, and their parents and carers, which showed that there is a significant overlap between the kind of training considered important for both mental health and non-specialist professionals when working with people who have self-harmed.\n\nBoth reviews found that formal training on how to work with people who have self-harmed was considered important by all participants, so the committee agreed that all staff who work with people who self-harm should receive regular, ongoing training to address the areas where people felt their skills needed developing. The committee discussed the overlap between the specialist and non-specialist skills reviews and agreed that, although the evidence showed that similar skills are required by all staff, there would be different levels of skill required for each group of people. The committee agreed that the list of topics should be considered by those running the training to ensure the training would be appropriate to each professional's level of responsibility, because it would be unreasonable and impractical to expect specialist and non-specialist staff to receive the same level of training.\n\nThe recommendation listing topics to cover in training was based on the evidence for the skills that both specialist and non-specialist staff need. The committee agreed that specialist staff should also receive additional training about how to conduct a psychosocial assessment and risk formulation.\n\nThe committee discussed using security staff for observation of people who have self-harmed, and agreed that this is not appropriate and usually results in people feeling intimidated and distressed. They agreed, based on their knowledge and experience, that training in observation methods that promote therapeutic engagement and rapport building would allow staff to undertake therapeutic observation in a way that is least distressing for patients.\n\n## How the recommendations might affect practice\n\nThese recommendations should increase the frequency of formal self-harm specific training for all staff. There may be cost implications associated with the provision of high-quality training depending on the current frequency of formal training deemed necessary within different settings.\n\nReturn to recommendations\n\n# Supervision\n\nRecommendations 1.15.1 and 1.15.2\n\n## Why the committee made the recommendations\n\nThere was evidence that staff value different types of supervision for specific purposes, and the committee agreed recommendations on regular formal supervision and accessible 'on-the-job' support. The committee agreed that all staff should have the opportunity to access supervision that is distinct from general clinical supervision and case load management, but that staff who work with people who self-harm have a particular need for high-quality formal supervision and support. There was limited evidence to determine the regularity of formal self-harm supervision, and the committee agreed this would be decided on setting-specific factors, such as rates of self-harm, the acuteness of self-harm and available resources.\n\nThe committee highlighted that supervision should focus on ongoing skills development, because there was evidence that staff feel that they are not suitably trained or confident in caring for people who had self-harmed, especially in crisis situations. There was evidence that staff view reflective practice as an invaluable means to learn and improve their clinical practice; however, often this was not prioritised because of time and resource constraints. The committee agreed that formal self-harm supervision should aim to promote confidence and competence in staff when caring for people who self-harm, and this is particularly important for non-specialist staff who may feel less capable of managing difficult situations.\n\nIn addition to formal supervision, there was evidence that staff value having accessible and immediate support from senior colleagues. The committee were concerned that anxiety around fear of litigation in difficult situations could impact quality of care, and agreed that support for staff working with people who self-harm should reinforce lines of responsibility and provide advice to facilitate staff in making the most appropriate decisions.\n\nThere was evidence of the value placed on professional emotional support after an episode of self-harm or suicide, with staff describing how it helped them to process their experience and normalise their feelings and reactions and return to practice. The committee agreed that in their experience and expertise, it is often more appropriate for the member of staff to speak to someone removed from the situation and not necessarily their clinical supervisor, and agreed that all staff should have access to emotional support or emotional support services, as preferred by the member of staff, when requested.\n\n## How the recommendations might affect practice\n\nThese recommendations should increase the frequency of formal self-harm specific supervision for all staff. There may be cost implications associated with the provision of high-quality supervision depending on the frequency of formal supervision deemed necessary within different settings.\n\nThe recommendations on everyday supervision and support are in line with recommended practice but should help to foster a culture of supervision within all settings for staff working with people who self-harm. The committee discussed the cost implications of providing accessible emotional support or emotional support services to all staff and concluded that in most clinical settings, 24‑hour support was already available.\n\nReturn to recommendations", 'Context': 'Self-harm is defined as intentional self-poisoning or self-injury irrespective of the apparent purpose of the act. Prevalence statistics are unreliable because it is a problem that is sometimes hidden, but a recent national study reported that 7.3% of girls aged 11\xa0to\xa016, and 3.6% of boys aged 11\xa0to\xa016, had self-harmed or attempted suicide at some point. The figures for 17‑ to 19‑year‑olds were 21.5% for girls and 9.7% for boys. Self-harm can occur at any age, but there is evidence that there has been a recent increase in self-harm among young people in England.\n\nOnly a minority of people who have self-harmed present to hospital services, but it remains one of the commonest reasons for hospital attendance. Some estimates suggest upwards of 200,000\xa0presentations in England every year, mostly for self‑poisoning. For some people, self-harm is a one-off episode but repetition is also common, with 20% of people repeating self‑harm within a year. People who have self-harmed are at greatly increased risk of suicide, with a 30‑ to 50‑fold increase in risk in the year after hospital presentation.\n\nSelf-harm can present in a variety of locations including community, home, educational, custodial, social care and healthcare settings. However, much of the evidence on management comes from hospitals. Despite the potential seriousness, only about half of the people who present to emergency departments after an episode of self-harm are assessed by a mental health professional. Treatments include psychosocial and pharmacological interventions, and harm minimisation strategies. People who have self-harmed have often had contact with primary care. About half of the people who attend an emergency department after an episode of self-harm will have visited their GP in the previous month.'}	https://www.nice.org.uk/guidance/ng225	This guideline covers assessment, management and preventing recurrence for children, young people and adults who have self-harmed. It includes those with a mental health problem, neurodevelopmental disorder or learning disability and applies to all sectors that work with people who have self-harmed.
c059f7bd291ca66650a2b531c8a243fbe7faaaed	nice	Faecal microbiota transplant for recurrent Clostridioides difficile infection	Faecal microbiota transplant for recurrent Clostridioides difficile infection Evidence-based recommendations on faecal microbiota transplant for recurrent Clostridioides difficile infection. # Recommendations Faecal microbiota transplant (FMT) is recommended as an option to treat recurrent Clostridioides difficile infection in adults who have had 2 or more previous confirmed episodes. FMT treatment is cheaper than almost all treatment options with antibiotics. It is not cost saving compared with vancomycin taper pulse if it's given using an enema. However, FMT via enema would only be an option for the minority of people who cannot have FMT by another route. Why the committee made these recommendations Clinical trial evidence shows that FMT treatment is significantly better than antibiotics alone at resolving a C. difficile infection in people who have had 2 or more previous infections. Modelling shows that FMT treatment is cheaper than almost all treatment options with antibiotics. It is cost saving by £769 compared with vancomycin taper pulse (VTP) if it's given using colonoscopy, and by £8,297 compared with vancomycin if it's given using an oral capsule. This assumes FMT costs £1,300 for 50 ml, and that a quarter of people having antibiotics alone are treated in the community (that is, outside hospital). FMT is not cost saving compared with VTP if it's given using an enema – this costs £1,287 per person more.# The technology # Technology Faecal microbiota transplant (FMT) aims to restore a healthy gut microbiome in people who have recurrent or refractory Clostridioides difficile infections. It involves transferring intestinal bacteria and other microorganisms from healthy donor faeces into the gut of the recipient. FMT can be used as a fresh or frozen preparation or in capsule form. It can be given via a lower gastrointestinal route (rectal enema, colonoscopy or flexible sigmoidoscopy), upper gastrointestinal route (using a nasogastric tube, nasoduodenal tube or nasojejunal tube) or via oral capsules. British Society of Gastroenterology and Healthcare Infection Society guidelines recommend a short course of antibiotics before transplantation, with a minimum washout period of 24 hours between the last dose of antibiotic and treatment with FMT. Bowel lavage is also recommended before FMT if it's given via lower gastrointestinal routes. FMT must be manufactured in accordance with Medicines and Healthcare products Regulatory Agency (MHRA) guidance for human medicines regulation. When FMT is supplied on a named patient basis, within a single organisation, a pharmacy exemption may be used, subject to ensuring proper governance and traceability. Before establishing an FMT service, NHS centres are legally required to seek advice from the MHRA and, if necessary, obtain licences to process, distribute and carry out FMT. A strict donor screening programme should also be in place for FMT in line with the British Society of Gastroenterology and Healthcare Infection Society guidelines. An FMT service should be delivered by a multidisciplinary team. # Care pathway First-line treatment for a C. difficile infection involves rehydration and antibiotic treatment. Some people have recurrent, relapsing, or refractory C. difficile infections and need further courses of antibiotics. NICE's guideline on antimicrobial prescribing for C. difficile infection recommends antibiotics for first and further C. difficile infections, and provides guidelines on antibiotic, dosage and course length. It also recommends considering FMT for a recurrent episode of C. difficile infection in adults who have had 2 or more previous episodes. NICE's interventional procedures guidance on FMT for recurrent C. difficile infection says that current evidence on the efficacy and safety of FMT for recurrent C. difficile infection is adequate to support the use of this procedure provided normal arrangements are in place for clinical governance, consent and audit. It also says that clinicians should ensure that a confidential record is kept of the donor and recipient of each FMT. # Innovative aspects The aim of the procedure is to treat the infection with transplanted gut microbiota instead of prescribing further courses of antibiotics. # Costs The cost of frozen FMT material is £850 per 50 ml or £1,700 for 150 ml. Including transportation and MHRA licensing, the cost is up to £1,300 per 50 ml (£2,600 for 150 ml). Oral capsules are likely to cost between £500 and £600, based on expert opinion. Additional costs include staff time, procedural costs, additional drugs given as part of the procedure and pretreatment short-course antibiotics.# Evidence NICE commissioned an external assessment centre (EAC) to review the evidence. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website. # Clinical evidence ## The clinical evidence includes 5 randomised controlled trials The EAC did a systematic review to identify randomised controlled trials (RCTs) comparing faecal microbiota transplant (FMT), by any route of delivery, with NICE-recommended comparators, to treat a Clostridioides difficile infection in people who have had at least 2 previous episodes. It identified and assessed 5 eligible RCTs including 274 adults in total. These trials compared FMT, given via different routes of administration and with a preceding course of antibiotics, with antibiotic treatment. For full details of the clinical evidence, see section 3 of the assessment report. ## More C. difficile infections were resolved with FMT than antibiotic treatment in 4 RCTs; there was no difference in 1 RCT FMT (with pretreatment antibiotics) was significantly better at resolving a C. difficile infection than: vancomycin in 4 RCTs (Cammarota et al. 2015, Hvas et al. 2019, Rode et al. 2021 and van Nood et al. 2013) fidaxomicin in 1 RCT (Hvas et al. 2019).C. difficile infection was resolved in 57% (Rode et al. 2021) to 94% (van Nood et al. 2013) of people having FMT (when any number of infusions was considered). In comparison, C. difficile infection was resolved in 19% (Hvas et al. 2019; vancomycin) to 46% (Rode et al. 2021; vancomycin taper pulse ) of people having antibiotic therapy in these RCTs. However, Hota et al. (2017) showed less C. difficile infection resolution in the FMT group (given via enema; 43.8%) compared with VTP (58.3%), although the study did not report statistical significance. ## Recurrence rate is comparable to or lower than antibiotic treatment Three trials found lower C. difficile infection recurrence in the FMT group (range 6% to 10%) compared with the antibiotic group (vancomycin range 62% to 69%, fidaxomicin 46%; Cammarota et al. 2015, Hvas et al. 2019 and van Nood et al. 2013). Hota et al. (2017) reported comparable C. difficile infection recurrence after FMT by enema (56.2%) and VTP (41.7%). However, none of the trials reported statistical significance. ## Gastrointestinal side effects can occur in the short term after FMT treatment Short-term gastrointestinal side effects were reported in 4 RCTs (Cammarota et al. 2015, Hota et al. 2017, Hvas et al. 2019 and van Nood et al. 2013). The most common effects included diarrhoea, bloating, abdominal pain or cramps. These symptoms lasted (when reported) between 3 hours (van Nood et al. 2013) and 12 hours (Cammarota et al. 2015), or were described as 'transient' (Hvas et al. 2019). ## Small sample sizes and the relevance of the population to the NHS limit the evidence The included studies had relatively small sample sizes, with a median of 39 and a range of 27 (Rode et al. 2021) to 64 adults (Hvas et al. 2019). This was partly because 4 of the trials stopped early; only 1 completed after recruiting the target number of people (Hvas et al. 2019). The evidence is also limited by not being done in the UK and the trial populations having fewer comorbidities and a lower chance of being hospitalised than the eligible UK population. ## Heterogeneous study characteristics may limit the evidence The included studies used different FMT administration routes: used an enema (Hota et al. 2017 and Rode et al. 2021) used colonoscopy (Cammarota et al. 2015) used a nasoduodenal tube (NDT; van Nood et al. 2013) used mixed routes (colonoscopy or nasojejunal tube; Hvas et al. 2019).None of the included trials evaluated FMT delivered via capsule, nasogastric tube (NGT) or flexible sigmoidoscopy. The number of times FMT was given also varied, from 1 to 4 infusions. In 3 of the trials a proportion of people taking part were being treated for a first recurrence of C. difficile infection (Cammarota et al. 2015, Hota et al. 2017 and van Nood et al. 2013). However, this was only a minority of cases. # Cost evidence ## Of 8 economic studies found, 1 used an NHS perspective The EAC did a systematic review to find economic evaluations comparing FMT, by any route of delivery, with NICE-recommended comparators, to treat a C. difficile infection in people who have had at least 2 previous episodes. It assessed 8 economic evaluation studies relevant to the decision problem. Abdali et al. (2020) was a UK-based cost–utility analysis comparing 4 treatments for recurrent C. difficile infection (FMT via NGT, FMT via colonoscopy, oral fidaxomicin, and oral vancomycin). The analysis used a Markov model with 4 health states (relapsed, recovered, recurrent C. difficile infection and dead) and had a cycle length of 2 months and time horizon of 1 year. The analysis found that fidaxomicin and vancomycin were dominated by FMT via NGT and FMT via colonoscopy (that is, FMT was cost saving and more effective).For full details of the cost evidence, see section 4 of the assessment report and the assessment report appendix. ## A Markov model compared FMT with antibiotic treatment The EAC created a cohort Markov model that included adults with recurrent C. difficile infection who have had 2 or more previous episodes. It had a time horizon of 6 months and cycle length of 2 months. The model included 4 routes of FMT administration (colonoscopy, enema, NDT and oral capsules) and 3 antibiotic comparators (vancomycin, fidaxomicin and VTP). It had 4 health states: recurrent C. difficile infection (starting state) persistent C. difficile infection (recurrent, relapsed or refractory C. difficile infection) recovered dead. ## The quality of the clinical evidence limits the economic model The quality of the clinical evidence leads to uncertainty in the clinical parameters used in the economic model. No eligible RCTs were identified comparing FMT oral capsules with antibiotics in people with 2 or more previous episodes of C. difficile infection. However, because 2 studies found oral capsules were comparable to FMT colonoscopy (Kao et al. 2017, Ramai et al. 2020) the EAC assumed the transition probabilities to be the same. FMT via NGT and flexible sigmoidoscopy were excluded from the economic model because of a lack of RCT-level data from the clinical evidence review. ## The economic model used a number of clinical assumptions The economic model used the following clinical assumptions: people are treated with the same treatment again if the first treatment does not work there are constant treatment response and recurrence rates in each cycle pretreatment with antibiotics is only used for the first FMT treatment for anyone in the recovered group there is the same risk of death as the general population initial treatment includes 5 days of hospital stay for FMT and 10 days for antibiotics costs of tests and follow up are assumed to be the same between groups and so are excluded from the model.After talking to clinical experts, the assumptions around hospital stay and pretreatment antibiotics were amended in the base case, as discussed in section 4.9 and section 4.10. ## FMT by all administration routes evaluated was cost saving in the base case The EAC's base case analysis found that all 4 routes of FMT were associated with increased health benefits and reduced costs against all 3 antibiotic comparators, with savings ranging from £3,369 (FMT enema compared with VTP) to £13,134 (FMT oral capsule compared with vancomycin). Health benefits ranged from a quality-adjusted life year (QALY) gain of 0.17 (FMT enema compared with VTP) to 0.66 (FMT via NDT compared with vancomycin). ## FMT via NGT could also be cost saving, although there is no RCT-level evidence The EAC identified a meta-analysis by Ramai et al. (2020), which suggested an overall cure rate of 78.1% when FMT is given via NGT. The cost of delivering FMT via NGT is estimated to be £740 (Abdali et al. 2020). Because the cure rate is estimated to be higher for FMT via NGT than via enema, and costs less, FMT via NGT is likely to be cost saving for recurrent C. difficile infections, against all 3 comparators considered. ## FMT remained cost saving in the sensitivity and scenario analyses The EAC did deterministic and probabilistic sensitivity analyses, and scenario analyses. The deterministic sensitivity analysis compared FMT via enema (the least cost saving FMT route) with VTP (the comparator with the second lowest cost and highest health benefit). It found that the largest cost drivers were the resolution probability for FMT via enema and VTP, followed by the hospital stay for any cases of C. difficile infection in subsequent cycles. The results of the probabilistic sensitivity analysis showed that FMT is estimated to be cost saving 96% to 100% of the time compared with antibiotic treatment. The EAC also did 5 scenario analyses. FMT remained cost saving in all of them: Pretreatment antibiotics for all FMT treatments, not just the index treatment (FMT was compared with the VTP treatment group only). Subsequent treatment with VTP for all treatment arms for people in the persistent C. difficile infection state. Threshold analysis on fidaxomicin cost discounting. Extending the time horizon from 6 months to 1 year. All treatment arms having a 1-day hospital stay for the index treatment instead of 5 or 10 days' stay in the FMT and antibiotic groups, respectively.For full details see assessment report appendix 1 in the supporting documents for this guidance.# Committee discussion # Clinical-effectiveness overview ## FMT is an effective treatment for recurrent C. difficile infection for people who have had 2 or more previous episodes The randomised controlled trial (RCT) evidence showed that faecal microbiota transplant (FMT) after pretreatment antibiotics was significantly better at resolving a recurrent Clostridioides difficile infection than vancomycin in 4 RCTs, and better than fidaxomicin in 1 RCT. Only 1 RCT found no statistical difference in the efficacy of FMT compared with antibiotics. The committee acknowledged that there are limitations to the evidence base. However, it considered that, because there is an unmet need in this population, FMT is likely to be an effective alternative to continued antibiotic use. It also acknowledged that FMT is already being used in the NHS for recurrent C. difficile infections and is recommended in NICE's guideline on antimicrobial prescribing for C. difficile infection. Therefore, the committee agreed that FMT should be recommended to treat a recurrent episode of C. difficile infection if people have had 2 or more previous episodes. ## The use of FMT for refractory C. difficile infections is uncertain because the definition of refractory is not clear The external assessment centre (EAC) did not identify any in-scope RCTs comparing FMT with antibiotics for refractory C. difficile infections. The clinical experts said that there is no consensus on the definition of refractory C. difficile infection, meaning that there is less available evidence. The committee acknowledged that FMT could benefit this population, but there was too much uncertainty about the definition of a refractory infection to make a recommendation in this population. ## FMT via enema is likely to be less effective but is a clinically appropriate option in some cases The clinical evidence presented showed that FMT given via enema is likely to be less effective than the other administration routes evaluated. However, the included studies were not designed to compare FMT administration routes with each other. Clinical experts said that FMT is usually done by NGT or colonoscopy, depending on patient preference and suitability of the procedure. They said that enema would only be an option for people who could not have FMT via other routes, and would be based on discussions with the patient. They said that the challenge of administering FMT via enema is around the FMT sample being retained for long enough for the treatment to be successful. The EAC's economic model showed that FMT via enema was less likely to be a cost saving route of FMT administration and could be cost incurring in some instances, as discussed in section 4.10. The committee concluded that, although enema may be a less effective route of administration, it could be available as an option for the minority of people who cannot have FMT by another route. ## There is no evidence in scope comparing FMT via oral capsules and antibiotics The EAC did not identify any RCTs comparing FMT given in oral capsules with antibiotics in people who have had 2 or more previous episodes of C. difficile infection. As a result, no evidence was presented for the clinical efficacy of oral capsules. However, the EAC did identify 2 studies for its economic evaluation (1 RCT and 1 systematic review and meta-analysis), which showed that oral capsules were comparable to FMT via colonoscopy. It also said there are 2 ongoing RCTs comparing the oral capsules with antibiotic treatment. Clinical experts said that, if oral capsules were more widely available, they would be preferred because of safety and patient acceptability, especially because newer capsules containing lyophilised FMT material can be given in fewer pills than older versions. The committee acknowledged that, although the comparative evidence presented was limited, oral capsules are a promising option for FMT treatment. # Safety ## A strict donor screening programme should be followed The British Society of Gastroenterology and Healthcare Infection Society guidelines say that donor screening should be done for all potential stool donors. This includes a questionnaire and personal interview, to establish risk factors for transmissible diseases and factors that could affect the gut microbiome. Blood and stool screening for transmissible disease must also be done. Clinical experts said that only a small proportion of donors pass screening, and they are generally young and healthy adults. The committee acknowledged that there is still a risk of disease transmission because screening tests are not 100% sensitive. However, it acknowledged that the strict donor screen programme currently used makes FMT relatively safe. The committee also acknowledged that there is a lack of long-term safety data on FMT treatment and thought that a registry to collect this information would be appropriate. It also recognised that NICE's interventional procedures guidance on FMT for recurrent C. difficile infection has reviewed the safety of FMT and concluded that there is adequate evidence to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit. # Other patient benefits or issues ## People with a recurrent C. difficile infection need to be informed about FMT Patient experts said that recurrent C. difficile infections reduce quality of life. Pain and diarrhoea mean people can need help with day to day living and may not be able to work, so lose income. Diarrhoea can also affect people's dignity, especially when it leads to incontinence or when the person is in a hospital or nursing home. The patient experts said patients and clinicians need to be made more aware that FMT is a treatment option for recurrent C. difficile infection. The committee also acknowledged there should be shared decision making with people with the condition, to help them understand their treatment options and the role of FMT in the treatment pathway. ## FMT may not be appropriate for some people The committee acknowledged that FMT may not be appropriate for some people with an anaphylactic food allergy. It also recognised that the diet and alcohol consumption of potential donors may be a barrier to having FMT for people from some faith groups or people with dietary preferences. The clinical experts said they had not experienced problems relating to religious beliefs but acknowledged that this is a valid consideration. The committee also acknowledged that there are some people who FMT treatment may not be appropriate for, or who will need treating with additional caution, such as people who are immunosuppressed or immunocompromised and people who are pregnant. # Cost modelling overview ## FMT is cost saving compared with antibiotics in the EAC's original economic model The base case showed that FMT is likely to be cost saving by at least £3,300 per person, compared with antibiotics. The committee acknowledged that the clinical evidence was very heterogeneous. But the cost savings were robust enough to recommend FMT for recurrent C. difficile infections for people who have had 2 or more previous episodes. ## The base case was updated to amend 4 assumptions used in the original model After feedback from clinical experts, the EAC updated the original base case to amend 4 assumptions. This is because clinical experts said that a short course of antibiotics is used before most FMT treatments and that the length of stay for treatment with FMT or antibiotics is likely to be short. They also said that not everyone in the antibiotic group would need hospitalisation for treatment. The unit cost in the EAC's original base case also did not take into account additional costs associated with sample transportation and of maintaining a Medicines and Healthcare products Regulatory Agency (MHRA) licence. The amended base case includes: the unit cost of FMT being £1,300 per 50 ml (£2,600 for 150 ml) a 1‑day hospital stay for all groups pretreatment with antibiotics for all FMT rounds % of people having antibiotic treatment being treated in the community (calculated as the cost of 2 GP appointments and a microbiology stool test, in addition to the antibiotics). ## FMT is cost saving compared with almost all antibiotic treatments Almost all routes of FMT remained cost saving against all 3 comparators considered, with cost savings ranging from £769 (FMT via colonoscopy compared with VTP) to £8,297 (FMT via oral capsule compared with vancomycin). The exception was FMT via enema, which was cost incurring compared with VTP by £1,287 per person. Threshold analysis found that FMT remained cost saving compared with VTP until the unit cost of FMT is approximately £1,650 to £4,620 (FMT via colonoscopy and oral capsules, respectively). For FMT via enema compared with VTP, the unit cost would have to be reduced to £640 for FMT to be cost neutral. The EAC also did a threshold analysis of the proportion treated in hospital in the comparator arm, in which FMT was compared with VTP. FMT remained cost saving until the proportion treated in hospital was between 14% and 92% (FMT via oral capsule and enema, respectively). The committee concluded that FMT was highly likely to be cost saving even when the cost changes are taken into account. ## Further data collection is welcome to address uncertainties in the evidence base The committee recognised that there is not much data on the long-term outcomes of FMT treatment and encouraged establishing a registry to collect them. This would help identify long-term adverse events and reduce uncertainty in the economic modelling. The committee also acknowledged that more RCT evidence comparing capsulised FMT with antibiotic treatment would improve the evidence base for this treatment.	{'Recommendations': "Faecal microbiota transplant (FMT) is recommended as an option to treat recurrent Clostridioides\xa0difficile infection in adults who have had 2 or more previous confirmed episodes.\n\nFMT treatment is cheaper than almost all treatment options with antibiotics. It is not cost saving compared with vancomycin taper pulse if it's given using an enema.\xa0However, FMT via enema would only be an option for the minority of people who cannot have FMT by another route.\n\nWhy the committee made these recommendations\n\nClinical trial evidence shows that FMT treatment is significantly better than antibiotics alone at resolving a C.\xa0difficile infection in people who have had 2 or more previous infections.\n\nModelling shows that FMT treatment is cheaper than almost all treatment options with antibiotics. It is cost saving by £769 compared with vancomycin taper pulse (VTP) if it's given using colonoscopy, and by £8,297 compared with vancomycin if it's given using an oral capsule. This assumes FMT costs £1,300 for 50\xa0ml, and that a quarter of people having antibiotics alone are treated in the community (that is, outside hospital). FMT is not cost saving compared with VTP if it's given using an enema – this costs £1,287 per person more.", 'The technology': "# Technology\n\nFaecal microbiota transplant (FMT) aims to restore a healthy gut microbiome in people who have recurrent or refractory Clostridioides\xa0difficile infections. It involves transferring intestinal bacteria and other microorganisms from healthy donor faeces into the gut of the recipient.\n\nFMT can be used as a fresh or frozen preparation or in capsule form. It can be given via a lower gastrointestinal route (rectal enema, colonoscopy or flexible sigmoidoscopy), upper gastrointestinal route (using a nasogastric tube, nasoduodenal tube or nasojejunal tube) or via oral capsules. British Society of Gastroenterology and Healthcare Infection Society guidelines recommend a short course of antibiotics before transplantation, with a minimum washout period of 24\xa0hours between the last dose of antibiotic and treatment with FMT. Bowel lavage is also recommended before FMT if it's given via lower gastrointestinal routes.\n\nFMT must be manufactured in accordance with Medicines and Healthcare products Regulatory Agency (MHRA) guidance for human medicines regulation. When FMT is supplied on a named patient basis, within a single organisation, a pharmacy exemption may be used, subject to ensuring proper governance and traceability. Before establishing an FMT service, NHS centres are legally required to seek advice from the MHRA and, if necessary, obtain licences to process, distribute and carry out FMT. A strict donor screening programme should also be in place for FMT in line with the British Society of Gastroenterology and Healthcare Infection Society guidelines. An FMT service should be delivered by a multidisciplinary team.\n\n# Care pathway\n\nFirst-line treatment for a C.\xa0difficile infection involves rehydration and antibiotic treatment. Some people have recurrent, relapsing, or refractory C.\xa0difficile infections and need further courses of antibiotics. NICE's guideline on antimicrobial prescribing for C.\xa0difficile infection recommends antibiotics for first and further C.\xa0difficile infections, and provides guidelines on antibiotic, dosage and course length. It also recommends considering FMT for a recurrent episode of C.\xa0difficile infection in adults who have had 2 or more previous episodes. NICE's interventional procedures guidance on FMT for recurrent C.\xa0difficile infection says that current evidence on the efficacy and safety of FMT for recurrent C.\xa0difficile infection is adequate to support the use of this procedure provided normal arrangements are in place for clinical governance, consent and audit. It also says that clinicians should ensure that a confidential record is kept of the donor and recipient of each FMT.\n\n# Innovative aspects\n\nThe aim of the procedure is to treat the infection with transplanted gut microbiota instead of prescribing further courses of antibiotics.\n\n# Costs\n\nThe cost of frozen FMT material is £850 per 50\xa0ml or £1,700 for 150\xa0ml. Including transportation and MHRA licensing, the cost is up to £1,300 per 50\xa0ml (£2,600 for 150\xa0ml). Oral capsules are likely to cost between £500 and £600, based on expert opinion. Additional costs include staff time, procedural costs, additional drugs given as part of the procedure and pretreatment short-course antibiotics.", 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## The clinical evidence includes 5 randomised controlled trials\n\nThe EAC did a systematic review to identify randomised controlled trials (RCTs) comparing faecal microbiota transplant (FMT), by any route of delivery, with NICE-recommended comparators, to treat a Clostridioides\xa0difficile infection in people who have had at least 2 previous episodes. It identified and assessed 5 eligible RCTs including 274 adults in total. These trials compared FMT, given via different routes of administration and with a preceding course of antibiotics, with antibiotic treatment. For full details of the clinical evidence, see section 3 of the assessment report.\n\n## More C.\xa0difficile infections were resolved with FMT than antibiotic treatment in 4 RCTs; there was no difference in 1 RCT\n\nFMT (with pretreatment antibiotics) was significantly better at resolving a C.\xa0difficile infection than:\n\nvancomycin in 4 RCTs (Cammarota et al. 2015, Hvas et al. 2019, Rode et al. 2021 and van Nood et al. 2013)\n\nfidaxomicin in 1 RCT (Hvas et al. 2019).C.\xa0difficile infection was resolved in 57% (Rode et al. 2021) to 94% (van Nood et al. 2013) of people having FMT (when any number of infusions was considered). In comparison, C.\xa0difficile infection was resolved in 19% (Hvas et al. 2019; vancomycin) to 46% (Rode et al. 2021; vancomycin taper pulse [VTP]) of people having antibiotic therapy in these RCTs. However, Hota et al. (2017) showed less C.\xa0difficile infection resolution in the FMT group (given via enema; 43.8%) compared with VTP (58.3%), although the study did not report statistical significance.\n\n## Recurrence rate is comparable to or lower than antibiotic treatment\n\nThree trials found lower C.\xa0difficile infection recurrence in the FMT group (range 6% to 10%) compared with the antibiotic group (vancomycin range 62% to 69%, fidaxomicin 46%; Cammarota et al. 2015, Hvas et al. 2019 and van Nood et al. 2013). Hota et al. (2017) reported comparable C.\xa0difficile infection recurrence after FMT by enema (56.2%) and VTP (41.7%). However, none of the trials reported statistical significance.\n\n## Gastrointestinal side effects can occur in the short term after FMT treatment\n\nShort-term gastrointestinal side effects were reported in 4 RCTs (Cammarota et al. 2015, Hota et al. 2017, Hvas et al. 2019 and van Nood et al. 2013). The most common effects included diarrhoea, bloating, abdominal pain or cramps. These symptoms lasted (when reported) between 3\xa0hours (van Nood et al. 2013) and 12\xa0hours (Cammarota et al. 2015), or were described as 'transient' (Hvas et al. 2019).\n\n## Small sample sizes and the relevance of the population to the NHS limit the evidence\n\nThe included studies had relatively small sample sizes, with a median of 39 and a range of 27 (Rode et al. 2021) to 64 adults (Hvas et al. 2019). This was partly because 4 of the trials stopped early; only 1 completed after recruiting the target number of people (Hvas et al. 2019). The evidence is also limited by not being done in the UK and the trial populations having fewer comorbidities and a lower chance of being hospitalised than the eligible UK population.\n\n## Heterogeneous study characteristics may limit the evidence\n\nThe included studies used different FMT administration routes:\n\nused an enema (Hota et al. 2017 and Rode et al. 2021)\n\nused colonoscopy (Cammarota et al. 2015)\n\nused a nasoduodenal tube (NDT; van Nood et al. 2013)\n\nused mixed routes (colonoscopy or nasojejunal tube; Hvas et al. 2019).None of the included trials evaluated FMT delivered via capsule, nasogastric tube (NGT) or flexible sigmoidoscopy. The number of times FMT was given also varied, from 1 to 4 infusions. In 3 of the trials a proportion of people taking part were being treated for a first recurrence of C.\xa0difficile infection (Cammarota et al. 2015, Hota et al. 2017 and van Nood et al. 2013). However, this was only a minority of cases.\n\n# Cost evidence\n\n## Of 8 economic studies found, 1 used an NHS perspective\n\nThe EAC did a systematic review to find economic evaluations comparing FMT, by any route of delivery, with NICE-recommended comparators, to treat a C.\xa0difficile infection in people who have had at least 2 previous episodes. It assessed 8 economic evaluation studies relevant to the decision problem. Abdali et al. (2020) was a UK-based cost–utility analysis comparing 4 treatments for recurrent C.\xa0difficile infection (FMT via NGT, FMT via colonoscopy, oral fidaxomicin, and oral vancomycin). The analysis used a Markov model with 4 health states (relapsed, recovered, recurrent C.\xa0difficile infection and dead) and had a cycle length of 2\xa0months and time horizon of 1\xa0year. The analysis found that fidaxomicin and vancomycin were dominated by FMT via NGT and FMT via colonoscopy (that is, FMT was cost saving and more effective).For full details of the cost evidence, see section 4 of the assessment report and the assessment report appendix.\n\n## A Markov model compared FMT with antibiotic treatment\n\nThe EAC created a cohort Markov model that included adults with recurrent C.\xa0difficile infection who have had 2 or more previous episodes. It had a time horizon of 6\xa0months and cycle length of 2\xa0months. The model included 4 routes of FMT administration (colonoscopy, enema, NDT and oral capsules) and 3 antibiotic comparators (vancomycin, fidaxomicin and VTP). It had 4 health states:\n\nrecurrent C.\xa0difficile infection (starting state)\n\npersistent C.\xa0difficile infection (recurrent, relapsed or refractory C.\xa0difficile infection)\n\nrecovered\n\ndead.\n\n## The quality of the clinical evidence limits the economic model\n\nThe quality of the clinical evidence leads to uncertainty in the clinical parameters used in the economic model. No eligible RCTs were identified comparing FMT oral capsules with antibiotics in people with 2 or more previous episodes of C. difficile infection. However, because 2 studies found oral capsules were comparable to FMT colonoscopy (Kao et al. 2017, Ramai et al. 2020) the EAC assumed the transition probabilities to be the same. FMT via NGT and flexible sigmoidoscopy were excluded from the economic model because of a lack of RCT-level data from the clinical evidence review.\n\n## The economic model used a number of clinical assumptions\n\nThe economic model used the following clinical assumptions:\n\npeople are treated with the same treatment again if the first treatment does not work\n\nthere are constant treatment response and recurrence rates in each cycle\n\npretreatment with antibiotics is only used for the first FMT treatment\n\nfor anyone in the recovered group there is the same risk of death as the general population\n\ninitial treatment includes 5\xa0days of hospital stay for FMT and 10\xa0days for antibiotics\n\ncosts of tests and follow up are assumed to be the same between groups and so are excluded from the model.After talking to clinical experts, the assumptions around hospital stay and pretreatment antibiotics were amended in the base case, as discussed in section 4.9 and section 4.10.\n\n## FMT by all administration routes evaluated was cost saving in the base case\n\nThe EAC's base case analysis found that all 4 routes of FMT were associated with increased health benefits and reduced costs against all 3 antibiotic comparators, with savings ranging from £3,369 (FMT enema compared with VTP) to £13,134 (FMT oral capsule compared with vancomycin). Health benefits ranged from a quality-adjusted life year (QALY) gain of 0.17 (FMT enema compared with VTP) to 0.66 (FMT via NDT compared with vancomycin).\n\n## FMT via NGT could also be cost saving, although there is no RCT-level evidence\n\nThe EAC identified a meta-analysis by Ramai et al. (2020), which suggested an overall cure rate of 78.1% when FMT is given via NGT. The cost of delivering FMT via NGT is estimated to be £740 (Abdali et al. 2020). Because the cure rate is estimated to be higher for FMT via NGT than via enema, and costs less, FMT via NGT is likely to be cost saving for recurrent C.\xa0difficile infections, against all 3 comparators considered.\n\n## FMT remained cost saving in the sensitivity and scenario analyses\n\nThe EAC did deterministic and probabilistic sensitivity analyses, and scenario analyses. The deterministic sensitivity analysis compared FMT via enema (the least cost saving FMT route) with VTP (the comparator with the second lowest cost and highest health benefit). It found that the largest cost drivers were the resolution probability for FMT via enema and VTP, followed by the hospital stay for any cases of C.\xa0difficile infection in subsequent cycles. The results of the probabilistic sensitivity analysis showed that FMT is estimated to be cost saving 96% to 100% of the time compared with antibiotic treatment. The EAC also did 5 scenario analyses. FMT remained cost saving in all of them:\n\nPretreatment antibiotics for all FMT treatments, not just the index treatment (FMT was compared with the VTP treatment group only).\n\nSubsequent treatment with VTP for all treatment arms for people in the persistent C.\xa0difficile infection state.\n\nThreshold analysis on fidaxomicin cost discounting.\n\nExtending the time horizon from 6\xa0months to 1\xa0year.\n\nAll treatment arms having a 1-day hospital stay for the index treatment instead of 5 or 10\xa0days' stay in the FMT and antibiotic groups, respectively.For full details see assessment report appendix\xa01 in the supporting documents for this guidance.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## FMT is an effective treatment for recurrent C.\xa0difficile infection for people who have had 2 or more previous episodes\n\nThe randomised controlled trial (RCT) evidence showed that faecal microbiota transplant (FMT) after pretreatment antibiotics was significantly better at resolving a recurrent Clostridioides\xa0difficile infection than vancomycin in 4 RCTs, and better than fidaxomicin in 1 RCT. Only 1 RCT found no statistical difference in the efficacy of FMT compared with antibiotics. The committee acknowledged that there are limitations to the evidence base. However, it considered that, because there is an unmet need in this population, FMT is likely to be an effective alternative to continued antibiotic use. It also acknowledged that FMT is already being used in the NHS for recurrent C.\xa0difficile infections and is recommended in NICE's guideline on antimicrobial prescribing for C.\xa0difficile infection. Therefore, the committee agreed that FMT should be recommended to treat a recurrent episode of C.\xa0difficile infection if people have had 2 or more previous episodes.\n\n## The use of FMT for refractory C.\xa0difficile infections is uncertain because the definition of refractory is not clear\n\nThe external assessment centre (EAC) did not identify any in-scope RCTs comparing FMT with antibiotics for refractory C.\xa0difficile infections. The clinical experts said that there is no consensus on the definition of refractory C.\xa0difficile infection, meaning that there is less available evidence. The committee acknowledged that FMT could benefit this population, but there was too much uncertainty about the definition of a refractory infection to make a recommendation in this population.\n\n## FMT via enema is likely to be less effective but is a clinically appropriate option in some cases\n\nThe clinical evidence presented showed that FMT given via enema is likely to be less effective than the other administration routes evaluated. However, the included studies were not designed to compare FMT administration routes with each other. Clinical experts said that FMT is usually done by NGT or colonoscopy, depending on patient preference and suitability of the procedure. They said that enema would only be an option for people who could not have FMT via other routes, and would be based on discussions with the patient. They said that the challenge of administering FMT via enema is around the FMT sample being retained for long enough for the treatment to be successful. The EAC's economic model showed that FMT via enema was less likely to be a cost saving route of FMT administration and could be cost incurring in some instances, as discussed in section 4.10. The committee concluded that, although enema may be a less effective route of administration, it could be available as an option for the minority of people who cannot have FMT by another route.\n\n## There is no evidence in scope comparing FMT via oral capsules and antibiotics\n\nThe EAC did not identify any RCTs comparing FMT given in oral capsules with antibiotics in people who have had 2 or more previous episodes of C.\xa0difficile infection. As a result, no evidence was presented for the clinical efficacy of oral capsules. However, the EAC did identify 2 studies for its economic evaluation (1 RCT and 1 systematic review and meta-analysis), which showed that oral capsules were comparable to FMT via colonoscopy. It also said there are 2 ongoing RCTs comparing the oral capsules with antibiotic treatment. Clinical experts said that, if oral capsules were more widely available, they would be preferred because of safety and patient acceptability, especially because newer capsules containing lyophilised FMT material can be given in fewer pills than older versions. The committee acknowledged that, although the comparative evidence presented was limited, oral capsules are a promising option for FMT treatment.\n\n# Safety\n\n## A strict donor screening programme should be followed\n\nThe British Society of Gastroenterology and Healthcare Infection Society guidelines say that donor screening should be done for all potential stool donors. This includes a questionnaire and personal interview, to establish risk factors for transmissible diseases and factors that could affect the gut microbiome. Blood and stool screening for transmissible disease must also be done. Clinical experts said that only a small proportion of donors pass screening, and they are generally young and healthy adults. The committee acknowledged that there is still a risk of disease transmission because screening tests are not 100% sensitive. However, it acknowledged that the strict donor screen programme currently used makes FMT relatively safe. The committee also acknowledged that there is a lack of long-term safety data on FMT treatment and thought that a registry to collect this information would be appropriate. It also recognised that NICE's interventional procedures guidance on FMT for recurrent C.\xa0difficile infection has reviewed the safety of FMT and concluded that there is adequate evidence to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\n# Other patient benefits or issues\n\n## People with a recurrent C.\xa0difficile infection need to be informed about FMT\n\nPatient experts said that recurrent C.\xa0difficile infections reduce quality of life. Pain and diarrhoea mean people can need help with day to day living and may not be able to work, so lose income. Diarrhoea can also affect people's dignity, especially when it leads to incontinence or when the person is in a hospital or nursing home. The patient experts said patients and clinicians need to be made more aware that FMT is a treatment option for recurrent C.\xa0difficile infection. The committee also acknowledged there should be shared decision making with people with the condition, to help them understand their treatment options and the role of FMT in the treatment pathway.\n\n## FMT may not be appropriate for some people\n\nThe committee acknowledged that FMT may not be appropriate for some people with an anaphylactic food allergy. It also recognised that the diet and alcohol consumption of potential donors may be a barrier to having FMT for people from some faith groups or people with dietary preferences. The clinical experts said they had not experienced problems relating to religious beliefs but acknowledged that this is a valid consideration. The committee also acknowledged that there are some people who FMT treatment may not be appropriate for, or who will need treating with additional caution, such as people who are immunosuppressed or immunocompromised and people who are pregnant.\n\n# Cost modelling overview\n\n## FMT is cost saving compared with antibiotics in the EAC's original economic model\n\nThe base case showed that FMT is likely to be cost saving by at least £3,300 per person, compared with antibiotics. The committee acknowledged that the clinical evidence was very heterogeneous. But the cost savings were robust enough to recommend FMT for recurrent C.\xa0difficile infections for people who have had 2 or more previous episodes.\n\n## The base case was updated to amend 4 assumptions used in the original model\n\nAfter feedback from clinical experts, the EAC updated the original base case to amend 4 assumptions. This is because clinical experts said that a short course of antibiotics is used before most FMT treatments and that the length of stay for treatment with FMT or antibiotics is likely to be short. They also said that not everyone in the antibiotic group would need hospitalisation for treatment. The unit cost in the EAC's original base case also did not take into account additional costs associated with sample transportation and of maintaining a Medicines and Healthcare products Regulatory Agency (MHRA) licence. The amended base case includes:\n\nthe unit cost of FMT being £1,300 per 50\xa0ml (£2,600 for 150\xa0ml)\n\na 1‑day hospital stay for all groups\n\npretreatment with antibiotics for all FMT rounds\n\n% of people having antibiotic treatment being treated in the community (calculated as the cost of 2\xa0GP appointments and a microbiology stool test, in addition to the antibiotics).\n\n## FMT is cost saving compared with almost all antibiotic treatments\n\nAlmost all routes of FMT remained cost saving against all 3 comparators considered, with cost savings ranging from £769 (FMT via colonoscopy compared with VTP) to £8,297 (FMT via oral capsule compared with vancomycin). The exception was FMT via enema, which was cost incurring compared with VTP by £1,287 per person. Threshold analysis found that FMT remained cost saving compared with VTP until the unit cost of FMT is approximately £1,650 to £4,620 (FMT via colonoscopy and oral capsules, respectively). For FMT via enema compared with VTP, the unit cost would have to be reduced to £640 for FMT to be cost neutral. The EAC also did a threshold analysis of the proportion treated in hospital in the comparator arm, in which FMT was compared with VTP. FMT remained cost saving until the proportion treated in hospital was between 14% and 92% (FMT via oral capsule and enema, respectively). The committee concluded that FMT was highly likely to be cost saving even when the cost changes are taken into account.\n\n## Further data collection is welcome to address uncertainties in the evidence base\n\nThe committee recognised that there is not much data on the long-term outcomes of FMT treatment and encouraged establishing a registry to collect them. This would help identify long-term adverse events and reduce uncertainty in the economic modelling. The committee also acknowledged that more RCT evidence comparing capsulised FMT with antibiotic treatment would improve the evidence base for this treatment."}	https://www.nice.org.uk/guidance/mtg71	Evidence-based recommendations on faecal microbiota transplant for recurrent Clostridioides difficile infection.
c415c976cd1561f6f0d3edb945ac26d3fbb434e3	nice	Brolucizumab for treating diabetic macular oedema	Brolucizumab for treating diabetic macular oedema Evidence-based recommendations on brolucizumab (Beovu) for diabetic macular oedema in adults. # Recommendations Brolucizumab is recommended as an option for treating visual impairment due to diabetic macular oedema in adults, only if: the eye has a central retinal thickness of 400 micrometres or more at the start of treatment the company provides brolucizumab according to the commercial arrangement. If patients and their clinicians consider brolucizumab to be 1 of a range of suitable first-line treatments (including aflibercept and ranibizumab), choose the least expensive treatment. Take account of administration costs, dosage, price per dose and commercial arrangements. These recommendations are not intended to affect treatment with brolucizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Diabetic macular oedema is usually treated first with aflibercept or ranibizumab, which are already recommended by NICE for treating diabetic macular oedema if the eye has a central retinal thickness of 400 micrometres or more when treatment starts. Brolucizumab is another treatment option that works in a similar way. Evidence from clinical trials shows that brolucizumab is as effective as aflibercept. An indirect comparison of brolucizumab with ranibizumab also suggests similar clinical effectiveness, although this is uncertain. A cost comparison suggests brolucizumab has similar costs and overall health benefits to aflibercept or ranibizumab. So, brolucizumab is recommended for treating diabetic macular oedema if it is used in the same population as aflibercept and ranibizumab.# Information about brolucizumab # Marketing authorisation indication Brolucizumab (Beovu, Novartis) is indicated 'for the treatment of visual impairment due to diabetic macular oedema'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for brolucizumab. # Price Brolucizumab costs £816 for 1 vial of 120 mg per 1 ml solution for injection (excluding VAT; BNF online, accessed July 2022). The company has a commercial arrangement. This makes brolucizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Novartis, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # Comparators ## Aflibercept and ranibizumab are appropriate comparators Aflibercept and ranibizumab are anti-vascular endothelial growth factor (anti-VEGF) injections recommended by NICE as a first treatment for diabetic macular oedema. Brolucizumab is another anti-VEGF injection that works in a similar way to aflibercept and ranibizumab. The company proposes that brolucizumab will extend the time needed between injections compared with aflibercept and ranibizumab. The committee was aware that NICE's technology appraisal guidance 799 recommends faricimab for treating diabetic macular oedema. However, this guidance was only published shortly before the committee considered brolucizumab. The committee was also aware that NICE's technology appraisal guidance 301 recommends fluocinolone acetonide implant if the diabetic macular oedema is insufficiently responsive to available therapies. Also, NICE's technology appraisal guidance 349 recommends dexamethasone intravitreal implant if the diabetic macular oedema does not respond to non-corticosteroid treatment, or such treatment is unsuitable. The EAG confirmed that, based on clinical expert opinion, aflibercept and ranibizumab are the standard first line treatments for diabetic macular oedema. The committee concluded that aflibercept and ranibizumab were both appropriate NICE-recommended comparators. # Clinical evidence ## Evidence from 2 clinical trials, KITE and KESTREL, shows similar clinical effectiveness of brolucizumab and aflibercept Clinical evidence for brolucizumab compared with aflibercept came from 2 clinical trials. These were KITE and KESTREL. Both were phase 3 randomised controlled trials that compared brolucizumab with aflibercept in 926 adults. In both trials, aflibercept was administered 5 times during the loading phase (once every 4 weeks), then every 8 weeks during the maintenance phase. Brolucizumab was administered 5 times during the loading phase (once every 6 weeks), then every 12 weeks during the maintenance phase (some people were reassigned to have brolucizumab every 8 weeks for the remainder of the study period, based on clinician assessment of disease activity). The primary outcome measure was the mean change in best corrected visual acuity from baseline to 1 year. The evidence suggested that both treatments were similarly effective. The EAG noted that the populations in KITE and KESTREL were broader than the population that is the focus of the cost comparison. The company also provided results from post hoc subgroup analyses of people with a central subfield thickness (considered to be clinically equivalent to central retinal thickness, commonly used in other trials for diabetic macular oedema) of 400 micrometres or more, in line with the population recommended in NICE's technology appraisal guidance on aflibercept and ranibizumab. This analysis also suggested the treatments were similar. However, the EAG noted that formal testing of non-inferiority for the primary outcome was not possible for the subgroup analysis as the studies were not powered for this. Overall, the committee considered that brolucizumab is likely to be similarly clinically effective as aflibercept. ## Despite uncertainty, brolucizumab is likely to have similar clinical effectiveness as ranibizumab The company compared brolucizumab with ranibizumab in a network meta-analysis. The primary analysis covered the broader population of patients with diabetic macular oedema, and an exploratory analysis addressed the subgroup of patients with central subfield thickness of 400 micrometres or more at baseline. The company used the broader diabetic macular oedema population for the primary analysis because it considered it was more robust. The results of this suggest brolucizumab and ranibizumab are broadly comparable. The EAG was concerned that the primary network meta-analysis did not reflect the population in the cost comparison. The findings of the network meta-analyses were also limited by the small number of studies informing some connections. In particular there were few studies linking ranibizumab at the correct dose in the subgroup of people with central subfield thickness of 400 micrometres or more. However, clinical opinion suggests that the treatments are similarly effective. The committee concluded that, despite these significant uncertainties, there was sufficient evidence of similar clinical efficacy for brolucizumab compared with ranibizumab. ## Intraocular inflammation is highlighted as a potential adverse event in the summary of product characteristics In KITE and KESTREL the overall rate of adverse events between brolucizumab and aflibercept was similar at week 52. The EAG's clinical experts noted that there was some concern about intraocular inflammation associated with brolucizumab. This had emerged during the post-marketing surveillance of brolucizumab for use in wet age-related macular degeneration. A clinical expert noted in their statement that intraocular inflammation occurred more commonly with brolucizumab than aflibercept in KESTREL. However, they considered that retinal vascular occlusion seems to occur less frequently in diabetic macular oedema than wet age-related macular degeneration. Overall, they considered brolucizumab to have a good benefit-risk profile. The committee was aware that the summary of product characteristics for brolucizumab highlights intraocular inflammation as a potential adverse event. It notes that it can occur at any time but has been observed more frequently at the beginning of treatment. It also notes that because of this, maintenance doses of brolucizumab should not be less than 8 weeks apart. The committee acknowledged these concerns and considered it important for clinicians to bear in mind the advice in the summary of product characteristics. However, it considered that because this adverse event is uncommon, a cost-comparison analysis continued to be appropriate. This is because averaged over the whole population, the effect on quality-adjusted life years that would be captured using a cost-utility model would be expected to be small. # Cost comparison ## Brolucizumab is likely to be cost saving or have similar costs compared with aflibercept and ranibizumab The EAG identified several issues in the company's base case model. First, because people stop brolucizumab, aflibercept and ranibizumab at different rates, the company's model had an unequal risk of bilateral diabetic macular oedema for people on different anti-VEGF treatments. The EAG preferred to equalise the risk by applying the same stopping rate to all treatment arms. Second, the company had applied pooled brolucizumab injection frequency estimates from the KITE and KESTREL studies. This concerned the EAG because people in KITE could have their treatment interval extended to 16 weeks, but the marketing authorisation only specifies extension to 12 weeks. To avoid underestimating brolucizumab injection frequency, the EAG preferred to apply unpooled data from KESTREL only. Third, the EAG were generally satisfied that the unit costs applied in the model were appropriate. But based on clinical expert advice, the EAG preferred that wide field fundus examinations be done at all monitoring visits rather than the single examination assumed in the company base case. Fourth, the company assumed brolucizumab would have lower monitoring frequency than the comparators. But the EAG's clinical experts thought it possible that people having brolucizumab would have closer monitoring in the first 6 months of treatment compared with people having aflibercept or ranibizumab. This was because they were concerned about the potentially higher risk of intraocular inflammation with brolucizumab treatment (see section 3.4). The committee considered these changes were appropriate and agreed that it was important to assess the costs of greater monitoring for brolucizumab. Using these assumptions and when taking account of the commercial arrangements for all treatments, the committee was satisfied that the total cost of brolucizumab was similar to or lower than aflibercept and ranibizumab (the exact results are confidential and cannot be reported here). The committee agreed that choosing the least expensive option from the available treatment options at the same point in the pathway was appropriate. The committee therefore recommended brolucizumab for treating diabetic macular oedema in line with the previous recommendations for aflibercept and ranibizumab. # Other factors ## There are no equality issues relevant to the recommendations The committee did not identify any equality issues.	{'Recommendations': 'Brolucizumab is recommended as an option for treating visual impairment due to diabetic macular oedema in adults, only if:\n\nthe eye has a central retinal thickness of 400\xa0micrometres or more at the start of treatment\n\nthe company provides brolucizumab according to the commercial arrangement.\n\nIf patients and their clinicians consider brolucizumab to be 1 of a range of suitable first-line treatments (including aflibercept and ranibizumab), choose the least expensive treatment. Take account of administration costs, dosage, price per dose and commercial arrangements.\n\nThese recommendations are not intended to affect treatment with brolucizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nDiabetic macular oedema is usually treated first with aflibercept or ranibizumab, which are already recommended by NICE for treating diabetic macular oedema if the eye has a central retinal thickness of 400\xa0micrometres or more when treatment starts. Brolucizumab is another treatment option that works in a similar way.\n\nEvidence from clinical trials shows that brolucizumab is as effective as aflibercept. An indirect comparison of brolucizumab with ranibizumab also suggests similar clinical effectiveness, although this is uncertain.\n\nA cost comparison suggests brolucizumab has similar costs and overall health benefits to aflibercept or ranibizumab. So, brolucizumab is recommended for treating diabetic macular oedema if it is used in the same population as aflibercept and ranibizumab.', 'Information about brolucizumab': "# Marketing authorisation indication\n\nBrolucizumab (Beovu, Novartis) is indicated 'for the treatment of visual impairment due to diabetic macular oedema'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for brolucizumab.\n\n# Price\n\nBrolucizumab costs £816 for 1\xa0vial of 120\xa0mg per 1\xa0ml solution for injection (excluding VAT; BNF online, accessed July 2022).\n\nThe company has a commercial arrangement. This makes brolucizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Novartis, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Comparators\n\n## Aflibercept and ranibizumab are appropriate comparators\n\nAflibercept and ranibizumab are anti-vascular endothelial growth factor (anti-VEGF) injections recommended by NICE as a first treatment for diabetic macular oedema. Brolucizumab is another anti-VEGF injection that works in a similar way to aflibercept and ranibizumab. The company proposes that brolucizumab will extend the time needed between injections compared with aflibercept and ranibizumab. The committee was aware that NICE's technology appraisal guidance 799 recommends faricimab for treating diabetic macular oedema. However, this guidance was only published shortly before the committee considered brolucizumab. The committee was also aware that NICE's technology appraisal guidance 301 recommends fluocinolone acetonide implant if the diabetic macular oedema is insufficiently responsive to available therapies. Also, NICE's technology appraisal guidance 349 recommends dexamethasone intravitreal implant if the diabetic macular oedema does not respond to non-corticosteroid treatment, or such treatment is unsuitable. The EAG confirmed that, based on clinical expert opinion, aflibercept and ranibizumab are the standard first line treatments for diabetic macular oedema. The committee concluded that aflibercept and ranibizumab were both appropriate NICE-recommended comparators.\n\n# Clinical evidence\n\n## Evidence from 2 clinical trials, KITE and KESTREL, shows similar clinical effectiveness of brolucizumab and aflibercept\n\nClinical evidence for brolucizumab compared with aflibercept came from 2\xa0clinical trials. These were KITE and KESTREL. Both were phase 3 randomised controlled trials that compared brolucizumab with aflibercept in 926\xa0adults. In both trials, aflibercept was administered 5\xa0times during the loading phase (once every 4\xa0weeks), then every 8\xa0weeks during the maintenance phase. Brolucizumab was administered 5\xa0times during the loading phase (once every 6\xa0weeks), then every 12\xa0weeks during the maintenance phase (some people were reassigned to have brolucizumab every 8\xa0weeks for the remainder of the study period, based on clinician assessment of disease activity). The primary outcome measure was the mean change in best corrected visual acuity from baseline to 1\xa0year. The evidence suggested that both treatments were similarly effective. The EAG noted that the populations in KITE and KESTREL were broader than the population that is the focus of the cost comparison. The company also provided results from post hoc subgroup analyses of people with a central subfield thickness (considered to be clinically equivalent to central retinal thickness, commonly used in other trials for diabetic macular oedema) of 400\xa0micrometres or more, in line with the population recommended in NICE's technology appraisal guidance on aflibercept and ranibizumab. This analysis also suggested the treatments were similar. However, the EAG noted that formal testing of non-inferiority for the primary outcome was not possible for the subgroup analysis as the studies were not powered for this. Overall, the committee considered that brolucizumab is likely to be similarly clinically effective as aflibercept.\n\n## Despite uncertainty, brolucizumab is likely to have similar clinical effectiveness as ranibizumab\n\nThe company compared brolucizumab with ranibizumab in a network meta-analysis. The primary analysis covered the broader population of patients with diabetic macular oedema, and an exploratory analysis addressed the subgroup of patients with central subfield thickness of 400\xa0micrometres or more at baseline. The company used the broader diabetic macular oedema population for the primary analysis because it considered it was more robust. The results of this suggest brolucizumab and ranibizumab are broadly comparable. The EAG was concerned that the primary network meta-analysis did not reflect the population in the cost comparison. The findings of the network meta-analyses were also limited by the small number of studies informing some connections. In particular there were few studies linking ranibizumab at the correct dose in the subgroup of people with central subfield thickness of 400\xa0micrometres or more. However, clinical opinion suggests that the treatments are similarly effective. The committee concluded that, despite these significant uncertainties, there was sufficient evidence of similar clinical efficacy for brolucizumab compared with ranibizumab.\n\n## Intraocular inflammation is highlighted as a potential adverse event in the summary of product characteristics\n\nIn KITE and KESTREL the overall rate of adverse events between brolucizumab and aflibercept was similar at week\xa052. The EAG's clinical experts noted that there was some concern about intraocular inflammation associated with brolucizumab. This had emerged during the post-marketing surveillance of brolucizumab for use in wet age-related macular degeneration. A clinical expert noted in their statement that intraocular inflammation occurred more commonly with brolucizumab than aflibercept in KESTREL. However, they considered that retinal vascular occlusion seems to occur less frequently in diabetic macular oedema than wet age-related macular degeneration. Overall, they considered brolucizumab to have a good benefit-risk profile. The committee was aware that the summary of product characteristics for brolucizumab highlights intraocular inflammation as a potential adverse event. It notes that it can occur at any time but has been observed more frequently at the beginning of treatment. It also notes that because of this, maintenance doses of brolucizumab should not be less than 8\xa0weeks apart. The committee acknowledged these concerns and considered it important for clinicians to bear in mind the advice in the summary of product characteristics. However, it considered that because this adverse event is uncommon, a cost-comparison analysis continued to be appropriate. This is because averaged over the whole population, the effect on quality-adjusted life years that would be captured using a cost-utility model would be expected to be small.\n\n# Cost comparison\n\n## Brolucizumab is likely to be cost saving or have similar costs compared with aflibercept and ranibizumab\n\nThe EAG identified several issues in the company's base case model. First, because people stop brolucizumab, aflibercept and ranibizumab at different rates, the company's model had an unequal risk of bilateral diabetic macular oedema for people on different anti-VEGF treatments. The EAG preferred to equalise the risk by applying the same stopping rate to all treatment arms. Second, the company had applied pooled brolucizumab injection frequency estimates from the KITE and KESTREL studies. This concerned the EAG because people in KITE could have their treatment interval extended to 16\xa0weeks, but the marketing authorisation only specifies extension to 12\xa0weeks. To avoid underestimating brolucizumab injection frequency, the EAG preferred to apply unpooled data from KESTREL only. Third, the EAG were generally satisfied that the unit costs applied in the model were appropriate. But based on clinical expert advice, the EAG preferred that wide field fundus examinations be done at all monitoring visits rather than the single examination assumed in the company base case. Fourth, the company assumed brolucizumab would have lower monitoring frequency than the comparators. But the EAG's clinical experts thought it possible that people having brolucizumab would have closer monitoring in the first 6 months of treatment compared with people having aflibercept or ranibizumab. This was because they were concerned about the potentially higher risk of intraocular inflammation with brolucizumab treatment (see section 3.4). The committee considered these changes were appropriate and agreed that it was important to assess the costs of greater monitoring for brolucizumab. Using these assumptions and when taking account of the commercial arrangements for all treatments, the committee was satisfied that the total cost of brolucizumab was similar to or lower than aflibercept and ranibizumab (the exact results are confidential and cannot be reported here). The committee agreed that choosing the least expensive option from the available treatment options at the same point in the pathway was appropriate. The committee therefore recommended brolucizumab for treating diabetic macular oedema in line with the previous recommendations for aflibercept and ranibizumab.\n\n# Other factors\n\n## There are no equality issues relevant to the recommendations\n\nThe committee did not identify any equality issues."}	https://www.nice.org.uk/guidance/ta820	Evidence-based recommendations on brolucizumab (Beovu) for diabetic macular oedema in adults.
aaecfeef39ff35748cc91be31ef446ec92ee9ca2	nice	iFuse for treating chronic sacroiliac joint pain	iFuse for treating chronic sacroiliac joint pain Evidence-based recommendations on iFuse for treating chronic sacroiliac joint pain. # Recommendations iFuse implant system is recommended as an option for treating chronic sacroiliac joint pain. iFuse should be considered for use in people with a confirmed diagnosis of chronic sacroiliac joint pain (based on clinical assessment and a positive response to a diagnostic injection of local anaesthetic in the sacroiliac joint) and whose pain is inadequately controlled by non-surgical management. Why the committee made these recommendations The clinical evidence suggests that using iFuse implant system to treat chronic sacroiliac pain is likely to lead to less pain, reduced disability and a better quality of life compared with non-surgical management. This guidance was amended in 2022 to include the iFuse-3D implant, which evidence suggests may be clinically equivalent to the original iFuse implant. Cost modelling indicates that iFuse is cost incurring until year 9, when using iFuse with the original implants instead of non-surgical management will save the NHS around £230 per person. Using iFuse-3D will be cost incurring until year 10 when it becomes cost saving (£172 per patient). It is likely that savings will then increase over time. Savings mainly come from fewer steroid joint injections and less pain relief medication with iFuse compared with non-surgical management. # The technology # Description of the technology The iFuse implant system (SI‑Bone) is a titanium implant intended for use in people with chronic sacroiliac joint pain. iFuse is placed across the sacroiliac joint using minimally invasive surgery, where it is intended to stabilise the joint and to correct any misalignment or weakness that can cause chronic pain. The implant is triangular, which is designed to limit movement and spread shear stresses evenly. The original iFuse implant has a porous metal coating, which the company claims promotes bone‑on‑bone growth and encourages joint fusion. iFuse-3D is a second‑generation 3D-printed implant that is very similar to the original iFuse implant. The company said that the primary difference between the 2 implants was in the manufacturing process. Typically, 3 implants are used per joint, depending on the size of the pelvis. Implanting iFuse is a technically challenging procedure for which surgeons need specific training (provided at no additional cost by the company). The cost of iFuse with the original implant is £4,122, which includes 3 implants and the necessary consumables for the procedure. iFuse with 3D-printed implants costs £4,671. Staff and hospital costs are estimated to be £1,455 per procedure (using the Healthcare Resource Group code HC53, 54, 60, 61, 62, 63, 64 – Elective, excess bed days for back pain interventions from NHS reference costs for 2015/16, inflated using Personal Social Services Research Unit ). The claimed benefits in the case for adoption presented by the company are listed in the final scope of this evaluation. # Current management Chronic sacroiliac joint pain can affect people of any age and usually needs lifelong management. The standard of care is escalating non‑surgical management, typically beginning with analgesic therapy (such as non-steroidal anti-inflammatory drugs or opioids) combined with physiotherapy. If these initial treatments are ineffective, invasive procedures may be considered. These include steroid injections into the sacroiliac joint itself and radiofrequency ablation to the nerves that supply the joint. Sacroiliac joint fusion may be considered if the chronic pain continues. This can be done through open surgery or through a minimally invasive procedure, using a device such as iFuse. Invasive procedures and surgical treatments for chronic sacroiliac joint pain are usually done by spinal surgeons and orthopaedic trauma pelvic surgeons working in specialist centres. NICE has published interventional procedures guidance on minimally invasive sacroiliac joint fusion surgery for chronic sacroiliac pain, which may be done using iFuse. The guidance recommends that the evidence supporting the procedure is adequate for it to be carried out with standard arrangements for clinical governance, consent and audit. The guidance also recommends that the procedure should only be done in people with a confirmed diagnosis of unilateral or bilateral sacroiliac joint dysfunction due to degenerative sacroiliitis or sacroiliac joint disruption; and should only be carried out by surgeons who regularly use image-guided surgery for implant placement and have had specific training and expertise in minimally invasive sacroiliac joint fusion surgery for chronic pain. The NICE guideline on low back pain and sciatica in over 16s refers to surgical interventions for treating low back pain and sciatica including spinal decompression, fusion and disc replacement. The guideline does not mention surgical interventions for treating sacroiliac joint pain.# Evidence This section summarises the evidence assessed in the original guidance for iFuse. All studies evaluated iFuse with titanium plasma spray coated implants. There is now evidence on iFuse-3D which suggests it may be clinically equivalent to the original iFuse implant. For more on this new evidence see the evidence review report. # Summary of clinical evidence The evidence for iFuse considered by the external assessment centre (EAC) came from 12 studies: randomised controlled trials (n=251), Dengler et al. (2017b) and Polly et al. (2016a) comparative studies non-comparative studies.Both randomised controlled trials compared iFuse with non-surgical management. In Dengler et al. (2017b), non-surgical management was analgesic therapy, physiotherapy and cognitive behavioural therapy; in Polly et al. (2016a), it was analgesic therapy, physiotherapy, steroid joint injections and radiofrequency ablation. Follow‑up in the randomised controlled trials was relatively short (12 and 24 months), but in 1 comparative study, follow‑up was 6 years after implanting iFuse. One study compared revision rates for iFuse with those for open surgery (Spain and Holt 2017). The company sponsored 9 of the 12 included studies, and in each sponsored study at least 1 author was a company employee. For full details of the clinical evidence, see section 2 of the assessment report. # EAC conclusions on the clinical evidence The EAC concluded that the evidence shows that iFuse improves pain, improves health-related quality of life and reduces disability compared with non-surgical management. The EAC noted that the definition of non‑surgical management differed between studies, but that it always included interventions that are representative of those used in the NHS for chronic sacroiliac joint pain. The EAC concluded that the evidence presented a reasonable estimate of the treatment effect of iFuse that was relevant to the population, intervention, comparators and outcomes detailed in the scope. # Summary of economic evidence Neither the company nor the EAC identified any published economic evidence relevant to the decision problem. The company submitted 2 cost models, 1 comparing iFuse with open surgery and the other comparing iFuse with non-surgical management. Non-surgical management comprised a treatment pathway of analgesic medication, steroid joint injections and radiofrequency ablation. The assumptions and inputs of both models were based on clinical advice and UK pricing data, and both models used a 7‑year time horizon. The EAC made some changes to the parameters and inputs of the company model. This included correcting errors and updating inputs and assumptions. For full details of the economic evidence and the EAC changes to the model, see section 3 of the assessment report. # EAC analysis of the economic evidence In its assessment report, the EAC concluded that the model comparing iFuse with non-surgical management was most relevant to NHS practice. The revised model showed that after 7 years, iFuse was cost incurring by about £560 per patient because of the higher initial costs (including acquisition and procedure costs). The EAC also noted that as time passes, the costs associated with non-surgical management continue to be accrued, whereas for iFuse most of the costs are upfront. It judged this to be relevant to the cost consequences because lifelong management is normally needed for chronic sacroiliac joint pain and people are likely to have iFuse in place for the rest of their lives. The EAC therefore considered that cost savings with iFuse were plausible beyond the time horizon of the company's model. The EAC extended the time horizon of the model to simulate the costs for lifelong management of chronic sacroiliac joint pain. The company also lowered the price of iFuse consumables at consultation stage from £275 to £136. Using this longer time horizon and lower consumable price, iFuse saves £129 per patient at 8 years, after which the savings continue to increase. For the guidance review, the EAC revised the model to reflect 2022 costs. Costs for iFuse were calculated separately for titanium plasma spray coated implants and 3D-printed implants. Details of the parameter changes are in the EAC costing update report. Results for the 2022 updated model shows iFuse is cost incurring up to 8 years (by £323) but becomes cost saving from year 9 (by £230.37) onwards. When using the cost of the iFuse-3D implant, it becomes cost saving from year 10 (by £172.31) onwards. # Committee discussion The committee discussion (in 2018) was on iFuse with the original titanium plasma spray coated implants, which is likely to be clinically equivalent to iFuse-3D. # Clinical effectiveness The committee recognised the uncertainties in the published evidence but concluded that using iFuse to treat chronic sacroiliac pain is likely to lead to less pain, reduced disability and a better quality of life compared with non-surgical management. The committee heard from a patient expert adviser who had complete pain relief soon after having iFuse implanted. They explained that iFuse had had a transformative effect on their life; after treatment, they were able to return to daily activities without being restricted by chronic pain. The clinical expert advisers confirmed that this accurately reflected the experience of their own patients who had iFuse implanted. The committee concluded that using iFuse could lead to considerable clinical benefits for people with chronic sacroiliac joint pain. ## Comparator The clinical expert advisers explained that people with sacroiliac joint pain are generally offered non-surgical management, with only a few centres offering sacroiliac joint fusion. When joint fusion is an option, minimally invasive techniques are usually preferred. The clinical expert advisers explained that open surgical sacroiliac joint fusion is not normally done because it is a technically challenging procedure that is associated with long recovery times, high revision rates and poor long-term results. The committee therefore concluded that non-surgical management was the most appropriate comparator in standard NHS practice against which iFuse should be assessed. ## Impact of the disease The clinical and patient expert advisers explained that chronic sacroiliac joint pain is an extremely debilitating condition that can restrict daily activities, affect mood and impair sleep. People with chronic sacroiliac joint pain are therefore likely to need strong analgesic medication that may include regular doses of opioids. People may also be offered steroid joint injections; the patient expert adviser explained that these injections are associated with a recovery period before discharge, such that they often involve taking time off work or away from other responsibilities. The clinical expert advisers explained that steroid joint injections may be done every 6 months, but that the effects often last for only around 3 months. This can lead to some patients having a recurrence of chronic pain after a period of relief. They also noted that some commissioning bodies may not fund ongoing and repeated steroid injections. The committee also heard from the expert advisers that radiofrequency ablation is of limited therapeutic benefit. It concluded that chronic sacroiliac joint pain is generally managed with non-surgical treatments that are associated with potential side effects, patient inconvenience, and recurrent and inadequately controlled symptoms. # NHS considerations ## Patient selection The clinical expert advisers explained that chronic sacroiliac joint pain typically affects adults in middle age and that it is more common in women. Most patients are younger than 60 years, so face living with recurring symptoms over many years. The clinical expert advisers explained that chronic sacroiliac joint pain may result from inflammatory conditions affecting the joint, previous pelvic trauma (including from childbirth) and the transmitted shear stresses associated with previous spinal fusion. Some inflammatory conditions may resolve over time or with medication, so joint fusion procedures may not always be appropriate. The clinical expert advisers stated that they would not recommend using iFuse in people with osteoporosis in the bone adjacent to the sacroiliac joint, because this would increase the risk of device instability and incomplete joint fusion. However, they noted that once iFuse is implanted and the joint has fused, the risk of device and joint instability is low. The clinical expert advisers explained the importance of an accurate diagnosis of chronic sacroiliac joint pain before iFuse is considered (that is, confirmation that the pain originates from sacroiliac joint dysfunction). The diagnosis needs to be confirmed by injecting local anaesthetic into the joint under image guidance. If the signs and symptoms are characteristic and the local anaesthetic joint injection provides pain relief, a diagnosis of chronic sacroiliac joint pain can be confirmed. MRI and CT scanning may also provide useful diagnostic information, particularly in people with multiple back issues. The clinical expert advisers stated that sacroiliac joint pain is often misdiagnosed as pain originating from the lumbar spine or hip joint, and that sacroiliac joint dysfunction may sometimes not be considered as the cause for back pain. The patient expert adviser explained that this was reflective of their own experience. The committee concluded that sacroiliac joint pain is likely to be underdiagnosed, and an increased awareness of the condition among clinicians when assessing and treating low back pain would be beneficial. ## Training of surgeons Implanting iFuse is a technically challenging procedure during which there is a risk of damaging nerve roots and blood vessels adjacent to the sacroiliac joint. The company provides relevant and necessary training. The clinical expert advisers described the importance of taking part in training courses and in first doing the procedure under the supervision of a trained and experienced surgeon. # Cost savings The committee noted that the company had submitted 2 models, 1 of which compared iFuse with open surgery. Having acknowledged that open surgical sacroiliac joint fusion is rarely done, the committee concluded that this model was not relevant to current NHS practice. It instead focused on the model that compared iFuse with non-surgical management. The committee agreed with the changes the external assessment centre (EAC) had made to the company's cost model comparing iFuse with non‑surgical management. The clinical expert advisers confirmed that the assumptions used in the cost models were representative of their experience with iFuse. For example, the model assumed that an overnight stay in hospital would usually be needed after having iFuse implanted, and that 3 (or occasionally 2 or 4) implants are used per joint treated. The expert advisers explained that single joint procedures are more common, but that some patients with bilateral disease may need a second procedure in the opposite joint months or years later. Around 60% of people have pain in both sacroiliac joints, but symptoms are usually more severe in 1 joint. The clinical expert advisers explained that standard practice would be to treat the joint with the most severe pain first, and then observe the treatment response before deciding on whether to use iFuse for the other joint. ## Additional modelling by the EAC The committee discussed the additional modelling by the EAC, which extended the time horizon to 30 years. The clinical expert advisers stated that most people with chronic sacroiliac joint pain will have repeated steroid joint injections (up to 3 a year) but that the injections will become less effective over time. They explained that it is unlikely anyone would have repeated steroid joint injections for up to 30 years because of the nature of the procedure and their reducing efficacy with time. After 30 years, people will have exhausted all other non-surgical management options and are likely to have to rely on analgesic medication alone. The committee noted that this was reflected in the longer 30‑year time horizon implemented by the EAC, but the rate at which steroid injections decreased was based on informed opinion because no data were available. The committee considered the longer time horizon to be appropriate and that it provided additional information but recognised that it introduced uncertainty. Nonetheless, the experts predicted that the long-term performance of iFuse is likely to be good and that the risk of fracture or need for revision is low. They explained that any revisions are usually needed in the first few years after implantation; after this, the bone grows over the implant and across the sacroiliac joint, creating a permanent fusion that is stronger than the original joint and the surrounding bone. A company representative stated that the first iFuse devices were implanted in 2010 and that there are, to date, no reports of device failure after 2 years. The committee considered it plausible that iFuse may permanently relieve the symptoms of chronic sacroiliac joint pain. The committee concluded that after 8 years, using iFuse instead of non‑surgical management could save around £129 per patient. It is likely after 8 years, these savings will increase over time to provide further value to the NHS. Results for the 2022 updated model shows iFuse is cost incurring up to 8 years (by £323) before becoming cost saving from year 9 (by £230.37). iFuse-3D becomes cost saving from year 10 (by £172.31) onwards.	{'Recommendations': 'iFuse implant system is recommended as an option for treating chronic sacroiliac joint pain.\n\niFuse should be considered for use in people with a confirmed diagnosis of chronic sacroiliac joint pain (based on clinical assessment and a positive response to a diagnostic injection of local anaesthetic in the sacroiliac joint) and whose pain is inadequately controlled by non-surgical management.\n\nWhy the committee made these recommendations\n\nThe clinical evidence suggests that using iFuse implant system to treat chronic sacroiliac pain is likely to lead to less pain, reduced disability and a better quality of life compared with non-surgical management.\n\nThis guidance was amended in 2022 to include the iFuse-3D implant, which evidence suggests may be clinically equivalent to the original iFuse implant.\n\nCost modelling indicates that iFuse is cost incurring until year\xa09, when using iFuse with the original implants instead of non-surgical management will save the NHS around £230 per person. Using iFuse-3D will be cost incurring until year\xa010 when it becomes cost saving (£172 per patient). It is likely that savings will then increase over time. Savings mainly come from fewer steroid joint injections and less pain relief medication with iFuse compared with non-surgical management. ', 'The technology': '# Description of the technology\n\nThe iFuse implant system (SI‑Bone) is a titanium implant intended for use in people with chronic sacroiliac joint pain. iFuse is placed across the sacroiliac joint using minimally invasive surgery, where it is intended to stabilise the joint and to correct any misalignment or weakness that can cause chronic pain. The implant is triangular, which is designed to limit movement and spread shear stresses evenly. The original iFuse implant has a porous metal coating, which the company claims promotes bone‑on‑bone growth and encourages joint fusion. iFuse-3D is a second‑generation 3D-printed implant that is very similar to the original iFuse implant. The company said that the primary difference between the 2\xa0implants was in the manufacturing process. Typically, 3\xa0implants are used per joint, depending on the size of the pelvis. Implanting iFuse is a technically challenging procedure for which surgeons need specific training (provided at no additional cost by the company). \n\nThe cost of iFuse with the original implant is £4,122, which includes 3\xa0implants and the necessary consumables for the procedure. iFuse with 3D-printed implants costs £4,671. Staff and hospital costs are estimated to be £1,455 per procedure (using the Healthcare Resource Group [HRG] code HC53, 54, 60, 61, 62, 63, 64 – Elective, excess bed days for back pain interventions from NHS reference costs for 2015/16, inflated using Personal Social Services Research Unit [PSSRU]). \n\nThe claimed benefits in the case for adoption presented by the company are listed in the final scope of this evaluation.\n\n# Current management\n\nChronic sacroiliac joint pain can affect people of any age and usually needs lifelong management. The standard of care is escalating non‑surgical management, typically beginning with analgesic therapy (such as non-steroidal anti-inflammatory drugs or opioids) combined with physiotherapy. If these initial treatments are ineffective, invasive procedures may be considered. These include steroid injections into the sacroiliac joint itself and radiofrequency ablation to the nerves that supply the joint. Sacroiliac joint fusion may be considered if the chronic pain continues. This can be done through open surgery or through a minimally invasive procedure, using a device such as iFuse. Invasive procedures and surgical treatments for chronic sacroiliac joint pain are usually done by spinal surgeons and orthopaedic trauma pelvic surgeons working in specialist centres.\n\nNICE has published interventional procedures guidance on minimally invasive sacroiliac joint fusion surgery for chronic sacroiliac pain, which may be done using iFuse. The guidance recommends that the evidence supporting the procedure is adequate for it to be carried out with standard arrangements for clinical governance, consent and audit. The guidance also recommends that the procedure should only be done in people with a confirmed diagnosis of unilateral or bilateral sacroiliac joint dysfunction due to degenerative sacroiliitis or sacroiliac joint disruption; and should only be carried out by surgeons who regularly use image-guided surgery for implant placement and have had specific training and expertise in minimally invasive sacroiliac joint fusion surgery for chronic pain.\n\nThe NICE guideline on low back pain and sciatica in over 16s refers to surgical interventions for treating low back pain and sciatica including spinal decompression, fusion and disc replacement. The guideline does not mention surgical interventions for treating sacroiliac joint pain.', 'Evidence': "This section summarises the evidence assessed in the original guidance for iFuse. All studies evaluated iFuse with titanium plasma spray coated implants. There is now evidence on iFuse-3D which suggests it may be clinically equivalent to the original iFuse implant. For more on this new evidence see the evidence review report. \n\n# Summary of clinical evidence\n\nThe evidence for iFuse considered by the external assessment centre (EAC) came from 12\xa0studies:\n\nrandomised controlled trials (n=251), Dengler et al. (2017b) and Polly et al. (2016a)\n\ncomparative studies\n\nnon-comparative studies.Both randomised controlled trials compared iFuse with non-surgical management. In Dengler et al. (2017b), non-surgical management was analgesic therapy, physiotherapy and cognitive behavioural therapy; in Polly et al. (2016a), it was analgesic therapy, physiotherapy, steroid joint injections and radiofrequency ablation. Follow‑up in the randomised controlled trials was relatively short (12\xa0and 24\xa0months), but in 1\xa0comparative study, follow‑up was 6\xa0years after implanting iFuse. One study compared revision rates for iFuse with those for open surgery (Spain and Holt 2017). The company sponsored 9\xa0of the 12\xa0included studies, and in each sponsored study at least 1\xa0author was a company employee. For full details of the clinical evidence, see section\xa02 of the assessment report.\n\n# EAC conclusions on the clinical evidence\n\nThe EAC concluded that the evidence shows that iFuse improves pain, improves health-related quality of life and reduces disability compared with non-surgical management. The EAC noted that the definition of non‑surgical management differed between studies, but that it always included interventions that are representative of those used in the NHS for chronic sacroiliac joint pain. The EAC concluded that the evidence presented a reasonable estimate of the treatment effect of iFuse that was relevant to the population, intervention, comparators and outcomes detailed in the scope.\n\n# Summary of economic evidence\n\nNeither the company nor the EAC identified any published economic evidence relevant to the decision problem. The company submitted 2\xa0cost models, 1\xa0comparing iFuse with open surgery and the other comparing iFuse with non-surgical management. Non-surgical management comprised a treatment pathway of analgesic medication, steroid joint injections and radiofrequency ablation. The assumptions and inputs of both models were based on clinical advice and UK pricing data, and both models used a 7‑year time horizon. The EAC made some changes to the parameters and inputs of the company model. This included correcting errors and updating inputs and assumptions. For full details of the economic evidence and the EAC changes to the model, see section\xa03 of the assessment report.\n\n# EAC analysis of the economic evidence\n\nIn its assessment report, the EAC concluded that the model comparing iFuse with non-surgical management was most relevant to NHS practice. The revised model showed that after 7\xa0years, iFuse was cost incurring by about £560 per patient because of the higher initial costs (including acquisition and procedure costs). The EAC also noted that as time passes, the costs associated with non-surgical management continue to be accrued, whereas for iFuse most of the costs are upfront. It judged this to be relevant to the cost consequences because lifelong management is normally needed for chronic sacroiliac joint pain and people are likely to have iFuse in place for the rest of their lives. The EAC therefore considered that cost savings with iFuse were plausible beyond the time horizon of the company's model.\n\nThe EAC extended the time horizon of the model to simulate the costs for lifelong management of chronic sacroiliac joint pain. The company also lowered the price of iFuse consumables at consultation stage from £275 to £136. Using this longer time horizon and lower consumable price, iFuse saves £129 per patient at 8\xa0years, after which the savings continue to increase.\n\nFor the guidance review, the EAC revised the model to reflect 2022 costs. Costs for iFuse were calculated separately for titanium plasma spray coated implants and 3D-printed implants. Details of the parameter changes are in the EAC costing update report. Results for the 2022 updated model shows iFuse is cost incurring up to 8\xa0years (by £323) but becomes cost saving from year\xa09 (by £230.37) onwards. When using the cost of the iFuse-3D implant, it becomes cost saving from year\xa010 (by £172.31) onwards. ", 'Committee discussion': "The committee discussion (in 2018) was on iFuse with the original titanium plasma spray coated implants, which is likely to be clinically equivalent to iFuse-3D. \n\n# Clinical effectiveness\n\nThe committee recognised the uncertainties in the published evidence but concluded that using iFuse to treat chronic sacroiliac pain is likely to lead to less pain, reduced disability and a better quality of life compared with non-surgical management.\n\nThe committee heard from a patient expert adviser who had complete pain relief soon after having iFuse implanted. They explained that iFuse had had a transformative effect on their life; after treatment, they were able to return to daily activities without being restricted by chronic pain. The clinical expert advisers confirmed that this accurately reflected the experience of their own patients who had iFuse implanted. The committee concluded that using iFuse could lead to considerable clinical benefits for people with chronic sacroiliac joint pain.\n\n## Comparator\n\nThe clinical expert advisers explained that people with sacroiliac joint pain are generally offered non-surgical management, with only a few centres offering sacroiliac joint fusion. When joint fusion is an option, minimally invasive techniques are usually preferred. The clinical expert advisers explained that open surgical sacroiliac joint fusion is not normally done because it is a technically challenging procedure that is associated with long recovery times, high revision rates and poor long-term results. The committee therefore concluded that non-surgical management was the most appropriate comparator in standard NHS practice against which iFuse should be assessed.\n\n## Impact of the disease\n\nThe clinical and patient expert advisers explained that chronic sacroiliac joint pain is an extremely debilitating condition that can restrict daily activities, affect mood and impair sleep. People with chronic sacroiliac joint pain are therefore likely to need strong analgesic medication that may include regular doses of opioids. People may also be offered steroid joint injections; the patient expert adviser explained that these injections are associated with a recovery period before discharge, such that they often involve taking time off work or away from other responsibilities. The clinical expert advisers explained that steroid joint injections may be done every 6\xa0months, but that the effects often last for only around 3\xa0months. This can lead to some patients having a recurrence of chronic pain after a period of relief. They also noted that some commissioning bodies may not fund ongoing and repeated steroid injections. The committee also heard from the expert advisers that radiofrequency ablation is of limited therapeutic benefit. It concluded that chronic sacroiliac joint pain is generally managed with non-surgical treatments that are associated with potential side effects, patient inconvenience, and recurrent and inadequately controlled symptoms.\n\n# NHS considerations\n\n## Patient selection\n\nThe clinical expert advisers explained that chronic sacroiliac joint pain typically affects adults in middle age and that it is more common in women. Most patients are younger than 60\xa0years, so face living with recurring symptoms over many years. The clinical expert advisers explained that chronic sacroiliac joint pain may result from inflammatory conditions affecting the joint, previous pelvic trauma (including from childbirth) and the transmitted shear stresses associated with previous spinal fusion. Some inflammatory conditions may resolve over time or with medication, so joint fusion procedures may not always be appropriate. The clinical expert advisers stated that they would not recommend using iFuse in people with osteoporosis in the bone adjacent to the sacroiliac joint, because this would increase the risk of device instability and incomplete joint fusion. However, they noted that once iFuse is implanted and the joint has fused, the risk of device and joint instability is low.\n\nThe clinical expert advisers explained the importance of an accurate diagnosis of chronic sacroiliac joint pain before iFuse is considered (that is, confirmation that the pain originates from sacroiliac joint dysfunction). The diagnosis needs to be confirmed by injecting local anaesthetic into the joint under image guidance. If the signs and symptoms are characteristic and the local anaesthetic joint injection provides pain relief, a diagnosis of chronic sacroiliac joint pain can be confirmed. MRI and CT scanning may also provide useful diagnostic information, particularly in people with multiple back issues.\n\nThe clinical expert advisers stated that sacroiliac joint pain is often misdiagnosed as pain originating from the lumbar spine or hip joint, and that sacroiliac joint dysfunction may sometimes not be considered as the cause for back pain. The patient expert adviser explained that this was reflective of their own experience. The committee concluded that sacroiliac joint pain is likely to be underdiagnosed, and an increased awareness of the condition among clinicians when assessing and treating low back pain would be beneficial.\n\n## Training of surgeons\n\nImplanting iFuse is a technically challenging procedure during which there is a risk of damaging nerve roots and blood vessels adjacent to the sacroiliac joint. The company provides relevant and necessary training. The clinical expert advisers described the importance of taking part in training courses and in first doing the procedure under the supervision of a trained and experienced surgeon.\n\n# Cost savings\n\nThe committee noted that the company had submitted 2\xa0models, 1 of which compared iFuse with open surgery. Having acknowledged that open surgical sacroiliac joint fusion is rarely done, the committee concluded that this model was not relevant to current NHS practice. It instead focused on the model that compared iFuse with non-surgical management.\n\nThe committee agreed with the changes the external assessment centre (EAC) had made to the company's cost model comparing iFuse with non‑surgical management. The clinical expert advisers confirmed that the assumptions used in the cost models were representative of their experience with iFuse. For example, the model assumed that an overnight stay in hospital would usually be needed after having iFuse implanted, and that 3\xa0(or occasionally 2\xa0or\xa04) implants are used per joint treated. The expert advisers explained that single joint procedures are more common, but that some patients with bilateral disease may need a second procedure in the opposite joint months or years later. Around 60% of people have pain in both sacroiliac joints, but symptoms are usually more severe in 1\xa0joint. The clinical expert advisers explained that standard practice would be to treat the joint with the most severe pain first, and then observe the treatment response before deciding on whether to use iFuse for the other joint.\n\n## Additional modelling by the EAC\n\nThe committee discussed the additional modelling by the EAC, which extended the time horizon to 30\xa0years. The clinical expert advisers stated that most people with chronic sacroiliac joint pain will have repeated steroid joint injections (up to 3 a year) but that the injections will become less effective over time. They explained that it is unlikely anyone would have repeated steroid joint injections for up to 30\xa0years because of the nature of the procedure and their reducing efficacy with time. After 30\xa0years, people will have exhausted all other non-surgical management options and are likely to have to rely on analgesic medication alone. The committee noted that this was reflected in the longer 30‑year time horizon implemented by the EAC, but the rate at which steroid injections decreased was based on informed opinion because no data were available.\n\nThe committee considered the longer time horizon to be appropriate and that it provided additional information but recognised that it introduced uncertainty. Nonetheless, the experts predicted that the long-term performance of iFuse is likely to be good and that the risk of fracture or need for revision is low. They explained that any revisions are usually needed in the first few years after implantation; after this, the bone grows over the implant and across the sacroiliac joint, creating a permanent fusion that is stronger than the original joint and the surrounding bone. A company representative stated that the first iFuse devices were implanted in 2010 and that there are, to date, no reports of device failure after 2\xa0years. The committee considered it plausible that iFuse may permanently relieve the symptoms of chronic sacroiliac joint pain. The committee concluded that after 8\xa0years, using iFuse instead of non‑surgical management could save around £129 per patient. It is likely after 8\xa0years, these savings will increase over time to provide further value to the NHS.\n\nResults for the 2022 updated model shows iFuse is cost incurring up to 8\xa0years (by £323) before becoming cost saving from year\xa09 (by £230.37). iFuse-3D becomes cost saving from year\xa010 (by £172.31) onwards. "}	https://www.nice.org.uk/guidance/mtg39	Evidence-based recommendations on iFuse for treating chronic sacroiliac joint pain.
9f40db4a266c7058cf0911379fba9b377311b769	nice	Focal resurfacing implants to treat articular cartilage damage in the knee	Focal resurfacing implants to treat articular cartilage damage in the knee Evidence-based recommendations on focal resurfacing implants to treat articular cartilage damage in the knee in adults. This involves replacing the damaged area with an artificial implant. # Recommendations Evidence on the efficacy of focal resurfacing implants to treat articular cartilage damage in the knee is limited in quality and quantity. Short-term evidence shows no major safety concerns, but long-term evidence on safety is limited in quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to use focal resurfacing implants to treat articular cartilage damage in the knee should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Ensure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes, including those in the long term, of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Enter details about everyone having focal resurfacing implants to treat articular cartilage damage in the knee into a suitable registry and review local clinical outcomes. Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Further research should report patient selection, including the site and size of the cartilage damage, and long-term outcomes, including the incidence of revision procedures and joint replacements. Patient selection should be done by a multidisciplinary team experienced in managing the condition. The procedure should only be done by surgeons experienced in focal articular cartilage resurfacing. Report any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.# The condition, current treatments and procedure # The condition Cartilage covers the end of the bones comprising the knee joint. There are 2 types of cartilage in the knee – articular (or chondral) and meniscal. Damage because of injury or disease to a focal area of articular cartilage, particularly in the main weightbearing areas, can cause pain, stiffness and reduced mobility. Cartilage tissue has very limited self-healing potential and, if left untreated, cartilage damage can progress to osteoarthritis. # Current treatments Treatment for focal articular cartilage damage typically involves arthroplasty or biological treatment. Types of arthroplasty include total, bicompartmental, unicompartmental and patellofemoral. Types of biological treatment include microfracture, osteochondral autograft transfer system and autologous chondrocyte implantation. # The procedure Focal articular resurfacing is aimed at people for whom biological treatments and arthroplasty may not be suitable because of age or other factors. Before surgery, the articular cartilage damage is assessed using a preplanned MRI, an arthroscopy or both. Then, either the implant is customised to fit the damaged area, or an implant is selected from a catalogue to closely match the damaged area. Various implant brands, designs and materials are used for the procedure. The procedure is done under regional (spinal) or general anaesthesia. An incision is made to access the damage site. The damaged area is prepared by removing the damaged bone and cartilage, and drilling a hole for the stem of the implant. The implant is then press-fitted into the damaged area with or without bone cement. The surface of the implant is slightly recessed below the surrounding articular cartilage. Rehabilitation after surgery depends on the person and implant. It typically includes either an immediate (as tolerated) or gradual return to full weight bearing and range of motion. The aim of this procedure is to alleviate pain, allow immediate weight bearing, preserve physiological joint function, slow progression to osteoarthritis, and reduce or delay the need for arthroplasty.	{'Recommendations': "Evidence on the efficacy of focal resurfacing implants to treat articular cartilage damage in the knee is limited in quality and quantity. Short-term evidence shows no major safety concerns, but long-term evidence on safety is limited in quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to use focal resurfacing implants to treat articular cartilage damage in the knee should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes, including those in the long term, of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nEnter details about everyone having focal resurfacing implants to treat articular cartilage damage in the knee into a suitable registry and review local clinical outcomes.\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nFurther research should report patient selection, including the site and size of the cartilage damage, and long-term outcomes, including the incidence of revision procedures and joint replacements.\n\nPatient selection should be done by a multidisciplinary team experienced in managing the condition.\n\nThe procedure should only be done by surgeons experienced in focal articular cartilage resurfacing.\n\nReport any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.", 'The condition, current treatments and procedure': '# The condition\n\nCartilage covers the end of the bones comprising the knee joint. There are 2\xa0types of cartilage in the knee – articular (or chondral) and meniscal. Damage because of injury or disease to a focal area of articular cartilage, particularly in the main weightbearing areas, can cause pain, stiffness and reduced mobility. Cartilage tissue has very limited self-healing potential and, if left untreated, cartilage damage can progress to osteoarthritis.\n\n# Current treatments\n\nTreatment for focal articular cartilage damage typically involves arthroplasty or biological treatment. Types of arthroplasty include total, bicompartmental, unicompartmental and patellofemoral. Types of biological treatment include microfracture, osteochondral autograft transfer system and autologous chondrocyte implantation.\n\n# The procedure\n\nFocal articular resurfacing is aimed at people for whom biological treatments and arthroplasty may not be suitable because of age or other factors.\n\nBefore surgery, the articular cartilage damage is assessed using a preplanned MRI, an arthroscopy or both. Then, either the implant is customised to fit the damaged area, or an implant is selected from a catalogue to closely match the damaged area. Various implant brands, designs and materials are used for the procedure. The procedure is done under regional (spinal) or general anaesthesia. An incision is made to access the damage site. The damaged area is prepared by removing the damaged bone and cartilage, and drilling a hole for the stem of the implant. The implant is then press-fitted into the damaged area with or without bone cement. The surface of the implant is slightly recessed below the surrounding articular cartilage.\n\nRehabilitation after surgery depends on the person and implant. It typically includes either an immediate (as tolerated) or gradual return to full weight bearing and range of motion.\n\nThe aim of this procedure is to alleviate pain, allow immediate weight bearing, preserve physiological joint function, slow progression to osteoarthritis, and reduce or delay the need for arthroplasty.'}	https://www.nice.org.uk/guidance/ipg734	Evidence-based recommendations on focal resurfacing implants to treat articular cartilage damage in the knee in adults. This involves replacing the damaged area with an artificial implant.
61c91652b099dce625d52943308472068209488a	nice	Transcutaneous electrical neuromuscular stimulation for urinary incontinence	Transcutaneous electrical neuromuscular stimulation for urinary incontinence Evidence-based recommendations on transcutaneous electrical neuromuscular stimulation for urinary incontinence in adults. This involves stimulating nerves and muscles in the pelvic floor to strengthen the muscles and reduce urine leaks. # Recommendations Evidence on the safety of transcutaneous electrical neuromuscular stimulation for urinary incontinence raises no major safety concerns. Evidence on its efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do transcutaneous electrical neuromuscular stimulation for urinary incontinence should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Ensure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Further research should include randomised controlled trials. These should compare transcutaneous neuromuscular electrical stimulation plus pelvic floor muscle exercises with pelvic floor muscle exercises alone.# The condition, current treatments and procedure # The condition Stress urinary incontinence is the involuntary leakage of urine during exercise or certain movements such as coughing, sneezing and laughing. Urge urinary incontinence is involuntary urine leakage with a feeling of urgency (a sudden need to urinate that is difficult to delay) during or just before the leakage. Mixed urinary incontinence is involuntary urine leakage associated with both urgency and exercise, effort, sneezing or coughing. # Current treatments NICE's guideline on urinary incontinence and pelvic organ prolapse in women has recommendations for the management of urinary incontinence in women, with a patient decision aid to promote shared decision making. NICE's guideline on lower urinary tract symptoms in men has recommendations for the management of urinary incontinence in men. Conventional treatment is conservative and includes lifestyle changes such as weight loss and pelvic floor muscle training. Surgical options are only offered if conservative measures and drug treatments do not help. # The procedure The procedure uses non-implanted electrodes connected to an external neuromuscular electrical stimulator device to stimulate muscles and nerves, to make the pelvic floor muscles contract. The electrical stimulation is delivered through the skin, typically with sticky pad electrodes. The number and placement of electrodes varies according to the system being used. This includes a design in which the electrodes are incorporated into a body garment worn like a pair of shorts. A controller is used to vary the intensity and frequency of stimulations, to achieve a lifting sensation throughout the pelvic floor. The device is typically used in sessions. The number and frequency of advised sessions varies, but the treatment period is typically 6 to 12 weeks. The aim of the procedure is to reduce symptoms associated with stress or urge urinary incontinence.	{'Recommendations': "Evidence on the safety of transcutaneous electrical neuromuscular stimulation for urinary incontinence raises no major safety concerns. Evidence on its efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do transcutaneous electrical neuromuscular stimulation for urinary incontinence should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nFurther research should include randomised controlled trials. These should compare transcutaneous neuromuscular electrical stimulation plus pelvic floor muscle exercises with pelvic floor muscle exercises alone.", 'The condition, current treatments and procedure': "# The condition\n\nStress urinary incontinence is the involuntary leakage of urine during exercise or certain movements such as coughing, sneezing and laughing. Urge urinary incontinence is involuntary urine leakage with a feeling of urgency (a sudden need to urinate that is difficult to delay) during or just before the leakage. Mixed urinary incontinence is involuntary urine leakage associated with both urgency and exercise, effort, sneezing or coughing.\n\n# Current treatments\n\nNICE's guideline on urinary incontinence and pelvic organ prolapse in women has recommendations for the management of urinary incontinence in women, with a patient decision aid to promote shared decision making. NICE's guideline on lower urinary tract symptoms in men has recommendations for the management of urinary incontinence in men. Conventional treatment is conservative and includes lifestyle changes such as weight loss and pelvic floor muscle training. Surgical options are only offered if conservative measures and drug treatments do not help.\n\n# The procedure\n\nThe procedure uses non-implanted electrodes connected to an external neuromuscular electrical stimulator device to stimulate muscles and nerves, to make the pelvic floor muscles contract. The electrical stimulation is delivered through the skin, typically with sticky pad electrodes. The number and placement of electrodes varies according to the system being used. This includes a design in which the electrodes are incorporated into a body garment worn like a pair of shorts. A controller is used to vary the intensity and frequency of stimulations, to achieve a lifting sensation throughout the pelvic floor.\n\nThe device is typically used in sessions. The number and frequency of advised sessions varies, but the treatment period is typically 6 to 12\xa0weeks.\n\nThe aim of the procedure is to reduce symptoms associated with stress or urge urinary incontinence."}	https://www.nice.org.uk/guidance/ipg735	Evidence-based recommendations on transcutaneous electrical neuromuscular stimulation for urinary incontinence in adults. This involves stimulating nerves and muscles in the pelvic floor to strengthen the muscles and reduce urine leaks.
a2f7d5c01dcd4add1d52ea61fb394f7307c04d45	nice	Superficial venous arterialisation for chronic limb threatening ischaemia	Superficial venous arterialisation for chronic limb threatening ischaemia Evidence-based recommendations on superficial venous arterialisation for chronic limb threatening ischaemia in adults. This involves joining an artery in the lower leg to a large vein to divert blood flow through the vein towards the foot, bypassing the blocked arteries. # Recommendations Evidence on the safety of superficial venous arterialisation for chronic limb threatening ischaemia shows well-recognised complications. Evidence on its efficacy is inadequate in quantity and quality. However, in people with no other option for revascularisation, this procedure can be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do superficial venous arterialisation for chronic limb threatening ischaemia should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Ensure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Patient selection should be done by a multidisciplinary team with specialist expertise in managing chronic limb threatening ischaemia. The procedure should only be done in specialist centres by surgeons with specific training and experience in this procedure.# The condition, current treatments and procedure # The condition Chronic limb threatening ischaemia (CLTI), also known as critical limb ischaemia, is a severe blockage in the arteries of the lower extremities. It is an advanced stage of peripheral arterial disease. CLTI is characterised by severely diminished circulation, ischaemic pain, ulceration, tissue loss or gangrene. It is associated with high amputation and mortality rates, and poor quality of life. # Current treatments CLTI needs urgent treatment to re-establish blood flow to the affected area and to prevent major amputation. Treatment options include medications, endovascular interventions (such as angioplasty, stents, laser atherectomy and directional atherectomy) and surgical treatments (such as bypass). Management of CLTI is described in NICE's guideline on peripheral arterial disease. # The procedure Preoperative investigation (such as angiography, arterial and venous duplex scan) is needed to assess the vascular system and its blood flow. During the operation, an arteriovenous fistula is created between the great saphenous vein (GSV) and the appropriate patent artery. The GSV is then anastomosed end‑to‑side to the artery below the knee. Side branches of the GSV to the ankle level are ligated and valvulotomy is done. This procedure arterialises the venous arch of the foot, with GSV maintained in situ and without compromising the existing collateral circulation. The aim is to improve symptoms and salvage the affected lower extremity.	{'Recommendations': "Evidence on the safety of superficial venous arterialisation for chronic limb threatening ischaemia shows well-recognised complications. Evidence on its efficacy is inadequate in quantity and quality. However, in people with no other option for revascularisation, this procedure can be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do superficial venous arterialisation for chronic limb threatening ischaemia should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a multidisciplinary team with specialist expertise in managing chronic limb threatening ischaemia.\n\nThe procedure should only be done in specialist centres by surgeons with specific training and experience in this procedure.", 'The condition, current treatments and procedure': "# The condition\n\nChronic limb threatening ischaemia (CLTI), also known as critical limb ischaemia, is a severe blockage in the arteries of the lower extremities. It is an advanced stage of peripheral arterial disease. CLTI is characterised by severely diminished circulation, ischaemic pain, ulceration, tissue loss or gangrene. It is associated with high amputation and mortality rates, and poor quality of life.\n\n# Current treatments\n\nCLTI needs urgent treatment to re-establish blood flow to the affected area and to prevent major amputation. Treatment options include medications, endovascular interventions (such as angioplasty, stents, laser atherectomy and directional atherectomy) and surgical treatments (such as bypass). Management of CLTI is described in NICE's guideline on peripheral arterial disease.\n\n# The procedure\n\nPreoperative investigation (such as angiography, arterial and venous duplex scan) is needed to assess the vascular system and its blood flow. During the operation, an arteriovenous fistula is created between the great saphenous vein (GSV) and the appropriate patent artery. The GSV is then anastomosed end‑to‑side to the artery below the knee. Side branches of the GSV to the ankle level are ligated and valvulotomy is done.\n\nThis procedure arterialises the venous arch of the foot, with GSV maintained in situ and without compromising the existing collateral circulation. The aim is to improve symptoms and salvage the affected lower extremity."}	https://www.nice.org.uk/guidance/ipg736	Evidence-based recommendations on superficial venous arterialisation for chronic limb threatening ischaemia in adults. This involves joining an artery in the lower leg to a large vein to divert blood flow through the vein towards the foot, bypassing the blocked arteries.
6f5e650c4db4fd0445e57442a74504a2331bca31	nice	Avalglucosidase alfa for treating Pompe disease	Avalglucosidase alfa for treating Pompe disease Evidence-based recommendations on avalglucosidase alfa (Nexviadyme) for Pompe disease. # Recommendations Avalglucosidase alfa (AVAL) is recommended, within its marketing authorisation, as an option for treating Pompe disease in babies, children, young people and adults, only if the company provides AVAL according to the commercial arrangement. Why the committee made this recommendation Pompe disease either occurs at birth (infantile onset; IOPD), or after 12 months (late onset; LOPD). The only treatment for Pompe disease is enzyme replacement therapy (ERT) with alglucosidase alfa (ALGLU). AVAL is an alternative ERT that works in the same way. Limited evidence shows AVAL can enter cells more easily, so reducing glycogen levels more efficiently than ALGLU. But the clinical benefit is uncertain. In LOPD, the cost-effectiveness estimates are uncertain because of uncertainties in the clinical evidence. But they are below what NICE normally considers an acceptable use of NHS resources, so AVAL is recommended for LOPD. Because IOPD is very rare, data is limited. So, assumptions about its efficacy were needed, which makes the cost-effectiveness estimates uncertain. When assuming that AVAL works as well as ALGLU, cost-effectiveness estimates are below what NICE normally considers an acceptable use of NHS resources. Given the high burden of Pompe disease on children and their carers, and the rarity of the condition, the committee accepted the uncertainties. So, AVAL is recommended for IOPD.# Information about avalglucosidase alfa # Marketing authorisation indication Avalglucosidase alfa (AVAL; Nexviadyme, Sanofi Genzyme) is indicated 'for long-term enzyme replacement therapy for the treatment of patients with Pompe disease (acid alpha-glucosidase deficiency).' # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for AVAL. # Price The list price of a 100‑mg vial of AVAL is £783.33 (excluding VAT; company submission). The company has a commercial arrangement. This makes AVAL available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Sanofi Genzyme, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Pompe disease is a rare genetic condition which is severely debilitating, affecting quality of life Pompe disease is a rare, genetic, chronic and progressive metabolic disease, resulting in severe disability and a reduced life expectancy. Pompe disease is caused by mutations in the gene that encodes the enzyme acid alpha-glucosidase (GAA), which is needed to break down glycogen into glucose. In Pompe disease, there is reduced or absent activity of GAA, which causes an accumulation of lysosomal glycogen in muscle cells resulting in irreversible muscle damage. Disease severity is influenced by the level of residual GAA activity. There is a range of phenotypes of Pompe disease, differing in age of onset, extent of organ involvement and rate of progression, which can be classified into 2 broad subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). IOPD presents in the first 12 months of life and is typically associated with cardiomyopathy, hypotonia and respiratory distress. If untreated, children will typically need ventilation by 6 months. Clinical experts stated that, in the absence of treatment, they would expect most children with IOPD to have a life expectancy of around 14 months because of heart complications. For LOPD, symptom onset is after 12 months and can happen any time up to late adulthood. LOPD typically affects multiple systems and is characterised by progressive muscle weakness and respiratory involvement. As the disease progresses, people with LOPD may need to use a wheelchair and need non-invasive or invasive ventilation, with respiratory failure being the leading cause of death. There is significant heterogeneity within people with LOPD, including time of symptom onset, time of diagnosis, symptom severity, rate of disease decline and life expectancy. The committee concluded that Pompe disease has a severe effect on both quality and length of life. # Treatment pathway ## There are limited treatment options for people with Pompe disease Currently, the only treatment option for Pompe disease is alglucosidase alfa (ALGLU), an enzyme replacement therapy (ERT) that has not previously been assessed by NICE. Alongside ALGLU, people with Pompe disease need tailored supportive care from multidisciplinary teams of health professionals. Response to ALGLU can vary between people. There is a well-recognised need to provide better options for people whose disease is not well managed or if the treatment effect has waned. Patient experts explained how symptom-relieving supportive care interventions can help but also come with additional disadvantages. The committee concluded that there is a need for more effective treatments for Pompe disease. ## The availability of avalglucosidase alfa would be expected to provide benefits for people with IOPD and LOPD Avalglucosidase alfa (AVAL) is indicated for the long-term treatment of Pompe disease. AVAL is expected to provide benefits as a treatment option for IOPD and LOPD. Clinical experts explained that AVAL is the same enzyme as ALGLU but has a better delivery mechanism which should get more enzyme into muscle cells. Therefore, they expect AVAL to have a positive effect for people with Pompe disease and be a better option than ALGLU. People with Pompe disease are optimistic about future treatment with AVAL. One person who has had treatment with AVAL told of the positive effect it has had on their life. Since treatment with AVAL in the clinical trial, they no longer have mobility or breathing problems, and do not have to worry about not being able to do things that people without the disease may be able to do. The committee concluded that clinicians and people with Pompe disease would welcome an effective alternative to current treatment. # Clinical evidence ## Clinical evidence is limited to 2 studies in the LOPD population Clinical data is limited in Pompe disease. The key clinical evidence comes from the COMET study and NEO1/NEO-EXT. COMET was a randomised, multicentre, double-blind, active-controlled 49‑week study comparing AVAL (n=51) with ALGLU (n=49) in people with LOPD who have not had ERT previously. COMET was a non-inferiority study, aiming to test whether AVAL is no less effective than ALGLU. The primary outcome in COMET was mean percentage change in forced vital capacity (FVC%), and key secondary outcomes included the 6‑minute walk test (6MWT), safety and health-related quality of life. NEO1/NEO-EXT was an open-label, multicentre, ascending dose study which assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of AVAL (n=24) and long-term extension (up to week 312; n=19). The primary outcome from NEO1/NEO-EXT was safety and tolerability of AVAL over different doses. NEO1/NEO-EXT also collected change from baseline in FVC% and 6MWT. The committee concluded that the evidence was limited, but acceptable for decision making. ## COMET reported no statistically significant benefits in LOPD, although FVC% and 6MWT did improve The COMET primary analysis at week 49 showed that AVAL was non-inferior to ALGLU in the FVC% and 6MWT outcome measures. There were some minor positive changes, but these were not statistically significant. AVAL showed a numerical improvement in FVC% from baseline, but this was not statistically significantly better than with ALGLU. There was also a numerical improvement in 6MWT with AVAL, but the statistical significance of this change compared with ALGLU was not reported. Health-related quality of life data collected in COMET showed utility values were generally higher over time than at baseline for both treatments. COMET safety data suggests AVAL and ALGLU are similarly tolerated. The most common adverse events were headache, nasopharyngitis, back pain, fatigue, diarrhoea and nausea. The committee and clinical experts noted that COMET is a non-inferiority study. The committee accepted that there was nothing to suggest that AVAL was inferior to the current treatment and that there is a theoretical potential for additional benefit. ## There appeared to be stability in treatment effect over time in NEO1/NEO-EXT, but data should be interpreted with caution Longer-term AVAL clinical data from NEO1/NEO-EXT showed that FVC% and 6MWT results were generally stable over time, although patient numbers in NEO1/NEO-EXT were small. The committee and clinical experts would have expected to see an improvement in FVC% and 6MWT after week 49 when people who were initially having ALGLU switched to AVAL, if AVAL was a more effective treatment, but this was not apparent in the data. Clinical experts explained that sometimes a maintenance of effect is a positive sign of slowing a progressive disease such as LOPD. The committee concluded that caution should be taken when interpreting long-term NEO1/NEO-EXT data. ## Data for the IOPD population comes from mini-COMET and is uncertain because of heterogeneity, small sample sizes and limited follow up Clinical data was very limited in the IOPD population. Clinical evidence for AVAL in the IOPD population came from a multi-stage, open-label, multicentre, ascending dose study including 3 cohorts (mini-COMET). Only cohort 3 compared AVAL with ALGLU. Children in mini-COMET had previously had ALGLU. There is no data for children with IOPD who have not previously had ERT. Cohort 1 and cohort 2 included children with clinical decline, cohort 1 had AVAL 20 mg/kg every 2 weeks and cohort 2 had AVAL 40 mg/kg every 2 weeks. Cohort 3 was the randomised portion of the trial, with children having either AVAL at the highest tolerated dose (n=5) or ALGLU at the current stable dose (n=6). Mini-COMET enrolled 22 people (cohort 1, n=6; cohort 2, n=5; cohort 3, n=11). Therefore, comparative data is only available from 11 children, all of whom had a suboptimal disease response to ALGLU. Clinical experts explained that for the purposes of the study, children were divided into groups classified as suboptimal response, or clinical decline, but the classification would depend on which outcome measure was used. There was also variation in the doses given. Some children had weekly treatment, and some had doses greater than currently used in NHS clinical practice. Clinical experts explained current practice is to offer ALGLU weekly 20 mg/kg at the start of treatment, at least for the first 12 weeks. They stated that evidence was emerging that a dose of 40 mg/kg ALGLU is more effective than 20 mg/kg. Clinical experts would expect any dose increase for ALGLU to also apply to AVAL. The committee was aware that it could only recommend any treatment in line with its marketing authorisation. Clinical experts considered the efficacy data from mini-COMET to be too heterogeneous and uncertain to be reliable, but the safety and pharmacokinetic data is satisfactory. Mini-COMET suggests AVAL and ALGLU are similarly tolerated. The committee concluded that the data on IOPD is very limited and uncertain but noted the rarity of the condition makes data collection difficult. # Economic model ## The company LOPD simulation model is appropriate for decision making The company LOPD model used a simulation approach with 6 health states. Each health state is associated with different costs, quality of life and mortality risks. The company included 8 profiles to model the population that would be likely to have treatment for LOPD in the UK. The profiles were informed by COMET patient-level data and were split by sex, age, time since diagnosis, weight, FVC%, 6MWT and utility. People entered the model not dependent on ventilators or wheelchairs. COMET changes in FVC% informed transitions through ventilator- or invasive ventilator-dependent health states and changes in 6MWT informed transitions through wheelchair-dependent health states. The duration of disease response was informed by NEO-EXT, after which benefits declined at a constant rate. The ERG thought the model health states captured the key aspects and progressive nature of the disease, and the simulation approach captured heterogeneity and patient history. However, the ERG thought that the profiles used by the company included less severely affected people than would typically be seen in NHS practice. Clinical experts would expect AVAL to slow the rate of clinical decline more than ALGLU. The committee concluded the structure of the model was appropriate for decision making. ## The committee accepted that a survival benefit for AVAL was possible, and should be explored Overall survival was informed by general population life tables, with hazard ratios (HRs) applied to adjust survival for people with LOPD. The company originally assumed people with LOPD who had AVAL and ALGLU had the same survival prospects. The ERG disagreed, and suggested AVAL should be associated with a survival benefit because of the expected clinical benefits associated with AVAL treatment. The ERG suggested that a HR of 0.85 should be applied to AVAL overall survival which translated into a 3‑month survival gain for people who had AVAL. The company accepted this HR approach and included it in the base-case analysis. Clinical experts stated that a survival benefit for people who had AVAL was possible but noted that there is no survival data to confirm or quantify this. The committee concluded that a survival benefit for AVAL over ALGLU was plausible, but unproven. It accepted that it was reasonable to explore the effect of an assumption of improved survival on cost effectiveness. ## The company IOPD 4-state partitioned survival model was appropriate, but needed assumptions in place of informative data The company IOPD model followed a partitioned survival model approach with 4 health states. People could be ventilation free, dependent on non-invasive ventilation, dependent on invasive ventilation or deceased. Overall survival, ventilator-free survival and invasive ventilator-free survival curves from Broomfield (a case-note review of 33 children who had previously had ALGLU) were extrapolated and formed the basis of the 4‑state partitioned survival model. Wheelchair dependence was captured separately to the core health states. The ERG accepted the approach chosen, indicating that the 4 health states captured disease progression, but noted the overall survival curve may not capture risk of death for children needing artificial ventilation. The committee highlighted that while data is limited for this population, the modelling approach used was appropriate. ## Equivalent survival outcomes were an area of uncertainty in the IOPD model Mini-COMET has short follow up and small patient numbers, so relative effectiveness is uncertain. In the absence of long-term survival data from trials in children with IOPD, the company used published data from the Broomfield case-note study of children who had ALGLU. The company assumed disease progression and survival prospects for children who had AVAL would be the same as seen in Broomfield (assuming equivalence). The ERG agreed that mini-COMET data is too limited to inform survival, or to confirm or reject equivalence. The ERG ultimately accepted the company's approach of equivalent survival but ran scenario analyses with a survival advantage for children who had AVAL. In these scenarios, children live longer and have treatment for longer, resulting in substantially higher incremental cost-effectiveness ratios (ICERs). Clinical experts suggested that it is plausible that children who had AVAL could have a survival advantage. However, they explained any benefit would also bring other benefits such as slower progression and better quality of life which has not been modelled in the scenarios. The ERG accepted the scenarios are an oversimplification of a complex progressive disease, but highlighted limitations of available IOPD data. The committee concluded that they were satisfied with equivalence assumptions in the IOPD population but accepted the uncertainty. # Cost-effectiveness estimates ## AVAL is likely to be cost effective in LOPD NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The company's and ERG's cost-effectiveness estimates for AVAL in people with LOPD were well below what NICE normally considers an acceptable use of NHS resources. The company's and ERG's base-case analyses differed only in the duration of response for ALGLU and AVAL. The company assumed a greater duration of response for AVAL, whereas the ERG assumed an equivalent duration for both treatments. Even when considering this change, AVAL would still be a dominant use of NHS resources when compared with ALGLU (that is, it costs less and is more effective). The committee concluded that AVAL would be a cost-effective treatment option for LOPD, so it is recommended. ## AVAL is also likely to be cost effective in IOPD, although results are more uncertain The company's and ERG's base-case cost-effectiveness estimates for AVAL in children with IOPD were also well below what NICE normally considers an acceptable use of NHS resources. The company's and ERG's base-case analyses differed in dosing, survival extrapolation and utility assumptions, but even when considering these differences, AVAL would still be a dominant use of NHS resources. Scenario analyses done by the ERG investigating survival gains for children who had AVAL saw ICERs increase to values not considered cost effective. The committee noted these scenarios were exploratory and informed by assumptions and not survival data. The committee would have preferred to have seen a full cost-utility analysis in IOPD, informed by robust comparative clinical data but acknowledged that, in this specific case, this was not available. However, given current limited IOPD evidence suggesting that AVAL is non-inferior to ALGLU, the high burden of Pompe disease on children and their carers, and the rarity of the condition, the committee accepted uncertainties in dosing, overall survival and duration of response in IOPD. The committee concluded that AVAL is likely to be a cost-effective treatment option for IOPD, so it is recommended. # Innovation AVAL is anticipated to address the unmet need of a population of people with Pompe disease for whom existing treatment is suboptimal. Clinical experts explained that AVAL is a second-generation ERT, and that alterations made to the GAA enzyme are designed to improve the efficiency of the uptake of the enzyme rather than being a step change in management. The company argued that AVAL is quicker to reconstitute than ALGLU which could reduce vial preparation time and free up capacity in the NHS. The committee concluded that all additional benefits of AVAL had already been taken into account. # Conclusion AVAL is recommended for use in the NHS for treating Pompe disease. The cost-effectiveness estimates for both IOPD and LOPD were uncertain. But they were likely to remain below what is considered an acceptable use of NHS resources even when accounting for the uncertainty.	{'Recommendations': 'Avalglucosidase alfa (AVAL) is recommended, within its marketing authorisation, as an option for treating Pompe disease in babies, children, young people and adults, only if the company provides AVAL according to the commercial arrangement.\n\nWhy the committee made this recommendation\n\nPompe disease either occurs at birth (infantile onset; IOPD), or after 12\xa0months (late onset; LOPD). The only treatment for Pompe disease is enzyme replacement therapy (ERT) with alglucosidase alfa (ALGLU). AVAL is an alternative ERT that works in the same way. Limited evidence shows AVAL can enter cells more easily, so reducing glycogen levels more efficiently than ALGLU. But the clinical benefit is uncertain.\n\nIn LOPD, the cost-effectiveness estimates are uncertain because of uncertainties in the clinical evidence. But they are below what NICE normally considers an acceptable use of NHS resources, so AVAL is recommended for LOPD.\n\nBecause IOPD is very rare, data is limited. So, assumptions about its efficacy were needed, which makes the cost-effectiveness estimates uncertain. When assuming that AVAL works as well as ALGLU, cost-effectiveness estimates are below what NICE normally considers an acceptable use of NHS resources. Given the high burden of Pompe disease on children and their carers, and the rarity of the condition, the committee accepted the uncertainties. So, AVAL is recommended for IOPD.', 'Information about avalglucosidase alfa': "# Marketing authorisation indication\n\nAvalglucosidase alfa (AVAL; Nexviadyme, Sanofi Genzyme) is indicated 'for long-term enzyme replacement therapy for the treatment of patients with Pompe disease (acid alpha-glucosidase deficiency).'\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for AVAL.\n\n# Price\n\nThe list price of a 100‑mg vial of AVAL is £783.33 (excluding VAT; company submission).\n\nThe company has a commercial arrangement. This makes AVAL available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Sanofi Genzyme, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Pompe disease is a rare genetic condition which is severely debilitating, affecting quality of life\n\nPompe disease is a rare, genetic, chronic and progressive metabolic disease, resulting in severe disability and a reduced life expectancy. Pompe disease is caused by mutations in the gene that encodes the enzyme acid alpha-glucosidase (GAA), which is needed to break down glycogen into glucose. In Pompe disease, there is reduced or absent activity of GAA, which causes an accumulation of lysosomal glycogen in muscle cells resulting in irreversible muscle damage. Disease severity is influenced by the level of residual GAA activity. There is a range of phenotypes of Pompe disease, differing in age of onset, extent of organ involvement and rate of progression, which can be classified into 2 broad subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). IOPD presents in the first 12\xa0months of life and is typically associated with cardiomyopathy, hypotonia and respiratory distress. If untreated, children will typically need ventilation by 6\xa0months. Clinical experts stated that, in the absence of treatment, they would expect most children with IOPD to have a life expectancy of around 14\xa0months because of heart complications. For LOPD, symptom onset is after 12\xa0months and can happen any time up to late adulthood. LOPD typically affects multiple systems and is characterised by progressive muscle weakness and respiratory involvement. As the disease progresses, people with LOPD may need to use a wheelchair and need non-invasive or invasive ventilation, with respiratory failure being the leading cause of death. There is significant heterogeneity within people with LOPD, including time of symptom onset, time of diagnosis, symptom severity, rate of disease decline and life expectancy. The committee concluded that Pompe disease has a severe effect on both quality and length of life.\n\n# Treatment pathway\n\n## There are limited treatment options for people with Pompe disease\n\nCurrently, the only treatment option for Pompe disease is alglucosidase alfa (ALGLU), an enzyme replacement therapy (ERT) that has not previously been assessed by NICE. Alongside ALGLU, people with Pompe disease need tailored supportive care from multidisciplinary teams of health professionals. Response to ALGLU can vary between people. There is a well-recognised need to provide better options for people whose disease is not well managed or if the treatment effect has waned. Patient experts explained how symptom-relieving supportive care interventions can help but also come with additional disadvantages. The committee concluded that there is a need for more effective treatments for Pompe disease.\n\n## The availability of avalglucosidase alfa would be expected to provide benefits for people with IOPD and LOPD\n\nAvalglucosidase alfa (AVAL) is indicated for the long-term treatment of Pompe disease. AVAL is expected to provide benefits as a treatment option for IOPD and LOPD. Clinical experts explained that AVAL is the same enzyme as ALGLU but has a better delivery mechanism which should get more enzyme into muscle cells. Therefore, they expect AVAL to have a positive effect for people with Pompe disease and be a better option than ALGLU. People with Pompe disease are optimistic about future treatment with AVAL. One person who has had treatment with AVAL told of the positive effect it has had on their life. Since treatment with AVAL in the clinical trial, they no longer have mobility or breathing problems, and do not have to worry about not being able to do things that people without the disease may be able to do. The committee concluded that clinicians and people with Pompe disease would welcome an effective alternative to current treatment.\n\n# Clinical evidence\n\n## Clinical evidence is limited to 2 studies in the LOPD population\n\nClinical data is limited in Pompe disease. The key clinical evidence comes from the COMET study and NEO1/NEO-EXT. COMET was a randomised, multicentre, double-blind, active-controlled 49‑week study comparing AVAL (n=51) with ALGLU (n=49) in people with LOPD who have not had ERT previously. COMET was a non-inferiority study, aiming to test whether AVAL is no less effective than ALGLU. The primary outcome in COMET was mean percentage change in forced vital capacity (FVC%), and key secondary outcomes included the 6‑minute walk test (6MWT), safety and health-related quality of life. NEO1/NEO-EXT was an open-label, multicentre, ascending dose study which assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of AVAL (n=24) and long-term extension (up to week\xa0312; n=19). The primary outcome from NEO1/NEO-EXT was safety and tolerability of AVAL over different doses. NEO1/NEO-EXT also collected change from baseline in FVC% and 6MWT. The committee concluded that the evidence was limited, but acceptable for decision making.\n\n## COMET reported no statistically significant benefits in LOPD, although FVC% and 6MWT did improve\n\nThe COMET primary analysis at week\xa049 showed that AVAL was non-inferior to ALGLU in the FVC% and 6MWT outcome measures. There were some minor positive changes, but these were not statistically significant. AVAL showed a numerical improvement in FVC% from baseline, but this was not statistically significantly better than with ALGLU. There was also a numerical improvement in 6MWT with AVAL, but the statistical significance of this change compared with ALGLU was not reported. Health-related quality of life data collected in COMET showed utility values were generally higher over time than at baseline for both treatments. COMET safety data suggests AVAL and ALGLU are similarly tolerated. The most common adverse events were headache, nasopharyngitis, back pain, fatigue, diarrhoea and nausea. The committee and clinical experts noted that COMET is a non-inferiority study. The committee accepted that there was nothing to suggest that AVAL was inferior to the current treatment and that there is a theoretical potential for additional benefit.\n\n## There appeared to be stability in treatment effect over time in NEO1/NEO-EXT, but data should be interpreted with caution\n\nLonger-term AVAL clinical data from NEO1/NEO-EXT showed that FVC% and 6MWT results were generally stable over time, although patient numbers in NEO1/NEO-EXT were small. The committee and clinical experts would have expected to see an improvement in FVC% and 6MWT after week\xa049 when people who were initially having ALGLU switched to AVAL, if AVAL was a more effective treatment, but this was not apparent in the data. Clinical experts explained that sometimes a maintenance of effect is a positive sign of slowing a progressive disease such as LOPD. The committee concluded that caution should be taken when interpreting long-term NEO1/NEO-EXT data.\n\n## Data for the IOPD population comes from mini-COMET and is uncertain because of heterogeneity, small sample sizes and limited follow up\n\nClinical data was very limited in the IOPD population. Clinical evidence for AVAL in the IOPD population came from a multi-stage, open-label, multicentre, ascending dose study including 3 cohorts (mini-COMET). Only cohort\xa03 compared AVAL with ALGLU. Children in mini-COMET had previously had ALGLU. There is no data for children with IOPD who have not previously had ERT. Cohort\xa01 and cohort\xa02 included children with clinical decline, cohort\xa01 had AVAL 20\xa0mg/kg every 2\xa0weeks and cohort\xa02 had AVAL 40\xa0mg/kg every 2\xa0weeks. Cohort\xa03 was the randomised portion of the trial, with children having either AVAL at the highest tolerated dose (n=5) or ALGLU at the current stable dose (n=6). Mini-COMET enrolled 22 people (cohort 1, n=6; cohort 2, n=5; cohort 3, n=11). Therefore, comparative data is only available from 11 children, all of whom had a suboptimal disease response to ALGLU. Clinical experts explained that for the purposes of the study, children were divided into groups classified as suboptimal response, or clinical decline, but the classification would depend on which outcome measure was used. There was also variation in the doses given. Some children had weekly treatment, and some had doses greater than currently used in NHS clinical practice. Clinical experts explained current practice is to offer ALGLU weekly 20\xa0mg/kg at the start of treatment, at least for the first 12\xa0weeks. They stated that evidence was emerging that a dose of 40\xa0mg/kg ALGLU is more effective than 20\xa0mg/kg. Clinical experts would expect any dose increase for ALGLU to also apply to AVAL. The committee was aware that it could only recommend any treatment in line with its marketing authorisation. Clinical experts considered the efficacy data from mini-COMET to be too heterogeneous and uncertain to be reliable, but the safety and pharmacokinetic data is satisfactory. Mini-COMET suggests AVAL and ALGLU are similarly tolerated. The committee concluded that the data on IOPD is very limited and uncertain but noted the rarity of the condition makes data collection difficult.\n\n# Economic model\n\n## The company LOPD simulation model is appropriate for decision making\n\nThe company LOPD model used a simulation approach with 6 health states. Each health state is associated with different costs, quality of life and mortality risks. The company included 8 profiles to model the population that would be likely to have treatment for LOPD in the UK. The profiles were informed by COMET patient-level data and were split by sex, age, time since diagnosis, weight, FVC%, 6MWT and utility. People entered the model not dependent on ventilators or wheelchairs. COMET changes in FVC% informed transitions through ventilator- or invasive ventilator-dependent health states and changes in 6MWT informed transitions through wheelchair-dependent health states. The duration of disease response was informed by NEO-EXT, after which benefits declined at a constant rate. The ERG thought the model health states captured the key aspects and progressive nature of the disease, and the simulation approach captured heterogeneity and patient history. However, the ERG thought that the profiles used by the company included less severely affected people than would typically be seen in NHS practice. Clinical experts would expect AVAL to slow the rate of clinical decline more than ALGLU. The committee concluded the structure of the model was appropriate for decision making.\n\n## The committee accepted that a survival benefit for AVAL was possible, and should be explored\n\nOverall survival was informed by general population life tables, with hazard ratios (HRs) applied to adjust survival for people with LOPD. The company originally assumed people with LOPD who had AVAL and ALGLU had the same survival prospects. The ERG disagreed, and suggested AVAL should be associated with a survival benefit because of the expected clinical benefits associated with AVAL treatment. The ERG suggested that a HR of 0.85 should be applied to AVAL overall survival which translated into a 3‑month survival gain for people who had AVAL. The company accepted this HR approach and included it in the base-case analysis. Clinical experts stated that a survival benefit for people who had AVAL was possible but noted that there is no survival data to confirm or quantify this. The committee concluded that a survival benefit for AVAL over ALGLU was plausible, but unproven. It accepted that it was reasonable to explore the effect of an assumption of improved survival on cost effectiveness.\n\n## The company IOPD 4-state partitioned survival model was appropriate, but needed assumptions in place of informative data\n\nThe company IOPD model followed a partitioned survival model approach with 4 health states. People could be ventilation free, dependent on non-invasive ventilation, dependent on invasive ventilation or deceased. Overall survival, ventilator-free survival and invasive ventilator-free survival curves from Broomfield (a case-note review of 33 children who had previously had ALGLU) were extrapolated and formed the basis of the 4‑state partitioned survival model. Wheelchair dependence was captured separately to the core health states. The ERG accepted the approach chosen, indicating that the 4 health states captured disease progression, but noted the overall survival curve may not capture risk of death for children needing artificial ventilation. The committee highlighted that while data is limited for this population, the modelling approach used was appropriate.\n\n## Equivalent survival outcomes were an area of uncertainty in the IOPD model\n\nMini-COMET has short follow up and small patient numbers, so relative effectiveness is uncertain. In the absence of long-term survival data from trials in children with IOPD, the company used published data from the Broomfield case-note study of children who had ALGLU. The company assumed disease progression and survival prospects for children who had AVAL would be the same as seen in Broomfield (assuming equivalence). The ERG agreed that mini-COMET data is too limited to inform survival, or to confirm or reject equivalence. The ERG ultimately accepted the company's approach of equivalent survival but ran scenario analyses with a survival advantage for children who had AVAL. In these scenarios, children live longer and have treatment for longer, resulting in substantially higher incremental cost-effectiveness ratios (ICERs). Clinical experts suggested that it is plausible that children who had AVAL could have a survival advantage. However, they explained any benefit would also bring other benefits such as slower progression and better quality of life which has not been modelled in the scenarios. The ERG accepted the scenarios are an oversimplification of a complex progressive disease, but highlighted limitations of available IOPD data. The committee concluded that they were satisfied with equivalence assumptions in the IOPD population but accepted the uncertainty.\n\n# Cost-effectiveness estimates\n\n## AVAL is likely to be cost effective in LOPD\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The company's and ERG's cost-effectiveness estimates for AVAL in people with LOPD were well below what NICE normally considers an acceptable use of NHS resources. The company's and ERG's base-case analyses differed only in the duration of response for ALGLU and AVAL. The company assumed a greater duration of response for AVAL, whereas the ERG assumed an equivalent duration for both treatments. Even when considering this change, AVAL would still be a dominant use of NHS resources when compared with ALGLU (that is, it costs less and is more effective). The committee concluded that AVAL would be a cost-effective treatment option for LOPD, so it is recommended.\n\n## AVAL is also likely to be cost effective in IOPD, although results are more uncertain\n\nThe company's and ERG's base-case cost-effectiveness estimates for AVAL in children with IOPD were also well below what NICE normally considers an acceptable use of NHS resources. The company's and ERG's base-case analyses differed in dosing, survival extrapolation and utility assumptions, but even when considering these differences, AVAL would still be a dominant use of NHS resources. Scenario analyses done by the ERG investigating survival gains for children who had AVAL saw ICERs increase to values not considered cost effective. The committee noted these scenarios were exploratory and informed by assumptions and not survival data. The committee would have preferred to have seen a full cost-utility analysis in IOPD, informed by robust comparative clinical data but acknowledged that, in this specific case, this was not available. However, given current limited IOPD evidence suggesting that AVAL is non-inferior to ALGLU, the high burden of Pompe disease on children and their carers, and the rarity of the condition, the committee accepted uncertainties in dosing, overall survival and duration of response in IOPD. The committee concluded that AVAL is likely to be a cost-effective treatment option for IOPD, so it is recommended.\n\n# Innovation\n\nAVAL is anticipated to address the unmet need of a population of people with Pompe disease for whom existing treatment is suboptimal. Clinical experts explained that AVAL is a second-generation ERT, and that alterations made to the GAA enzyme are designed to improve the efficiency of the uptake of the enzyme rather than being a step change in management. The company argued that AVAL is quicker to reconstitute than ALGLU which could reduce vial preparation time and free up capacity in the NHS. The committee concluded that all additional benefits of AVAL had already been taken into account.\n\n# Conclusion\n\nAVAL is recommended for use in the NHS for treating Pompe disease. The cost-effectiveness estimates for both IOPD and LOPD were uncertain. But they were likely to remain below what is considered an acceptable use of NHS resources even when accounting for the uncertainty."}	https://www.nice.org.uk/guidance/ta821	Evidence-based recommendations on avalglucosidase alfa (Nexviadyme) for Pompe disease.
135b9cdc5833b9c953312f41ef4570c993d28a42	nice	Nivolumab with ipilimumab for untreated unresectable malignant pleural mesothelioma	Nivolumab with ipilimumab for untreated unresectable malignant pleural mesothelioma Evidence-based recommendations on nivolumab (Opdivo) with ipilimumab (Yervoy) for untreated unresectable malignant pleural mesothelioma in adults. # Recommendations Nivolumab plus ipilimumab is recommended as an option for untreated unresectable malignant pleural mesothelioma in adults, only if: they have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 the company provides it according to the commercial arrangement. This recommendation is not intended to affect treatment with nivolumab plus ipilimumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Standard care for untreated unresectable malignant pleural mesothelioma is chemotherapy. The clinical trial evidence was in people with an ECOG performance status of 0 or 1. It suggests that nivolumab plus ipilimumab is likely to extend how long people live compared with chemotherapy. Nivolumab plus ipilimumab likely meets NICE's criteria for being a life-extending treatment at the end of life. Taking this into account, the cost-effectiveness estimates for nivolumab plus ipilimumab were within the range that NICE normally considers an acceptable use of NHS resources. So, it is recommended.# Information about nivolumab with ipilimumab # Marketing authorisation indication Nivolumab (Opdivo, Bristol Myers Squibb) plus ipilimumab (Yervoy, Bristol Myers Squibb) has a marketing authorisation 'for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma'. # Dosage in the marketing authorisation Nivolumab and ipilimumab are administered intravenously. The recommended dose is 360 mg over 30 minutes every 3 weeks for nivolumab and 1 mg per kilogram over 30 minutes every 6 weeks for ipilimumab. Treatment continues for up to 24 months or until the disease progresses. More details are available in the summary of product characteristics for nivolumab. # Price The list price of nivolumab is £2,633 per 240‑mg, 24‑ml vial (excluding VAT; BNF online, accessed June 2022). The list price of ipilimumab is £15,000 per 200‑mg, 40‑ml vial (excluding VAT; BNF online, accessed June 2022). The company has separate commercial arrangements for nivolumab and ipilimumab. These make nivolumab and ipilimumab available to the NHS with discounts. The sizes of the discounts are commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discounts.# Committee discussion The appraisal committee considered evidence submitted by Bristol Myers Squibb, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Malignant pleural mesothelioma has a poor prognosis and there is an unmet need for new treatment options Malignant pleural mesothelioma is an aggressive cancer of the pleura, the mesothelial cells surrounding the lungs. Most cases are linked to occupational exposure to asbestos, and it typically presents 20 to 50 years after exposure. The UK banned asbestos in 1999, and is now experiencing what is considered to be a peak in cases of mesothelioma. Consultation comments noted that although mesothelioma was once a disease of men in industry, it is also now being seen in women and younger people. Symptoms include breathlessness, chest pain, fatigue, lethargy, weight loss and cough. Malignant pleural mesothelioma progresses quickly and has a poor prognosis, with 8% to 10% of patients alive after 3 years according to the UK National Mesothelioma Audit in 2020 and the National Cancer Analysis System registry. A clinical expert noted that people with the condition often have comorbidities, which may also affect survival. The most common histology is epithelioid; tumours with non-epithelioid histology, which includes sarcomatoid and combined sarcomatoid–epithelioid, are less common but more aggressive, and more poorly differentiated, than epithelioid tumours. Tumours with non-epithelioid histology are associated with higher symptom burden and poorer prognosis, and respond less well to current treatment options than tumours with epithelioid histology. The expression of PD‑L1 varies in malignant pleural mesothelioma. Current treatment of mesothelioma is platinum-doublet chemotherapy using pemetrexed with either cisplatin or carboplatin. A patient expert noted that immunotherapies such as nivolumab and ipilimumab offer hope for people with malignant pleural mesothelioma. The committee concluded that malignant pleural mesothelioma is an aggressive disease with a poor prognosis and there is an unmet need for new treatment options. # Tumour subtype testing ## Histological testing is routine in NHS practice The NHS tests for histological subtype of mesothelioma, but not for PD‑L1 status. The testing and scoring methods for PD‑L1 are not standardised in malignant pleural mesothelioma and threshold cut offs vary. There is also uncertainty about whether PD‑L1 expression is associated with disease prognosis. The Cancer Drugs Fund clinical lead stated that histological testing is routine and relatively straightforward. A clinical expert stated that occasionally tissue sampling can make histological subtyping difficult. The committee concluded that histological testing of mesothelioma is standard practice in the NHS but determining PD‑L1 status is not. # The company's positioning of nivolumab plus ipilimumab ## Chemotherapy is the only relevant comparator for nivolumab plus ipilimumab as a first-line treatment option The company proposes that nivolumab plus ipilimumab would offer an alternative to the standard first-line care of platinum-doublet chemotherapy using pemetrexed with either cisplatin or carboplatin. The patient experts noted that chemotherapy is associated with adverse events including nausea, vomiting, a sore mouth and alopecia. Some people may not be eligible for chemotherapy if they are frail or unable to travel for treatments, which would also apply to treatment with nivolumab plus ipilimumab. The company's pivotal trial (see section 3.4) included only people with an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1, so the company does not consider best supportive care a relevant comparator. A clinical expert noted that chemotherapy is not suitable for some people, or some may choose not to have chemotherapy. For these people, best supportive care and active symptom control are standard care. However, these people would be unlikely to be offered nivolumab plus ipilimumab. The clinical expert and the Cancer Drugs Fund clinical lead both considered that excluding best supportive care as a comparator was appropriate. The clinical expert noted that only 5% to 10% of people with the condition do not have chemotherapy. Raltitrexed was listed in the NICE scope, but the company excluded it as a comparator, arguing that it is not used in the UK. The clinical experts and the Cancer Drugs Fund clinical lead confirmed this. The committee concluded that the company's positioning of nivolumab plus ipilimumab as first-line treatment as an alternative to chemotherapy, the only relevant comparator, was appropriate. # Clinical evidence ## The company provided 2 interim data cuts for the Checkmate 743 trial The pivotal trial, CheckMate 743, is an ongoing, phase 3, randomised, controlled, open-label multicentre trial (n=605). The primary endpoint was overall survival. The company presented the committee with 2 interim data cuts. The first was an interim analysis planned at around 403 events (419 actual); this had a median follow up of 29.7 months and a minimum of 22.1 months (referred to as the '2‑year data'). After the committee's first meeting, the company provided a second analysis that was not included in the protocol; this had a median follow up of 43 months and a minimum of 35.5 months (referred to as the '3‑year data'). The company considered the number of deaths at the 3‑year follow up to be confidential so it cannot be reported here. The committee noted that this number was close to 473, which was the target number of events in the statistical analysis plan. The trial is ongoing and event driven; the company stated that although it had planned to stop the trial after at least 473 deaths, the trial will run until April 2023 so that the company can perform an analysis of 5‑year overall survival. ## The CheckMate 743 trial population is generalisable to people in UK clinical practice with ECOG scores of 0 or 1 Histological subtype was a stratification factor for randomisation in CheckMate 743, but the company stated that histological subtype was not a planned subgroup analysis. The trial enrolled adults with histologically confirmed epithelioid or non-epithelioid disease, and with an ECOG performance status of 0 or 1. It compared the treatment effect of nivolumab 3 mg per kg every 2 weeks plus ipilimumab 1 mg per kg every 6 weeks (n=303) with pemetrexed every 3 weeks, with the investigator's choice of adding either cisplatin or carboplatin to pemetrexed (n=302). Both treatments would stop if disease progressed, if there was unacceptable toxicity, after 2 years of treatment for nivolumab plus ipilimumab, or after 6 cycles of chemotherapy. The clinical experts considered that the trial population represented patients seen in the NHS, and that if recommended, nivolumab and ipilimumab would be offered only to people with an ECOG status of 0 or 1. The committee concluded that the trial population was generalisable to patients in UK clinical practice with an ECOG score of 0 or 1. ## The licensed fixed dose and weight-based dosing of nivolumab from the trial are likely to have similar efficacy The ERG noted that the trial used body weight-based dosing of nivolumab (see section 3.4), but that the company's model used fixed dosing (360 mg every 3 weeks) to align with nivolumab's marketing authorisation. The ERG considered the effectiveness and safety of fixed dosing to be unproven because the trial provided no evidence for fixed dosing. The patient expert noted that fixed dosing requires fewer visits to hospitals and is more convenient. The clinical experts and the Cancer Drugs Fund clinical lead noted that the efficacy of fixed and weight-based dosing is similar, and explained that fixed dosing is standard practice. The committee concluded that the trial's weight-based dosing for nivolumab and the licensed fixed dose are likely to have similar efficacy, and that it is appropriate to use fixed dosing in the economic model and any recommendations. ## The comparator used in Checkmate 743 reflects UK clinical practice for people with ECOG scores of 0 or 1 The committee understood that for people with ECOG performance status scores of 0 or 1, chemotherapy is the only relevant comparator (see section 3.3). The comparator in CheckMate 743 was pemetrexed plus either cisplatin or carboplatin based on investigator's choice. Among the people randomised to chemotherapy (n=302), about 66% had carboplatin and 34% had cisplatin. The ERG expressed concerns that the proportion of carboplatin compared with cisplatin used in the trial did not reflect the NICE scope and may not be generalisable to UK clinical practice. The NICE scope specified using pemetrexed with cisplatin, or carboplatin when cisplatin is unsuitable. The company provided evidence from different sources explaining that carboplatin is more widely used with pemetrexed and therefore the results in the trial represented UK practice. For example, the UK National Mesothelioma Audit in 2020, an audit of people diagnosed with mesothelioma between 2016 and 2018, reported carboplatin use in 48% of people compared with cisplatin in 20% of people with malignant pleural mesothelioma. The company considered the proportions of carboplatin and cisplatin from other sources to be confidential, so they cannot be reported here. The ERG noted that the proportions of carboplatin and cisplatin from the trial were different to those from the sources provided. The clinical experts noted that the choice between carboplatin and cisplatin is pragmatic; for example, carboplatin can be given over a shorter period of time, is less toxic, and is less expensive. The committee noted that using a 'blended comparator' could mask a clinically and cost-ineffective treatment. However, the clinical experts noted that adding carboplatin or cisplatin to pemetrexed has a similar treatment effect, and the Cancer Drugs Fund clinical lead noted that pemetrexed rather than carboplatin or cisplatin comprises the bulk of the cost of treatment. The committee concluded that proportions of cisplatin and carboplatin in the chemotherapy treatment arm in CheckMate 743 reflected UK clinical practice. It further concluded that any recommendation would be limited to people who were candidates for chemotherapy, that is, people with an ECOG score of 0 or 1. # Clinical effectiveness ## Nivolumab plus ipilimumab improves overall survival compared with chemotherapy, but its long-term treatment effect is uncertain The primary outcome of CheckMate 743 was overall survival. The sample size was set at 606 with a targeted power of 90% and an alpha of 0.05 (2‑sided) to detect a difference in mortality between the 2 treatments when 473 deaths occurred (see section 3.4) of a targeted hazard ratio (HR) 0.72. At the 2‑year data cut, with a median follow up of 29.7 months, 419 deaths had occurred (89% of 473 planned for statistical analysis); 98% of people taking nivolumab plus ipilimumab and all people on chemotherapy had stopped treatment. At the 3‑year data cut, the median follow up was 43 months after people had stopped treatment for at least 1 year (see section 3.4). The company considered the number of deaths at 3‑year follow up to be confidential, but explained that 23% (70 out of 303) of people who had treatment with nivolumab plus ipilimumab and 15% (45 out of 302) who had treatment with chemotherapy were alive (numerators estimated from percentages). Results from both the interim and post-hoc analyses showed that median overall survival was 18.1 months for nivolumab plus ipilimumab and 14.1 months for chemotherapy. Nivolumab plus ipilimumab was associated with longer overall survival than chemotherapy at both the 2‑year (HR 0.74, 95% confidence interval 0.60 to 0.91) and 3‑year follow up (HR 0.73, 95% CI 0.61 to 0.87). The company explained that the data suggested the treatment effect of nivolumab plus ipilimumab was largely maintained at 3‑year follow up, and the ERG agreed. The committee noted that overall survival with chemotherapy was around 20% at 3 years on the Kaplan–Meier curve of the trial data. This was much higher than the 8% to 10% survival at 3 years from the UK registry and UK audit data provided by the company (see section 3.1). The Cancer Drugs Fund clinical lead noted that the epidemiological data sources, for example the Cancer Analysis System, were from as far back as 2013. He noted that mesothelioma management has evolved, so survival rates have likely improved, which could explain the difference between the overall survival results for chemotherapy in the trial and the registry and audit data. A consultation comment suggested that the lower survival in the registry may be because the registry includes people with worse performance status (ECOG performance status of 2 or 3). The ERG noted that there was little change to the hazard ratio at the 3‑year data cut, but that there was still uncertainty because people are alive beyond the observed period. The committee noted the sustained benefit from the 2- and 3‑year data cuts and the relatively short follow up of the trial. It concluded that nivolumab plus ipilimumab reduces the risk of death in people with malignant pleural mesothelioma compared with chemotherapy, but there is uncertainty about its long-term treatment effect. ## Nivolumab plus ipilimumab might improve progression-free survival but the evidence is uncertain Progression-free survival was a secondary outcome in CheckMate 743. Disease progression was determined by blinded independent central review. Results from the 2- and 3‑year data cuts showed median progression-free survival was 6.8 months for nivolumab plus ipilimumab and 7.2 months for chemotherapy. Both data cuts showed no difference between the 2 treatments according to hazard ratio estimates, but benefits started to appear at the 3‑year data cut: at the 2‑year data cut, the hazard ratio was 1.00 (95% CI 0.82 to 1.21; median follow up 29.7 months), but at the 3‑year data cut the hazard ratio was 0.92 (95% CI 0.76 to 1.11; median follow up 43 months). The ERG also noted that 14% of people whose cancer was treated with nivolumab plus ipilimumab and 1% whose cancer was treated with chemotherapy remained progression free at 3 years. During its first meeting, the committee questioned the clinical relevance of progression-free survival in mesothelioma and its use in modelling because of the lack of evidence on nivolumab plus ipilimumab's treatment effect on this outcome at the 2‑year data cut. It also noted that the Kaplan–Meier curves by treatment allocation crossed, and although the company analysed the results in the model assuming non-proportional hazards (see section 3.17), the hazard ratio estimated from the trial assumed proportional hazards and was of limited value. The company explained that progression-free survival determined radiographically is not a reliable endpoint in mesothelioma because tumours may not have demarcated margins. It noted that the initial response to chemotherapy may reflect an 'early but transient' effect compared with a 'delayed but durable' effect of immunotherapy. It further explained that the progression-free survival benefit of nivolumab plus ipilimumab will only show in longer-term data. It noted that this was starting to show in the 3‑year data, with 28% of people whose disease responded to nivolumab plus ipilimumab still 'in response' compared with no one who had treatment with chemotherapy. The company also explained at the second meeting that it is useful to measure progression-free survival because it can provide an element of quality of life. The committee understood that there might be some delayed but durable response to the treatment in the longer term, which may benefit survival. However, because of the non-proportional hazards as suggested by the Kaplan–Meier curves of the trial, the committee considered that the hazard ratios over time implied by the company's selected parametric distributions in modelling should be explored (see section 3.17). The committee concluded that the evidence from CheckMate 743 showed that nivolumab plus ipilimumab may improve progression-free survival compared with chemotherapy, but there is some uncertainty in the evidence. ## The effect of nivolumab plus ipilimumab compared with chemotherapy is modified by histological subtype The company presented evidence on the treatment effect of nivolumab plus ipilimumab compared with chemotherapy by histological subtype and by PD‑L1 status. Results from the 2- and 3‑year data cuts showed that nivolumab plus ipilimumab lowered mortality in the non-epithelioid group (median overall survival 18.1 months) compared with chemotherapy (median overall survival 8.8 months): HR 0.46, 95% CI 0.31 to 0.68 at the 2‑year data cut and HR 0.48, 95% CI 0.34 to 0.69 at the 3‑year data cut. For epithelioid disease, median overall survival reduced slightly from 18.7 months at the 2‑year data cut to 18.2 months at the 3‑year data cut in the nivolumab plus ipilimumab arm. It increased slightly from 16.5 months to 16.7 months in the chemotherapy arm: HR 0.86, 95% CI 0.69 to 1.08 at the 2‑year data cut and 0.85, 95% CI 0.69 to 1.04 at the 3‑year data cut. During its first meeting, the committee noted that the treatment effect of nivolumab plus ipilimumab may be modified by histology subtype. It therefore asked the company to provide the results of a statistical analysis testing the interaction between treatment effect and histology subtype. The company provided these results during consultation, which suggested a highly significant interaction between treatment effect and histological subtype. The company noted that the trial was not powered for subgroup analyses and that these analyses were descriptive in nature. The committee, however, noted that in a small sample size, a false negative interaction test is more of a concern than a false positive. The committee noted that the Kaplan–Meier curves for epithelioid and non-epithelioid disease were similar for nivolumab plus ipilimumab (median overall survival 18.1 and 18.2 months, respectively, at 3 years), but that non-epithelioid tumours responded less well to chemotherapy. However, the committee recalled its remit to compare treatments with standard care. The committee concluded that the effect of nivolumab plus ipilimumab compared with chemotherapy is likely modified by histological subtype. The committee was also aware of its remit to appraise the technology across its indication-specific marketing authorisation and took this into account during its decision making. ## PD-L1 status is not tested routinely in the NHS, so is not considered in decision making Evidence from CheckMate 743 also showed a possible effect of PD‑L1 status on mortality at the 2‑year data cut, based on positive PD‑L1 tumours (using a threshold of 1% or greater) or negative PD‑L1 tumours, for nivolumab plus ipilimumab compared with chemotherapy. Because testing of PD‑L1 in mesothelioma is not routine in the NHS (see section 3.2), the committee concluded that it was not appropriate to consider it when making recommendations. ## Nivolumab plus ipilimumab may improve quality of life CheckMate 743 measured patient quality of life using the 3‑level EQ‑5D (EQ‑5D‑3L) instrument. In England, EQ‑5D utility index scores range from -0.594 to 1, with higher scores indicating better quality of life. The company considered a change of 0.08 in the score of EQ‑5D‑3L utility index from baseline to be 'clinically meaningful' in malignant pleural mesothelioma. The company based this estimate on a randomised controlled trial (Sarna et al. 2008). This trial assessed the impact on the quality of life of people with advanced non-small-cell lung cancer of adding amifostine to radiation therapy plus chemotherapy compared with not adding it. Results from CheckMate 743 suggested that, at the 2‑year data cut, the mean score of the EQ‑5D‑3L utility index increased over time in the nivolumab plus ipilimumab arm, from 0.70 (standard deviation 0.27) at baseline to 0.84 (SD 0.20) at week 72. In the chemotherapy arm, it remained relatively stable from baseline (mean 0.71 ) but started deteriorating from week 30 (mean 0.70 ), and the trend of deterioration continued onwards. The ERG noted that the trends suggested stability or improvement in quality of life for nivolumab plus ipilimumab and deterioration for chemotherapy. The committee acknowledged the trend for quality-of-life improvement for nivolumab plus ipilimumab, but noted that the company did not report a group difference in EQ‑5D‑3L utility scores from baseline at the 2‑year data cut. Also, it was not clear how the clinically meaningful change of 0.08 was defined because it was based on a single study and was in people with advanced non-small-cell lung cancer. Considering the evidence, the committee concluded that nivolumab plus ipilimumab may improve quality of life compared with chemotherapy. # Adverse events ## The safety profile of nivolumab plus ipilimumab is acceptable Evidence on adverse events was from the 2‑year data cut of CheckMate 743. The company did not present additional data at the trial's 3‑year data cut. The results showed that, at the 2‑year data cut, more people (55%; 164 out of 300) on nivolumab plus ipilimumab experienced severe treatment-related adverse events than those on chemotherapy (25%; 72 out of 284; p value not reported). Stopping because of drug toxicity was more frequent in the nivolumab plus ipilimumab arm (23%; 69 out of 300) compared with the chemotherapy arm (16%; 45 out of 284; p value not reported). The most common adverse events with nivolumab plus ipilimumab were diarrhoea and pruritis. Respiratory tract infections were more common with chemotherapy. The company noted that most treatment-related adverse events and immune-mediated adverse events had resolved at the time of the database lock, but that endocrine-related events had not. The ERG noted that 3 people died from drug toxicity after having nivolumab plus ipilimumab because of pneumonitis, encephalitis and heart failure, compared with 1 person who had treatment with chemotherapy because of myelosuppression. The committee concluded that the safety profile of nivolumab plus ipilimumab was acceptable. # Second-line treatments ## Second-line treatments used in Checkmate 743 do not reflect UK clinical practice For the 3‑year data cut, the company provided only the percentages rather than the numbers of people who had second-line treatments, and could not provide these numbers during the committee meeting. The data suggested that, at 3‑year follow up, 45% (137 out of 303) of people randomised to nivolumab plus ipilimumab and 42% (128 out of 302) of people randomised to chemotherapy had second-line treatments after disease progression (numerators estimated from percentages). From the same data cut, among the people randomised to nivolumab plus ipilimumab, about 4% (12 out of 303) had immunotherapy as second-line treatment compared with 22% (65 out of 302) of the people randomised to chemotherapy (numerators estimated from percentages). Also, at the 3‑year data cut, about 43% (131 out of 303) of the people randomised to nivolumab plus ipilimumab had chemotherapy as second-line treatment compared with 33% (100 out of 302) of people randomised to chemotherapy (numerators estimated from percentages). The ERG was concerned that the second-line treatments in CheckMate 743, particularly immunotherapies, do not represent UK clinical practice. The company explained that because more people who initially had treatment with chemotherapy had immunotherapy as their second-line treatment in the trial, the trial underestimated the true treatment effect of nivolumab plus ipilimumab compared with chemotherapy (see also section 3.23). The Cancer Drugs Fund clinical lead noted that despite nivolumab having been used as second-line treatment for malignant pleural mesothelioma during the COVID‑19 pandemic, it is not routinely available in the UK as a second-line treatment. The committee also noted that the NHS does not offer immunotherapy twice in practice. The company explained that the proportions of people having second-line treatments in the trial were similar to those reported in the English National Cancer Analysis System registry. This is a retrospective cohort of people with malignant pleural mesothelioma diagnosed in England between 2013 and 2017. In this registry, 44% had second-line chemotherapy, 24% had second-line vinorelbine and 19% had second-line treatment in a clinical trial. The ERG noted that these proportions were different from those in the trial, in which 16% had pemetrexed and 8% had vinorelbine as second-line treatment. The clinical experts also noted that currently there are no defined second-line treatments for the condition and their treatment effects remain unclear. The committee concluded that the second-line treatments used in CheckMate 743, particularly the immunotherapies, did not represent UK clinical practice. # Stopping rule ## A 2-year stopping rule for nivolumab plus ipilimumab and a 6-cycle stopping rule for chemotherapy is appropriate In CheckMate 743, people stopped treatment with nivolumab plus ipilimumab after 2 years if they had not already stopped treatment because of progression or unacceptable toxicity. The stopping rule did not depend on disease progression. The committee appreciated that chemotherapy was associated with a 6‑cycle stopping rule to limit toxicity. The ERG noted that in the CheckMate 743 trial, some people had nivolumab plus ipilimumab for longer than 2 years. The ERG was concerned that if the stopping rule were not feasible in clinical practice, it may affect the clinical and cost effectiveness. After the first committee meeting, the company noted that 2 people remained on treatment beyond 24 months, because they had a delay in the final dose, but did not have additional doses. It considered the impact negligible. The committee considered this reasoning acceptable. The Cancer Drugs Fund clinical lead noted that if recommended, the NHS would only fund treatment for up to 2 years in clinical practice. The committee noted that the stopping rule for nivolumab plus ipilimumab is included in the marketing authorisation for the combined therapy. It concluded that the stopping rules for nivolumab plus ipilimumab and chemotherapy were appropriate and would be applied in clinical practice. # The economic model ## The model structure is acceptable, but the extrapolations are uncertain The company made the case that people having treatment with nivolumab plus ipilimumab accrue more quality-adjusted life years (QALYs) than people on chemotherapy. This is because they live longer, and have a higher quality of life because their disease takes longer to progress. The company used a partitioned survival model to estimate the cost effectiveness of nivolumab plus ipilimumab compared with chemotherapy. The model included 3 health states: progression-free, progressed, and dead. The probability of being in a given health state was defined by the area under the curves for progression-free survival, overall survival, and their difference. The cycle length was 1 week, and the time horizon was 20 years. The ERG noted that the company's model structure was consistent with the approach adopted in previous NICE technology appraisals in oncology, and accounted for the CheckMate 743 trial's primary (overall survival) and secondary (progression-free survival) endpoints. However, it was concerned that in the model, a substantial proportion of life years and progression-free life years accrued in the nivolumab plus ipilimumab arm during the extrapolated period. During its first meeting, the committee noted that this was not supported by the evidence from CheckMate 743 at the 2‑year data cut and questioned the clinical relevance of progression-free survival. The committee recalled that the company noted that progression-free survival improves quality of life for people in this health state. The ERG had provided analyses showing that most of the life-year gains in the model were from the progression-free period. However, the committee noted that there was still a large proportion of life years and progression-free life years accrued from the extrapolated period when using the 3‑year data. The 3‑year data cut showed that the treatment effect of nivolumab plus ipilimumab was largely maintained (see sections 3.8 and 3.9), but there was no evidence on how long it would last. The committee was aware that an alternative model structure would be subject to the same uncertainties. It concluded that the company's model structure was acceptable for decision making, but that there were uncertainties in the company's extrapolations. # Modelling survival ## The committee asked for further information on hazard ratios for overall survival over time, and treatment effect over time The company assumed non-proportional hazards for overall survival because nivolumab plus ipilimumab and chemotherapy have different mechanisms of action. It fitted parametric distributions to the 2 arms separately to extrapolate overall survival beyond the trial data. It also used data from the chemotherapy arm of the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) trial to validate the overall survival extrapolations for the chemotherapy arm. For the nivolumab plus ipilimumab arm, the company considered that the survival probability would be higher than that of the chemotherapy arm of the MAPS trial because of nivolumab plus ipilimumab's survival benefits over chemotherapy in CheckMate 743. MAPS is an ongoing, randomised, controlled, open-label trial comparing bevacizumab plus chemotherapy with chemotherapy alone in people with newly diagnosed pleural mesothelioma (median follow up 39 months). At baseline, 97% (433 out of 448) of people had an ECOG status of 0 or 1, and 81% (361 out of 448) of people had epithelioid disease compared with 19% (87 out of 448) with non-epithelioid disease. The committee noted that the MAPS study also included people with an ECOG status of 2, who were potentially at higher risk of death than people in CheckMate 743 (which excluded people with an ECOG status of 2). Data from the MAPS trial showed that the modelled hazard function should first increase, then decrease in the long term, and that survival on chemotherapy was 8% at 5 years and 0% at 10 years. To extrapolate treatment effects for the nivolumab plus ipilimumab arm, both the company and ERG agreed that the log-logistic distribution provided clinically plausible predictions and was the most appropriate. However, the committee noted that at the end of the modelled time period, the log-logistic distribution predicted better survival in the nivolumab plus ipilimumab arm than other distributions. The ERG also noted that the extrapolated overall survival from the log-logistic distribution was higher than the Kaplan–Meier curve from the trial. For the chemotherapy arm, the company preferred a 1‑knot spline normal model when including data from the 3‑year data cut. This model predicted survival at 5 years to be 5.2%, which the company considered was aligned with its clinical expert's estimate (5%). The clinical expert at the first meeting, who had also advised the company, expected survival of about 5% at 5 years, and 2% at 10 years in the chemotherapy arm. The ERG preferred a log-logistic model for both arms, noting that the hazard functions for both arms should be the same, both initially increasing followed by a long-term decreasing hazard. The committee recalled that nivolumab plus ipilimumab's treatment effect on overall survival may be maintained, but there was uncertainty in how long it will last (see section 3.8). Because the treatment might be associated with a survival benefit that was not yet seen in the data (see section 3.9), the committee asked to see the hazard ratios for overall survival over time implied by both the company and ERG's independent distributions, as well as the treatment effect over time as implied by the observed trial data. ## Using a log-logistic distribution to extrapolate overall survival for both treatments may be appropriate but there are uncertainties In response, the company plotted the hazard ratios implied by both the company and ERG's preferred extrapolations for overall survival, alongside the smoothed hazard ratio and its 95% confidence intervals based on the observed data from CheckMate 743. The figure indicated that the hazard ratios implied by the selected distributions, as well as the smoothed hazard ratio based on observed trial data, fluctuated over time but were all below 1, and the 95% confidence interval of the smoothed hazard ratio was wide. The company stated that the plotted hazard ratios over time showed sustained treatment effect and the selected distributions aligned with the smoothed hazard ratio. However, the ERG commented that neither extrapolation could be ruled out and that they may not be so informative, especially given the increasingly wide confidence interval at the end of the smoothed hazard ratio. The committee noted the implied treatment effects in the longer term were based on a small number of patients. It also noted the high uncertainty beyond 24 months, at which point the extrapolated curves started to diverge. The committee noted that there were minor differences between the company and ERG's extrapolations, and that the ERG's extrapolations indicated a smaller treatment effect over time and were more reasonable. The committee concluded that the log-logistic distribution was appropriate for extrapolating overall survival in both arms, but that how long the treatment effect would continue in the long term was uncertain. ## The company's parametric distributions for extrapolating progression-free survival are appropriate The company fitted independent parametric distributions to model progression-free survival in the 2 treatment arms guided by the best statistical and visual fit to the Kaplan–Meier curve of CheckMate 743. The company and ERG agreed that for extrapolating progression-free survival, the generalised gamma distribution was appropriate for nivolumab plus ipilimumab, and the log-logistic distribution was appropriate for chemotherapy. However, the ERG was concerned that a substantial proportion of progression-free life years accrued beyond the observed data in the model, extrapolated from either the 2- or 3‑year data cuts (see section 3.16). The committee noted that, at the 3‑year data cut, the evidence from CheckMate 743 appeared to show some benefit of nivolumab plus ipilimumab in the period before progression. The evidence also suggested there may be a continued response to treatment and a survival benefit (see section 3.9). Given that there was no long-term evidence, the committee also looked at the hazard ratios for progression-free survival over time implied by the extrapolation agreed between the company and ERG, as well as the treatment effect over time as implied by the observed trial data. The company provided these figures, which were all below 1, suggesting the treatment effect may be maintained. The committee noted that the hazard ratios implied by the company and the ERG's preferred distributions were largely aligned with the smoothed hazard ratio and within the bounds of its 95% confidence interval. However, it also noted the uncertainties, given the short follow up of the trial and the fact that the extrapolations were based on a small number of patients. The committee concluded that it was appropriate to use the generalised gamma distribution to extrapolate progression-free survival for nivolumab plus ipilimumab, and use the log-logistic for chemotherapy. ## It is reasonable to assume some treatment effect waning The company's base case predicted survival for the 20‑year horizon of the model based on independently fitted models for overall survival; the company did not factor waning of treatment effect into the analysis. The ERG considered that this was not reasonable in the absence of long-term clinical experience. It noted that the company based its argument on expert opinion, but it was not clear how the company chose the experts or elicited their opinion. The ERG considered it appropriate to assume that the treatment effect would wane 5 years after treatment starts and 3 years after treatment stops. It acknowledged that this duration was arbitrary, but had been accepted in other NICE technology appraisals, including NICE's technology appraisal guidance on nivolumab for treating recurrent or metastatic squamous cell carcinoma of the head and neck after platinum-based chemotherapy. During its first meeting, the committee also noted the evidence presented by the company in its response to clarification questions, which suggested that the treatment effect of immunotherapies is maintained for up to 4 years in non-small-cell lung cancer (Antonia et al. 2019). However, the Cancer Drugs Fund clinical lead noted that some tumours treated with immunotherapies relapsed. The committee considered that there appeared to be a continuing benefit after stopping treatment, but it was unclear how long it would last, so it would be reasonable to assume some treatment effect waning. ## When nivolumab plus ipilimumab is stopped at 2 years, it is acceptable to assume an additional survival benefit for 3 more years At the committee's second meeting, the company provided 6 scenario analyses that assumed treatment effect waning at 5, 7, or 10 years after starting treatment (with a duration of treatment effect waning of 5 or 10 years for each). All of the scenarios worsened the cost-effectiveness estimates, and the longer after starting the treatment the waning occurred, the better the cost-effectiveness estimate. The committee recalled the uncertainties around the treatment effects over time as implied by the company and ERG's extrapolations for overall survival (see section 3.18) and progression-free survival (see section 3.19). It was also aware that most people in the CheckMate 743 trial had died by the 3‑year data cut (see section 3.8). It therefore did not consider it reasonable to rule out the possibility of treatment effect waning in the model. The Cancer Drugs Fund clinical lead noted that treatment effect waning 5 years after starting treatment has been accepted in previous NICE technology appraisals for immunotherapies in which there was a 2‑year stopping rule. Considering this and the uncertainties in the evidence base, the committee concluded that it is acceptable to assume that if the treatment is stopped at 2 years, it is likely that its survival benefit would continue for 3 more years, and treatment waning could reasonably start at this point. # Utility values ## Using treatment-dependent utility benefits up to 3 years is appropriate The company used patient-level data on utility from CheckMate 743 to estimate the utility values for the progression-based health states in the model. The company's analysis showed that having treatment or not significantly impacted utility values. The company therefore adopted treatment-dependent health state utilities in its base case and assumed that the treatment-dependent utility benefits would last for the whole duration of the time horizon. The ERG considered that implausible. For its base case, the ERG adopted treatment-dependent utilities (with the nivolumab plus ipilimumab utility benefit) for up to 3 years, and treatment-independent utilities after this. The ERG chose 3 years because only 3 people were at risk of death at 3 years in the trial according to the evidence at the 2‑year data cut that the company presented at the first committee meeting (see section 3.8). The company adopted the ERG's assumption after technical engagement. The committee agreed that using treatment-dependent utility benefits up to 3 years and treatment-independent utilities afterwards was appropriate. # Adjusting for second-line treatments ## It is appropriate to use the inverse probability censoring weights method to adjust for second-line treatments not used in the NHS The company modelled second-line treatment based on the distribution of the second-line treatments used in CheckMate 743, but these treatments did not reflect UK clinical practice (see section 3.14). Second-line treatments used in the trial included pemetrexed, carboplatin, cisplatin, gemcitabine, vinorelbine, bevacizumab and several immunotherapies (nivolumab, ipilimumab, pembrolizumab). During its first meeting, the committee suggested that the company adjust the overall survival results and remove the costs for second-line treatments that do not reflect NHS practice and may be associated with improving survival. After consultation, the company presented analyses adjusting for second-line treatment using 4 methods: inverse probability censoring weights (IPCW), 2‑stage estimation, rank preserving structural failure time model (RPSFTM), and iterative parameter estimation. The company preferred the IPCW method because it addresses informative censoring. It did not prefer the RPSFTM and iterative parameter estimation methods because they assume the same treatment effect for all patients regardless of when they have treatment, or the 2‑stage estimation method because it could result in informative censoring when patients do not die during the study. The ERG did not critique the company's methods in detail but noted that the methods were appropriate and the results were similar across the different methods. Because of the lack of reporting, the committee asked to see further details of the methods considered. The company provided these details at the second committee meeting. It also removed all non-NHS second-line treatment costs from both arms. The committee's discussion on adjusting for second-line non-NHS-treatments focused on the intention-to-treatment population during its second meeting. It noted that, for the intention-to-treat population, the company still preferred the IPCW method for its base case. The ERG agreed that theoretically the IPCW method was preferable, but stated that all methods gave similar results. The committee concluded that the IPCW method may be appropriate for adjusting for second-line non-NHS treatments for the intention-to-treat population, but that it was based on important assumptions around there being no unmeasured confounding. # End of life ## Nivolumab plus ipilimumab is likely to meet NICE's end of life criteria for the population in the marketing authorisation The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The Cancer Analysis System registry reported 13‑month median survival with first-line chemotherapy. Median overall survival was 14 months with chemotherapy in CheckMate 743 for people who had an ECOG status of 0 or 1; and mean overall survival for chemotherapy estimated from the model was about 20 months. Overall survival in the chemotherapy arm in the ERG base case was up to 21 months. The committee agreed that life expectancy for people with unresectable malignant pleural mesothelioma who have standard care is likely to be less than 24 months. Results from CheckMate 743 showed a median 4‑month survival benefit for nivolumab plus ipilimumab compared with chemotherapy at a median 43‑month follow up. The ERG base case also supported a mean survival gain of greater than 3 months. The committee acknowledged that these survival estimations were based on the company and ERG base cases, so there was an element of uncertainty. But it concluded that nivolumab plus ipilimumab was likely to meet the end of life criteria for untreated unresectable malignant pleural mesothelioma for the population in the marketing authorisation. # Cost effectiveness ## The cost-effectiveness estimates are within the range considered an acceptable use of NHS resources The patient access schemes for the comparator treatments mean that the costs and cost-effectiveness estimates are confidential and cannot be presented. Taking into account the end of life criteria, the committee noted that the incremental cost-effectiveness ratio (ICER) that reflected its preferred assumptions was less than £50,000 per QALY gained for the intention-to-treat population. It concluded that the ICER for nivolumab plus ipilimumab for treating malignant pleural mesothelioma is within the range normally considered a cost-effective use of NHS resources. # Conclusions ## Nivolumab plus ipilimumab is recommended for routine use in the NHS The committee concluded that it could recommend nivolumab plus ipilimumab for treating malignant pleural mesothelioma. # Equality issues ## There are no equality issues related to protected characteristics The committee considered several potential equalities issues raised by stakeholders: The condition is a preventable occupational-related disease with a higher incidence in heavy industries. People with the condition may have lower socioeconomic status than people with other cancer types. People with mesothelioma are often old, and the cancer is diagnosed at a late stage when they can be too frail to travel for treatment. This may limit their treatment options. Some people are unable to self-fund or do not have access to funding from compensation claims.The committee noted the prevalence of mesothelioma in certain areas of the country. It noted that people too frail to travel would be unlikely to be offered treatment (see section 3.3). It was aware that the prevalence of a disease, physical access to the treatment, and socioeconomic status are not protected characteristics and are therefore not within NICE's remit when making recommendations. The technology will be available for all people regardless of age, geographical location and socioeconomic status. The committee concluded that these are not equality issues. ## Guidance for pleural mesothelioma should also cover mesothelioma of the pericardium or peritoneum The committee heard from the Cancer Drugs Fund clinical lead that, rarely, mesotheliomas can occur in the pericardium or peritoneum. They noted that any guidance for pleural mesothelioma should extend to these individuals. The committee agreed. # Innovation ## Nivolumab plus ipilimumab is not innovative NICE defines innovation as a 'step-change' in treatment with benefits not accounted for in the modelling. The company considers nivolumab plus ipilimumab innovative because it is the first-in-class immunotherapy for a condition for which there have been no new therapies in the last 2 decades. The clinical experts considered it a step-change in treatment. The committee agreed, but did not hear of any additional gains in health-related quality of life not already captured in the modelling. A clinical expert noted that the cost-effectiveness estimates may not capture the benefit of nivolumab plus ipilimumab in reducing anger about having an occupational disease, but the committee was not presented with evidence for this. The committee concluded that the technology may be a step-change in treatment, but it did not identify benefits not captured by the company's economic modelling. It therefore considered that nivolumab plus ipilimumab is not innovative for untreated unresectable malignant pleural mesothelioma.	{'Recommendations': "Nivolumab plus ipilimumab is recommended as an option for untreated unresectable malignant pleural mesothelioma in adults, only if:\n\nthey have an Eastern Cooperative Oncology Group (ECOG) performance status of 0\xa0or\xa01\n\nthe company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with nivolumab plus ipilimumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard care for untreated unresectable malignant pleural mesothelioma is chemotherapy.\n\nThe clinical trial evidence was in people with an ECOG performance status of 0 or 1. It suggests that nivolumab plus ipilimumab is likely to extend how long people live compared with chemotherapy.\n\nNivolumab plus ipilimumab likely meets NICE's criteria for being a life-extending treatment at the end of life. Taking this into account, the cost-effectiveness estimates for nivolumab plus ipilimumab were within the range that NICE normally considers an acceptable use of NHS resources. So, it is recommended.", 'Information about nivolumab with ipilimumab': "# Marketing authorisation indication\n\nNivolumab (Opdivo, Bristol Myers Squibb) plus ipilimumab (Yervoy, Bristol Myers Squibb) has a marketing authorisation 'for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma'.\n\n# Dosage in the marketing authorisation\n\nNivolumab and ipilimumab are administered intravenously. The recommended dose is 360\xa0mg over 30\xa0minutes every 3\xa0weeks for nivolumab and 1\xa0mg per kilogram over 30\xa0minutes every 6\xa0weeks for ipilimumab. Treatment continues for up to 24\xa0months or until the disease progresses. More details are available in the summary of product characteristics for nivolumab.\n\n# Price\n\nThe list price of nivolumab is £2,633 per 240‑mg, 24‑ml vial (excluding VAT; BNF online, accessed June\xa02022). The list price of ipilimumab is £15,000 per 200‑mg, 40‑ml vial (excluding VAT; BNF online, accessed June\xa02022). The company has separate commercial arrangements for nivolumab and ipilimumab. These make nivolumab and ipilimumab available to the NHS with discounts. The sizes of the discounts are commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bristol Myers Squibb, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Malignant pleural mesothelioma has a poor prognosis and there is an unmet need for new treatment options\n\nMalignant pleural mesothelioma is an aggressive cancer of the pleura, the mesothelial cells surrounding the lungs. Most cases are linked to occupational exposure to asbestos, and it typically presents 20 to 50\xa0years after exposure. The UK banned asbestos in 1999, and is now experiencing what is considered to be a peak in cases of mesothelioma. Consultation comments noted that although mesothelioma was once a disease of men in industry, it is also now being seen in women and younger people. Symptoms include breathlessness, chest pain, fatigue, lethargy, weight loss and cough. Malignant pleural mesothelioma progresses quickly and has a poor prognosis, with 8% to 10% of patients alive after 3\xa0years according to the UK National Mesothelioma Audit in 2020 and the National Cancer Analysis System registry. A clinical expert noted that people with the condition often have comorbidities, which may also affect survival. The most common histology is epithelioid; tumours with non-epithelioid histology, which includes sarcomatoid and combined sarcomatoid–epithelioid, are less common but more aggressive, and more poorly differentiated, than epithelioid tumours. Tumours with non-epithelioid histology are associated with higher symptom burden and poorer prognosis, and respond less well to current treatment options than tumours with epithelioid histology. The expression of PD‑L1 varies in malignant pleural mesothelioma. Current treatment of mesothelioma is platinum-doublet chemotherapy using pemetrexed with either cisplatin or carboplatin. A patient expert noted that immunotherapies such as nivolumab and ipilimumab offer hope for people with malignant pleural mesothelioma. The committee concluded that malignant pleural mesothelioma is an aggressive disease with a poor prognosis and there is an unmet need for new treatment options.\n\n# Tumour subtype testing\n\n## Histological testing is routine in NHS practice\n\nThe NHS tests for histological subtype of mesothelioma, but not for PD‑L1 status. The testing and scoring methods for PD‑L1 are not standardised in malignant pleural mesothelioma and threshold cut offs vary. There is also uncertainty about whether PD‑L1 expression is associated with disease prognosis. The Cancer Drugs Fund clinical lead stated that histological testing is routine and relatively straightforward. A clinical expert stated that occasionally tissue sampling can make histological subtyping difficult. The committee concluded that histological testing of mesothelioma is standard practice in the NHS but determining PD‑L1 status is not.\n\n# The company's positioning of nivolumab plus ipilimumab\n\n## Chemotherapy is the only relevant comparator for nivolumab plus ipilimumab as a first-line treatment option\n\nThe company proposes that nivolumab plus ipilimumab would offer an alternative to the standard first-line care of platinum-doublet chemotherapy using pemetrexed with either cisplatin or carboplatin. The patient experts noted that chemotherapy is associated with adverse events including nausea, vomiting, a sore mouth and alopecia. Some people may not be eligible for chemotherapy if they are frail or unable to travel for treatments, which would also apply to treatment with nivolumab plus ipilimumab. The company's pivotal trial (see section\xa03.4) included only people with an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1, so the company does not consider best supportive care a relevant comparator. A clinical expert noted that chemotherapy is not suitable for some people, or some may choose not to have chemotherapy. For these people, best supportive care and active symptom control are standard care. However, these people would be unlikely to be offered nivolumab plus ipilimumab. The clinical expert and the Cancer Drugs Fund clinical lead both considered that excluding best supportive care as a comparator was appropriate. The clinical expert noted that only 5% to 10% of people with the condition do not have chemotherapy. Raltitrexed was listed in the NICE scope, but the company excluded it as a comparator, arguing that it is not used in the UK. The clinical experts and the Cancer Drugs Fund clinical lead confirmed this. The committee concluded that the company's positioning of nivolumab plus ipilimumab as first-line treatment as an alternative to chemotherapy, the only relevant comparator, was appropriate.\n\n# Clinical evidence\n\n## The company provided 2 interim data cuts for the Checkmate\xa0743 trial\n\nThe pivotal trial, CheckMate\xa0743, is an ongoing, phase\xa03, randomised, controlled, open-label multicentre trial (n=605). The primary endpoint was overall survival. The company presented the committee with 2 interim data cuts. The first was an interim analysis planned at around 403 events (419 actual); this had a median follow\xa0up of 29.7\xa0months and a minimum of 22.1\xa0months (referred to as the '2‑year data'). After the committee's first meeting, the company provided a second analysis that was not included in the protocol; this had a median follow up of 43\xa0months and a minimum of 35.5\xa0months (referred to as the '3‑year data'). The company considered the number of deaths at the 3‑year follow up to be confidential so it cannot be reported here. The committee noted that this number was close to 473, which was the target number of events in the statistical analysis plan. The trial is ongoing and event driven; the company stated that although it had planned to stop the trial after at least 473 deaths, the trial will run until April 2023 so that the company can perform an analysis of 5‑year overall survival.\n\n## The CheckMate\xa0743 trial population is generalisable to people in UK clinical practice with ECOG scores of 0 or 1\n\nHistological subtype was a stratification factor for randomisation in CheckMate\xa0743, but the company stated that histological subtype was not a planned subgroup analysis. The trial enrolled adults with histologically confirmed epithelioid or non-epithelioid disease, and with an ECOG performance status of 0 or 1. It compared the treatment effect of nivolumab 3\xa0mg per kg every 2\xa0weeks plus ipilimumab 1\xa0mg per kg every 6\xa0weeks (n=303) with pemetrexed every 3\xa0weeks, with the investigator's choice of adding either cisplatin or carboplatin to pemetrexed (n=302). Both treatments would stop if disease progressed, if there was unacceptable toxicity, after 2\xa0years of treatment for nivolumab plus ipilimumab, or after 6\xa0cycles of chemotherapy. The clinical experts considered that the trial population represented patients seen in the NHS, and that if recommended, nivolumab and ipilimumab would be offered only to people with an ECOG status of 0 or 1. The committee concluded that the trial population was generalisable to patients in UK clinical practice with an ECOG score of 0 or 1.\n\n## The licensed fixed dose and weight-based dosing of nivolumab from the trial are likely to have similar efficacy\n\nThe ERG noted that the trial used body weight-based dosing of nivolumab (see section\xa03.4), but that the company's model used fixed dosing (360\xa0mg every 3\xa0weeks) to align with nivolumab's marketing authorisation. The ERG considered the effectiveness and safety of fixed dosing to be unproven because the trial provided no evidence for fixed dosing. The patient expert noted that fixed dosing requires fewer visits to hospitals and is more convenient. The clinical experts and the Cancer Drugs Fund clinical lead noted that the efficacy of fixed and weight-based dosing is similar, and explained that fixed dosing is standard practice. The committee concluded that the trial's weight-based dosing for nivolumab and the licensed fixed dose are likely to have similar efficacy, and that it is appropriate to use fixed dosing in the economic model and any recommendations.\n\n## The comparator used in Checkmate\xa0743 reflects UK clinical practice for people with ECOG scores of 0 or 1\n\nThe committee understood that for people with ECOG performance status scores of 0 or 1, chemotherapy is the only relevant comparator (see section\xa03.3). The comparator in CheckMate\xa0743 was pemetrexed plus either cisplatin or carboplatin based on investigator's choice. Among the people randomised to chemotherapy (n=302), about 66% had carboplatin and 34% had cisplatin. The ERG expressed concerns that the proportion of carboplatin compared with cisplatin used in the trial did not reflect the NICE scope and may not be generalisable to UK clinical practice. The NICE scope specified using pemetrexed with cisplatin, or carboplatin when cisplatin is unsuitable. The company provided evidence from different sources explaining that carboplatin is more widely used with pemetrexed and therefore the results in the trial represented UK practice. For example, the UK National Mesothelioma Audit in 2020, an audit of people diagnosed with mesothelioma between 2016 and 2018, reported carboplatin use in 48% of people compared with cisplatin in 20% of people with malignant pleural mesothelioma. The company considered the proportions of carboplatin and cisplatin from other sources to be confidential, so they cannot be reported here. The ERG noted that the proportions of carboplatin and cisplatin from the trial were different to those from the sources provided. The clinical experts noted that the choice between carboplatin and cisplatin is pragmatic; for example, carboplatin can be given over a shorter period of time, is less toxic, and is less expensive. The committee noted that using a 'blended comparator' could mask a clinically and cost-ineffective treatment. However, the clinical experts noted that adding carboplatin or cisplatin to pemetrexed has a similar treatment effect, and the Cancer Drugs Fund clinical lead noted that pemetrexed rather than carboplatin or cisplatin comprises the bulk of the cost of treatment. The committee concluded that proportions of cisplatin and carboplatin in the chemotherapy treatment arm in CheckMate\xa0743 reflected UK clinical practice. It further concluded that any recommendation would be limited to people who were candidates for chemotherapy, that is, people with an ECOG score of 0 or 1.\n\n# Clinical effectiveness\n\n## Nivolumab plus ipilimumab improves overall survival compared with chemotherapy, but its long-term treatment effect is uncertain\n\nThe primary outcome of CheckMate\xa0743 was overall survival. The sample size was set at 606 with a targeted power of 90% and an alpha of 0.05 (2‑sided) to detect a difference in mortality between the 2 treatments when 473 deaths occurred (see section\xa03.4) of a targeted hazard ratio (HR) 0.72. At the 2‑year data cut, with a median follow up of 29.7\xa0months, 419 deaths had occurred (89% of 473 planned for statistical analysis); 98% of people taking nivolumab plus ipilimumab and all people on chemotherapy had stopped treatment. At the 3‑year data cut, the median follow up was 43\xa0months after people had stopped treatment for at least 1\xa0year (see section\xa03.4). The company considered the number of deaths at 3‑year follow up to be confidential, but explained that 23% (70 out of 303) of people who had treatment with nivolumab plus ipilimumab and 15% (45\xa0out of 302) who had treatment with chemotherapy were alive (numerators estimated from percentages). Results from both the interim and post-hoc analyses showed that median overall survival was 18.1\xa0months for nivolumab plus ipilimumab and 14.1\xa0months for chemotherapy. Nivolumab plus ipilimumab was associated with longer overall survival than chemotherapy at both the 2‑year (HR 0.74, 95% confidence interval [CI] 0.60 to 0.91) and 3‑year follow up (HR 0.73, 95% CI 0.61 to 0.87). The company explained that the data suggested the treatment effect of nivolumab plus ipilimumab was largely maintained at 3‑year follow up, and the ERG agreed. The committee noted that overall survival with chemotherapy was around 20% at 3\xa0years on the Kaplan–Meier curve of the trial data. This was much higher than the 8% to 10% survival at 3\xa0years from the UK registry and UK audit data provided by the company (see section\xa03.1). The Cancer Drugs Fund clinical lead noted that the epidemiological data sources, for example the Cancer Analysis System, were from as far back as 2013. He noted that mesothelioma management has evolved, so survival rates have likely improved, which could explain the difference between the overall survival results for chemotherapy in the trial and the registry and audit data. A consultation comment suggested that the lower survival in the registry may be because the registry includes people with worse performance status (ECOG performance status of 2 or 3). The ERG noted that there was little change to the hazard ratio at the 3‑year data cut, but that there was still uncertainty because people are alive beyond the observed period. The committee noted the sustained benefit from the 2- and 3‑year data cuts and the relatively short follow up of the trial. It concluded that nivolumab plus ipilimumab reduces the risk of death in people with malignant pleural mesothelioma compared with chemotherapy, but there is uncertainty about its long-term treatment effect.\n\n## Nivolumab plus ipilimumab might improve progression-free survival but the evidence is uncertain\n\nProgression-free survival was a secondary outcome in CheckMate\xa0743. Disease progression was determined by blinded independent central review. Results from the 2- and 3‑year data cuts showed median progression-free survival was 6.8\xa0months for nivolumab plus ipilimumab and 7.2\xa0months for chemotherapy. Both data cuts showed no difference between the 2\xa0treatments according to hazard ratio estimates, but benefits started to appear at the 3‑year data cut: at the 2‑year data cut, the hazard ratio was 1.00 (95% CI 0.82 to 1.21; median follow up 29.7\xa0months), but at the 3‑year data cut the hazard ratio was 0.92 (95% CI 0.76 to 1.11; median follow up 43\xa0months). The ERG also noted that 14% of people whose cancer was treated with nivolumab plus ipilimumab and 1% whose cancer was treated with chemotherapy remained progression free at 3\xa0years. During its first meeting, the committee questioned the clinical relevance of progression-free survival in mesothelioma and its use in modelling because of the lack of evidence on nivolumab plus ipilimumab's treatment effect on this outcome at the 2‑year data cut. It also noted that the Kaplan–Meier curves by treatment allocation crossed, and although the company analysed the results in the model assuming non-proportional hazards (see section\xa03.17), the hazard ratio estimated from the trial assumed proportional hazards and was of limited value. The company explained that progression-free survival determined radiographically is not a reliable endpoint in mesothelioma because tumours may not have demarcated margins. It noted that the initial response to chemotherapy may reflect an 'early but transient' effect compared with a 'delayed but durable' effect of immunotherapy. It further explained that the progression-free survival benefit of nivolumab plus ipilimumab will only show in longer-term data. It noted that this was starting to show in the 3‑year data, with 28% of people whose disease responded to nivolumab plus ipilimumab still 'in response' compared with no one who had treatment with chemotherapy. The company also explained at the second meeting that it is useful to measure progression-free survival because it can provide an element of quality of life. The committee understood that there might be some delayed but durable response to the treatment in the longer term, which may benefit survival. However, because of the non-proportional hazards as suggested by the Kaplan–Meier curves of the trial, the committee considered that the hazard ratios over time implied by the company's selected parametric distributions in modelling should be explored (see section\xa03.17). The committee concluded that the evidence from CheckMate\xa0743 showed that nivolumab plus ipilimumab may improve progression-free survival compared with chemotherapy, but there is some uncertainty in the evidence.\n\n## The effect of nivolumab plus ipilimumab compared with chemotherapy is modified by histological subtype\n\nThe company presented evidence on the treatment effect of nivolumab plus ipilimumab compared with chemotherapy by histological subtype and by PD‑L1 status. Results from the 2- and 3‑year data cuts showed that nivolumab plus ipilimumab lowered mortality in the non-epithelioid group (median overall survival 18.1\xa0months) compared with chemotherapy (median overall survival 8.8\xa0months): HR 0.46, 95% CI 0.31 to 0.68 at the 2‑year data cut and HR 0.48, 95% CI 0.34 to 0.69 at the 3‑year data cut. For epithelioid disease, median overall survival reduced slightly from 18.7\xa0months at the 2‑year data cut to 18.2\xa0months at the 3‑year data cut in the nivolumab plus ipilimumab arm. It increased slightly from 16.5\xa0months to 16.7\xa0months in the chemotherapy arm: HR 0.86, 95% CI 0.69 to 1.08 at the 2‑year data cut and 0.85, 95% CI 0.69 to 1.04 at the 3‑year data cut. During its first meeting, the committee noted that the treatment effect of nivolumab plus ipilimumab may be modified by histology subtype. It therefore asked the company to provide the results of a statistical analysis testing the interaction between treatment effect and histology subtype. The company provided these results during consultation, which suggested a highly significant interaction between treatment effect and histological subtype. The company noted that the trial was not powered for subgroup analyses and that these analyses were descriptive in nature. The committee, however, noted that in a small sample size, a false negative interaction test is more of a concern than a false positive. The committee noted that the Kaplan–Meier curves for epithelioid and non-epithelioid disease were similar for nivolumab plus ipilimumab (median overall survival 18.1 and 18.2\xa0months, respectively, at 3\xa0years), but that non-epithelioid tumours responded less well to chemotherapy. However, the committee recalled its remit to compare treatments with standard care. The committee concluded that the effect of nivolumab plus ipilimumab compared with chemotherapy is likely modified by histological subtype. The committee was also aware of its remit to appraise the technology across its indication-specific marketing authorisation and took this into account during its decision making.\n\n## PD-L1 status is not tested routinely in the NHS, so is not considered in decision making\n\nEvidence from CheckMate\xa0743 also showed a possible effect of PD‑L1 status on mortality at the 2‑year data cut, based on positive PD‑L1 tumours (using a threshold of 1% or greater) or negative PD‑L1 tumours, for nivolumab plus ipilimumab compared with chemotherapy. Because testing of PD‑L1 in mesothelioma is not routine in the NHS (see section\xa03.2), the committee concluded that it was not appropriate to consider it when making recommendations.\n\n## Nivolumab plus ipilimumab may improve quality of life\n\nCheckMate\xa0743 measured patient quality of life using the 3‑level EQ‑5D (EQ‑5D‑3L) instrument. In England, EQ‑5D utility index scores range from -0.594 to 1, with higher scores indicating better quality of life. The company considered a change of 0.08 in the score of EQ‑5D‑3L utility index from baseline to be 'clinically meaningful' in malignant pleural mesothelioma. The company based this estimate on a randomised controlled trial (Sarna et al. 2008). This trial assessed the impact on the quality of life of people with advanced non-small-cell lung cancer of adding amifostine to radiation therapy plus chemotherapy compared with not adding it. Results from CheckMate\xa0743 suggested that, at the 2‑year data cut, the mean score of the EQ‑5D‑3L utility index increased over time in the nivolumab plus ipilimumab arm, from 0.70 (standard deviation [SD] 0.27) at baseline to 0.84 (SD 0.20) at week\xa072. In the chemotherapy arm, it remained relatively stable from baseline (mean 0.71 [SD 0.27]) but started deteriorating from week\xa030 (mean 0.70 [SD 0.20]), and the trend of deterioration continued onwards. The ERG noted that the trends suggested stability or improvement in quality of life for nivolumab plus ipilimumab and deterioration for chemotherapy. The committee acknowledged the trend for quality-of-life improvement for nivolumab plus ipilimumab, but noted that the company did not report a group difference in EQ‑5D‑3L utility scores from baseline at the 2‑year data cut. Also, it was not clear how the clinically meaningful change of 0.08 was defined because it was based on a single study and was in people with advanced non-small-cell lung cancer. Considering the evidence, the committee concluded that nivolumab plus ipilimumab may improve quality of life compared with chemotherapy.\n\n# Adverse events\n\n## The safety profile of nivolumab plus ipilimumab is acceptable\n\nEvidence on adverse events was from the 2‑year data cut of CheckMate\xa0743. The company did not present additional data at the trial's 3‑year data cut. The results showed that, at the 2‑year data cut, more people (55%; 164\xa0out of 300) on nivolumab plus ipilimumab experienced severe treatment-related adverse events than those on chemotherapy (25%; 72\xa0out of 284; p\xa0value not reported). Stopping because of drug toxicity was more frequent in the nivolumab plus ipilimumab arm (23%; 69\xa0out of 300) compared with the chemotherapy arm (16%; 45 out of 284; p\xa0value not reported). The most common adverse events with nivolumab plus ipilimumab were diarrhoea and pruritis. Respiratory tract infections were more common with chemotherapy. The company noted that most treatment-related adverse events and immune-mediated adverse events had resolved at the time of the database lock, but that endocrine-related events had not. The ERG noted that 3\xa0people died from drug toxicity after having nivolumab plus ipilimumab because of pneumonitis, encephalitis and heart failure, compared with 1 person who had treatment with chemotherapy because of myelosuppression. The committee concluded that the safety profile of nivolumab plus ipilimumab was acceptable.\n\n# Second-line treatments\n\n## Second-line treatments used in Checkmate\xa0743 do not reflect UK clinical practice\n\nFor the 3‑year data cut, the company provided only the percentages rather than the numbers of people who had second-line treatments, and could not provide these numbers during the committee meeting. The data suggested that, at 3‑year follow up, 45% (137 out of 303) of people randomised to nivolumab plus ipilimumab and 42% (128 out of 302) of people randomised to chemotherapy had second-line treatments after disease progression (numerators estimated from percentages). From the same data cut, among the people randomised to nivolumab plus ipilimumab, about 4% (12 out of 303) had immunotherapy as second-line treatment compared with 22% (65 out of 302) of the people randomised to chemotherapy (numerators estimated from percentages). Also, at the 3‑year data cut, about 43% (131 out of 303) of the people randomised to nivolumab plus ipilimumab had chemotherapy as second-line treatment compared with 33% (100 out of 302) of people randomised to chemotherapy (numerators estimated from percentages). The ERG was concerned that the second-line treatments in CheckMate\xa0743, particularly immunotherapies, do not represent UK clinical practice. The company explained that because more people who initially had treatment with chemotherapy had immunotherapy as their second-line treatment in the trial, the trial underestimated the true treatment effect of nivolumab plus ipilimumab compared with chemotherapy (see also section\xa03.23). The Cancer Drugs Fund clinical lead noted that despite nivolumab having been used as second-line treatment for malignant pleural mesothelioma during the COVID‑19 pandemic, it is not routinely available in the UK as a second-line treatment. The committee also noted that the NHS does not offer immunotherapy twice in practice. The company explained that the proportions of people having second-line treatments in the trial were similar to those reported in the English National Cancer Analysis System registry. This is a retrospective cohort of people with malignant pleural mesothelioma diagnosed in England between 2013 and 2017. In this registry, 44% had second-line chemotherapy, 24% had second-line vinorelbine and 19% had second-line treatment in a clinical trial. The ERG noted that these proportions were different from those in the trial, in which 16% had pemetrexed and 8% had vinorelbine as second-line treatment. The clinical experts also noted that currently there are no defined second-line treatments for the condition and their treatment effects remain unclear. The committee concluded that the second-line treatments used in CheckMate\xa0743, particularly the immunotherapies, did not represent UK clinical practice.\n\n# Stopping rule\n\n## A 2-year stopping rule for nivolumab plus ipilimumab and a 6-cycle stopping rule for chemotherapy is appropriate\n\nIn CheckMate\xa0743, people stopped treatment with nivolumab plus ipilimumab after 2\xa0years if they had not already stopped treatment because of progression or unacceptable toxicity. The stopping rule did not depend on disease progression. The committee appreciated that chemotherapy was associated with a 6‑cycle stopping rule to limit toxicity. The ERG noted that in the CheckMate\xa0743 trial, some people had nivolumab plus ipilimumab for longer than 2\xa0years. The ERG was concerned that if the stopping rule were not feasible in clinical practice, it may affect the clinical and cost effectiveness. After the first committee meeting, the company noted that 2 people remained on treatment beyond 24\xa0months, because they had a delay in the final dose, but did not have additional doses. It considered the impact negligible. The committee considered this reasoning acceptable. The Cancer Drugs Fund clinical lead noted that if recommended, the NHS would only fund treatment for up to 2\xa0years in clinical practice. The committee noted that the stopping rule for nivolumab plus ipilimumab is included in the marketing authorisation for the combined therapy. It concluded that the stopping rules for nivolumab plus ipilimumab and chemotherapy were appropriate and would be applied in clinical practice.\n\n# The economic model\n\n## The model structure is acceptable, but the extrapolations are uncertain\n\nThe company made the case that people having treatment with nivolumab plus ipilimumab accrue more quality-adjusted life years (QALYs) than people on chemotherapy. This is because they live longer, and have a higher quality of life because their disease takes longer to progress. The company used a partitioned survival model to estimate the cost effectiveness of nivolumab plus ipilimumab compared with chemotherapy. The model included 3 health states: progression-free, progressed, and dead. The probability of being in a given health state was defined by the area under the curves for progression-free survival, overall survival, and their difference. The cycle length was 1\xa0week, and the time horizon was 20\xa0years. The ERG noted that the company's model structure was consistent with the approach adopted in previous NICE technology appraisals in oncology, and accounted for the CheckMate\xa0743 trial's primary (overall survival) and secondary (progression-free survival) endpoints. However, it was concerned that in the model, a substantial proportion of life years and progression-free life years accrued in the nivolumab plus ipilimumab arm during the extrapolated period. During its first meeting, the committee noted that this was not supported by the evidence from CheckMate\xa0743 at the 2‑year data cut and questioned the clinical relevance of progression-free survival. The committee recalled that the company noted that progression-free survival improves quality of life for people in this health state. The ERG had provided analyses showing that most of the life-year gains in the model were from the progression-free period. However, the committee noted that there was still a large proportion of life years and progression-free life years accrued from the extrapolated period when using the 3‑year data. The 3‑year data cut showed that the treatment effect of nivolumab plus ipilimumab was largely maintained (see sections\xa03.8 and 3.9), but there was no evidence on how long it would last. The committee was aware that an alternative model structure would be subject to the same uncertainties. It concluded that the company's model structure was acceptable for decision making, but that there were uncertainties in the company's extrapolations.\n\n# Modelling survival\n\n## The committee asked for further information on hazard ratios for overall survival over time, and treatment effect over time\n\nThe company assumed non-proportional hazards for overall survival because nivolumab plus ipilimumab and chemotherapy have different mechanisms of action. It fitted parametric distributions to the 2 arms separately to extrapolate overall survival beyond the trial data. It also used data from the chemotherapy arm of the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) trial to validate the overall survival extrapolations for the chemotherapy arm. For the nivolumab plus ipilimumab arm, the company considered that the survival probability would be higher than that of the chemotherapy arm of the MAPS trial because of nivolumab plus ipilimumab's survival benefits over chemotherapy in CheckMate\xa0743. MAPS is an ongoing, randomised, controlled, open-label trial comparing bevacizumab plus chemotherapy with chemotherapy alone in people with newly diagnosed pleural mesothelioma (median follow up 39\xa0months). At baseline, 97% (433 out of 448) of people had an ECOG status of 0 or 1, and 81% (361 out of 448) of people had epithelioid disease compared with 19% (87 out of 448) with non-epithelioid disease. The committee noted that the MAPS study also included people with an ECOG status of 2, who were potentially at higher risk of death than people in CheckMate\xa0743 (which excluded people with an ECOG status of 2). Data from the MAPS trial showed that the modelled hazard function should first increase, then decrease in the long term, and that survival on chemotherapy was 8% at 5\xa0years and 0% at 10\xa0years. To extrapolate treatment effects for the nivolumab plus ipilimumab arm, both the company and ERG agreed that the log-logistic distribution provided clinically plausible predictions and was the most appropriate. However, the committee noted that at the end of the modelled time period, the log-logistic distribution predicted better survival in the nivolumab plus ipilimumab arm than other distributions. The ERG also noted that the extrapolated overall survival from the log-logistic distribution was higher than the Kaplan–Meier curve from the trial. For the chemotherapy arm, the company preferred a 1‑knot spline normal model when including data from the 3‑year data cut. This model predicted survival at 5\xa0years to be 5.2%, which the company considered was aligned with its clinical expert's estimate (5%). The clinical expert at the first meeting, who had also advised the company, expected survival of about 5% at 5\xa0years, and 2% at 10\xa0years in the chemotherapy arm. The ERG preferred a log-logistic model for both arms, noting that the hazard functions for both arms should be the same, both initially increasing followed by a long-term decreasing hazard. The committee recalled that nivolumab plus ipilimumab's treatment effect on overall survival may be maintained, but there was uncertainty in how long it will last (see section\xa03.8). Because the treatment might be associated with a survival benefit that was not yet seen in the data (see section\xa03.9), the committee asked to see the hazard ratios for overall survival over time implied by both the company and ERG's independent distributions, as well as the treatment effect over time as implied by the observed trial data.\n\n## Using a log-logistic distribution to extrapolate overall survival for both treatments may be appropriate but there are uncertainties\n\nIn response, the company plotted the hazard ratios implied by both the company and ERG's preferred extrapolations for overall survival, alongside the smoothed hazard ratio and its 95% confidence intervals based on the observed data from CheckMate\xa0743. The figure indicated that the hazard ratios implied by the selected distributions, as well as the smoothed hazard ratio based on observed trial data, fluctuated over time but were all below 1, and the 95% confidence interval of the smoothed hazard ratio was wide. The company stated that the plotted hazard ratios over time showed sustained treatment effect and the selected distributions aligned with the smoothed hazard ratio. However, the ERG commented that neither extrapolation could be ruled out and that they may not be so informative, especially given the increasingly wide confidence interval at the end of the smoothed hazard ratio. The committee noted the implied treatment effects in the longer term were based on a small number of patients. It also noted the high uncertainty beyond 24\xa0months, at which point the extrapolated curves started to diverge. The committee noted that there were minor differences between the company and ERG's extrapolations, and that the ERG's extrapolations indicated a smaller treatment effect over time and were more reasonable. The committee concluded that the log-logistic distribution was appropriate for extrapolating overall survival in both arms, but that how long the treatment effect would continue in the long term was uncertain.\n\n## The company's parametric distributions for extrapolating progression-free survival are appropriate\n\nThe company fitted independent parametric distributions to model progression-free survival in the 2 treatment arms guided by the best statistical and visual fit to the Kaplan–Meier curve of CheckMate\xa0743. The company and ERG agreed that for extrapolating progression-free survival, the generalised gamma distribution was appropriate for nivolumab plus ipilimumab, and the log-logistic distribution was appropriate for chemotherapy. However, the ERG was concerned that a substantial proportion of progression-free life years accrued beyond the observed data in the model, extrapolated from either the 2- or 3‑year data cuts (see section\xa03.16). The committee noted that, at the 3‑year data cut, the evidence from CheckMate\xa0743 appeared to show some benefit of nivolumab plus ipilimumab in the period before progression. The evidence also suggested there may be a continued response to treatment and a survival benefit (see section\xa03.9). Given that there was no long-term evidence, the committee also looked at the hazard ratios for progression-free survival over time implied by the extrapolation agreed between the company and ERG, as well as the treatment effect over time as implied by the observed trial data. The company provided these figures, which were all below 1, suggesting the treatment effect may be maintained. The committee noted that the hazard ratios implied by the company and the ERG's preferred distributions were largely aligned with the smoothed hazard ratio and within the bounds of its 95% confidence interval. However, it also noted the uncertainties, given the short follow up of the trial and the fact that the extrapolations were based on a small number of patients. The committee concluded that it was appropriate to use the generalised gamma distribution to extrapolate progression-free survival for nivolumab plus ipilimumab, and use the log-logistic for chemotherapy.\n\n## It is reasonable to assume some treatment effect waning\n\nThe company's base case predicted survival for the 20‑year horizon of the model based on independently fitted models for overall survival; the company did not factor waning of treatment effect into the analysis. The ERG considered that this was not reasonable in the absence of long-term clinical experience. It noted that the company based its argument on expert opinion, but it was not clear how the company chose the experts or elicited their opinion. The ERG considered it appropriate to assume that the treatment effect would wane 5\xa0years after treatment starts and 3\xa0years after treatment stops. It acknowledged that this duration was arbitrary, but had been accepted in other NICE technology appraisals, including NICE's technology appraisal guidance on nivolumab for treating recurrent or metastatic squamous cell carcinoma of the head and neck after platinum-based chemotherapy. During its first meeting, the committee also noted the evidence presented by the company in its response to clarification questions, which suggested that the treatment effect of immunotherapies is maintained for up to 4\xa0years in non-small-cell lung cancer (Antonia et al. 2019). However, the Cancer Drugs Fund clinical lead noted that some tumours treated with immunotherapies relapsed. The committee considered that there appeared to be a continuing benefit after stopping treatment, but it was unclear how long it would last, so it would be reasonable to assume some treatment effect waning.\n\n## When nivolumab plus ipilimumab is stopped at 2\xa0years, it is acceptable to assume an additional survival benefit for 3 more years\n\nAt the committee's second meeting, the company provided 6 scenario analyses that assumed treatment effect waning at 5, 7, or 10\xa0years after starting treatment (with a duration of treatment effect waning of 5 or 10\xa0years for each). All of the scenarios worsened the cost-effectiveness estimates, and the longer after starting the treatment the waning occurred, the better the cost-effectiveness estimate. The committee recalled the uncertainties around the treatment effects over time as implied by the company and ERG's extrapolations for overall survival (see section\xa03.18) and progression-free survival (see section\xa03.19). It was also aware that most people in the CheckMate\xa0743 trial had died by the 3‑year data cut (see section\xa03.8). It therefore did not consider it reasonable to rule out the possibility of treatment effect waning in the model. The Cancer Drugs Fund clinical lead noted that treatment effect waning 5\xa0years after starting treatment has been accepted in previous NICE technology appraisals for immunotherapies in which there was a 2‑year stopping rule. Considering this and the uncertainties in the evidence base, the committee concluded that it is acceptable to assume that if the treatment is stopped at 2\xa0years, it is likely that its survival benefit would continue for 3 more years, and treatment waning could reasonably start at this point.\n\n# Utility values\n\n## Using treatment-dependent utility benefits up to 3\xa0years is appropriate\n\nThe company used patient-level data on utility from CheckMate\xa0743 to estimate the utility values for the progression-based health states in the model. The company's analysis showed that having treatment or not significantly impacted utility values. The company therefore adopted treatment-dependent health state utilities in its base case and assumed that the treatment-dependent utility benefits would last for the whole duration of the time horizon. The ERG considered that implausible. For its base case, the ERG adopted treatment-dependent utilities (with the nivolumab plus ipilimumab utility benefit) for up to 3\xa0years, and treatment-independent utilities after this. The ERG chose 3\xa0years because only 3\xa0people were at risk of death at 3\xa0years in the trial according to the evidence at the 2‑year data cut that the company presented at the first committee meeting (see section\xa03.8). The company adopted the ERG's assumption after technical engagement. The committee agreed that using treatment-dependent utility benefits up to 3\xa0years and treatment-independent utilities afterwards was appropriate.\n\n# Adjusting for second-line treatments\n\n## It is appropriate to use the inverse probability censoring weights method to adjust for second-line treatments not used in the NHS\n\nThe company modelled second-line treatment based on the distribution of the second-line treatments used in CheckMate\xa0743, but these treatments did not reflect UK clinical practice (see section\xa03.14). Second-line treatments used in the trial included pemetrexed, carboplatin, cisplatin, gemcitabine, vinorelbine, bevacizumab and several immunotherapies (nivolumab, ipilimumab, pembrolizumab). During its first meeting, the committee suggested that the company adjust the overall survival results and remove the costs for second-line treatments that do not reflect NHS practice and may be associated with improving survival. After consultation, the company presented analyses adjusting for second-line treatment using 4 methods: inverse probability censoring weights (IPCW), 2‑stage estimation, rank preserving structural failure time model (RPSFTM), and iterative parameter estimation. The company preferred the IPCW method because it addresses informative censoring. It did not prefer the RPSFTM and iterative parameter estimation methods because they assume the same treatment effect for all patients regardless of when they have treatment, or the 2‑stage estimation method because it could result in informative censoring when patients do not die during the study. The ERG did not critique the company's methods in detail but noted that the methods were appropriate and the results were similar across the different methods. Because of the lack of reporting, the committee asked to see further details of the methods considered. The company provided these details at the second committee meeting. It also removed all non-NHS second-line treatment costs from both arms. The committee's discussion on adjusting for second-line non-NHS-treatments focused on the intention-to-treatment population during its second meeting. It noted that, for the intention-to-treat population, the company still preferred the IPCW method for its base case. The ERG agreed that theoretically the IPCW method was preferable, but stated that all methods gave similar results. The committee concluded that the IPCW method may be appropriate for adjusting for second-line non-NHS treatments for the intention-to-treat population, but that it was based on important assumptions around there being no unmeasured confounding.\n\n# End of life\n\n## Nivolumab plus ipilimumab is likely to meet NICE's end of life criteria for the population in the marketing authorisation\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The Cancer Analysis System registry reported 13‑month median survival with first-line chemotherapy. Median overall survival was 14\xa0months with chemotherapy in CheckMate\xa0743 for people who had an ECOG status of 0 or 1; and mean overall survival for chemotherapy estimated from the model was about 20\xa0months. Overall survival in the chemotherapy arm in the ERG base case was up to 21\xa0months. The committee agreed that life expectancy for people with unresectable malignant pleural mesothelioma who have standard care is likely to be less than 24\xa0months. Results from CheckMate\xa0743 showed a median 4‑month survival benefit for nivolumab plus ipilimumab compared with chemotherapy at a median 43‑month follow up. The ERG base case also supported a mean survival gain of greater than 3\xa0months. The committee acknowledged that these survival estimations were based on the company and ERG base cases, so there was an element of uncertainty. But it concluded that nivolumab plus ipilimumab was likely to meet the end of life criteria for untreated unresectable malignant pleural mesothelioma for the population in the marketing authorisation.\n\n# Cost effectiveness\n\n## The cost-effectiveness estimates are within the range considered an acceptable use of NHS resources\n\nThe patient access schemes for the comparator treatments mean that the costs and cost-effectiveness estimates are confidential and cannot be presented. Taking into account the end of life criteria, the committee noted that the incremental cost-effectiveness ratio (ICER) that reflected its preferred assumptions was less than £50,000 per QALY gained for the intention-to-treat population. It concluded that the ICER for nivolumab plus ipilimumab for treating malignant pleural mesothelioma is within the range normally considered a cost-effective use of NHS resources.\n\n# Conclusions\n\n## Nivolumab plus ipilimumab is recommended for routine use in the NHS\n\nThe committee concluded that it could recommend nivolumab plus ipilimumab for treating malignant pleural mesothelioma.\n\n# Equality issues\n\n## There are no equality issues related to protected characteristics\n\nThe committee considered several potential equalities issues raised by stakeholders:\n\nThe condition is a preventable occupational-related disease with a higher incidence in heavy industries. People with the condition may have lower socioeconomic status than people with other cancer types.\n\nPeople with mesothelioma are often old, and the cancer is diagnosed at a late stage when they can be too frail to travel for treatment. This may limit their treatment options.\n\nSome people are unable to self-fund or do not have access to funding from compensation claims.The committee noted the prevalence of mesothelioma in certain areas of the country. It noted that people too frail to travel would be unlikely to be offered treatment (see section\xa03.3). It was aware that the prevalence of a disease, physical access to the treatment, and socioeconomic status are not protected characteristics and are therefore not within NICE's remit when making recommendations. The technology will be available for all people regardless of age, geographical location and socioeconomic status. The committee concluded that these are not equality issues.\n\n## Guidance for pleural mesothelioma should also cover mesothelioma of the pericardium or peritoneum\n\nThe committee heard from the Cancer Drugs Fund clinical lead that, rarely, mesotheliomas can occur in the pericardium or peritoneum. They noted that any guidance for pleural mesothelioma should extend to these individuals. The committee agreed.\n\n# Innovation\n\n## Nivolumab plus ipilimumab is not innovative\n\nNICE defines innovation as a 'step-change' in treatment with benefits not accounted for in the modelling. The company considers nivolumab plus ipilimumab innovative because it is the first-in-class immunotherapy for a condition for which there have been no new therapies in the last 2\xa0decades. The clinical experts considered it a step-change in treatment. The committee agreed, but did not hear of any additional gains in health-related quality of life not already captured in the modelling. A clinical expert noted that the cost-effectiveness estimates may not capture the benefit of nivolumab plus ipilimumab in reducing anger about having an occupational disease, but the committee was not presented with evidence for this. The committee concluded that the technology may be a step-change in treatment, but it did not identify benefits not captured by the company's economic modelling. It therefore considered that nivolumab plus ipilimumab is not innovative for untreated unresectable malignant pleural mesothelioma."}	https://www.nice.org.uk/guidance/ta818	Evidence-based recommendations on nivolumab (Opdivo) with ipilimumab (Yervoy) for untreated unresectable malignant pleural mesothelioma in adults.
b3bbba08a8929208d4b452b7ef01894d8b499dbf	nice	Sacituzumab govitecan for treating unresectable triple-negative advanced breast cancer after 2 or more therapies	Sacituzumab govitecan for treating unresectable triple-negative advanced breast cancer after 2 or more therapies Evidence-based recommendations on sacituzumab govetican (Trodelvy) for treating unresectable, triple-negative locally advanced or metastatic breast cancer in adults after 2 or more systemic therapies, at least 1 of which was for advanced disease. # Recommendations Sacituzumab govitecan is recommended, within its marketing authorisation, as an option for treating unresectable triple-negative locally advanced or metastatic breast cancer in adults after 2 or more systemic therapies, at least 1 of which was for advanced disease. It is recommended only if the company provides sacituzumab govitecan according to the commercial arrangement. Why the committee made these recommendations Usual treatment for triple-negative locally advanced or metastatic breast cancer is chemotherapy. Clinical trial evidence shows that sacituzumab govitecan increases how long people have before their disease gets worse and how long they live compared with chemotherapy. Sacituzumab govitecan meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates are within what NICE usually considers an acceptable use of NHS resources. Therefore, it is recommended.# Information about sacituzumab govitecan # Marketing authorisation indication Sacituzumab govitecan (Trodelvy, Gilead Sciences) has a marketing authorisation for 'the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior lines of systemic therapies, at least one of them given for unresectable locally advanced or metastatic disease'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for sacituzumab govitecan. # Price The list price of sacituzumab govitecan is £793.00 per 180 mg vial (excluding VAT; BNF online accessed May 2022). The company has a commercial arrangement. This makes sacituzumab govitecan available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Gilead, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need and treatment pathway ## Triple-negative breast cancer has a high disease burden Triple-negative breast cancer accounts for about 15% of breast cancers and lacks all 3 molecular markers (oestrogen, progesterone and HER2 receptors), which affects treatment options and prognosis. Chemotherapy is the mainstay of treatment because triple-negative breast cancer is not sensitive to endocrine therapy or molecular targeted therapy. The patient expert explained that being diagnosed with locally recurrent unresectable or metastatic breast cancer is extremely difficult for people, and their family and friends. It can cause considerable anxiety and fear, and the uncertainty of the outcome can be very difficult to deal with. The aim of treatment is to stop progression of the disease, extend life, and maintain or improve quality of life for as long as possible. Treatment is continued for as long as it is controlling the disease. The committee concluded that there is a high disease burden for people with triple-negative breast cancer. ## There is a high unmet need for effective treatments for triple-negative locally advanced or metastatic breast cancer The marketing authorisation for sacituzumab govitecan specifies its use after 2 or more prior systemic therapies, 1 of which should have been for advanced disease. For people who have triple-negative advanced or metastatic breast cancer, first-line therapies are paclitaxel, docetaxel, nab-paclitaxel, anthracycline-based chemotherapy, gemcitabine with or without carboplatin, or atezolizumab plus nab-paclitaxel for programmed death‑ligand 1 (PD‑L1)‑positive disease (see NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel for untreated PD-L1-positive, locally advanced or metastatic, triple-negative breast cancer ). Second-line therapies are single-agent vinorelbine or capecitabine. Third-line therapies are eribulin (see NICE's technology appraisal guidance on eribulin for treating locally advanced or metastatic breast cancer after 2 or more chemotherapy regimens ) or single-agent vinorelbine or capecitabine (whichever was not used previously) (see NICE's clinical guideline on advanced breast cancer: diagnosis and management). In the locally advanced or metastatic setting, the proposed positioning for sacituzumab govitecan is either second line (for people who received a systemic treatment for early disease) or third line (for people who initially presented with de novo metastatic disease). The clinical experts clarified that, in the locally advanced or metastatic setting, most people would have sacituzumab govitecan as a second-line therapy. Clinicians prefer to use the most effective treatments earlier in the treatment pathway. Therefore, people will have already had anthracyclines, taxanes and capecitabine. The clinical experts noted that because early triple-negative breast cancer tends to relapse quickly after treatment, rechallenge with these therapies is not appropriate, leaving very few effective treatment options. The committee concluded that there is a high unmet need for effective treatments for locally advanced or metastatic triple‑negative breast cancer. # Clinical evidence ## Sacituzumab govitecan offers considerable benefit compared with standard care The clinical evidence was based on ASCENT, a randomised, open-label clinical trial that enrolled people with relapsed or refractory, unresectable, triple-negative, locally advanced or metastatic breast cancer after 2 or more previous therapies. ASCENT compared sacituzumab govitecan with treatment of physician's choice, which included eribulin, capecitabine, gemcitabine and vinorelbine. The company reported trial results from a March 2020 data cut. This showed a consistent clinically meaningful and statistically significant benefit for sacituzumab govitecan compared with treatment of physician's choice for objective response rate, progression-free survival and overall survival. The objective response rate was considerably greater in the sacituzumab govitecan arm: 31.1% compared with 4.2% in the treatment of physician's choice arm. Median progression-free survival was 4.8 months in the sacituzumab govitecan arm compared with 1.7 months in the treatment of physician's choice arm (hazard ratio 0.43, 95% confidence interval 0.35 to 0.54). Median overall survival was 11.8 months with sacituzumab govitecan compared with 6.9 months in the treatment of physician's choice arm (hazard ratio 0.51, 95% confidence interval 0.41 to 0.62). The patient expert experienced tumour shrinkage while on sacituzumab govitecan, and explained that initial gastrointestinal side effects were well managed with a dose reduction and concomitant medication. The company provided a later data cut from February 2021 during technical engagement. The ERG noted that the survival data was similar across the 2 data cuts, with no changes to the median estimates, and marginal changes to the mean estimates. The committee considered sacituzumab govitecan to be a highly effective treatment for people with triple-negative locally advanced or metastatic breast cancer who have a poor prognosis. ## The results of the trial are generalisable to NHS clinical practice In ASCENT, 32.7% of people had previously had eribulin, which is only used as a third-line treatment in the UK (after 2 or more chemotherapy regimens, in line with TA423). In the UK, eribulin would be given after sacituzumab govitecan. The ERG noted that prior eribulin in ASCENT could impact the trial efficacy results for sacituzumab govitecan. The clinical experts explained that because the trial also included people who had not had prior eribulin, the trial demonstrated that sacituzumab govitecan is effective before and after eribulin. They felt that the efficacy of sacituzumab govitecan is not affected by prior treatment with eribulin. The committee accepted that although approximately a third of the people in ASCENT had received eribulin, which does not reflect UK practice, the results were generalisable to people in the NHS. ## The effect of a higher dropout rate in the comparator arm is unknown In ASCENT, 14.5% of people randomised to the comparator arm (treatment of physician's choice including eribulin, gemcitabine, capecitabine and vinorelbine) chose not to have treatment, compared with 3.4% of people in the sacituzumab govitecan arm. The ERG noted that this differential dropout rate could introduce bias because it is unclear if common patient characteristics affected the choice to start treatment. The ERG suggested that it may have been people with a better prognosis who felt they had better options outside of participating in ASCENT. The clinical experts disagreed and explained that people who dropped out of the trial were more likely to be those with poor prognosis who chose not to have further chemotherapy as part of the comparator arm. They said that dropout was inevitable in an open-label trial, and that people may be unwilling to remain in the comparator arm when there is already published data showing that sacituzumab govitecan is an effective treatment. The safety population included only those who started treatment, and the company used this population to conduct the quality of life analyses. The committee concluded that the survival data from ASCENT is generalisable to the NHS, and that the effect of differential dropout rates on the measured outcomes is unknown. ## ASCENT trial data is appropriate for decision making The committee noted issues with the generalisability of ASCENT including previous eribulin use (see section 3.4) and differential dropout rates between sacituzumab govitecan and treatment of physician's choice (see section 3.5), but concluded that the trial data was appropriate for decision making. ## There is uncertainty in the quality of life data and therefore in the utility values used in the model ASCENT collected data on European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 scores, which informed the utilities in the model. Scores were missing for 11.7% of the treatment arm and 30.2% of the comparator arm. The clinical experts explained that this was probably because of people in the comparator arm having earlier disease progression and their condition deteriorating more quickly; attrition for collection of data on quality of life is inevitable when people's condition progresses because they are less willing or able to complete questionnaires. The ERG highlighted that this might have biased the treatment effect estimates and noted the wide confidence intervals around the EORTC QLQ-C30 scores. It deemed the quality of life data collected in ASCENT highly uncertain. During consultation, the company did a post hoc analysis of people on treatment of physicians' choice who were not followed up for quality of life data. This group had worse overall survival than those who were followed up. The clinical experts noted that using quality of life estimates that excluded people who were not followed up could lead to an overestimate of health-related quality of life. The committee concluded that uncertainty related to follow up had an unknown effect on the utility values used in the model. ## It is plausible that quality of life is better during sacituzumab govitecan treatment than during standard chemotherapy, but not necessarily after progression The company argued that ASCENT indicated that quality of life was better for those on sacituzumab govitecan. It assumed a quality of life benefit for those on sacituzumab govitecan compared with treatment of physician's choice in both the pre-progression and post-progression health states. The clinical experts explained that this is plausible because of the considerably greater objective response rate for sacituzumab govitecan (31.1% compared with 4.2% for treatment of physician's choice). This increased tumour shrinkage with sacituzumab govitecan would reduce symptoms associated with tumour burden and lead to improved quality of life. They considered it plausible that this would carry over upon disease progression, because people on sacituzumab govitecan enter the progressed health state with a reduced tumour burden compared with those who had treatment of physician's choice. The patient expert agreed that sacituzumab govitecan gave a good quality of life and that they were able to complete normal daily activities. Their initial gastrointestinal symptoms were managed with a dose reduction. The patient expert emphasised the psychological benefits of knowing that you were on an effective treatment compared with standard chemotherapy, and added that the hope this brings, and the potential for the treatment to act as a bridge to future effective therapies, improved their quality of life. The committee noted that to inform the post-progression utility values in the model, the company used a quality of life questionnaire completed 4 weeks after the last dose, which would be in early post-progression. The committee questioned whether this represented the true quality of life throughout the whole post-progression period. The committee concluded that it is plausible that quality of life is better while taking sacituzumab govitecan compared with standard chemotherapy, but once the disease progresses and the people stop the therapy that is no longer effective, their quality of life would deteriorate. In addition, the committee noted that there was no evidence that the quality of life of people who had received sacituzumab govitecan would remain better right up to the time of death compared with people who had received other therapies pre-progression. However, in response to consultation comments, the committee considered scenarios in which there was a limited carry-over beneficial effect on quality of life after progression on sacituzumab govitecan. # Cost-effectiveness evidence ## The company's model structure is appropriate The company submitted a partitioned survival model to estimate the cost effectiveness of sacituzumab govitecan compared with treatment of physician's choice: eribulin, capecitabine, gemcitabine and vinorelbine. It had 3 health states: progression-free survival, post-progression survival and death. The committee considered that a partitioned survival model is a standard approach to estimate the cost effectiveness of cancer drugs and was appropriate for decision making. # Costs in the economic model ## Treatment acquisition and administration costs are between the company and ERG estimates Four assumptions contributed to the acquisition and administration costs of treatments in the model: costing by model or treatment cycle, relative dose intensity (RDI), the weight distribution applied to each treatment arm and allowance for any vial sharing. Costing by cycle: the company included drug costs in the model as a cost per 1‑week model cycle. The ERG explained that this was not appropriate because anyone who died during a model cycle would still have received the full treatment at the start of the treatment cycle, and this should be costed. It preferred a cost per 3‑week treatment cycle which removed the risk of underestimating acquisition and administration costs. The Cancer Drugs Fund clinical lead explained that using a cost by treatment cycle was logical and the normal approach for modelling the costs of cancer drugs. RDI: the company included an RDI of 94.2%, which was informed by dose reduction, incomplete infusions and delays in the ASCENT trial, which the committee considered reasonable. Weight distribution: all treatments included in the model were dosed by weight. The company applied different weight distributions to the sacituzumab govitecan and treatment of physician's choice arms, which reflected the weight distribution of people in the ASCENT trial. It used a non-parametric distribution for the sacituzumab govitecan arm and a parametric distribution for the treatment of physician's choice arm. The ERG advised that, methodologically, the weight distribution should be identical in both arms and noted that the non-parametric distribution for sacituzumab govitecan was slightly skewed towards lower percentiles. The ERG did not prefer either distribution as long as the same distribution was applied to both arms. The company did a scenario analysis using parametric distributions for both arms. This had a minimal impact on the incremental cost-effectiveness ratio (ICER), and the change was in favour of sacituzumab govitecan. Vial sharing: the company assumed wastage for 50% of people having sacituzumab govitecan but that vials would be perfectly shared for the remaining 50%. The ERG felt this did not take an NHS perspective because these savings occurred at the hospital level and did not result in a reduced number of prescriptions. The committee considered the feasibility of vial sharing in practice based on the patient numbers. The Cancer Drugs Fund clinical expert agreed with the company, that 50% is a reasonable assumption for vial sharing. The committee considered costing per treatment cycle (the ERG's approach), an RDI of 94.2%, and 50% vial sharing (the company's approach) to be most appropriate. The committee preferred using the same weight distribution in both arms but noted that varying this assumption had a small impact on the ICER and therefore did not discuss this at length. ## The appropriate proportion of people having subsequent eribulin in the treatment of physician's choice arm of the model is 47% The model included eribulin, paclitaxel, carboplatin, capecitabine, epirubicin and vinorelbine as subsequent treatments. Eribulin is the most expensive, and so the cost-effectiveness estimates were sensitive to the proportion of people assumed to have eribulin as a subsequent treatment. The committee appreciated that it was difficult to appropriately incorporate subsequent eribulin costs in the model given that a third of people in the trial had prior eribulin, which does not reflect UK clinical practice (see section 3.4) or the expected treatment pathway (see section 3.2). The committee recalled the clinical experts' view that prior eribulin use would not affect future outcomes and would predominately affect costs. The company sought UK clinical expert opinion about the expected proportions of people having subsequent eribulin in UK practice. The estimated proportion of people having eribulin after sacituzumab govitecan is commercial in confidence and cannot be reported here, but the ERG agreed with the company's estimate. The proportion of people having subsequent eribulin in the comparator arm of the model was 47%; this was based on those who did not get eribulin in the treatment of physician's choice arm in ASCENT, and would therefore get it subsequently. The ERG was concerned that a large proportion of people in the treatment of physician's choice arm of the model had eribulin twice because of the proportion of people who had it before entering the trial. This would overestimate eribulin costs in the comparator arm only and would underestimate the ICER for sacituzumab govitecan. The ERG's preferred approach was to only model subsequent eribulin for the 14% of people in the treatment of physician's choice arm of ASCENT who had not previously had eribulin. The committee acknowledged the complexity of the issue but concluded that it was appropriate to assume subsequent eribulin for all who had not had it as part of the treatment of physician's choice (47%) arm, because this reflects what would happen in clinical practice in the NHS. # Utility values in the economic model ## Higher pre-progression utilities for sacituzumab govitecan than for treatment of physician's choice are acceptable The company used utility values in the pre-progression state that were 0.084 higher for people on sacituzumab govitecan than for those on treatment of physician's choice. These values came from the company's safety population analysis of the EORTC QLQ-C30 data collected in ASCENT. The ERG considered that this health-related quality of life analysis was invalid because of the attrition in quality of life data (see section 3.7) and the higher dropout rate of people assigned to treatment of physician's choice (see section 3.5), noting that this broke the randomisation. The clinical and patient experts provided a rationale to support the company case for higher utilities for people on sacituzumab govitecan compared with treatment of physician's choice (see section 3.8). The committee accepted the biological plausibility and magnitude of quality of life benefit and agreed that utility values would be higher in the pre-progression state for those on sacituzumab govitecan. ## A higher utility value for the whole of the post-progression state for sacituzumab govitecan is not plausible The company used the same analysis to inform the utility values in the post-progression and pre-progression states, meaning the post-progression utility was higher for people who had sacituzumab govitecan. The clinical experts stated that it was clinically plausible for sacituzumab govitecan to confer better quality of life in the post-progression state, because people who had it before progression had reduced tumour burden and therefore symptoms, and this quality of life would carry through to the post-progression state. The committee questioned the numerical connection between tumour burden and quality of life improvement. The clinical experts noted that improvement in tumour burden is closely related to symptoms and therefore quality of life, but agreed it does not necessarily have a simple linear numerical relationship to utility because quality of life could also be related to, for example, the site of disease. The Cancer Drugs Fund clinical lead noted that tumour burden is a contributor to quality of life, but also that side effects of chemotherapy and factors such as further lines of chemotherapy, which was more likely in people having sacituzumab govitecan, also influenced quality of life. In the company's original submission, the pre-progression utility benefit (0.084) associated with sacituzumab govitecan compared with treatment of physician's choice was carried over into post-progression until death. The ERG was concerned that the data informing post-progression quality of life had been collected in ASCENT only 4 weeks after the last dose, which it considered did not reliably reflect post-progression utility over the longer term. The Cancer Drugs Fund clinical lead noted that utility would continue to decline in the progressed state as people neared death and would not be maintained at the 4‑week level. The ERG preferred to use a post-progression utility (0.653) accepted in a previous appraisal in locally advanced or metastatic triple-negative breast cancer (TA639). The committee agreed that a higher utility for the whole of the post-progression state for people who had sacituzumab govitecan compared with those who had treatment of physician's choice is not plausible. ## The company's revised base case with a restricted post-progression utility benefit for sacituzumab govitecan is the least flawed approach After consultation, the company maintained its position that the post-progression utility benefit of sacituzumab govitecan compared with treatment of physician's choice would continue for the duration of the person's life. But it also provided an alternative approach, in which people who had previously had sacituzumab govitecan had a higher utility than those on treatment of physician's choice for 6 months, after which the utilities converged. The converged utility after 6 months was slightly higher than post-progression utility for the first 6 months for people having treatment of physician's choice, constituting a rebound in post-progression utility for this group. The clinical experts did not consider this rebound to be clinically plausible. The committee acknowledged that if it accepted the company's pre-progression utility difference, and the ERG's preferred post-progression utility, this also resulted in an increase in the quality of life estimates in the treatment of physician's choice arm on progression. The ERG raised concerns about the lack of detail in the methodology in the company's revised approach. It preferred its initial base case of equal post-progression utilities for both arms, as with a previous appraisal (TA639). The ERG noted that the convergence of post-progression utility substantially affected the cost-effectiveness results, and did scenario analyses to further explore the company's approach of higher post-progression utility for people on sacituzumab govitecan for a limited time. The ERG's analysis was informed by ASCENT trial data and limited the higher utility to: (i) a period of continued response in the post-progression state and (ii) the proportion of people who had a clinical response to sacituzumab govitecan in the clinical trial. This increased the ICER compared with the company's adjustment. The committee noted that the ERG's analysis explored the effect of different response rates, but also noted that because the average utility used for the analysis included people whose disease responded and those whose disease did not respond, this approach was not entirely satisfactory. In total, the committee considered 4 different approaches to modelling post-progression utilities. It noted the uncertainties associated with each of the approaches and considered that none was entirely satisfactory. The committee acknowledged the challenges surrounding the post-progression utilities explored, noting the substantial effect on the cost-effectiveness estimates despite the inherent uncertainty. But it concluded that the company's revised base case with a carry-over utility benefit for 6 months was the least flawed approach. # Long-term survival estimates ## The long-term overall survival benefit for sacituzumab govitecan is uncertain The company chose a jointly fitted log-logistic model to extrapolate overall survival. It chose this approach based on goodness of fit statistics and visual fit to the trial data. The company noted that the more mature data from the February 2021 data cut validated the joint log-logistic model. The ERG did not have a strong preference but recommended that the company explored both jointly and independently fitted curves. It noted that the jointly fitted generalised gamma curve had a similar statistical fit and a better visual fit than the joint log-logistic curve, but gave lower longer-term survival estimates. The committee noted that the trial data was mature and therefore the extrapolated overall survival was a true area of uncertainty rather than uncertainty because of data immaturity. It agreed that the true survival extrapolation could be anywhere between the log-logistic and the more pessimistic generalised gamma models. The committee concluded that the joint log-logistic model of extrapolating overall survival as suggested by the company was uncertain, but acceptable. # End of life ## End of life criteria are met The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It considered that all scenario analyses presented by the company and the ERG indicated that sacituzumab govitecan offers more than 3 months' extension to life in a population that has a life expectancy of less than 24 months. Therefore, it concluded that sacituzumab govitecan fulfils the end of life criteria. # Cost-effectiveness results ## The cost-effectiveness estimates are within what NICE considers a cost-effective use of NHS resources The company's revised base case ICER, using the confidential patient access scheme discount for sacituzumab govitecan and the undiscounted list prices for the comparators and subsequent treatments, was £47,170 per quality-adjusted life year (QALY) gained. The company used some of the committee's preferred assumptions in its response to consultation. When the confidential discounts for the comparators and subsequent treatments were applied, the ICER was within the range NICE considers a cost-effective use of NHS resources for an end of life treatment. The ICER was subject to several uncertainties, including the extent of eribulin use, the extrapolation of long-term survival and the post-progression utility values. However, the committee concluded that the ICER was acceptable because of the high unmet need, and the substantial improvement in response rates compared with standard care. Overall, the committee concluded that sacituzumab govitecan is cost effective. # Conclusion ## Sacituzumab govitecan is recommended for use in the NHS The committee concluded that the cost-effectiveness estimates for sacituzumab govitecan were within the range NICE considers an acceptable use of NHS resources, in the context of the end of life criteria being met. Therefore, the committee recommended sacituzumab govitecan for use in the NHS.	{'Recommendations': "Sacituzumab govitecan is recommended, within its marketing authorisation, as an option for treating unresectable triple-negative locally advanced or metastatic breast cancer in adults after 2 or more systemic therapies, at least 1 of which was for advanced disease. It is recommended only if the company provides sacituzumab govitecan according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nUsual treatment for triple-negative locally advanced or metastatic breast cancer is chemotherapy.\n\nClinical trial evidence shows that sacituzumab govitecan increases how long people have before their disease gets worse and how long they live compared with chemotherapy.\n\nSacituzumab govitecan meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates are within what NICE usually considers an acceptable use of NHS resources. Therefore, it is recommended.", 'Information about sacituzumab govitecan': "# Marketing authorisation indication\n\nSacituzumab govitecan (Trodelvy, Gilead Sciences) has a marketing authorisation for 'the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior lines of systemic therapies, at least one of them given for unresectable locally advanced or metastatic disease'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for sacituzumab govitecan.\n\n# Price\n\nThe list price of sacituzumab govitecan is £793.00 per 180\xa0mg vial (excluding VAT; BNF online accessed May 2022).\n\nThe company has a commercial arrangement. This makes sacituzumab govitecan available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Gilead, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need and treatment pathway\n\n## Triple-negative breast cancer has a high disease burden\n\nTriple-negative breast cancer accounts for about 15% of breast cancers and lacks all 3\xa0molecular markers (oestrogen, progesterone and HER2 receptors), which affects treatment options and prognosis. Chemotherapy is the mainstay of treatment because triple-negative breast cancer is not sensitive to endocrine therapy or molecular targeted therapy. The patient expert explained that being diagnosed with locally recurrent unresectable or metastatic breast cancer is extremely difficult for people, and their family and friends. It can cause considerable anxiety and fear, and the uncertainty of the outcome can be very difficult to deal with. The aim of treatment is to stop progression of the disease, extend life, and maintain or improve quality of life for as long as possible. Treatment is continued for as long as it is controlling the disease. The committee concluded that there is a high disease burden for people with triple-negative breast cancer.\n\n## There is a high unmet need for effective treatments for triple-negative locally advanced or metastatic breast cancer\n\nThe marketing authorisation for sacituzumab govitecan specifies its use after 2 or more prior systemic therapies, 1 of which should have been for advanced disease. For people who have triple-negative advanced or metastatic breast cancer, first-line therapies are paclitaxel, docetaxel, nab-paclitaxel, anthracycline-based chemotherapy, gemcitabine with or without carboplatin, or atezolizumab plus nab-paclitaxel for programmed death‑ligand 1 (PD‑L1)‑positive disease (see NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel for untreated PD-L1-positive, locally advanced or metastatic, triple-negative breast cancer [TA639]). Second-line therapies are single-agent vinorelbine or capecitabine. Third-line therapies are eribulin (see NICE's technology appraisal guidance on eribulin for treating locally advanced or metastatic breast cancer after 2 or more chemotherapy regimens [TA423]) or single-agent vinorelbine or capecitabine (whichever was not used previously) (see NICE's clinical guideline on advanced breast cancer: diagnosis and management). In the locally advanced or metastatic setting, the proposed positioning for sacituzumab govitecan is either second line (for people who received a systemic treatment for early disease) or third line (for people who initially presented with de\xa0novo metastatic disease). The clinical experts clarified that, in the locally advanced or metastatic setting, most people would have sacituzumab govitecan as a second-line therapy. Clinicians prefer to use the most effective treatments earlier in the treatment pathway. Therefore, people will have already had anthracyclines, taxanes and capecitabine. The clinical experts noted that because early triple-negative breast cancer tends to relapse quickly after treatment, rechallenge with these therapies is not appropriate, leaving very few effective treatment options. The committee concluded that there is a high unmet need for effective treatments for locally advanced or metastatic triple‑negative breast cancer.\n\n# Clinical evidence\n\n## Sacituzumab govitecan offers considerable benefit compared with standard care\n\nThe clinical evidence was based on ASCENT, a randomised, open-label clinical trial that enrolled people with relapsed or refractory, unresectable, triple-negative, locally advanced or metastatic breast cancer after 2 or more previous therapies. ASCENT compared sacituzumab govitecan with treatment of physician's choice, which included eribulin, capecitabine, gemcitabine and vinorelbine. The company reported trial results from a March 2020 data cut. This showed a consistent clinically meaningful and statistically significant benefit for sacituzumab govitecan compared with treatment of physician's choice for objective response rate, progression-free survival and overall survival. The objective response rate was considerably greater in the sacituzumab govitecan arm: 31.1% compared with 4.2% in the treatment of physician's choice arm. Median progression-free survival was 4.8\xa0months in the sacituzumab govitecan arm compared with 1.7\xa0months in the treatment of physician's choice arm (hazard ratio 0.43, 95% confidence interval 0.35 to 0.54). Median overall survival was 11.8\xa0months with sacituzumab govitecan compared with 6.9\xa0months in the treatment of physician's choice arm (hazard ratio 0.51, 95% confidence interval 0.41 to 0.62). The patient expert experienced tumour shrinkage while on sacituzumab govitecan, and explained that initial gastrointestinal side effects were well managed with a dose reduction and concomitant medication. The company provided a later data cut from February 2021 during technical engagement. The ERG noted that the survival data was similar across the 2 data cuts, with no changes to the median estimates, and marginal changes to the mean estimates. The committee considered sacituzumab govitecan to be a highly effective treatment for people with triple-negative locally advanced or metastatic breast cancer who have a poor prognosis.\n\n## The results of the trial are generalisable to NHS clinical practice\n\nIn ASCENT, 32.7% of people had previously had eribulin, which is only used as a third-line treatment in the UK (after 2 or more chemotherapy regimens, in line with TA423). In the UK, eribulin would be given after sacituzumab govitecan. The ERG noted that prior eribulin in ASCENT could impact the trial efficacy results for sacituzumab govitecan. The clinical experts explained that because the trial also included people who had not had prior eribulin, the trial demonstrated that sacituzumab govitecan is effective before and after eribulin. They felt that the efficacy of sacituzumab govitecan is not affected by prior treatment with eribulin. The committee accepted that although approximately a third of the people in ASCENT had received eribulin, which does not reflect UK practice, the results were generalisable to people in the NHS.\n\n## The effect of a higher dropout rate in the comparator arm is unknown\n\nIn ASCENT, 14.5% of people randomised to the comparator arm (treatment of physician's choice including eribulin, gemcitabine, capecitabine and vinorelbine) chose not to have treatment, compared with 3.4% of people in the sacituzumab govitecan arm. The ERG noted that this differential dropout rate could introduce bias because it is unclear if common patient characteristics affected the choice to start treatment. The ERG suggested that it may have been people with a better prognosis who felt they had better options outside of participating in ASCENT. The clinical experts disagreed and explained that people who dropped out of the trial were more likely to be those with poor prognosis who chose not to have further chemotherapy as part of the comparator arm. They said that dropout was inevitable in an open-label trial, and that people may be unwilling to remain in the comparator arm when there is already published data showing that sacituzumab govitecan is an effective treatment. The safety population included only those who started treatment, and the company used this population to conduct the quality of life analyses. The committee concluded that the survival data from ASCENT is generalisable to the NHS, and that the effect of differential dropout rates on the measured outcomes is unknown.\n\n## ASCENT trial data is appropriate for decision making\n\nThe committee noted issues with the generalisability of ASCENT including previous eribulin use (see section 3.4) and differential dropout rates between sacituzumab govitecan and treatment of physician's choice (see section 3.5), but concluded that the trial data was appropriate for decision making.\n\n## There is uncertainty in the quality of life data and therefore in the utility values used in the model\n\nASCENT collected data on European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 scores, which informed the utilities in the model. Scores were missing for 11.7% of the treatment arm and 30.2% of the comparator arm. The clinical experts explained that this was probably because of people in the comparator arm having earlier disease progression and their condition deteriorating more quickly; attrition for collection of data on quality of life is inevitable when people's condition progresses because they are less willing or able to complete questionnaires. The ERG highlighted that this might have biased the treatment effect estimates and noted the wide confidence intervals around the EORTC QLQ-C30 scores. It deemed the quality of life data collected in ASCENT highly uncertain. During consultation, the company did a post hoc analysis of people on treatment of physicians' choice who were not followed up for quality of life data. This group had worse overall survival than those who were followed up. The clinical experts noted that using quality of life estimates that excluded people who were not followed up could lead to an overestimate of health-related quality of life. The committee concluded that uncertainty related to follow up had an unknown effect on the utility values used in the model.\n\n## It is plausible that quality of life is better during sacituzumab govitecan treatment than during standard chemotherapy, but not necessarily after progression\n\nThe company argued that ASCENT indicated that quality of life was better for those on sacituzumab govitecan. It assumed a quality of life benefit for those on sacituzumab govitecan compared with treatment of physician's choice in both the pre-progression and post-progression health states. The clinical experts explained that this is plausible because of the considerably greater objective response rate for sacituzumab govitecan (31.1% compared with 4.2% for treatment of physician's choice). This increased tumour shrinkage with sacituzumab govitecan would reduce symptoms associated with tumour burden and lead to improved quality of life. They considered it plausible that this would carry over upon disease progression, because people on sacituzumab govitecan enter the progressed health state with a reduced tumour burden compared with those who had treatment of physician's choice. The patient expert agreed that sacituzumab govitecan gave a good quality of life and that they were able to complete normal daily activities. Their initial gastrointestinal symptoms were managed with a dose reduction. The patient expert emphasised the psychological benefits of knowing that you were on an effective treatment compared with standard chemotherapy, and added that the hope this brings, and the potential for the treatment to act as a bridge to future effective therapies, improved their quality of life. The committee noted that to inform the post-progression utility values in the model, the company used a quality of life questionnaire completed 4\xa0weeks after the last dose, which would be in early post-progression. The committee questioned whether this represented the true quality of life throughout the whole post-progression period. The committee concluded that it is plausible that quality of life is better while taking sacituzumab govitecan compared with standard chemotherapy, but once the disease progresses and the people stop the therapy that is no longer effective, their quality of life would deteriorate. In addition, the committee noted that there was no evidence that the quality of life of people who had received sacituzumab govitecan would remain better right up to the time of death compared with people who had received other therapies pre-progression. However, in response to consultation comments, the committee considered scenarios in which there was a limited carry-over beneficial effect on quality of life after progression on sacituzumab govitecan.\n\n# Cost-effectiveness evidence\n\n## The company's model structure is appropriate\n\nThe company submitted a partitioned survival model to estimate the cost effectiveness of sacituzumab govitecan compared with treatment of physician's choice: eribulin, capecitabine, gemcitabine and vinorelbine. It had 3\xa0health states: progression-free survival, post-progression survival and death. The committee considered that a partitioned survival model is a standard approach to estimate the cost effectiveness of cancer drugs and was appropriate for decision making.\n\n# Costs in the economic model\n\n## Treatment acquisition and administration costs are between the company and ERG estimates\n\nFour assumptions contributed to the acquisition and administration costs of treatments in the model: costing by model or treatment cycle, relative dose intensity (RDI), the weight distribution applied to each treatment arm and allowance for any vial sharing.\n\nCosting by cycle: the company included drug costs in the model as a cost per 1‑week model cycle. The ERG explained that this was not appropriate because anyone who died during a model cycle would still have received the full treatment at the start of the treatment cycle, and this should be costed. It preferred a cost per 3‑week treatment cycle which removed the risk of underestimating acquisition and administration costs. The Cancer Drugs Fund clinical lead explained that using a cost by treatment cycle was logical and the normal approach for modelling the costs of cancer drugs.\n\nRDI: the company included an RDI of 94.2%, which was informed by dose reduction, incomplete infusions and delays in the ASCENT trial, which the committee considered reasonable.\n\nWeight distribution: all treatments included in the model were dosed by weight. The company applied different weight distributions to the sacituzumab govitecan and treatment of physician's choice arms, which reflected the weight distribution of people in the ASCENT trial. It used a non-parametric distribution for the sacituzumab govitecan arm and a parametric distribution for the treatment of physician's choice arm. The ERG advised that, methodologically, the weight distribution should be identical in both arms and noted that the non-parametric distribution for sacituzumab govitecan was slightly skewed towards lower percentiles. The ERG did not prefer either distribution as long as the same distribution was applied to both arms. The company did a scenario analysis using parametric distributions for both arms. This had a minimal impact on the incremental cost-effectiveness ratio (ICER), and the change was in favour of sacituzumab govitecan.\n\nVial sharing: the company assumed wastage for 50% of people having sacituzumab govitecan but that vials would be perfectly shared for the remaining 50%. The ERG felt this did not take an NHS perspective because these savings occurred at the hospital level and did not result in a reduced number of prescriptions. The committee considered the feasibility of vial sharing in practice based on the patient numbers. The Cancer Drugs Fund clinical expert agreed with the company, that 50% is a reasonable assumption for vial sharing. The committee considered costing per treatment cycle (the ERG's approach), an RDI of 94.2%, and 50% vial sharing (the company's approach) to be most appropriate. The committee preferred using the same weight distribution in both arms but noted that varying this assumption had a small impact on the ICER and therefore did not discuss this at length.\n\n## The appropriate proportion of people having subsequent eribulin in the treatment of physician's choice arm of the model is 47%\n\nThe model included eribulin, paclitaxel, carboplatin, capecitabine, epirubicin and vinorelbine as subsequent treatments. Eribulin is the most expensive, and so the cost-effectiveness estimates were sensitive to the proportion of people assumed to have eribulin as a subsequent treatment. The committee appreciated that it was difficult to appropriately incorporate subsequent eribulin costs in the model given that a third of people in the trial had prior eribulin, which does not reflect UK clinical practice (see section 3.4) or the expected treatment pathway (see section 3.2). The committee recalled the clinical experts' view that prior eribulin use would not affect future outcomes and would predominately affect costs. The company sought UK clinical expert opinion about the expected proportions of people having subsequent eribulin in UK practice. The estimated proportion of people having eribulin after sacituzumab govitecan is commercial in confidence and cannot be reported here, but the ERG agreed with the company's estimate. The proportion of people having subsequent eribulin in the comparator arm of the model was 47%; this was based on those who did not get eribulin in the treatment of physician's choice arm in ASCENT, and would therefore get it subsequently. The ERG was concerned that a large proportion of people in the treatment of physician's choice arm of the model had eribulin twice because of the proportion of people who had it before entering the trial. This would overestimate eribulin costs in the comparator arm only and would underestimate the ICER for sacituzumab govitecan. The ERG's preferred approach was to only model subsequent eribulin for the 14% of people in the treatment of physician's choice arm of ASCENT who had not previously had eribulin. The committee acknowledged the complexity of the issue but concluded that it was appropriate to assume subsequent eribulin for all who had not had it as part of the treatment of physician's choice (47%) arm, because this reflects what would happen in clinical practice in the NHS.\n\n# Utility values in the economic model\n\n## Higher pre-progression utilities for sacituzumab govitecan than for treatment of physician's choice are acceptable\n\nThe company used utility values in the pre-progression state that were 0.084 higher for people on sacituzumab govitecan than for those on treatment of physician's choice. These values came from the company's safety population analysis of the EORTC QLQ-C30 data collected in ASCENT. The ERG considered that this health-related quality of life analysis was invalid because of the attrition in quality of life data (see section 3.7) and the higher dropout rate of people assigned to treatment of physician's choice (see section 3.5), noting that this broke the randomisation. The clinical and patient experts provided a rationale to support the company case for higher utilities for people on sacituzumab govitecan compared with treatment of physician's choice (see section 3.8). The committee accepted the biological plausibility and magnitude of quality of life benefit and agreed that utility values would be higher in the pre-progression state for those on sacituzumab govitecan.\n\n## A higher utility value for the whole of the post-progression state for sacituzumab govitecan is not plausible\n\nThe company used the same analysis to inform the utility values in the post-progression and pre-progression states, meaning the post-progression utility was higher for people who had sacituzumab govitecan. The clinical experts stated that it was clinically plausible for sacituzumab govitecan to confer better quality of life in the post-progression state, because people who had it before progression had reduced tumour burden and therefore symptoms, and this quality of life would carry through to the post-progression state. The committee questioned the numerical connection between tumour burden and quality of life improvement. The clinical experts noted that improvement in tumour burden is closely related to symptoms and therefore quality of life, but agreed it does not necessarily have a simple linear numerical relationship to utility because quality of life could also be related to, for example, the site of disease. The Cancer Drugs Fund clinical lead noted that tumour burden is a contributor to quality of life, but also that side effects of chemotherapy and factors such as further lines of chemotherapy, which was more likely in people having sacituzumab govitecan, also influenced quality of life. In the company's original submission, the pre-progression utility benefit (0.084) associated with sacituzumab govitecan compared with treatment of physician's choice was carried over into post-progression until death. The ERG was concerned that the data informing post-progression quality of life had been collected in ASCENT only 4\xa0weeks after the last dose, which it considered did not reliably reflect post-progression utility over the longer term. The Cancer Drugs Fund clinical lead noted that utility would continue to decline in the progressed state as people neared death and would not be maintained at the 4‑week level. The ERG preferred to use a post-progression utility (0.653) accepted in a previous appraisal in locally advanced or metastatic triple-negative breast cancer (TA639). The committee agreed that a higher utility for the whole of the post-progression state for people who had sacituzumab govitecan compared with those who had treatment of physician's choice is not plausible.\n\n## The company's revised base case with a restricted post-progression utility benefit for sacituzumab govitecan is the least flawed approach\n\nAfter consultation, the company maintained its position that the post-progression utility benefit of sacituzumab govitecan compared with treatment of physician's choice would continue for the duration of the person's life. But it also provided an alternative approach, in which people who had previously had sacituzumab govitecan had a higher utility than those on treatment of physician's choice for 6\xa0months, after which the utilities converged. The converged utility after 6\xa0months was slightly higher than post-progression utility for the first 6\xa0months for people having treatment of physician's choice, constituting a rebound in post-progression utility for this group. The clinical experts did not consider this rebound to be clinically plausible. The committee acknowledged that if it accepted the company's pre-progression utility difference, and the ERG's preferred post-progression utility, this also resulted in an increase in the quality of life estimates in the treatment of physician's choice arm on progression. The ERG raised concerns about the lack of detail in the methodology in the company's revised approach. It preferred its initial base case of equal post-progression utilities for both arms, as with a previous appraisal (TA639). The ERG noted that the convergence of post-progression utility substantially affected the cost-effectiveness results, and did scenario analyses to further explore the company's approach of higher post-progression utility for people on sacituzumab govitecan for a limited time. The ERG's analysis was informed by ASCENT trial data and limited the higher utility to: (i) a period of continued response in the post-progression state and (ii) the proportion of people who had a clinical response to sacituzumab govitecan in the clinical trial. This increased the ICER compared with the company's adjustment. The committee noted that the ERG's analysis explored the effect of different response rates, but also noted that because the average utility used for the analysis included people whose disease responded and those whose disease did not respond, this approach was not entirely satisfactory. In total, the committee considered 4 different approaches to modelling post-progression utilities. It noted the uncertainties associated with each of the approaches and considered that none was entirely satisfactory. The committee acknowledged the challenges surrounding the post-progression utilities explored, noting the substantial effect on the cost-effectiveness estimates despite the inherent uncertainty. But it concluded that the company's revised base case with a carry-over utility benefit for 6\xa0months was the least flawed approach.\n\n# Long-term survival estimates\n\n## The long-term overall survival benefit for sacituzumab govitecan is uncertain\n\nThe company chose a jointly fitted log-logistic model to extrapolate overall survival. It chose this approach based on goodness of fit statistics and visual fit to the trial data. The company noted that the more mature data from the February 2021 data cut validated the joint log-logistic model. The ERG did not have a strong preference but recommended that the company explored both jointly and independently fitted curves. It noted that the jointly fitted generalised gamma curve had a similar statistical fit and a better visual fit than the joint log-logistic curve, but gave lower longer-term survival estimates. The committee noted that the trial data was mature and therefore the extrapolated overall survival was a true area of uncertainty rather than uncertainty because of data immaturity. It agreed that the true survival extrapolation could be anywhere between the log-logistic and the more pessimistic generalised gamma models. The committee concluded that the joint log-logistic model of extrapolating overall survival as suggested by the company was uncertain, but acceptable.\n\n# End of life\n\n## End of life criteria are met\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It considered that all scenario analyses presented by the company and the ERG indicated that sacituzumab govitecan offers more than 3\xa0months' extension to life in a population that has a life expectancy of less than 24\xa0months. Therefore, it concluded that sacituzumab govitecan fulfils the end of life criteria.\n\n# Cost-effectiveness results\n\n## The cost-effectiveness estimates are within what NICE considers a cost-effective use of NHS resources\n\nThe company's revised base case ICER, using the confidential patient access scheme discount for sacituzumab govitecan and the undiscounted list prices for the comparators and subsequent treatments, was £47,170 per quality-adjusted life year (QALY) gained. The company used some of the committee's preferred assumptions in its response to consultation. When the confidential discounts for the comparators and subsequent treatments were applied, the ICER was within the range NICE considers a cost-effective use of NHS resources for an end of life treatment. The ICER was subject to several uncertainties, including the extent of eribulin use, the extrapolation of long-term survival and the post-progression utility values. However, the committee concluded that the ICER was acceptable because of the high unmet need, and the substantial improvement in response rates compared with standard care. Overall, the committee concluded that sacituzumab govitecan is cost effective.\n\n# Conclusion\n\n## Sacituzumab govitecan is recommended for use in the NHS\n\nThe committee concluded that the cost-effectiveness estimates for sacituzumab govitecan were within the range NICE considers an acceptable use of NHS resources, in the context of the end of life criteria being met. Therefore, the committee recommended sacituzumab govitecan for use in the NHS."}	https://www.nice.org.uk/guidance/ta819	Evidence-based recommendations on sacituzumab govetican (Trodelvy) for treating unresectable, triple-negative locally advanced or metastatic breast cancer in adults after 2 or more systemic therapies, at least 1 of which was for advanced disease.
d331e98acabecb0058c52626bab78dc775366234	nice	Type 1 diabetes in adults: diagnosis and management	Type 1 diabetes in adults: diagnosis and management This guideline covers care and treatment for adults (aged 18 and over) with type 1 diabetes. It includes advice on diagnosis, education and support, blood glucose management, cardiovascular risk, and identifying and managing long-term complications. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. Blood glucose and plasma glucose 'Blood glucose' is the more commonly used term. However, a lot of the evidence this guideline is based on uses 'plasma' rather than 'blood' glucose, and patient‑held glucose meters and monitoring systems are calibrated to plasma glucose equivalents. Because of this, in this guideline we use the term 'blood glucose', except when referring to specific concentration values. # Diagnosis and early care plan ## Initial diagnosis Make an initial diagnosis of type 1 diabetes on clinical grounds in adults presenting with hyperglycaemia. Bear in mind that people with type 1 diabetes typically (but not always) have 1 or more of: ketosis rapid weight loss age of onset under 50 years body mass index (BMI) below 25 kg/m2 personal and/or family history of autoimmune disease. Do not use age or BMI alone to exclude or diagnose type 1 diabetes in adults. Take into consideration the possibility of other diabetes subtypes and revisit the diagnosis at subsequent clinical reviews. Carry out further investigations if there is uncertainty (see recommendations 1.1.7 and 1.1.8). Measure diabetes-specific autoantibodies in adults with an initial diagnosis of type 1 diabetes, taking into account that: the false negative rate of diabetes-specific autoantibody tests is lowest at the time of diagnosis the false negative rate can be reduced by carrying out quantitative tests for 2 different diabetes-specific autoantibodies (with at least 1 being positive). Do not routinely measure serum C‑peptide to confirm type 1 diabetes in adults. In people with a negative diabetes-specific autoantibody result, and if diabetes classification remains uncertain, consider measuring non-fasting serum C‑peptide (with a paired blood glucose). ## Revisiting initial diagnosis At subsequent clinical reviews, consider using serum C‑peptide to revisit the diabetes classification if there is doubt that type 1 diabetes is the correct diagnosis. Take into account that the discriminative value of serum C‑peptide to diagnose type 1 diabetes increases the longer the test is done after initial diagnosis of diabetes. For people aged 60 and over presenting with weight loss and new-onset diabetes, follow recommendations on assessing for pancreatic cancer in the section on pancreatic cancer in the NICE guideline on suspected cancer: recognition and referral. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnosis . Full details of the evidence and the committee's discussion are in evidence review C: diagnosis of diabetes. Loading. Please wait. ## Early care plan At diagnosis (or, if necessary, after managing critically decompensated metabolism), the diabetes professional team should work with adults with type 1 diabetes to develop a plan for their early care. This will generally require: medical assessment to: ensure the diagnosis is accurate (see recommendations 1.1.1 to 1.1.5) ensure appropriate acute care is given when needed review medicines and detect potentially associated disease detect adverse vascular risk factors environmental assessment to understand: the social, home, work and recreational circumstances of the person and their carers their lifestyle (including diet and physical activity) -ther relevant factors, such as substance use cultural and educational assessment to: find out what they know about diabetes help with tailoring advice, and with planning treatments and diabetes education programmes assessment of their emotional wellbeing to decide how to pace diabetes education. Use the results of the initial diabetes assessment to agree a future care plan. This assessment should include: acute medical history social, cultural and educational history, and lifestyle review complications history and symptoms diabetes history (recent and long term) -ther medical history family history of diabetes and cardiovascular disease medication history vascular risk factors smoking general examination weight and BMI foot, eye and vision examination urine albumin:creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) psychological wellbeing attitudes to medicine and self‑care immediate family and social relationships, and availability of informal support. Include the following in an individualised and culturally appropriate diabetes plan: when and where they will have their diabetes education, including their dietary advice (see the sections on education and information and dietary management) initial treatment, including guidance on insulin injection and insulin regimens (see the sections on insulin therapy and insulin delivery) self‑monitoring and targets (see the section on blood glucose management) symptoms, and the risk of hypoglycaemia and how it is treated management of special situations, such as driving communicating with the diabetes professional team (how often and how to contact them) management of cardiovascular risk factors (see the section on control of cardiovascular risk) implications for pregnancy and family planning advice (see NICE's guideline on diabetes in pregnancy) how often they will have follow‑up appointments, and what these will cover (including review of HbA1c levels, experience of hypoglycaemia, and annual reviews). After the initial plan is agreed, implement it without inappropriate delay. Based on discussion with the adult with type 1 diabetes, modify the plan as needed over the following weeks. # Support and individualised care Take account of any disabilities, including visual impairment, when planning and delivering care for adults with type 1 diabetes. Advice to adults with type 1 diabetes should be provided by a range of professionals with skills in diabetes care, working together in a coordinated approach. Provide adults with type 1 diabetes with: access to services by different methods (including phone and email) during working hours information about out-of-hours services staffed by people with diabetes expertise. View each adult with type 1 diabetes as an individual, rather than as a member of any cultural, economic or health-affected group (also see recommendations 1.4.5 and 1.4.14 on cultural preferences in the section on dietary advice). Jointly agree an individual care plan with the adult with type 1 diabetes. Review this plan annually and amend it as needed, taking into account changes in the person's wishes, circumstances and medical findings. Individual care plans should include: diabetes education, including dietary advice (see the sections on education and information and dietary management) insulin therapy, including dosage adjustment (see the sections on insulin therapy and insulin delivery) self-monitoring (see the section on blood glucose management) avoiding hypoglycaemia and maintaining hypoglycaemia awareness family planning, contraception and pregnancy planning (see NICE's guideline on diabetes in pregnancy) cardiovascular risk factor monitoring and management (see the section on control of cardiovascular risk) complications monitoring and management (see the section on managing complications) communicating with the diabetes professional team (how often and how to contact them) how often they will have follow‑up appointments, and what these will cover (including review of HbA1c levels, experience of hypoglycaemia, and annual reviews). Use population, practice‑based and clinic diabetes registers (as specified by the Department of Health and Social Care's national service framework for diabetes) to assist programmed recall for annual reviews and assessments of complications and cardiovascular risk. At diagnosis and periodically after this, give adults with type 1 diabetes up‑to‑date information about diabetes support groups (local and national), how to contact them and their benefits. # Education and information Offer all adults with type 1 diabetes a structured education programme of proven benefit, for example, the DAFNE (dose adjustment for normal eating) programme. Offer the structured education programme 6 to 12 months after diagnosis. For adults who have not had a structured education programme by 12 months, offer it at any time that is clinically appropriate and suitable for the person, regardless of how long they have had type 1 diabetes. For adults with type 1 diabetes who are unable or prefer not to take part in group education, provide an alternative of equal standard. Ensure that any structured education programme for adults with type 1 diabetes: is evidence-based, and suits the needs of the person has specific aims and learning objectives, and supports the person and their family members and carers in developing attitudes, beliefs, knowledge and skills to self‑manage diabetes has a structured curriculum that is theory driven, evidence-based and resource effective and has supporting materials, and is written down is delivered by trained educators who: have an understanding of educational theory appropriate to the age and needs of the person and are trained and competent to deliver the principles and content of the programme is quality assured, and reviewed by trained, competent, independent assessors who measure it against criteria that ensure consistency has outcomes that are audited regularly. Explain to adults with type 1 diabetes that structured education is an integral part of diabetes care. Provide information about type 1 diabetes and its management to adults with type 1 diabetes at all opportunities from diagnosis onwards. Follow the principles in NICE's guideline on patient experience in adult NHS services. Consider the Blood Glucose Awareness Training (BGAT) programme for adults with type 1 diabetes who are having recurrent episodes of hypoglycaemia (see also the section on hypoglycaemia awareness and management). Carry out an annual review of self‑care and needs for all adults with type 1 diabetes. Decide what to cover each year by agreeing priorities with the adult with type 1 diabetes. # Dietary management ## Carbohydrate counting Offer carbohydrate‑counting training to adults with type 1 diabetes as part of structured education programmes for self‑management (see the section on education and information). Consider carbohydrate‑counting courses for adults with type 1 diabetes who are waiting for a more detailed structured education programme or who are unable to take part in a standalone structured education programme. ## Glycaemic index diets Do not advise adults with type 1 diabetes to follow a low glycaemic index diet for blood glucose control. ## Dietary advice Offer dietary advice to adults with type 1 diabetes about issues other than blood glucose control (such as managing weight and cardiovascular risk), as needed. From diagnosis, provide nutritional information that is sensitive to the personal needs and culture of each adult with type 1 diabetes. Provide nutritional information individually and as part of a structured education programme (see the section on education and information). Include advice from professionals who are trained and accredited to provide dietary advice to people with health conditions. Offer opportunities to receive dietary advice at intervals agreed between adults with type 1 diabetes and their healthcare professionals. Discuss the hyperglycaemic effects of the different foods the adult with type 1 diabetes wants to eat in the context of the insulin regimens chosen to match those food choices. Provide education programmes for adults with type 1 diabetes to help them with: healthy eating and a balanced diet changing their insulin dosage to reduce glucose excursions when varying their diet. Discuss snacks with the adult with type 1 diabetes: Cover the choice of snack, the quantity, and when to eat them. Explain the effects of eating different food types, and how long these effects last. Explain which insulin regimens are available to match different food types. Discuss changes in choice of snack if needed, based on the results of self‑monitoring tests. Provide information on: the effects of different alcohol‑containing drinks on blood glucose excursions and calorie intake high‑calorie and high‑sugar 'treats'. As part of dietary education after diagnosis (and as needed after this), provide information on how healthy eating can reduce cardiovascular risk. Include information about fruit and vegetables, types and amounts of fat, and how to make the appropriate dietary changes. Modify nutritional recommendations to adults with type 1 diabetes to take account of associated features of diabetes, including: excess weight and obesity underweight disordered eating hypertension renal failure. Healthcare professionals giving dietary advice to adults with type 1 diabetes should be able to advise about common topics of concern and interest, and should seek advice from specialists when needed. Suggested common topics include: body weight, energy balance and obesity management cultural and religious diets, feasts and fasts foods sold as 'diabetic' sweeteners dietary fibre intake protein intake vitamin and mineral supplements alcohol matching carbohydrate intake, insulin and physical activity salt intake in hypertension comorbidities, including nephropathy and renal failure, coeliac disease, cystic fibrosis or eating disorders peer support groups. # Physical activity Advise adults with type 1 diabetes that physical activity can reduce their enhanced cardiovascular risk in the medium and long term. For adults with type 1 diabetes who choose to increase their level of physical activity as part of a healthier lifestyle, provide information about: appropriate intensity and frequency of physical activity self‑monitoring their changed insulin and or nutritional needs the effect of physical activity on blood glucose levels (which are likely to fall) when insulin levels are adequate the effect of physical activity on blood glucose levels when hyperglycaemic and hypoinsulinaemic (there is a risk of worsening hyperglycaemia and ketonaemia) appropriate adjustments of insulin dosage and or nutritional intake for periods during and immediately after physical activity, and the 24 hours after this interactions of physical activity and alcohol further contacts and sources of information. # Blood glucose management ## HbA1c measurement and targets Measure HbA1c levels every 3 to 6 months in adults with type 1 diabetes. Consider measuring HbA1c levels more often in adults with type 1 diabetes if their blood glucose control is suspected to be changing rapidly; for example, if their HbA1c level has risen unexpectedly above a previously sustained target. Measure HbA1c using methods calibrated according to International Federation of Clinical Chemistry (IFCC) standardisation. Tell adults with type 1 diabetes their HbA1c results after each measurement and have their most recent result available at consultations. Follow the principles on communication in NICE's guideline on patient experience in adult NHS services. If HbA1c monitoring is invalid because of disturbed erythrocyte turnover or abnormal haemoglobin type, estimate trends in blood glucose control using 1 of the following: fructosamine estimation quality-controlled blood glucose profiles total glycated haemoglobin estimation (if abnormal haemoglobins). Support adults with type 1 diabetes to aim for a target HbA1c level of 48 mmol/mol (6.5%) or lower, to minimise the risk of long‑term vascular complications. Agree an individualised HbA1c target with each adult with type 1 diabetes. Take into account factors such as their daily activities, aspirations, likelihood of complications, comorbidities, occupation and history of hypoglycaemia. Ensure that aiming for an HbA1c target is not accompanied by problematic hypoglycaemia in adults with type 1 diabetes. Diabetes services should document the proportion of adults with type 1 diabetes who reach an HbA1c level of 53 mmol/mol (7%) or lower. ## Continuous glucose monitoring NICE's diagnostics guidance on integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes is being updated. The guidance is being updated as a multiple technology appraisal and will assess hybrid closed loop systems. Offer adults with type 1 diabetes a choice of real-time continuous glucose monitoring (rtCGM) or intermittently scanned continuous glucose monitoring (isCGM, commonly referred to as 'flash'), based on their individual preferences, needs, characteristics, and the functionality of the devices available. See box 1 for examples of factors to consider as part of this discussion. When choosing a continuous glucose monitoring (CGM) device: use shared decision making to identify the person's needs and preferences, and offer them an appropriate device if multiple devices meet their needs and preferences, offer the device with the lowest cost. Accuracy of the device Whether the device provides predictive alerts or alarms and if these need to be shared with anyone else (for example, a carer) Whether using the device requires access to particular technologies (such as a smartphone and up-to-date phone software) How easy the device is to use and take readings from, including for people with limited dexterity Fear, frequency, awareness and severity of hypoglycaemia Psychosocial factors The person's insulin regimen or type of insulin pump, if relevant (taking into account whether a particular device integrates with their pump as part of a hybrid closed loop or insulin suspend function) Whether, how often, and how the device needs to be calibrated, and how easy it is for the person to do this themselves How data can be collected, compatibility of the device with other technology, and whether data can be shared with the person's healthcare provider to help inform treatment Whether the device will affect the person's ability to do their job How unpredictable the person's activity and blood glucose levels are and whether erratic blood glucose is affecting their quality of life Whether the person has situations when symptoms of hypoglycaemia cannot be communicated or can be confused (for example, during exercise) Clinical factors that may make devices easier or harder to use Frequency of sensor replacement Sensitivities to the device, for example local skin reactions Body image concerns CGM should be provided by a team with expertise in its use, as part of supporting people to self-manage their diabetes. Advise adults with type 1 diabetes who are using CGM that they will still need to take capillary blood glucose measurements (although they can do this less often). Explain that this is because: they will need to use capillary blood glucose measurements to check the accuracy of their CGM device they will need capillary blood glucose monitoring as a back-up (for example, when their blood glucose levels are changing quickly or if the device stops working). Provide them with enough test strips to take capillary blood glucose measurements as needed. If a person cannot use or does not want rtCGM or isCGM, offer capillary blood glucose monitoring. Include CGM in the structured education programme provided to all adults with type 1 diabetes (see the section on education and information), and ensure that people are empowered to use CGM devices (see the section on empowering people to self-monitor blood glucose). Monitor and review the person's use of CGM as part of reviewing their diabetes care plan (see recommendations 1.1.7, 1.2.5 and 1.2.6 on what to consider when agreeing a care plan and what a care plan should cover). If there are concerns about the way a person is using the CGM device: ask if they are having problems using their device look at ways to address any problems or concerns to improve their use of the device, including further education and emotional and psychological support. For guidance on CGM for pregnant women, see the NICE guideline on diabetes in pregnancy. Commissioners, providers and healthcare professionals should address inequalities in CGM access and uptake by: monitoring who is using CGM identifying groups who are eligible but who have a lower uptake making plans to engage with these groups to encourage them to consider CGM. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on continuous glucose monitoring . Full details of the evidence and the committee's discussion are in evidence review B: continuous glucose monitoring in adults with type 1 diabetes. Loading. Please wait. ## Self-monitoring of capillary blood glucose Advise adults with type 1 diabetes who are using capillary blood glucose monitoring to routinely self‑monitor their blood glucose levels, and to measure at least 4 times a day (including before each meal and before bed). Support adults with type 1 diabetes who are using capillary blood glucose monitoring to measure at least 4 times a day, and up to 10 times a day: if their target for blood glucose control, measured by HbA1c level (see recommendation 1.6.6), is not reached if they are having more frequent hypoglycaemic episodes if there is a legal requirement to do so, such as before driving (see the Driver and Vehicle Licensing Agency guide for medical professionals) during periods of illness before, during and after sport when planning pregnancy, during pregnancy and while breastfeeding (see NICE's guideline on diabetes in pregnancy) if they need to know their blood glucose levels more than 4 times a day for other reasons (for example, impaired hypoglycaemia awareness, or they are undertaking high‑risk activities). Enable additional blood glucose measurement (more than 10 times a day) for adults with type 1 diabetes who are using capillary blood glucose monitoring if this is necessary because of: the person's lifestyle (for example, they drive for long periods of time, they undertake high‑risk activities or have a high‑risk occupation, or they are travelling) or impaired hypoglycaemia awareness. Advise adults with type 1 diabetes to aim for: a fasting plasma glucose level of 5 to 7 mmol/litre on waking and a plasma glucose level of 4 to 7 mmol/litre before meals at other times of the day. Advise adults with type 1 diabetes who choose to measure after meals to aim for a plasma glucose level of 5 to 9 mmol/litre at least 90 minutes after eating. (This timing may be different in pregnancy – for guidance on plasma glucose targets in pregnancy, see NICE's guideline on diabetes in pregnancy.) Agree bedtime target plasma glucose levels with each adult with type 1 diabetes. Take into account the timing of their last meal of the day and the related insulin dose, and ensure the target is consistent with the recommended fasting level on waking (see recommendation 1.6.22). Teach self‑monitoring skills at the time of diagnosis and the start of insulin therapy. When choosing blood glucose meters: take the needs of the adult with type 1 diabetes into account ensure that meters meet current ISO standards. Teach adults with type 1 diabetes how to measure their blood glucose level, interpret the results and take appropriate action. Review these skills at least annually. Support adults with type 1 diabetes through structured education (see the section on education and information) to make the best use of data from self‑monitoring of blood glucose. Monitoring blood glucose using sites other than the fingertips cannot be recommended as a routine alternative to conventional self‑monitoring of blood glucose. # Insulin therapy ## Insulin regimens Offer multiple daily injection basal–bolus insulin regimens as the insulin injection regimen of choice for all adults with type 1 diabetes. Provide guidance on using this regimen. Do not offer adults newly diagnosed with type 1 diabetes non‑basal–bolus insulin regimens (that is, twice‑daily mixed, basal only or bolus only). ## Long-acting insulin Offer twice‑daily insulin detemir as basal insulin therapy for adults with type 1 diabetes. Consider 1 of the following as an alternative basal insulin therapy to twice-daily insulin detemir for adults with type 1 diabetes: an insulin regimen that is already being used by the person if it is meeting their agreed treatment goals (such as meeting their HbA1c targets or time in target glucose range and minimising hypoglycaemia) -nce-daily insulin glargine (100 units/ml) if insulin detemir is not tolerated or the person has a strong preference for once‑daily basal injections -nce-daily insulin degludec (100 units/ml) if there is a particular concern about nocturnal hypoglycaemia -nce-daily ultra-long-acting insulin such as degludec (100 units/ml) for people who need help from a carer or healthcare professional to administer injections. There is a risk of severe harm and death due to inappropriately withdrawing insulin from pen devices. See NHS England's patient safety alert for further information. When starting an insulin for which a biosimilar is available, use the product with the lowest acquisition cost. Ensure the risk of medication errors with insulins is minimised by following Medicines and Healthcare products Regulatory Agency (MHRA) guidance on minimising the risk of medication error with high strength, fixed combination and biosimilar insulin products, which includes advice for healthcare professionals when starting treatment with a biosimilar. When people are already using an insulin for which a lower cost biosimilar is available, discuss the possibility of switching to the biosimilar. Make a shared decision with the person after discussing their preferences. Consider other basal insulin regimens for adults with type 1 diabetes only if the regimens in recommendations 1.7.3 and 1.7.4 do not meet their agreed treatment goals. When choosing an alternative insulin regimen, take account of: the person's preferences comorbidities risk of hypoglycaemia and diabetic ketoacidosis any concerns around adherence acquisition cost. When prescribing, ensure that insulins are prescribed by brand name. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on long-acting insulin . Full details of the evidence and the committee's discussion are in evidence review A: long-acting insulins in type 1 diabetes. Loading. Please wait. ## Insulin pumps For guidance on the use of insulin pumps for adults with type 1 diabetes, see NICE's technology appraisal guidance on continuous subcutaneous insulin infusion for the treatment of diabetes mellitus. ## Rapid-acting insulin Offer rapid‑acting insulin analogues that are injected before meals, rather than rapid‑acting soluble human or animal insulins, for mealtime insulin replacement for adults with type 1 diabetes. Do not advise routine use of rapid‑acting insulin analogues after meals for adults with type 1 diabetes. If an adult with type 1 diabetes has a strong preference for an alternative mealtime insulin, respect their wishes and offer the preferred insulin. ## Mixed insulin Consider a twice‑daily human mixed insulin regimen for adults with type 1 diabetes if a multiple daily injection basal–bolus insulin regimen is not possible and a twice‑daily mixed insulin regimen is used. Consider a trial of a twice‑daily analogue mixed insulin regimen if an adult using a twice‑daily human mixed insulin regimen has hypoglycaemia that affects their quality of life. ## Optimising insulin therapy For adults with erratic and unpredictable blood glucose control (hyperglycaemia and hypoglycaemia at no consistent times), consider the following rather than changing a previously optimised insulin regimen: injection technique injection sites self-monitoring skills knowledge and self‑management skills lifestyle mental health and psychosocial problems possible organic causes, such as gastroparesis. Give clear guidelines and protocols ('sick‑day rules') to all adults with type 1 diabetes, to help them adjust insulin doses appropriately when they are ill. ## Adjuncts Consider adding metformin to insulin therapy for adults with type 1 diabetes if: they have a BMI of 25 kg/m2 or above (23 kg/m2 or above for people from South Asian and related family backgrounds) and they want to improve their blood glucose control while minimising their effective insulin dose.In August 2015, this was an off-label use of metformin. See NICE's information on prescribing medicines. # Insulin delivery For adults with type 1 diabetes who inject insulin, provide their preferred insulin injection delivery device (this often means using one or more types of insulin injection pen). For adults with type 1 diabetes and special visual or psychological needs, provide injection devices or needle‑free systems that they can use independently for accurate dosing. Offer needles of different lengths to adults with type 1 diabetes who are having problems such as pain, local skin reactions and injection site leakages. After taking clinical factors into account, choose needles with the lowest acquisition cost to use with pre‑filled and reusable insulin pen injectors. Advise adults with type 1 diabetes to rotate insulin injection sites and avoid repeated injections at the same point within sites. Provide adults with type 1 diabetes with: suitable containers for collecting used needles and other sharps a way to safely get rid of these containers. See also the section on safe use and disposal of sharps in NICE's guideline on healthcare-associated infections: prevention and control in primary and community care. Check injection site condition at least annually, and whenever new problems with blood glucose control occur. # Referral for islet or pancreas transplantation For adults with type 1 diabetes who have recurrent severe hypoglycaemia that has not responded to other treatments (see the section on hypoglycaemia awareness and management), consider referral to a centre that assesses people for islet and/or pancreas transplantation. Consider islet or pancreas transplantation for adults with type 1 diabetes with suboptimal diabetes control, if they have had a renal transplant and are currently on immunosuppressive therapy. # Hypoglycaemia awareness and management ## Identifying and quantifying impaired hypoglycaemia awareness Assess hypoglycaemia awareness in adults with type 1 diabetes at each annual review. Use the Gold score or Clarke score to quantify hypoglycaemia awareness in adults with type 1 diabetes, checking that the questionnaire items have been answered correctly. Explain to adults with type 1 diabetes that impaired awareness of the symptoms of plasma glucose levels below 3 mmol/litre is associated with a significantly increased risk of severe hypoglycaemia. ## Managing impaired hypoglycaemia awareness Ensure that adults with type 1 diabetes and impaired hypoglycaemia awareness have had structured education in flexible insulin therapy using basal–bolus regimens, and are following its principles correctly. Offer additional education focusing on avoiding and treating hypoglycaemia to adults with type 1 diabetes who still have impaired hypoglycaemia awareness after structured education in flexible insulin therapy. Avoid relaxing individualised blood glucose targets to address impaired hypoglycaemia awareness for adults with type 1 diabetes. For adults with type 1 diabetes and impaired hypoglycaemia awareness who are using lower target blood glucose levels than recommended in this guideline, encourage them to use the recommended targets (see the recommendations on blood glucose targets). Review insulin regimens and doses, and prioritise ways to avoid hypoglycaemia in adults with type 1 diabetes with impaired hypoglycaemia awareness, including: reinforcing the principles of structured education -ffering an insulin pump -ffering real‑time continuous glucose monitoring. If, despite these interventions, an adult with type 1 diabetes has impaired hypoglycaemia awareness that is associated with recurrent severe hypoglycaemia, consider referring them to a specialist centre. ## Preventing and managing hypoglycaemia Explain to adults with type 1 diabetes that a fast‑acting form of glucose is needed for managing hypoglycaemic symptoms or signs in people who can swallow. Adults with type 1 diabetes who have a decreased level of consciousness because of hypoglycaemia and so cannot safely take oral treatment should be: given intramuscular glucagon by a family member or friend who has been shown how to use it (intravenous glucose may be used by healthcare professionals skilled in getting intravenous access) checked for response at 10 minutes, and then given intravenous glucose if their level of consciousness is not improving significantly then given oral carbohydrate when it is safe to administer it, and put under continued observation by someone who has been warned about the risk of relapse. Explain to adults with type 1 diabetes that: it is very common to experience some hypoglycaemic episodes with any insulin regimen they should use a regimen that avoids or reduces the frequency of hypoglycaemic episodes, while maintaining the most optimal blood glucose control possible. Make hypoglycaemia advice available to all adults with type 1 diabetes, to help them find the best possible balance with any insulin regimen. (See the sections on insulin therapy and insulin delivery.) If hypoglycaemia becomes unusually problematic or increases in frequency, review the following possible causes: inappropriate insulin regimens (incorrect dose distributions and insulin types) meal and activity patterns, including alcohol injection technique and skills, including insulin resuspension if necessary injection site problems possible organic causes, including gastroparesis changes in insulin sensitivity (including drugs affecting the renin–angiotensin system and renal failure) mental health problems previous physical activity lack of appropriate knowledge and skills for self‑management. Manage nocturnal hypoglycaemia (symptomatic or detected on monitoring) by: reviewing knowledge and self‑management skills reviewing current insulin regimen, evening eating habits and previous physical activity choosing an insulin type and regimen that is less likely to cause low glucose levels at night. If early cognitive decline occurs in adults on long‑term insulin therapy, then in addition to normal investigations consider possible brain damage from overt or covert hypoglycaemia, and the need to manage this. # Ketone monitoring and managing diabetic ketoacidosis ## Ketone self-monitoring to prevent diabetic ketoacidosis Consider ketone monitoring (blood or urine) as part of 'sick‑day rules' for adults with type 1 diabetes, to help with self‑management of hyperglycaemia. ## Ketone monitoring in hospital In adults with type 1 diabetes presenting to emergency services, consider capillary blood ketone testing if: diabetic ketoacidosis (DKA) is suspected or the person has uncontrolled diabetes during an illness, and urine ketone testing is positive. Consider capillary blood ketone testing (incorporated into a formal protocol) for inpatient management of DKA in adults with type 1 diabetes. ## Management of DKA Professionals managing DKA in adults should have adequate and up-to-date training, and be familiar with all aspects of DKA management that are associated with mortality and morbidity. These topics should include: fluid balance acidosis cerebral oedema electrolyte imbalance that DKA can affect the results of standard diagnostic tests (white cell count, body temperature, electrocardiogram ) respiratory distress syndrome cardiac abnormalities precipitating causes infection management, including opportunistic infections gastroparesis use of high dependency and intensive care units recommendations 1.11.5 to 1.11.12 in this guideline.Management of DKA in adults should be in line with local clinical governance. Use isotonic saline for primary fluid replacement in adults with DKA, not given too rapidly except in cases of circulatory collapse. Do not generally use bicarbonate for managing DKA in adults. Give intravenous insulin by infusion to adults with DKA. When the plasma glucose concentration has fallen to 10 to 15 mmol/litre in adults with DKA, give glucose‑containing fluids (not more than 2 litres in 24 hours) so that the insulin infusion can be continued at a sufficient rate to clear ketones (for example, 6 units/hour, monitored for effect). Begin potassium replacement early in DKA in adults, with frequent monitoring for hypokalaemia. Do not generally use phosphate replacement when managing DKA in adults. In adults with DKA who have reduced consciousness, think about: inserting a nasogastric tube and monitoring urine output using a urinary catheter and giving venous thromboembolism (VTE) prophylaxis. To reduce the risk of catastrophic outcomes in adults with DKA, use continuous monitoring and frequent reviews that cover all aspects of clinical management. # Associated illness In adults with type 1 diabetes who have unexplained weight loss, assess for coeliac disease. For guidance on testing for coeliac disease, see NICE's guideline on coeliac disease. Be alert to the possibility of other autoimmune diseases in adults with type 1 diabetes (including Addison's disease and pernicious anaemia). For advice on monitoring for thyroid disease, see the recommendation on thyroid disease monitoring. # Control of cardiovascular risk ## Aspirin Do not offer aspirin for the primary prevention of cardiovascular disease in adults with type 1 diabetes. ## Identifying cardiovascular risk Assess cardiovascular risk factors annually, including: estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (ACR) smoking blood glucose control blood pressure full lipid profile (including high-density lipoprotein and low-density lipoprotein cholesterol, and triglycerides) age family history of cardiovascular disease abdominal adiposity. For guidance on tools for assessing risk of cardiovascular disease in adults with type 1 diabetes, see the recommendations on full formal risk assessment in NICE's guideline on lipid modification. ## Interventions to reduce risk and manage cardiovascular disease For guidance on the primary prevention of cardiovascular disease in adults with type 1 diabetes, see the section on primary prevention for people with type 1 diabetes in NICE's guideline on lipid modification. Give adults with type 1 diabetes who smoke advice on stopping smoking and stop smoking services, including NICE guidance‑recommended therapies (see the NICE topic page on smoking and tobacco). Reinforce these messages annually for people who currently do not plan to stop smoking, and at all clinical contacts if there is a prospect of the person stopping. Advise adults who do not smoke never to start smoking. Provide intensive management for adults who have had myocardial infarction or stroke, according to relevant non‑diabetes guidelines. For angina or other ischaemic heart disease, beta-blockers should be considered (for insulin use in these circumstances, see the section on caring for adults with type 1 diabetes in hospital). For guidance on secondary prevention of myocardial infarction, see NICE's guideline on acute coronary syndromes. ## Blood pressure management In adults with type 1 diabetes aim for blood pressure targets as follows: For adults with a urine albumin:creatinine ratio (ACR) less than 70 mg/mmol, aim for a clinic systolic blood pressure less than 140 mmHg (target range 120 to 139 mmHg) and a clinic diastolic blood pressure less than 90 mmHg. For adults with an ACR of 70 mg/mmol or more, aim for a clinic systolic blood pressure less than 130 mmHg (target range 120 to 129 mmHg) and a clinic diastolic blood pressure less than 80 mmHg. In adults aged 80 or more, whatever the ACR, aim for a clinic systolic blood pressure less than 150 mmHg and a clinic diastolic blood pressure less than 90 mmHg.Use clinical judgement for adults with frailty, target organ damage (damage to organs because of diabetes, for example, to nerves or eyes) or multimorbidity. See the recommendations on pharmacotherapy in NICE's guideline on chronic kidney disease, and NICE's guidelines on hypertension in adults and multimorbidity. Discuss the following with adults with type 1 diabetes who have hypertension to help them make an informed choice: reasons for the choice of intervention level the substantial potential gains from small improvements in blood pressure control any possible negative consequences of therapy. Start a trial of a renin–angiotensin system blocking drug as first‑line therapy for hypertension in adults with type 1 diabetes. Provide information to adults with type 1 diabetes on how lifestyle changes can improve their blood pressure control and associated outcomes, and offer help to achieve their aims in this area. Do not allow concerns over potential side effects to inhibit advising and offering the necessary use of any class of drugs, unless side effects become symptomatic or otherwise clinically significant. In particular: do not avoid selective beta-blockers for adults on insulin if these are indicated low-dose thiazides may be combined with beta‑blockers when prescribing calcium channel antagonists, only use long‑acting preparations ask adults directly about potential side effects of erectile dysfunction, lethargy and orthostatic hypotension with different drug classes. Deleted. # Caring for adults with type 1 diabetes in hospital ## Blood glucose control Aim for a target plasma glucose level of 5 to 8 mmol/litre for adults with type 1 diabetes during surgery or acute illness. Establish a local protocol for controlling blood glucose levels in adults with type 1 diabetes during surgery or acute illness to reach the target level. Use intravenous rather than subcutaneous insulin regimens for adults with type 1 diabetes if: they are unable to eat or are predicted to miss more than 1 meal or an acute situation is expected to result in unpredictable blood glucose levels – for example, major surgery, high‑dose steroid treatment, inotrope treatment or sepsis or insulin absorption is expected to be unpredictable, for example, because of circulatory compromise. Consider continuing the person's existing basal insulin regimen (including basal rate if they are using insulin pump therapy) together with protocol‑driven insulin delivery for controlling blood glucose levels in adults with type 1 diabetes during surgery or acute illness. Use subcutaneous insulin regimens (including rapid‑acting insulin before meals) if an adult with type 1 diabetes and acute illness is eating. Enable adults with type 1 diabetes who are hospital inpatients to self‑administer subcutaneous insulin if they are willing and able and it is safe for them to do so. ## Delivering care in hospital and other institutions These recommendations are for care teams caring for adults with type 1 diabetes in hospital and in institutions such as nursing homes, residential homes and prisons. From admission, provide ongoing advice to adults with type 1 diabetes and the team caring for them from a trained multidisciplinary team with expertise in diabetes. Throughout inpatient admission, respect the personal expertise of adults with type 1 diabetes in managing their own diabetes and incorporate this into routine ward‑based blood glucose monitoring and insulin delivery. Throughout inpatient admission, support adults with type 1 diabetes to make their own food choices based on their personal knowledge of their dietary needs, except when illness or medical or surgical intervention significantly disturbs those requirements. Provide optimal insulin therapy, which can be achieved using intravenous insulin and glucose, to all adults with type 1 diabetes with threatened or actual stroke. Critical care and emergency departments should have a protocol for such management. # Managing complications ## Periodontitis Advise adults with type 1 diabetes at their annual review of self‑care and needs that: they are at higher risk of periodontitis if they get periodontitis, managing it can improve their blood glucose control and can reduce their risk of hyperglycaemia. Advise adults with type 1 diabetes to have regular oral health reviews (their oral healthcare or dental team will tell them how often, in line with the NICE guideline on dental checks: intervals between oral health reviews). For guidance for oral healthcare and dental teams on how to provide oral health advice, see the NICE guideline on oral health promotion. For adults with type 1 diabetes who have been diagnosed with periodontitis by an oral healthcare or dental team, offer dental appointments to manage and treat their periodontitis (at a frequency based on their oral health needs). For a short explanation of why the committee made these recommendations, see the rationale and impact section on periodontitis . Full details of the evidence and the committee's discussion are in evidence review D: periodontitis. Loading. Please wait. ## Eye disease When adults are diagnosed with type 1 diabetes, refer them immediately to the local eye screening service. Encourage adults to attend eye screening, and explain that it will help them to keep their eyes healthy and help to prevent problems with their vision. Explain that the screening service is effective at identifying problems so that they can be treated early. Arrange emergency review by an ophthalmologist for: sudden loss of vision rubeosis iridis pre-retinal or vitreous haemorrhage retinal detachment. Refer to an ophthalmologist in accordance with the UK National Screening Committee criteria and timelines for any large sudden unexplained drop in visual acuity. ## Diabetic kidney disease For guidance on managing kidney disease in adults with type 1 diabetes, see NICE's guideline on chronic kidney disease. Ask all adults with type 1 diabetes, with or without detected nephropathy, to bring in the first urine sample of the day ('early morning urine') once a year. Send this for estimation of albumin:creatinine ratio (estimating urine albumin concentration alone is a poor alternative) and measure eGFR at the same time. See NICE's guideline on chronic kidney disease. Suspect other renal disease if: progressive retinopathy is absent blood pressure is particularly high proteinuria develops suddenly significant haematuria is present (see NICE's guideline on chronic kidney disease) the person is systemically unwell. If albuminuria is found, discuss with the person what this means. For guidance on medicines for managing chronic kidney disease, see the section on pharmacotherapy for CKD in adults, children, and young people with related persistent proteinuria in the NICE guideline on chronic kidney disease. Maintain the person's blood pressure (see recommendation 1.1.3.8 for blood pressure targets) by adding other anti‑hypertensive drugs if necessary. Advise adults with type 1 diabetes and nephropathy about the advantages of avoiding a high‑protein diet. Referral criteria for tertiary care should be agreed between local diabetes specialists and nephrologists. See NICE's guideline on chronic kidney disease. ## Chronic painful diabetic neuropathy For guidance on managing chronic painful diabetic neuropathy in adults with type 1 diabetes, see NICE's guideline on neuropathic pain in adults. ## Autonomic neuropathy Think about the possibility of autonomic neuropathy affecting the gut if adults with type 1 diabetes have unexplained diarrhoea, particularly at night. When prescribing antihypertensive medicines, take care not to increase the risk of orthostatic hypotension from the combined effects of sympathetic autonomic neuropathy and blood pressure lowering medicines. For adults with type 1 diabetes who have bladder emptying problems, investigate the possibility of autonomic neuropathy affecting the bladder, unless another explanation is found. When managing the symptoms of autonomic neuropathy, include specific interventions for the manifestations encountered (for example, for abnormal sweating and postural hypotension). Anaesthetists should be aware of the possibility of parasympathetic autonomic neuropathy affecting the heart in adults with type 1 diabetes who: are listed for procedures under general anaesthetic and have evidence of somatic neuropathy or other manifestations of autonomic neuropathy. ## Gastroparesis Advise adults with type 1 diabetes who have vomiting caused by gastroparesis to follow a small‑particle‑size diet (mashed or pureed food) to relieve their symptoms. Be aware that gastroparesis needing specific therapy can only be diagnosed in the absence of hyperglycaemia at the time of testing, because hyperglycaemia delays gastric emptying. Consider insulin pump therapy for adults with type 1 diabetes who have gastroparesis. For adults with type 1 diabetes who have vomiting caused by gastroparesis, explain that: there is no strong evidence that any available antiemetic therapy is effective some people have had benefit with domperidone (see the Medicines and Healthcare products Regulatory Agency (MHRA) guidance on domperidone: risks of cardiac side effects), erythromycin or metoclopramide (see the MHRA guidance on metoclopramide: risks of neurological adverse effects) the strongest evidence for effectiveness is for domperidone, but prescribers must take into account its safety profile, in particular its cardiac risk and potential interactions with other medicines.In August 2015, this was an off-label use of erythromycin and many higher doses or treatment durations of domperidone. See NICE's information on prescribing medicines. To treat vomiting caused by gastroparesis in adults with type 1 diabetes: consider alternating erythromycin and metoclopramide (see the MHRA guidance on metoclopramide: risks of neurological adverse effects) consider domperidone only in exceptional circumstances (that is, when it is the only effective treatment) and in accordance with the MHRA guidance on domperidone: risks of cardiac side effects.In August 2015, this was an off-label use of erythromycin and many higher doses or treatment durations of domperidone. See NICE's information on prescribing medicines. Refer adults with type 1 diabetes who have gastroparesis for specialist advice if the interventions in this section have not helped or are not appropriate. ## Acute painful neuropathy from rapid improvement of blood glucose control Reassure adults with type 1 diabetes that acute painful neuropathy resulting from rapid improvement of blood glucose control is a self‑limiting condition and symptoms improve over time. Explain to adults with type 1 diabetes that the specific treatments for acute painful neuropathy resulting from rapid improvement of blood glucose control: aim to make symptoms tolerable until the condition resolves may not relieve pain immediately and may need to be taken regularly for several weeks to be effective. Use simple analgesics (paracetamol, aspirin) and local measures (bed cradles) as a first step to treat acute painful neuropathy, and if these do not help, try other measures. Do not relax diabetes control to address acute painful neuropathy resulting from rapid improvement of blood glucose control in adults with type 1 diabetes. If simple analgesia does not provide sufficient pain relief for adults with type 1 diabetes who have acute painful neuropathy resulting from rapid improvement of blood glucose control, offer treatment as described in NICE's guideline on neuropathic pain in adults. Simple analgesia may be continued until the effects of additional treatments have been established. When offering medicines for managing acute painful neuropathy resulting from rapid improvement of blood glucose control to adults with type 1 diabetes, be aware of the risk of dependency associated with opioids. For more information, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. ## Diabetic foot problems For guidance on preventing and managing foot problems in adults with type 1 diabetes, see NICE's guideline on diabetic foot problems. ## Erectile dysfunction Offer men with type 1 diabetes the opportunity to discuss erectile dysfunction as part of their regular review. Offer a phosphodiesterase‑5 inhibitor to men with type 1 diabetes with isolated erectile dysfunction unless contraindicated. Choose the phosphodiesterase‑5 inhibitor with the lowest acquisition cost. Consider referring men with type 1 diabetes to a service offering further assessment and other medical, surgical or psychological management of erectile dysfunction if phosphodiesterase‑5 inhibitor treatment is unsuccessful or contraindicated. ## Thyroid disease monitoring Measure blood thyroid‑stimulating hormone (TSH) levels in adults with type 1 diabetes at their annual review. ## Mental health problems Members of diabetes professional teams providing care or advice to adults with type 1 diabetes should be alert to possible clinical or subclinical depression and/or anxiety, particularly if someone reports or appears to be having difficulties with self‑management. Diabetes professionals should: ensure they have appropriate skills to identify and provide basic management of non‑severe mental health problems in people from different cultural backgrounds be familiar with appropriate counselling techniques and drug therapy, while arranging prompt referral to specialists for people whose mental health problems continue to interfere significantly with their wellbeing or diabetes self‑management. See also the: NICE guideline on common mental health problems NICE guideline on generalised anxiety disorder and panic disorder in adults NICE guideline on depression in adults with a chronic physical health problem. ## Eating disorders and disordered eating Members of diabetes professional teams should be alert to the possibility of bulimia nervosa, anorexia nervosa and disordered eating in adults with type 1 diabetes with: -ver-concern with body shape and weight low BMI hypoglycaemia suboptimal overall blood glucose control. See also NICE's guideline on eating disorders. Think about making an early (or if needed, urgent) referral to local eating disorder services for adults with type 1 diabetes with an eating disorder. From diagnosis, the diabetes professional team should provide regular high-quality support and counselling about lifestyle and diet for all adults with type 1 diabetes (see the sections on education and information and dietary management). # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. ## Continuous glucose monitoring This covers both real-time (rtCGM) and intermittently scanned (isCGM, commonly referred to as 'flash') continuous glucose monitoring. A continuous glucose monitor is a device that measures blood glucose levels and sends the readings to a display device or smartphone. ## Disordered eating Disordered eating describes a range of irregular eating behaviours. These can include symptoms that reflect many but not all of the symptoms of eating disorders, such as anorexia nervosa, bulimia nervosa and binge eating disorder. Examples of disordered eating include fasting or chronic restrained eating, skipping meals, binge eating, self-induced vomiting, restrictive dieting, and laxative or diuretic misuse. ## Periodontitis A chronic inflammatory gum disease that destroys the supporting tissues of the teeth (the periodontium). Gingivitis is a milder form of periodontal disease than periodontitis. However, gingivitis still causes inflammation in the gum, and if not treated it can lead to periodontitis. ## Ultra-long-acting insulin Insulin analogues that have a longer duration of action (beyond 24 hours) compared with standard long-acting insulins.# Recommendations for research The guideline committee has made the following recommendations for research. # Clinical features for distinguishing between type 1 diabetes and other types of diabetes What are the best clinical features or combination of features for distinguishing between type 1 diabetes and other types of diabetes? For a short explanation of why the committee made the recommendation for research, see the rationale section on diagnosis . Full details of the evidence and the committee's discussion are in evidence review C: diagnosis of diabetes. Loading. Please wait. # The use of C-peptide in diagnosing diabetes What is the effectiveness of C‑peptide at correcting misclassification of diabetes diagnosis and what is the optimal timing for the test in distinguishing subtypes of diabetes? For a short explanation of why the committee made the recommendation for research, see the rationale section on diagnosis . Full details of the evidence and the committee's discussion are in evidence review C: diagnosis of diabetes. Loading. Please wait. # Use of routinely collected real-world data to examine the effectiveness and cost effectiveness of continuous glucose monitoring Based on routinely collected real-world data, what is the effectiveness and cost effectiveness of continuous glucose monitoring (CGM) devices to improve glycaemic control? For a short explanation of why the committee made the recommendation for research, see the rationale section on CGM . Full details of the evidence and the committee's discussion are in evidence review A: continuous glucose monitoring in adults with type 1 diabetes. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the 2021 and 2022 recommendations and how they might affect practice. # Diagnosis Recommendations 1.1.1 to 1.1.9 ## Why the committee made the recommendations The committee wanted to highlight the importance of distinguishing between type 1 diabetes and other diabetes types because these conditions are treated differently (particularly in terms of insulin use). The most common misdiagnosis is type 1 diabetes being misdiagnosed as type 2, which could lead to the person not receiving insulin treatment and a subsequent risk of diabetic ketoacidosis. It is less harmful to be diagnosed with type 1 diabetes when the person actually has type 2 diabetes. However, there are still harms, including: the long-term effects and costs of unnecessary insulin therapy the missed opportunity for oral diabetes therapies the psychological impact of misdiagnosis. There was no new definitive evidence on clinical features for identifying diabetes type, so recommendation 1.1.1 remains unchanged from the 2015 guideline. Because of this lack of new evidence, the committee made a recommendation for research on identifying diabetes type. The evidence showed that no single clinical feature had a sufficient predictive value to make a diagnosis by itself. The committee were particularly concerned that age and body mass index (BMI) might be used in isolation. They noted that the average BMI in people with type 1 diabetes is increasing, and the age at which people are diagnosed with type 2 diabetes is decreasing. This means these clinical features are becoming less useful on their own to differentiate between the subtypes. Despite this, the committee agreed that these characteristics are still useful for making an initial working diagnosis of diabetes subtype in many people. However, further testing is increasingly needed, as previously 'atypical' features of type 1 and 'uncertain' classifications become more common. In a change from the 2015 guideline, the committee agreed it was important to encourage the use of diabetes-specific autoantibody testing at diagnosis, to avoid misclassifying diabetes subtype. They also clarified that autoantibody testing is appropriate for people with suspected type 1 diabetes. There was no high-quality evidence on tests to distinguish type 1 from type 2 or other types of diabetes, so the committee based the recommendations on the timings when the tests might be most useful (autoantibody testing is best used at the time of presentation, and C‑peptide is best used with increasing time from initial presentation) rather than which tests were most accurate. Based on clinical experience, the committee were confident that measuring autoantibodies in people with suspected type 1 diabetes would be cost effective. This is because: autoantibody tests are cheap when compared with the much higher costs associated with inaccurate diagnosis misclassification using clinical criteria alone results in additional costs, both from the use of ineffective treatments and from clinical harm. Further, because autoantibody tests are more accurate when done at the time of presentation rather than later at a clinical review, they would also be more cost effective at that time rather than later, since the cost will be the same but more useful information will be obtained from the test at the time of diagnosis. The committee noted that using autoantibody testing also means that healthcare professionals do not have to rely on characteristics alone when people first present. This can help avoid assumptions about links between ethnicity and diabetes type (for example, assuming that people in Black, Asian and other minority ethnic groups are more likely to have type 2 diabetes). The committee could not recommend routine non-fasting serum C‑peptide testing because of a lack of high-quality and clinical evidence, and this would be a significant and costly change in clinical practice. However, they thought it would be an appropriate test if clinical presentation and autoantibody testing did not provide a clear classification of diabetes (for example, if clinical features were consistent with type 1 diabetes but autoantibody results were negative). The committee noted that serum C‑peptide is more appropriate in individual clinical diagnosis settings as it can be paired with blood glucose, while urine C‑peptide is mainly used in epidemiological studies. Because of the lack of high-quality evidence, the committee made a recommendation for research to examine the effectiveness of C-peptide at correcting misclassification of diabetes at initial diagnosis and the optimal timing for this test in distinguishing between subtypes of diabetes. ## How the recommendations might affect practice It is likely that these recommendations will lead to increased autoantibody testing in people presenting with suspected type 1 diabetes. This will increase testing costs, but this increase is not expected to be substantial, because of the low costs of the tests themselves. An increased use of serum C‑peptide testing in the classification of diabetes is less likely, because the guideline only recommends this be done if there is still diagnostic uncertainty after the use of autoantibody testing. Although there is a cost associated with some of the new recommendations and concerns about the availability of the tests in all settings, the committee felt this would be balanced out by benefits from reducing the misclassification of diabetes at presentation and ensuring early appropriate treatment of type 1 (and in some cases type 2) diabetes. This will avoid unnecessary tests, treatment and side effects from prolonged insulin use. Return to recommendations # Continuous glucose monitoring Recommendations 1.6.10 to 1.6.18 ## Why the committee made the recommendations The committee agreed that there was enough evidence in key outcomes, such as HbA1c, time in range and severe or nocturnal hypoglycaemia, to demonstrate that both real-time continuous glucose monitoring (rtCGM) and intermittently scanned CGM (isCGM) provide clinical benefits over standard self-monitoring of blood glucose. However, they considered that the evidence for rtCGM compared with isCGM was not good enough in terms of quality or sample size to clearly show clinical benefits of 1 technology over the other. The committee also acknowledged that CGM technologies were changing very quickly, with increasing overlap between rtCGM and isCGM as features such as predictive alerts are added to newer isCGM devices. The health economic modelling found that, when the benefit of reduced fear of hypoglycaemia with CGM was included, both technologies were cost effective for the full population of adults with type 1 diabetes compared with standard self-monitoring of blood glucose. Based on the above factors and the evidence, the committee agreed that there was no advantage to recommending 1 specific device over another compared with standard self-monitoring of blood glucose. They concluded that the specific functionality of isCGM versus rtCGM devices should be discussed between the person and their healthcare professional. In particular, finding the right device for each person is likely to improve adherence, which means the device will provide more benefits and so will be more cost effective. The committee did not make a recommendation on using specific devices because CGM technologies are changing very quickly, and this recommendation would soon be out of date. Local healthcare services are better placed to assess which devices are evidence-based and suitable for use at any given time. There are benefits of providing a choice of different CGM devices because the most suitable device would vary for each person. The committee produced a list of factors to consider when choosing a CGM device with people. The committee agreed that this freedom of choice is beneficial, particularly because adherence to the technology is likely to be higher if the device is matched to the person's needs and preferences. The committee retained the 2015 recommendation on providing people with support from a healthcare specialist team with expertise in diabetes and the use of CGM. Community-based specialist teams are now available and are no longer always based in secondary care, so 'centre' was changed to 'team' to make this clearer. Despite the positive recommendations on CGM, the committee were concerned that existing health inequalities may still lead to lower uptake of CGM in some groups of people. To address this, the committee made a recommendation outlining actions for commissioners, providers and healthcare professionals. Given the rapid advances in technology, the committee made a recommendation for research on using routinely collected real-world data to examine the effectiveness and cost effectiveness of CGM. If routine healthcare data is collected, it can show the direct effect of implemented technology on the population, rather than it being interpreted through the results of clinical trials. Increased monitoring of routine healthcare data including registries and audits would ensure that the findings from a broader population is captured. ## How the recommendations might affect practice These recommendations are likely to result in broader access to isCGM and rtCGM devices, as opposed to a binary decision on access based on stringent criteria. This should reduce inequalities and enable more people to use CGM. Currently, people with more time and knowledge to self-advocate are often more likely to gain access to these devices. Some people have insulin insufficiency because of other conditions. The committee noted that these people would get the same care as people with type 1 diabetes, so they should have access to CGM in the same way. There is likely to be an increase in costs from more use of CGM devices. A number of different devices are available, so if more than 1 device would be appropriate for a person and would meet their needs and preferences, using the lowest cost device among those options would help to reduce the cost impact. Return to recommendations # Long-acting insulin Recommendations 1.7.3 to 1.7.9 ## Why the committee made the recommendations Evidence showed that there were fewer severe and nocturnal hypoglycaemic events with insulin detemir twice daily compared with neutral protamine Hagedorn (NPH). Insulin detemir twice daily was also found to be the most cost-effective treatment strategy in the economic analysis. Based on this evidence and their clinical experience, the committee recommended twice-daily insulin detemir as a basal insulin therapy for adults with type 1 diabetes. The committee agreed there were situations in which an insulin other than twice-daily insulin detemir might be preferred, and set out specific clinical scenarios where alternative long-acting insulins could be used. This includes if the person is already using an insulin regimen that is working well for them and helping them meet their treatment goals. Some people may not be able to tolerate insulin detemir, or for some, a once-daily regimen may be necessary (either because the person has a strong preference for once-daily injections or there are circumstances that make twice daily not practical). Glargine (100 units/ml) was found to be the most cost-effective once-daily insulin (particularly when the costs of glargine biosimilars were considered) so it was recommended as the appropriate alternative in these cases. People on insulin therapies can still have hypoglycaemic episodes. This can be a cause of concern, particularly if they have nocturnal hypoglycaemic events. Evidence showed a lower proportion of nocturnal hypoglycaemic events with degludec (100 units/ml), when compared with other once-daily insulins. Degludec (100 units/ml) is an ultra-long-acting insulin, which means it has a longer duration of action compared with long-acting insulins. The committee agreed that once-daily degludec could therefore be considered as an alternative basal insulin therapy if there is a particular concern about nocturnal hypoglycaemia. The committee agreed that once-daily ultra-long-acting insulin regimens, such as insulin degludec (100 units/ml), may also be needed by people who need support from a carer or healthcare professional to administer injections, for example, because they are frail or have a physical or mental health condition, or learning disability. Insulins that offer flexibility in dosing time, such as insulin degludec (100 units/ml), have a long duration of action and may be particularly useful because they give more flexibility in when the dose can be given. Insulin glargine (300 units/ml) is another example of an ultra-long-acting insulin. Healthcare professionals should also refer to NHS England's patient safety alert on the risk of severe harm and death from inappropriately withdrawing insulin from pen devices. Biosimilars have the potential to offer the NHS considerable cost savings. To gain approval for use, biosimilar medicines have to be shown to be safe and as effective as the original reference medicine, and have the same quality. Based on this understanding, the committee noted it was appropriate when starting a new prescription of an insulin where a biosimilar is available, to use the one with the lowest cost. Additionally, people may be using an insulin for which a lower cost biosimilar is available. In such cases, the committee recommended discussing with people the possibility of switching to the biosimilar. This could happen at the person's routine review. They also agreed that switching to the biosimilar should be carefully planned, taking into consideration the dose-switching protocols, monitoring and the person's concerns about switching from their existing regimen, and a shared decision reached. Healthcare professionals should also refer to the summary of product characteristics for further information when considering switching to biosimilars. The committee retained the recommendation from the 2015 version of the guideline on considering the use of other basal insulin regimens not covered by other recommendations. Based on their clinical understanding, they added comorbidities (such as renal function), risks of hypoglycaemia and diabetic ketoacidosis and concerns about adherence to the factors to take into account when considering alternative regimens. To support pharmacovigilance and patient safety, the committee also recommended that insulins should be prescribed by brand name. ## How the recommendations might affect practice Use of long-acting insulins varies across the country, with some centres offering twice-daily insulin detemir to people who are newly diagnosed, whereas other centres start with once-daily regimens. A major shift in practice is unlikely but the recommendations do set out scenarios where other insulins such as ultra-long-acting insulins and biosimilars may be useful and cost effective. Return to recommendations # Periodontitis Recommendations 1.15.1 to 1.15.4 ## Why the committee made the recommendations The evidence showed that people with diabetes are at increased risk of periodontitis, and that non-surgical periodontal treatment can improve diabetic control. Although most of the research was focused on type 2 diabetes, the committee thought that the evidence on the bidirectional link between increased HbA1c and periodontitis was also applicable to people with type 1 diabetes. In the committee's experience, people with diabetes are often unaware of the link between diabetes and periodontitis and may not be having regular oral health reviews. To address this, the committee recommended routinely discussing the risk of periodontitis at annual reviews, alongside eye disease and foot problems. The evidence also showed that periodontal treatment is cost effective for people with type 1 diabetes, assuming improvements in HbA1c are maintained. This was tested with health economic modelling in a range of different scenarios. The only situation in which treatment would not be cost effective is if the analysis only considered up to the first 10 years of periodontal treatment. However, the committee did not think this was realistic, as this excludes the benefits from reducing diabetic complications, which often happen later in life. ## How the recommendations might affect practice For oral healthcare professionals, the long-term impact of the recommendations is uncertain. The recommendations specify that people should follow existing NICE guidelines on oral health. However, the recommendations may also increase awareness of periodontitis, leading to a possible short-term increase in the number of oral health reviews. Any increase in the number of oral health reviews will potentially impact on services, as NHS dental services already have capacity issues. A short-term increase in the number of oral health reviews will also lead to a short-term increase in costs. However, there is likely to be a larger long-term reduction in costs from the improvement to oral health and diabetes control. Oral healthcare and dental teams will need clear advice on what they need to do for people with diabetes. They will need clear care pathways to improve quality of care and service delivery, in line with the NHS England commissioning standard on dental care for people with diabetes. Many people do not have regular oral health reviews, even if they are eligible for free NHS dental care. People are eligible for free dental care if they are: pregnant mothers with babies under 1 year old -n low income benefits, or under 20 and dependent on someone who is receiving low income benefits having treatment in an NHS hospital by the hospital dentist. The recommendations may encourage more people with diabetes to have regular oral health reviews. Combined with proactive engagement and enhanced support for people with diabetes, this may broaden access to dental and oral healthcare and help to reduce oral health inequalities. Return to recommendations# Context Type 1 diabetes affects over 370,000 adults in the UK. It results from destruction of the cells that normally make insulin. Loss of insulin secretion results in high blood glucose and other metabolic and haematological abnormalities, which have both short‑term and long‑term adverse effects on health. Over years, type 1 diabetes causes tissue damage which, if not detected and managed early, can result in disability: blindness, kidney failure, periodontitis, and foot ulceration leading to amputation, as well as premature heart disease, stroke and death. The risk of all of these complications is greatly reduced by treatment that keeps circulating glucose levels to as near normal as possible, reducing tissue damage. Disability from complications that are not avoided can often be prevented by early detection and active management. Type 1 diabetes is treated by insulin replacement and supported by active management of other cardiovascular risk factors, such as hypertension and high circulating lipids. Modern insulin replacement therapy aims to recreate normal fluctuations in circulating insulin concentrations. This supports a flexible lifestyle with minimal restrictions and, properly done, can improve blood glucose levels, reducing the risk of both structural complications and episodes of hypoglycaemia. Flexible insulin therapy usually involves self‑injecting multiple daily doses of insulin, with doses adjusted based on taken or planned exercise, intended food intake and other factors, including current blood glucose, which the insulin user needs to test on a regular basis. This self‑management needs the insulin user to have the skills and confidence to manage the regimen. One of the most important roles of healthcare professionals providing diabetes care to adults with type 1 diabetes is to ensure that systems are in place to provide informed expert support, education and training for insulin users, as well as a range of other more conventional biomedical services and interventions. Although type 1 diabetes in adults is not rare, it is not common enough that all healthcare professionals who deal with it are able to acquire and maintain all the necessary skills for its management. The aim of this guideline is to provide evidence‑based, practical advice on supporting adults with type 1 diabetes to live full, largely unrestricted, lives and to avoid the short‑term and long‑term complications of both the disease and of its treatment.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nBlood glucose and plasma glucose\n\n'Blood glucose' is the more commonly used term. However, a lot of the evidence this guideline is based on uses 'plasma' rather than 'blood' glucose, and patient‑held glucose meters and monitoring systems are calibrated to plasma glucose equivalents. Because of this, in this guideline we use the term 'blood glucose', except when referring to specific concentration values.\n\n# Diagnosis and early care plan\n\n## Initial diagnosis\n\nMake an initial diagnosis of type\xa01 diabetes on clinical grounds in adults presenting with hyperglycaemia. Bear in mind that people with type\xa01 diabetes typically (but not always) have 1 or more of:\n\nketosis\n\nrapid weight loss\n\nage of onset under 50\xa0years\n\nbody mass index (BMI) below 25\xa0kg/m2\n\npersonal and/or family history of autoimmune disease. [2015, amended 2022]\n\nDo not use age or BMI alone to exclude or diagnose type\xa01 diabetes in adults. \n\nTake into consideration the possibility of other diabetes subtypes and revisit the diagnosis at subsequent clinical reviews. Carry out further investigations if there is uncertainty (see recommendations 1.1.7 and 1.1.8). \n\nMeasure diabetes-specific autoantibodies in adults with an initial diagnosis of type\xa01 diabetes, taking into account that:\n\nthe false negative rate of diabetes-specific autoantibody tests is lowest at the time of diagnosis\n\nthe false negative rate can be reduced by carrying out quantitative tests for 2\xa0different diabetes-specific autoantibodies (with at least 1 being positive). \n\nDo not routinely measure serum C‑peptide to confirm type\xa01 diabetes in adults. \n\nIn people with a negative diabetes-specific autoantibody result, and if diabetes classification remains uncertain, consider measuring non-fasting serum C‑peptide (with a paired blood glucose). \n\n## Revisiting initial diagnosis\n\nAt subsequent clinical reviews, consider using serum C‑peptide to revisit the diabetes classification if there is doubt that type\xa01 diabetes is the correct diagnosis. \n\nTake into account that the discriminative value of serum C‑peptide to diagnose type\xa01 diabetes increases the longer the test is done after initial diagnosis of diabetes. \n\nFor people aged 60\xa0and over presenting with weight loss and new-onset diabetes, follow recommendations on assessing for pancreatic cancer in the section on pancreatic cancer in the NICE guideline on suspected cancer: recognition and referral. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: diagnosis of diabetes.\n\nLoading. Please wait.\n\n## Early care plan\n\nAt diagnosis (or, if necessary, after managing critically decompensated metabolism), the diabetes professional team should work with adults with type\xa01 diabetes to develop a plan for their early care. This will generally require:\n\nmedical assessment to:\n\n\n\nensure the diagnosis is accurate (see recommendations 1.1.1 to 1.1.5)\n\nensure appropriate acute care is given when needed\n\nreview medicines and detect potentially associated disease\n\ndetect adverse vascular risk factors\n\n\n\nenvironmental assessment to understand:\n\n\n\nthe social, home, work and recreational circumstances of the person and their carers\n\ntheir lifestyle (including diet and physical activity)\n\nother relevant factors, such as substance use\n\n\n\ncultural and educational assessment to:\n\n\n\nfind out what they know about diabetes\n\nhelp with tailoring advice, and with planning treatments and diabetes education programmes\n\n\n\nassessment of their emotional wellbeing to decide how to pace diabetes education. \n\nUse the results of the initial diabetes assessment to agree a future care plan. This assessment should include:\n\nacute medical history\n\nsocial, cultural and educational history, and lifestyle review\n\ncomplications history and symptoms\n\ndiabetes history (recent and long term)\n\nother medical history\n\nfamily history of diabetes and cardiovascular disease\n\nmedication history\n\nvascular risk factors\n\nsmoking\n\ngeneral examination\n\nweight and BMI\n\nfoot, eye and vision examination\n\nurine albumin:creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR)\n\npsychological wellbeing\n\nattitudes to medicine and self‑care\n\nimmediate family and social relationships, and availability of informal support. [2004, amended 2021]\n\nInclude the following in an individualised and culturally appropriate diabetes plan:\n\nwhen and where they will have their diabetes education, including their dietary advice (see the sections on education and information and dietary management)\n\ninitial treatment, including guidance on insulin injection and insulin regimens (see the sections on insulin therapy and insulin delivery)\n\nself‑monitoring and targets (see the section on blood glucose management)\n\nsymptoms, and the risk of hypoglycaemia and how it is treated\n\nmanagement of special situations, such as driving\n\ncommunicating with the diabetes professional team (how often and how to contact them)\n\nmanagement of cardiovascular risk factors (see the section on control of cardiovascular risk)\n\nimplications for pregnancy and family planning advice (see NICE's guideline on diabetes in pregnancy)\n\nhow often they will have follow‑up appointments, and what these will cover (including review of HbA1c levels, experience of hypoglycaemia, and annual reviews). [2004, amended 2015]\n\nAfter the initial plan is agreed, implement it without inappropriate delay. Based on discussion with the adult with type\xa01 diabetes, modify the plan as needed over the following weeks. \n\n# Support and individualised care\n\nTake account of any disabilities, including visual impairment, when planning and delivering care for adults with type\xa01 diabetes. \n\nAdvice to adults with type\xa01 diabetes should be provided by a range of professionals with skills in diabetes care, working together in a coordinated approach. [2004, amended 2021]\n\nProvide adults with type\xa01 diabetes with:\n\naccess to services by different methods (including phone and email) during working hours\n\ninformation about out-of-hours services staffed by people with diabetes expertise. \n\nView each adult with type\xa01 diabetes as an individual, rather than as a member of any cultural, economic or health-affected group (also see recommendations\xa01.4.5 and 1.4.14 on cultural preferences in the section on dietary advice). [2004, amended 2015]\n\nJointly agree an individual care plan with the adult with type\xa01 diabetes. Review this plan annually and amend it as needed, taking into account changes in the person's wishes, circumstances and medical findings. [2004, amended 2015]\n\nIndividual care plans should include:\n\ndiabetes education, including dietary advice (see the sections on education and information and dietary management)\n\ninsulin therapy, including dosage adjustment (see the sections on insulin therapy and insulin delivery)\n\nself-monitoring (see the section on blood glucose management)\n\navoiding hypoglycaemia and maintaining hypoglycaemia awareness\n\nfamily planning, contraception and pregnancy planning (see NICE's guideline on diabetes in pregnancy)\n\ncardiovascular risk factor monitoring and management (see the section on control of cardiovascular risk)\n\ncomplications monitoring and management (see the section on managing complications)\n\ncommunicating with the diabetes professional team (how often and how to contact them)\n\nhow often they will have follow‑up appointments, and what these will cover (including review of HbA1c levels, experience of hypoglycaemia, and annual reviews). [2004, amended 2015]\n\nUse population, practice‑based and clinic diabetes registers (as specified by the Department of Health and Social Care's national service framework for diabetes) to assist programmed recall for annual reviews and assessments of complications and cardiovascular risk. \n\nAt diagnosis and periodically after this, give adults with type\xa01 diabetes up‑to‑date information about diabetes support groups (local and national), how to contact them and their benefits. \n\n# Education and information\n\nOffer all adults with type\xa01 diabetes a structured education programme of proven benefit, for example, the DAFNE (dose adjustment for normal eating) programme. \n\nOffer the structured education programme 6\xa0to 12\xa0months after diagnosis. For adults who have not had a structured education programme by 12\xa0months, offer it at any time that is clinically appropriate and suitable for the person, regardless of how long they have had type\xa01 diabetes. \n\nFor adults with type\xa01 diabetes who are unable or prefer not to take part in group education, provide an alternative of equal standard. \n\nEnsure that any structured education programme for adults with type\xa01 diabetes:\n\nis evidence-based, and suits the needs of the person\n\nhas specific aims and learning objectives, and supports the person and their family members and carers in developing attitudes, beliefs, knowledge and skills to self‑manage diabetes\n\nhas a structured curriculum that is theory driven, evidence-based and resource effective and has supporting materials, and is written down\n\nis delivered by trained educators who:\n\n\n\nhave an understanding of educational theory appropriate to the age and needs of the person and\n\nare trained and competent to deliver the principles and content of the programme\n\n\n\nis quality assured, and reviewed by trained, competent, independent assessors who measure it against criteria that ensure consistency\n\nhas outcomes that are audited regularly. \n\nExplain to adults with type\xa01 diabetes that structured education is an integral part of diabetes care. \n\nProvide information about type\xa01 diabetes and its management to adults with type\xa01 diabetes at all opportunities from diagnosis onwards. Follow the principles in NICE's guideline on patient experience in adult NHS services. \n\nConsider the Blood Glucose Awareness Training (BGAT) programme for adults with type\xa01 diabetes who are having recurrent episodes of hypoglycaemia (see also the section on hypoglycaemia awareness and management). \n\nCarry out an annual review of self‑care and needs for all adults with type\xa01 diabetes. Decide what to cover each year by agreeing priorities with the adult with type\xa01 diabetes. [2004, amended 2015]\n\n# Dietary management\n\n## Carbohydrate counting\n\nOffer carbohydrate‑counting training to adults with type\xa01 diabetes as part of structured education programmes for self‑management (see the section on education and information). \n\nConsider carbohydrate‑counting courses for adults with type\xa01 diabetes who are waiting for a more detailed structured education programme or who are unable to take part in a standalone structured education programme. \n\n## Glycaemic index diets\n\nDo not advise adults with type\xa01 diabetes to follow a low glycaemic index diet for blood glucose control. \n\n## Dietary advice\n\nOffer dietary advice to adults with type\xa01 diabetes about issues other than blood glucose control (such as managing weight and cardiovascular risk), as needed. \n\nFrom diagnosis, provide nutritional information that is sensitive to the personal needs and culture of each adult with type\xa01 diabetes. \n\nProvide nutritional information individually and as part of a structured education programme (see the section on education and information). Include advice from professionals who are trained and accredited to provide dietary advice to people with health conditions. \n\nOffer opportunities to receive dietary advice at intervals agreed between adults with type\xa01 diabetes and their healthcare professionals. \n\nDiscuss the hyperglycaemic effects of the different foods the adult with type\xa01 diabetes wants to eat in the context of the insulin regimens chosen to match those food choices. \n\nProvide education programmes for adults with type\xa01 diabetes to help them with:\n\nhealthy eating and a balanced diet\n\nchanging their insulin dosage to reduce glucose excursions when varying their diet. [2004, amended 2015]\n\nDiscuss snacks with the adult with type\xa01 diabetes:\n\nCover the choice of snack, the quantity, and when to eat them.\n\nExplain the effects of eating different food types, and how long these effects last.\n\nExplain which insulin regimens are available to match different food types.\n\nDiscuss changes in choice of snack if needed, based on the results of self‑monitoring tests. \n\nProvide information on:\n\nthe effects of different alcohol‑containing drinks on blood glucose excursions and calorie intake\n\nhigh‑calorie and high‑sugar 'treats'. [2004, amended 2015]\n\nAs part of dietary education after diagnosis (and as needed after this), provide information on how healthy eating can reduce cardiovascular risk. Include information about fruit and vegetables, types and amounts of fat, and how to make the appropriate dietary changes. [2004, amended 2015]\n\nModify nutritional recommendations to adults with type\xa01 diabetes to take account of associated features of diabetes, including:\n\nexcess weight and obesity\n\nunderweight\n\ndisordered eating\n\nhypertension\n\nrenal failure. [2004, amended 2021]\n\nHealthcare professionals giving dietary advice to adults with type\xa01 diabetes should be able to advise about common topics of concern and interest, and should seek advice from specialists when needed. Suggested common topics include:\n\nbody weight, energy balance and obesity management\n\ncultural and religious diets, feasts and fasts\n\nfoods sold as 'diabetic'\n\nsweeteners\n\ndietary fibre intake\n\nprotein intake\n\nvitamin and mineral supplements\n\nalcohol\n\nmatching carbohydrate intake, insulin and physical activity\n\nsalt intake in hypertension\n\ncomorbidities, including nephropathy and renal failure, coeliac disease, cystic fibrosis or eating disorders\n\npeer support groups. [2004, amended 2015]\n\n# Physical activity\n\nAdvise adults with type\xa01 diabetes that physical activity can reduce their enhanced cardiovascular risk in the medium and long term. \n\nFor adults with type\xa01 diabetes who choose to increase their level of physical activity as part of a healthier lifestyle, provide information about:\n\nappropriate intensity and frequency of physical activity\n\nself‑monitoring their changed insulin and or nutritional needs\n\nthe effect of physical activity on blood glucose levels (which are likely to fall) when insulin levels are adequate\n\nthe effect of physical activity on blood glucose levels when hyperglycaemic and hypoinsulinaemic (there is a risk of worsening hyperglycaemia and ketonaemia)\n\nappropriate adjustments of insulin dosage and or nutritional intake for periods during and immediately after physical activity, and the 24\xa0hours after this\n\ninteractions of physical activity and alcohol\n\nfurther contacts and sources of information. \n\n# Blood glucose management\n\n## HbA1c measurement and targets\n\nMeasure HbA1c levels every 3\xa0to 6\xa0months in adults with type\xa01 diabetes. \n\nConsider measuring HbA1c levels more often in adults with type\xa01 diabetes if their blood glucose control is suspected to be changing rapidly; for example, if their HbA1c level has risen unexpectedly above a previously sustained target. \n\nMeasure HbA1c using methods calibrated according to International Federation of Clinical Chemistry (IFCC) standardisation. \n\nTell adults with type\xa01 diabetes their HbA1c results after each measurement and have their most recent result available at consultations. Follow the principles on communication in NICE's guideline on patient experience in adult NHS services. \n\nIf HbA1c monitoring is invalid because of disturbed erythrocyte turnover or abnormal haemoglobin type, estimate trends in blood glucose control using 1\xa0of the following:\n\nfructosamine estimation\n\nquality-controlled blood glucose profiles\n\ntotal glycated haemoglobin estimation (if abnormal haemoglobins). \n\nSupport adults with type\xa01 diabetes to aim for a target HbA1c level of 48\xa0mmol/mol (6.5%) or lower, to minimise the risk of long‑term vascular complications. \n\nAgree an individualised HbA1c target with each adult with type\xa01 diabetes. Take into account factors such as their daily activities, aspirations, likelihood of complications, comorbidities, occupation and history of hypoglycaemia. \n\nEnsure that aiming for an HbA1c target is not accompanied by problematic hypoglycaemia in adults with type\xa01 diabetes. \n\nDiabetes services should document the proportion of adults with type\xa01 diabetes who reach an HbA1c level of 53\xa0mmol/mol (7%) or lower. \n\n## Continuous glucose monitoring\n\nNICE's diagnostics guidance on integrated sensor-augmented pump therapy systems for managing blood glucose levels in type\xa01 diabetes is being updated. The guidance is being updated as a multiple technology appraisal and will assess hybrid closed loop systems.\n\nOffer adults with type\xa01 diabetes a choice of real-time continuous glucose monitoring (rtCGM) or intermittently scanned continuous glucose monitoring (isCGM, commonly referred to as 'flash'), based on their individual preferences, needs, characteristics, and the functionality of the devices available. See box\xa01 for examples of factors to consider as part of this discussion. \n\nWhen choosing a continuous glucose monitoring (CGM) device:\n\nuse shared decision making to identify the person's needs and preferences, and offer them an appropriate device\n\nif multiple devices meet their needs and preferences, offer the device with the lowest cost. \n\nAccuracy of the device\n\nWhether the device provides predictive alerts or alarms and if these need to be shared with anyone else (for example, a carer)\n\nWhether using the device requires access to particular technologies (such as a smartphone and up-to-date phone software)\n\nHow easy the device is to use and take readings from, including for people with limited dexterity\n\nFear, frequency, awareness and severity of hypoglycaemia\n\nPsychosocial factors\n\nThe person's insulin regimen or type of insulin pump, if relevant (taking into account whether a particular device integrates with their pump as part of a hybrid closed loop or insulin suspend function)\n\nWhether, how often, and how the device needs to be calibrated, and how easy it is for the person to do this themselves\n\nHow data can be collected, compatibility of the device with other technology, and whether data can be shared with the person's healthcare provider to help inform treatment\n\nWhether the device will affect the person's ability to do their job\n\nHow unpredictable the person's activity and blood glucose levels are and whether erratic blood glucose is affecting their quality of life\n\nWhether the person has situations when symptoms of hypoglycaemia cannot be communicated or can be confused (for example, during exercise)\n\nClinical factors that may make devices easier or harder to use\n\nFrequency of sensor replacement\n\nSensitivities to the device, for example local skin reactions\n\nBody image concerns\n\nCGM should be provided by a team with expertise in its use, as part of supporting people to self-manage their diabetes. [2015, amended 2022]\n\nAdvise adults with type 1 diabetes who are using CGM that they will still need to take capillary blood glucose measurements (although they can do this less often). Explain that this is because:\n\nthey will need to use capillary blood glucose measurements to check the accuracy of their CGM device\n\nthey will need capillary blood glucose monitoring as a back-up (for example, when their blood glucose levels are changing quickly or if the device stops working). Provide them with enough test strips to take capillary blood glucose measurements as needed. \n\nIf a person cannot use or does not want rtCGM or isCGM, offer capillary blood glucose monitoring. \n\nInclude CGM in the structured education programme provided to all adults with type\xa01 diabetes (see the section on education and information), and ensure that people are empowered to use CGM devices (see the section on empowering people to self-monitor blood glucose). \n\nMonitor and review the person's use of CGM as part of reviewing their diabetes care plan (see recommendations 1.1.7, 1.2.5 and 1.2.6 on what to consider when agreeing a care plan and what a care plan should cover). \n\nIf there are concerns about the way a person is using the CGM device:\n\nask if they are having problems using their device\n\nlook at ways to address any problems or concerns to improve their use of the device, including further education and emotional and psychological support. For guidance on CGM for pregnant women, see the NICE guideline on diabetes in pregnancy. \n\nCommissioners, providers and healthcare professionals should address inequalities in CGM access and uptake by:\n\nmonitoring who is using CGM\n\nidentifying groups who are eligible but who have a lower uptake\n\nmaking plans to engage with these groups to encourage them to consider CGM. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on continuous glucose monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: continuous glucose monitoring in adults with type\xa01 diabetes.\n\nLoading. Please wait.\n\n## Self-monitoring of capillary blood glucose\n\nAdvise adults with type\xa01 diabetes who are using capillary blood glucose monitoring to routinely self‑monitor their blood glucose levels, and to measure at least 4\xa0times a day (including before each meal and before bed). [2015, amended 2022]\n\nSupport adults with type\xa01 diabetes who are using capillary blood glucose monitoring to measure at least 4\xa0times a day, and up to 10\xa0times a day:\n\nif their target for blood glucose control, measured by HbA1c level (see recommendation\xa01.6.6), is not reached\n\nif they are having more frequent hypoglycaemic episodes\n\nif there is a legal requirement to do so, such as before driving (see the Driver and Vehicle Licensing Agency [DVLA] guide for medical professionals)\n\nduring periods of illness\n\nbefore, during and after sport\n\nwhen planning pregnancy, during pregnancy and while breastfeeding (see NICE's guideline on diabetes in pregnancy)\n\nif they need to know their blood glucose levels more than 4\xa0times a day for other reasons (for example, impaired hypoglycaemia awareness, or they are undertaking high‑risk activities). [2015, amended 2022]\n\nEnable additional blood glucose measurement (more than 10\xa0times a day) for adults with type\xa01 diabetes who are using capillary blood glucose monitoring if this is necessary because of:\n\nthe person's lifestyle (for example, they drive for long periods of time, they undertake high‑risk activities or have a high‑risk occupation, or they are travelling) or\n\nimpaired hypoglycaemia awareness. [2015, amended 2022]\n\nAdvise adults with type\xa01 diabetes to aim for:\n\na fasting plasma glucose level of 5\xa0to 7\xa0mmol/litre on waking and\n\na plasma glucose level of 4\xa0to 7\xa0mmol/litre before meals at other times of the day. \n\nAdvise adults with type\xa01 diabetes who choose to measure after meals to aim for a plasma glucose level of 5\xa0to 9\xa0mmol/litre at least 90\xa0minutes after eating. (This timing may be different in pregnancy – for guidance on plasma glucose targets in pregnancy, see NICE's guideline on diabetes in pregnancy.) \n\nAgree bedtime target plasma glucose levels with each adult with type\xa01 diabetes. Take into account the timing of their last meal of the day and the related insulin dose, and ensure the target is consistent with the recommended fasting level on waking (see recommendation\xa01.6.22). \n\nTeach self‑monitoring skills at the time of diagnosis and the start of insulin therapy. [2004, amended 2015]\n\nWhen choosing blood glucose meters:\n\ntake the needs of the adult with type\xa01 diabetes into account\n\nensure that meters meet current ISO standards. \n\nTeach adults with type\xa01 diabetes how to measure their blood glucose level, interpret the results and take appropriate action. Review these skills at least annually. \n\nSupport adults with type\xa01 diabetes through structured education (see the section on education and information) to make the best use of data from self‑monitoring of blood glucose. \n\nMonitoring blood glucose using sites other than the fingertips cannot be recommended as a routine alternative to conventional self‑monitoring of blood glucose. [2004, amended 2015]\n\n# Insulin therapy\n\n## Insulin regimens\n\nOffer multiple daily injection basal–bolus insulin regimens as the insulin injection regimen of choice for all adults with type\xa01 diabetes. Provide guidance on using this regimen. \n\nDo not offer adults newly diagnosed with type\xa01 diabetes non‑basal–bolus insulin regimens (that is, twice‑daily mixed, basal only or bolus only). \n\n## Long-acting insulin\n\nOffer twice‑daily insulin detemir as basal insulin therapy for adults with type\xa01 diabetes. \n\nConsider 1 of the following as an alternative basal insulin therapy to twice-daily insulin detemir for adults with type\xa01 diabetes:\n\nan insulin regimen that is already being used by the person if it is meeting their agreed treatment goals (such as meeting their HbA1c targets or time in target glucose range and minimising hypoglycaemia)\n\nonce-daily insulin glargine (100\xa0units/ml) if insulin detemir is not tolerated or the person has a strong preference for once‑daily basal injections\n\nonce-daily insulin degludec (100\xa0units/ml) if there is a particular concern about nocturnal hypoglycaemia\n\nonce-daily ultra-long-acting insulin such as degludec (100\xa0units/ml) for people who need help from a carer or healthcare professional to administer injections. There is a risk of severe harm and death due to inappropriately withdrawing insulin from pen devices. See NHS England's patient safety alert for further information. \n\nWhen starting an insulin for which a biosimilar is available, use the product with the lowest acquisition cost. \n\nEnsure the risk of medication errors with insulins is minimised by following Medicines and Healthcare products Regulatory Agency (MHRA) guidance on minimising the risk of medication error with high strength, fixed combination and biosimilar insulin products, which includes advice for healthcare professionals when starting treatment with a biosimilar. \n\nWhen people are already using an insulin for which a lower cost biosimilar is available, discuss the possibility of switching to the biosimilar. Make a shared decision with the person after discussing their preferences. \n\nConsider other basal insulin regimens for adults with type\xa01 diabetes only if the regimens in recommendations\xa01.7.3 and 1.7.4 do not meet their agreed treatment goals. When choosing an alternative insulin regimen, take account of:\n\nthe person's preferences\n\ncomorbidities\n\nrisk of hypoglycaemia and diabetic ketoacidosis\n\nany concerns around adherence\n\nacquisition cost. \n\nWhen prescribing, ensure that insulins are prescribed by brand name. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on long-acting insulin\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: long-acting insulins in type\xa01 diabetes.\n\nLoading. Please wait.\n\n## Insulin pumps\n\nFor guidance on the use of insulin pumps for adults with type\xa01 diabetes, see NICE's technology appraisal guidance on continuous subcutaneous insulin infusion for the treatment of diabetes mellitus. \n\n## Rapid-acting insulin\n\nOffer rapid‑acting insulin analogues that are injected before meals, rather than rapid‑acting soluble human or animal insulins, for mealtime insulin replacement for adults with type\xa01 diabetes. \n\nDo not advise routine use of rapid‑acting insulin analogues after meals for adults with type\xa01 diabetes. \n\nIf an adult with type\xa01 diabetes has a strong preference for an alternative mealtime insulin, respect their wishes and offer the preferred insulin. \n\n## Mixed insulin\n\nConsider a twice‑daily human mixed insulin regimen for adults with type\xa01 diabetes if a multiple daily injection basal–bolus insulin regimen is not possible and a twice‑daily mixed insulin regimen is used. \n\nConsider a trial of a twice‑daily analogue mixed insulin regimen if an adult using a twice‑daily human mixed insulin regimen has hypoglycaemia that affects their quality of life. \n\n## Optimising insulin therapy\n\nFor adults with erratic and unpredictable blood glucose control (hyperglycaemia and hypoglycaemia at no consistent times), consider the following rather than changing a previously optimised insulin regimen:\n\ninjection technique\n\ninjection sites\n\nself-monitoring skills\n\nknowledge and self‑management skills\n\nlifestyle\n\nmental health and psychosocial problems\n\npossible organic causes, such as gastroparesis. [2004, amended 2015]\n\nGive clear guidelines and protocols ('sick‑day rules') to all adults with type\xa01 diabetes, to help them adjust insulin doses appropriately when they are ill. \n\n## Adjuncts\n\nConsider adding metformin to insulin therapy for adults with type\xa01 diabetes if:\n\nthey have a BMI of 25\xa0kg/m2 or above (23\xa0kg/m2 or above for people from South Asian and related family backgrounds) and\n\nthey want to improve their blood glucose control while minimising their effective insulin dose.In August\xa02015, this was an off-label use of metformin. See NICE's information on prescribing medicines. \n\n# Insulin delivery\n\nFor adults with type\xa01 diabetes who inject insulin, provide their preferred insulin injection delivery device (this often means using one or more types of insulin injection pen). \n\nFor adults with type\xa01 diabetes and special visual or psychological needs, provide injection devices or needle‑free systems that they can use independently for accurate dosing. \n\nOffer needles of different lengths to adults with type\xa01 diabetes who are having problems such as pain, local skin reactions and injection site leakages. \n\nAfter taking clinical factors into account, choose needles with the lowest acquisition cost to use with pre‑filled and reusable insulin pen injectors. \n\nAdvise adults with type\xa01 diabetes to rotate insulin injection sites and avoid repeated injections at the same point within sites. \n\nProvide adults with type\xa01 diabetes with:\n\nsuitable containers for collecting used needles and other sharps\n\na way to safely get rid of these containers. See also the section on safe use and disposal of sharps in NICE's guideline on healthcare-associated infections: prevention and control in primary and community care. [2004, amended 2015]\n\nCheck injection site condition at least annually, and whenever new problems with blood glucose control occur. [2004, amended 2015]\n\n# Referral for islet or pancreas transplantation\n\nFor adults with type\xa01 diabetes who have recurrent severe hypoglycaemia that has not responded to other treatments (see the section on hypoglycaemia awareness and management), consider referral to a centre that assesses people for islet and/or pancreas transplantation. \n\nConsider islet or pancreas transplantation for adults with type\xa01 diabetes with suboptimal diabetes control, if they have had a renal transplant and are currently on immunosuppressive therapy. \n\n# Hypoglycaemia awareness and management\n\n## Identifying and quantifying impaired hypoglycaemia awareness\n\nAssess hypoglycaemia awareness in adults with type\xa01 diabetes at each annual review. \n\nUse the Gold score or Clarke score to quantify hypoglycaemia awareness in adults with type\xa01 diabetes, checking that the questionnaire items have been answered correctly. \n\nExplain to adults with type\xa01 diabetes that impaired awareness of the symptoms of plasma glucose levels below 3\xa0mmol/litre is associated with a significantly increased risk of severe hypoglycaemia. \n\n## Managing impaired hypoglycaemia awareness\n\nEnsure that adults with type\xa01 diabetes and impaired hypoglycaemia awareness have had structured education in flexible insulin therapy using basal–bolus regimens, and are following its principles correctly. \n\nOffer additional education focusing on avoiding and treating hypoglycaemia to adults with type\xa01 diabetes who still have impaired hypoglycaemia awareness after structured education in flexible insulin therapy. \n\nAvoid relaxing individualised blood glucose targets to address impaired hypoglycaemia awareness for adults with type\xa01 diabetes. \n\nFor adults with type\xa01 diabetes and impaired hypoglycaemia awareness who are using lower target blood glucose levels than recommended in this guideline, encourage them to use the recommended targets (see the recommendations on blood glucose targets). \n\nReview insulin regimens and doses, and prioritise ways to avoid hypoglycaemia in adults with type\xa01 diabetes with impaired hypoglycaemia awareness, including:\n\nreinforcing the principles of structured education\n\noffering an insulin pump\n\noffering real‑time continuous glucose monitoring. \n\nIf, despite these interventions, an adult with type\xa01 diabetes has impaired hypoglycaemia awareness that is associated with recurrent severe hypoglycaemia, consider referring them to a specialist centre. \n\n## Preventing and managing hypoglycaemia\n\nExplain to adults with type\xa01 diabetes that a fast‑acting form of glucose is needed for managing hypoglycaemic symptoms or signs in people who can swallow. [2004, amended 2015]\n\nAdults with type\xa01 diabetes who have a decreased level of consciousness because of hypoglycaemia and so cannot safely take oral treatment should be:\n\ngiven intramuscular glucagon by a family member or friend who has been shown how to use it (intravenous glucose may be used by healthcare professionals skilled in getting intravenous access)\n\nchecked for response at 10\xa0minutes, and then given intravenous glucose if their level of consciousness is not improving significantly\n\nthen given oral carbohydrate when it is safe to administer it, and put under continued observation by someone who has been warned about the risk of relapse. [2004, amended 2015]\n\nExplain to adults with type\xa01 diabetes that:\n\nit is very common to experience some hypoglycaemic episodes with any insulin regimen\n\nthey should use a regimen that avoids or reduces the frequency of hypoglycaemic episodes, while maintaining the most optimal blood glucose control possible. \n\nMake hypoglycaemia advice available to all adults with type\xa01 diabetes, to help them find the best possible balance with any insulin regimen. (See the sections on insulin therapy and insulin delivery.) \n\nIf hypoglycaemia becomes unusually problematic or increases in frequency, review the following possible causes:\n\ninappropriate insulin regimens (incorrect dose distributions and insulin types)\n\nmeal and activity patterns, including alcohol\n\ninjection technique and skills, including insulin resuspension if necessary\n\ninjection site problems\n\npossible organic causes, including gastroparesis\n\nchanges in insulin sensitivity (including drugs affecting the renin–angiotensin system and renal failure)\n\nmental health problems\n\nprevious physical activity\n\nlack of appropriate knowledge and skills for self‑management. \n\nManage nocturnal hypoglycaemia (symptomatic or detected on monitoring) by:\n\nreviewing knowledge and self‑management skills\n\nreviewing current insulin regimen, evening eating habits and previous physical activity\n\nchoosing an insulin type and regimen that is less likely to cause low glucose levels at night. [2004, amended 2015]\n\nIf early cognitive decline occurs in adults on long‑term insulin therapy, then in addition to normal investigations consider possible brain damage from overt or covert hypoglycaemia, and the need to manage this. \n\n# Ketone monitoring and managing diabetic ketoacidosis\n\n## Ketone self-monitoring to prevent diabetic ketoacidosis\n\nConsider ketone monitoring (blood or urine) as part of 'sick‑day rules' for adults with type\xa01 diabetes, to help with self‑management of hyperglycaemia. \n\n## Ketone monitoring in hospital\n\nIn adults with type\xa01 diabetes presenting to emergency services, consider capillary blood ketone testing if:\n\ndiabetic ketoacidosis (DKA) is suspected or\n\nthe person has uncontrolled diabetes during an illness, and urine ketone testing is positive. \n\nConsider capillary blood ketone testing (incorporated into a formal protocol) for inpatient management of DKA in adults with type\xa01 diabetes. \n\n## Management of DKA\n\nProfessionals managing DKA in adults should have adequate and up-to-date training, and be familiar with all aspects of DKA management that are associated with mortality and morbidity. These topics should include:\n\nfluid balance\n\nacidosis\n\ncerebral oedema\n\nelectrolyte imbalance\n\nthat DKA can affect the results of standard diagnostic tests (white cell count, body temperature, electrocardiogram [ECG])\n\nrespiratory distress syndrome\n\ncardiac abnormalities\n\nprecipitating causes\n\ninfection management, including opportunistic infections\n\ngastroparesis\n\nuse of high dependency and intensive care units\n\nrecommendations\xa01.11.5 to\xa01.11.12 in this guideline.Management of DKA in adults should be in line with local clinical governance. \n\nUse isotonic saline for primary fluid replacement in adults with DKA, not given too rapidly except in cases of circulatory collapse. \n\nDo not generally use bicarbonate for managing DKA in adults. [2004, amended 2015]\n\nGive intravenous insulin by infusion to adults with DKA. \n\nWhen the plasma glucose concentration has fallen to 10\xa0to 15\xa0mmol/litre in adults with DKA, give glucose‑containing fluids (not more than 2\xa0litres in 24\xa0hours) so that the insulin infusion can be continued at a sufficient rate to clear ketones (for example, 6\xa0units/hour, monitored for effect). [2004, amended 2015]\n\nBegin potassium replacement early in DKA in adults, with frequent monitoring for hypokalaemia. \n\nDo not generally use phosphate replacement when managing DKA in adults. [2004, amended 2015]\n\nIn adults with DKA who have reduced consciousness, think about:\n\ninserting a nasogastric tube and\n\nmonitoring urine output using a urinary catheter and\n\ngiving venous thromboembolism (VTE) prophylaxis. [2004, amended 2021]\n\nTo reduce the risk of catastrophic outcomes in adults with DKA, use continuous monitoring and frequent reviews that cover all aspects of clinical management. [2004, amended 2015]\n\n# Associated illness\n\nIn adults with type\xa01 diabetes who have unexplained weight loss, assess for coeliac disease. For guidance on testing for coeliac disease, see NICE's guideline on coeliac disease. [2004, amended 2015]\n\nBe alert to the possibility of other autoimmune diseases in adults with type\xa01 diabetes (including Addison's disease and pernicious anaemia). For advice on monitoring for thyroid disease, see the recommendation on thyroid disease monitoring. [2004, amended 2015]\n\n# Control of cardiovascular risk\n\n## Aspirin\n\nDo not offer aspirin for the primary prevention of cardiovascular disease in adults with type\xa01 diabetes. \n\n## Identifying cardiovascular risk\n\nAssess cardiovascular risk factors annually, including:\n\nestimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (ACR)\n\nsmoking\n\nblood glucose control\n\nblood pressure\n\nfull lipid profile (including high-density lipoprotein [HDL] and low-density lipoprotein [LDL] cholesterol, and triglycerides)\n\nage\n\nfamily history of cardiovascular disease\n\nabdominal adiposity. [2004, amended 2015 and 2021]\n\nFor guidance on tools for assessing risk of cardiovascular disease in adults with type\xa01 diabetes, see the recommendations on full formal risk assessment in NICE's guideline on lipid modification. \n\n## Interventions to reduce risk and manage cardiovascular disease\n\nFor guidance on the primary prevention of cardiovascular disease in adults with type\xa01 diabetes, see the section on primary prevention for people with type\xa01 diabetes in NICE's guideline on lipid modification. \n\nGive adults with type\xa01 diabetes who smoke advice on stopping smoking and stop smoking services, including NICE guidance‑recommended therapies (see the NICE topic page on smoking and tobacco). Reinforce these messages annually for people who currently do not plan to stop smoking, and at all clinical contacts if there is a prospect of the person stopping. \n\nAdvise adults who do not smoke never to start smoking. [2004, amended 2021]\n\nProvide intensive management for adults who have had myocardial infarction or stroke, according to relevant non‑diabetes guidelines. For angina or other ischaemic heart disease, beta-blockers should be considered (for insulin use in these circumstances, see the section on caring for adults with type\xa01 diabetes in hospital). For guidance on secondary prevention of myocardial infarction, see NICE's guideline on acute coronary syndromes. [2004, amended 2015]\n\n## Blood pressure management\n\nIn adults with type 1 diabetes aim for blood pressure targets as follows:\n\nFor adults with a urine albumin:creatinine ratio (ACR) less than 70 mg/mmol, aim for a clinic systolic blood pressure less than 140 mmHg (target range 120 to 139 mmHg) and a clinic diastolic blood pressure less than 90 mmHg.\n\nFor adults with an ACR of 70 mg/mmol or more, aim for a clinic systolic blood pressure less than 130 mmHg (target range 120 to 129 mmHg) and a clinic diastolic blood pressure less than 80 mmHg.\n\nIn adults aged 80 or more, whatever the ACR, aim for a clinic systolic blood pressure less than 150 mmHg and a clinic diastolic blood pressure less than 90 mmHg.Use clinical judgement for adults with frailty, target organ damage (damage to organs because of diabetes, for example, to nerves or eyes) or multimorbidity. See the recommendations on pharmacotherapy in NICE's guideline on chronic kidney disease, and NICE's guidelines on hypertension in adults and multimorbidity. [2004, amended 2022]\n\nDiscuss the following with adults with type\xa01 diabetes who have hypertension to help them make an informed choice:\n\nreasons for the choice of intervention level\n\nthe substantial potential gains from small improvements in blood pressure control\n\nany possible negative consequences of therapy. [2004, amended 2015]\n\nStart a trial of a renin–angiotensin system blocking drug as first‑line therapy for hypertension in adults with type\xa01 diabetes. [2004, amended 2015]\n\nProvide information to adults with type\xa01 diabetes on how lifestyle changes can improve their blood pressure control and associated outcomes, and offer help to achieve their aims in this area. \n\nDo not allow concerns over potential side effects to inhibit advising and offering the necessary use of any class of drugs, unless side effects become symptomatic or otherwise clinically significant. In particular:\n\ndo not avoid selective beta-blockers for adults on insulin if these are indicated\n\nlow-dose thiazides may be combined with beta‑blockers\n\nwhen prescribing calcium channel antagonists, only use long‑acting preparations\n\nask adults directly about potential side effects of erectile dysfunction, lethargy and orthostatic hypotension with different drug classes. [2004, amended 2015]\n\nDeleted.\n\n# Caring for adults with type\xa01 diabetes in hospital\n\n## Blood glucose control\n\nAim for a target plasma glucose level of 5\xa0to 8\xa0mmol/litre for adults with type\xa01 diabetes during surgery or acute illness. \n\nEstablish a local protocol for controlling blood glucose levels in adults with type\xa01 diabetes during surgery or acute illness to reach the target level. \n\nUse intravenous rather than subcutaneous insulin regimens for adults with type\xa01 diabetes if:\n\nthey are unable to eat or are predicted to miss more than 1\xa0meal or\n\nan acute situation is expected to result in unpredictable blood glucose levels – for example, major surgery, high‑dose steroid treatment, inotrope treatment or sepsis or\n\ninsulin absorption is expected to be unpredictable, for example, because of circulatory compromise. \n\nConsider continuing the person's existing basal insulin regimen (including basal rate if they are using insulin pump therapy) together with protocol‑driven insulin delivery for controlling blood glucose levels in adults with type\xa01 diabetes during surgery or acute illness. \n\nUse subcutaneous insulin regimens (including rapid‑acting insulin before meals) if an adult with type\xa01 diabetes and acute illness is eating. \n\nEnable adults with type\xa01 diabetes who are hospital inpatients to self‑administer subcutaneous insulin if they are willing and able and it is safe for them to do so. \n\n## Delivering care in hospital and other institutions\n\nThese recommendations are for care teams caring for adults with type\xa01 diabetes in hospital and in institutions such as nursing homes, residential homes and prisons.\n\nFrom admission, provide ongoing advice to adults with type\xa01 diabetes and the team caring for them from a trained multidisciplinary team with expertise in diabetes. \n\nThroughout inpatient admission, respect the personal expertise of adults with type\xa01 diabetes in managing their own diabetes and incorporate this into routine ward‑based blood glucose monitoring and insulin delivery. [2004, amended 2015]\n\nThroughout inpatient admission, support adults with type\xa01 diabetes to make their own food choices based on their personal knowledge of their dietary needs, except when illness or medical or surgical intervention significantly disturbs those requirements. \n\nProvide optimal insulin therapy, which can be achieved using intravenous insulin and glucose, to all adults with type\xa01 diabetes with threatened or actual stroke. Critical care and emergency departments should have a protocol for such management. [2004, amended 2011]\n\n# Managing complications\n\n## Periodontitis\n\nAdvise adults with type\xa01 diabetes at their annual review of self‑care and needs that:\n\nthey are at higher risk of periodontitis\n\nif they get periodontitis, managing it can improve their blood glucose control and can reduce their risk of hyperglycaemia. \n\nAdvise adults with type\xa01 diabetes to have regular oral health reviews (their oral healthcare or dental team will tell them how often, in line with the NICE guideline on dental checks: intervals between oral health reviews). \n\nFor guidance for oral healthcare and dental teams on how to provide oral health advice, see the NICE guideline on oral health promotion.\n\nFor adults with type\xa01 diabetes who have been diagnosed with periodontitis by an oral healthcare or dental team, offer dental appointments to manage and treat their periodontitis (at a frequency based on their oral health needs). \n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on periodontitis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: periodontitis.\n\nLoading. Please wait.\n\n## Eye disease\n\nWhen adults are diagnosed with type\xa01 diabetes, refer them immediately to the local eye screening service. [2004, amended 2020]\n\nEncourage adults to attend eye screening, and explain that it will help them to keep their eyes healthy and help to prevent problems with their vision. Explain that the screening service is effective at identifying problems so that they can be treated early. \n\nArrange emergency review by an ophthalmologist for:\n\nsudden loss of vision\n\nrubeosis iridis\n\npre-retinal or vitreous haemorrhage\n\nretinal detachment. [2004, amended 2015]\n\nRefer to an ophthalmologist in accordance with the UK National Screening Committee criteria and timelines for any large sudden unexplained drop in visual acuity. [2004, amended 2020]\n\n## Diabetic kidney disease\n\nFor guidance on managing kidney disease in adults with type\xa01 diabetes, see NICE's guideline on chronic kidney disease. \n\nAsk all adults with type\xa01 diabetes, with or without detected nephropathy, to bring in the first urine sample of the day ('early morning urine') once a year. Send this for estimation of albumin:creatinine ratio (estimating urine albumin concentration alone is a poor alternative) and measure eGFR at the same time. See NICE's guideline on chronic kidney disease. [2004, amended 2021]\n\nSuspect other renal disease if:\n\nprogressive retinopathy is absent\n\nblood pressure is particularly high\n\nproteinuria develops suddenly\n\nsignificant haematuria is present (see NICE's guideline on chronic kidney disease)\n\nthe person is systemically unwell. \n\nIf albuminuria is found, discuss with the person what this means. [2004, amended 2015]\n\nFor guidance on medicines for managing chronic kidney disease, see the section on pharmacotherapy for CKD in adults, children, and young people with related persistent proteinuria in the NICE guideline on chronic kidney disease. \n\nMaintain the person's blood pressure (see recommendation 1.1.3.8 for blood pressure targets) by adding other anti‑hypertensive drugs if necessary. \n\nAdvise adults with type\xa01 diabetes and nephropathy about the advantages of avoiding a high‑protein diet. \n\nReferral criteria for tertiary care should be agreed between local diabetes specialists and nephrologists. See NICE's guideline on chronic kidney disease. \n\n## Chronic painful diabetic neuropathy\n\nFor guidance on managing chronic painful diabetic neuropathy in adults with type\xa01 diabetes, see NICE's guideline on neuropathic pain in adults. \n\n## Autonomic neuropathy\n\nThink about the possibility of autonomic neuropathy affecting the gut if adults with type\xa01 diabetes have unexplained diarrhoea, particularly at night. \n\nWhen prescribing antihypertensive medicines, take care not to increase the risk of orthostatic hypotension from the combined effects of sympathetic autonomic neuropathy and blood pressure lowering medicines. \n\nFor adults with type\xa01 diabetes who have bladder emptying problems, investigate the possibility of autonomic neuropathy affecting the bladder, unless another explanation is found. \n\nWhen managing the symptoms of autonomic neuropathy, include specific interventions for the manifestations encountered (for example, for abnormal sweating and postural hypotension). [2004, amended 2015]\n\nAnaesthetists should be aware of the possibility of parasympathetic autonomic neuropathy affecting the heart in adults with type\xa01 diabetes who:\n\nare listed for procedures under general anaesthetic and\n\nhave evidence of somatic neuropathy or other manifestations of autonomic neuropathy. \n\n## Gastroparesis\n\nAdvise adults with type\xa01 diabetes who have vomiting caused by gastroparesis to follow a small‑particle‑size diet (mashed or pureed food) to relieve their symptoms. \n\nBe aware that gastroparesis needing specific therapy can only be diagnosed in the absence of hyperglycaemia at the time of testing, because hyperglycaemia delays gastric emptying. \n\nConsider insulin pump therapy for adults with type\xa01 diabetes who have gastroparesis. \n\nFor adults with type\xa01 diabetes who have vomiting caused by gastroparesis, explain that:\n\nthere is no strong evidence that any available antiemetic therapy is effective\n\nsome people have had benefit with domperidone (see the Medicines and Healthcare products Regulatory Agency (MHRA) guidance on domperidone: risks of cardiac side effects), erythromycin or metoclopramide (see the MHRA guidance on metoclopramide: risks of neurological adverse effects)\n\nthe strongest evidence for effectiveness is for domperidone, but prescribers must take into account its safety profile, in particular its cardiac risk and potential interactions with other medicines.In August\xa02015, this was an off-label use of erythromycin and many higher doses or treatment durations of domperidone. See NICE's information on prescribing medicines. \n\nTo treat vomiting caused by gastroparesis in adults with type\xa01 diabetes:\n\nconsider alternating erythromycin and metoclopramide (see the MHRA guidance on metoclopramide: risks of neurological adverse effects)\n\nconsider domperidone only in exceptional circumstances (that is, when it is the only effective treatment) and in accordance with the MHRA guidance on domperidone: risks of cardiac side effects.In August\xa02015, this was an off-label use of erythromycin and many higher doses or treatment durations of domperidone. See NICE's information on prescribing medicines. \n\nRefer adults with type\xa01 diabetes who have gastroparesis for specialist advice if the interventions in this section have not helped or are not appropriate. \n\n## Acute painful neuropathy from rapid improvement of blood glucose control\n\nReassure adults with type\xa01 diabetes that acute painful neuropathy resulting from rapid improvement of blood glucose control is a self‑limiting condition and symptoms improve over time. \n\nExplain to adults with type\xa01 diabetes that the specific treatments for acute painful neuropathy resulting from rapid improvement of blood glucose control:\n\naim to make symptoms tolerable until the condition resolves\n\nmay not relieve pain immediately and may need to be taken regularly for several weeks to be effective. \n\nUse simple analgesics (paracetamol, aspirin) and local measures (bed cradles) as a first step to treat acute painful neuropathy, and if these do not help, try other measures. [2004, amended 2021]\n\nDo not relax diabetes control to address acute painful neuropathy resulting from rapid improvement of blood glucose control in adults with type\xa01 diabetes. \n\nIf simple analgesia does not provide sufficient pain relief for adults with type\xa01 diabetes who have acute painful neuropathy resulting from rapid improvement of blood glucose control, offer treatment as described in NICE's guideline on neuropathic pain in adults. Simple analgesia may be continued until the effects of additional treatments have been established. \n\nWhen offering medicines for managing acute painful neuropathy resulting from rapid improvement of blood glucose control to adults with type\xa01 diabetes, be aware of the risk of dependency associated with opioids. For more information, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. \n\n## Diabetic foot problems\n\nFor guidance on preventing and managing foot problems in adults with type\xa01 diabetes, see NICE's guideline on diabetic foot problems. \n\n## Erectile dysfunction\n\nOffer men with type\xa01 diabetes the opportunity to discuss erectile dysfunction as part of their regular review. \n\nOffer a phosphodiesterase‑5 inhibitor to men with type\xa01 diabetes with isolated erectile dysfunction unless contraindicated. Choose the phosphodiesterase‑5 inhibitor with the lowest acquisition cost. \n\nConsider referring men with type\xa01 diabetes to a service offering further assessment and other medical, surgical or psychological management of erectile dysfunction if phosphodiesterase‑5 inhibitor treatment is unsuccessful or contraindicated. \n\n## Thyroid disease monitoring\n\nMeasure blood thyroid‑stimulating hormone (TSH) levels in adults with type\xa01 diabetes at their annual review. \n\n## Mental health problems\n\nMembers of diabetes professional teams providing care or advice to adults with type\xa01 diabetes should be alert to possible clinical or subclinical depression and/or anxiety, particularly if someone reports or appears to be having difficulties with self‑management. \n\nDiabetes professionals should:\n\nensure they have appropriate skills to identify and provide basic management of non‑severe mental health problems in people from different cultural backgrounds\n\nbe familiar with appropriate counselling techniques and drug therapy, while arranging prompt referral to specialists for people whose mental health problems continue to interfere significantly with their wellbeing or diabetes self‑management. See also the:\n\nNICE guideline on common mental health problems\n\nNICE guideline on generalised anxiety disorder and panic disorder in adults\n\nNICE guideline on depression in adults with a chronic physical health problem. [2004, amended 2015]\n\n## Eating disorders and disordered eating\n\nMembers of diabetes professional teams should be alert to the possibility of bulimia nervosa, anorexia nervosa and disordered eating in adults with type\xa01 diabetes with:\n\nover-concern with body shape and weight\n\nlow BMI\n\nhypoglycaemia\n\nsuboptimal overall blood glucose control. See also NICE's guideline on eating disorders. [2004, amended 2021]\n\nThink about making an early (or if needed, urgent) referral to local eating disorder services for adults with type\xa01 diabetes with an eating disorder. [2004, amended 2021]\n\nFrom diagnosis, the diabetes professional team should provide regular high-quality support and counselling about lifestyle and diet for all adults with type\xa01 diabetes (see the sections on education and information and dietary management). \n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Continuous glucose monitoring\n\nThis covers both real-time (rtCGM) and intermittently scanned (isCGM, commonly referred to as 'flash') continuous glucose monitoring.\n\nA continuous glucose monitor is a device that measures blood glucose levels and sends the readings to a display device or smartphone.\n\n## Disordered eating\n\nDisordered eating describes a range of irregular eating behaviours. These can include symptoms that reflect many but not all of the symptoms of eating disorders, such as anorexia nervosa, bulimia nervosa and binge eating disorder. Examples of disordered eating include fasting or chronic restrained eating, skipping meals, binge eating, self-induced vomiting, restrictive dieting, and laxative or diuretic misuse.\n\n## Periodontitis\n\nA chronic inflammatory gum disease that destroys the supporting tissues of the teeth (the periodontium).\n\nGingivitis is a milder form of periodontal disease than periodontitis. However, gingivitis still causes inflammation in the gum, and if not treated it can lead to periodontitis.\n\n## Ultra-long-acting insulin\n\nInsulin analogues that have a longer duration of action (beyond 24\xa0hours) compared with standard long-acting insulins.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Clinical features for distinguishing between type\xa01 diabetes and other types of diabetes\n\nWhat are the best clinical features or combination of features for distinguishing between type\xa01 diabetes and other types of diabetes? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: diagnosis of diabetes.\n\nLoading. Please wait.\n\n# The use of C-peptide in diagnosing diabetes\n\nWhat is the effectiveness of C‑peptide at correcting misclassification of diabetes diagnosis and what is the optimal timing for the test in distinguishing subtypes of diabetes? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: diagnosis of diabetes.\n\nLoading. Please wait.\n\n# Use of routinely collected real-world data to examine the effectiveness and cost effectiveness of continuous glucose monitoring\n\nBased on routinely collected real-world data, what is the effectiveness and cost effectiveness of continuous glucose monitoring (CGM) devices to improve glycaemic control? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on CGM\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: continuous glucose monitoring in adults with type\xa01 diabetes.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the 2021 and 2022 recommendations and how they might affect practice.\n\n# Diagnosis\n\nRecommendations 1.1.1 to 1.1.9\n\n## Why the committee made the recommendations\n\nThe committee wanted to highlight the importance of distinguishing between type\xa01 diabetes and other diabetes types because these conditions are treated differently (particularly in terms of insulin use).\n\nThe most common misdiagnosis is type\xa01 diabetes being misdiagnosed as type\xa02, which could lead to the person not receiving insulin treatment and a subsequent risk of diabetic ketoacidosis.\n\nIt is less harmful to be diagnosed with type\xa01 diabetes when the person actually has type\xa02 diabetes. However, there are still harms, including:\n\nthe long-term effects and costs of unnecessary insulin therapy\n\nthe missed opportunity for oral diabetes therapies\n\nthe psychological impact of misdiagnosis.\n\nThere was no new definitive evidence on clinical features for identifying diabetes type, so recommendation\xa01.1.1 remains unchanged from the 2015 guideline. Because of this lack of new evidence, the committee made a recommendation for research on identifying diabetes type.\n\nThe evidence showed that no single clinical feature had a sufficient predictive value to make a diagnosis by itself. The committee were particularly concerned that age and body mass index (BMI) might be used in isolation. They noted that the average BMI in people with type\xa01 diabetes is increasing, and the age at which people are diagnosed with type\xa02 diabetes is decreasing. This means these clinical features are becoming less useful on their own to differentiate between the subtypes. Despite this, the committee agreed that these characteristics are still useful for making an initial working diagnosis of diabetes subtype in many people. However, further testing is increasingly needed, as previously 'atypical' features of type\xa01 and 'uncertain' classifications become more common.\n\nIn a change from the 2015 guideline, the committee agreed it was important to encourage the use of diabetes-specific autoantibody testing at diagnosis, to avoid misclassifying diabetes subtype. They also clarified that autoantibody testing is appropriate for people with suspected type\xa01 diabetes.\n\nThere was no high-quality evidence on tests to distinguish type\xa01 from type\xa02 or other types of diabetes, so the committee based the recommendations on the timings when the tests might be most useful (autoantibody testing is best used at the time of presentation, and C‑peptide is best used with increasing time from initial presentation) rather than which tests were most accurate.\n\nBased on clinical experience, the committee were confident that measuring autoantibodies in people with suspected type\xa01 diabetes would be cost effective. This is because:\n\nautoantibody tests are cheap when compared with the much higher costs associated with inaccurate diagnosis\n\nmisclassification using clinical criteria alone results in additional costs, both from the use of ineffective treatments and from clinical harm.\n\nFurther, because autoantibody tests are more accurate when done at the time of presentation rather than later at a clinical review, they would also be more cost effective at that time rather than later, since the cost will be the same but more useful information will be obtained from the test at the time of diagnosis.\n\nThe committee noted that using autoantibody testing also means that healthcare professionals do not have to rely on characteristics alone when people first present. This can help avoid assumptions about links between ethnicity and diabetes type (for example, assuming that people in Black, Asian and other minority ethnic groups are more likely to have type\xa02 diabetes).\n\nThe committee could not recommend routine non-fasting serum C‑peptide testing because of a lack of high-quality and clinical evidence, and this would be a significant and costly change in clinical practice. However, they thought it would be an appropriate test if clinical presentation and autoantibody testing did not provide a clear classification of diabetes (for example, if clinical features were consistent with type\xa01 diabetes but autoantibody results were negative).\n\nThe committee noted that serum C‑peptide is more appropriate in individual clinical diagnosis settings as it can be paired with blood glucose, while urine C‑peptide is mainly used in epidemiological studies.\n\nBecause of the lack of high-quality evidence, the committee made a recommendation for research to examine the effectiveness of C-peptide at correcting misclassification of diabetes at initial diagnosis and the optimal timing for this test in distinguishing between subtypes of diabetes.\n\n## How the recommendations might affect practice\n\nIt is likely that these recommendations will lead to increased autoantibody testing in people presenting with suspected type\xa01 diabetes. This will increase testing costs, but this increase is not expected to be substantial, because of the low costs of the tests themselves. An increased use of serum C‑peptide testing in the classification of diabetes is less likely, because the guideline only recommends this be done if there is still diagnostic uncertainty after the use of autoantibody testing.\n\nAlthough there is a cost associated with some of the new recommendations and concerns about the availability of the tests in all settings, the committee felt this would be balanced out by benefits from reducing the misclassification of diabetes at presentation and ensuring early appropriate treatment of type\xa01 (and in some cases type\xa02) diabetes. This will avoid unnecessary tests, treatment and side effects from prolonged insulin use.\n\nReturn to recommendations\n\n# Continuous glucose monitoring\n\nRecommendations 1.6.10 to 1.6.18\n\n## Why the committee made the recommendations\n\nThe committee agreed that there was enough evidence in key outcomes, such as HbA1c, time in range and severe or nocturnal hypoglycaemia, to demonstrate that both real-time continuous glucose monitoring (rtCGM) and intermittently scanned CGM (isCGM) provide clinical benefits over standard self-monitoring of blood glucose. However, they considered that the evidence for rtCGM compared with isCGM was not good enough in terms of quality or sample size to clearly show clinical benefits of 1\xa0technology over the other.\n\nThe committee also acknowledged that CGM technologies were changing very quickly, with increasing overlap between rtCGM and isCGM as features such as predictive alerts are added to newer isCGM devices.\n\nThe health economic modelling found that, when the benefit of reduced fear of hypoglycaemia with CGM was included, both technologies were cost effective for the full population of adults with type\xa01 diabetes compared with standard self-monitoring of blood glucose.\n\nBased on the above factors and the evidence, the committee agreed that there was no advantage to recommending 1\xa0specific device over another compared with standard self-monitoring of blood glucose. They concluded that the specific functionality of isCGM versus rtCGM devices should be discussed between the person and their healthcare professional. In particular, finding the right device for each person is likely to improve adherence, which means the device will provide more benefits and so will be more cost effective.\n\nThe committee did not make a recommendation on using specific devices because CGM technologies are changing very quickly, and this recommendation would soon be out of date. Local healthcare services are better placed to assess which devices are evidence-based and suitable for use at any given time.\n\nThere are benefits of providing a choice of different CGM devices because the most suitable device would vary for each person. The committee produced a list of factors to consider when choosing a CGM device with people. The committee agreed that this freedom of choice is beneficial, particularly because adherence to the technology is likely to be higher if the device is matched to the person's needs and preferences.\n\nThe committee retained the 2015 recommendation on providing people with support from a healthcare specialist team with expertise in diabetes and the use of CGM. Community-based specialist teams are now available and are no longer always based in secondary care, so 'centre' was changed to 'team' to make this clearer.\n\nDespite the positive recommendations on CGM, the committee were concerned that existing health inequalities may still lead to lower uptake of CGM in some groups of people. To address this, the committee made a recommendation outlining actions for commissioners, providers and healthcare professionals.\n\nGiven the rapid advances in technology, the committee made a recommendation for research on using routinely collected real-world data to examine the effectiveness and cost effectiveness of CGM. If routine healthcare data is collected, it can show the direct effect of implemented technology on the population, rather than it being interpreted through the results of clinical trials. Increased monitoring of routine healthcare data including registries and audits would ensure that the findings from a broader population is captured.\n\n## How the recommendations might affect practice\n\nThese recommendations are likely to result in broader access to isCGM and rtCGM devices, as opposed to a binary decision on access based on stringent criteria. This should reduce inequalities and enable more people to use CGM. Currently, people with more time and knowledge to self-advocate are often more likely to gain access to these devices.\n\nSome people have insulin insufficiency because of other conditions. The committee noted that these people would get the same care as people with type\xa01 diabetes, so they should have access to CGM in the same way.\n\nThere is likely to be an increase in costs from more use of CGM devices. A number of different devices are available, so if more than 1\xa0device would be appropriate for a person and would meet their needs and preferences, using the lowest cost device among those options would help to reduce the cost impact.\n\nReturn to recommendations\n\n# Long-acting insulin\n\nRecommendations 1.7.3 to 1.7.9\n\n## Why the committee made the recommendations\n\nEvidence showed that there were fewer severe and nocturnal hypoglycaemic events with insulin detemir twice daily compared with neutral protamine Hagedorn (NPH). Insulin detemir twice daily was also found to be the most cost-effective treatment strategy in the economic analysis. Based on this evidence and their clinical experience, the committee recommended twice-daily insulin detemir as a basal insulin therapy for adults with type\xa01 diabetes.\n\nThe committee agreed there were situations in which an insulin other than twice-daily insulin detemir might be preferred, and set out specific clinical scenarios where alternative long-acting insulins could be used. This includes if the person is already using an insulin regimen that is working well for them and helping them meet their treatment goals.\n\nSome people may not be able to tolerate insulin detemir, or for some, a once-daily regimen may be necessary (either because the person has a strong preference for once-daily injections or there are circumstances that make twice daily not practical). Glargine (100\xa0units/ml) was found to be the most cost-effective once-daily insulin (particularly when the costs of glargine biosimilars were considered) so it was recommended as the appropriate alternative in these cases.\n\nPeople on insulin therapies can still have hypoglycaemic episodes. This can be a cause of concern, particularly if they have nocturnal hypoglycaemic events. Evidence showed a lower proportion of nocturnal hypoglycaemic events with degludec (100\xa0units/ml), when compared with other once-daily insulins. Degludec (100\xa0units/ml) is an ultra-long-acting insulin, which means it has a longer duration of action compared with long-acting insulins. The committee agreed that once-daily degludec could therefore be considered as an alternative basal insulin therapy if there is a particular concern about nocturnal hypoglycaemia.\n\nThe committee agreed that once-daily ultra-long-acting insulin regimens, such as insulin degludec (100\xa0units/ml), may also be needed by people who need support from a carer or healthcare professional to administer injections, for example, because they are frail or have a physical or mental health condition, or learning disability. Insulins that offer flexibility in dosing time, such as insulin degludec (100\xa0units/ml), have a long duration of action and may be particularly useful because they give more flexibility in when the dose can be given. Insulin glargine (300\xa0units/ml) is another example of an ultra-long-acting insulin. Healthcare professionals should also refer to NHS England's patient safety alert on the risk of severe harm and death from inappropriately withdrawing insulin from pen devices.\n\nBiosimilars have the potential to offer the NHS considerable cost savings. To gain approval for use, biosimilar medicines have to be shown to be safe and as effective as the original reference medicine, and have the same quality. Based on this understanding, the committee noted it was appropriate when starting a new prescription of an insulin where a biosimilar is available, to use the one with the lowest cost.\n\nAdditionally, people may be using an insulin for which a lower cost biosimilar is available. In such cases, the committee recommended discussing with people the possibility of switching to the biosimilar. This could happen at the person's routine review. They also agreed that switching to the biosimilar should be carefully planned, taking into consideration the dose-switching protocols, monitoring and the person's concerns about switching from their existing regimen, and a shared decision reached. Healthcare professionals should also refer to the summary of product characteristics for further information when considering switching to biosimilars.\n\nThe committee retained the recommendation from the 2015 version of the guideline on considering the use of other basal insulin regimens not covered by other recommendations. Based on their clinical understanding, they added comorbidities (such as renal function), risks of hypoglycaemia and diabetic ketoacidosis and concerns about adherence to the factors to take into account when considering alternative regimens. To support pharmacovigilance and patient safety, the committee also recommended that insulins should be prescribed by brand name.\n\n## How the recommendations might affect practice\n\nUse of long-acting insulins varies across the country, with some centres offering twice-daily insulin detemir to people who are newly diagnosed, whereas other centres start with once-daily regimens. A major shift in practice is unlikely but the recommendations do set out scenarios where other insulins such as ultra-long-acting insulins and biosimilars may be useful and cost effective.\n\nReturn to recommendations\n\n# Periodontitis\n\nRecommendations 1.15.1 to 1.15.4\n\n## Why the committee made the recommendations\n\nThe evidence showed that people with diabetes are at increased risk of periodontitis, and that non-surgical periodontal treatment can improve diabetic control. Although most of the research was focused on type\xa02 diabetes, the committee thought that the evidence on the bidirectional link between increased HbA1c and periodontitis was also applicable to people with type\xa01 diabetes.\n\nIn the committee's experience, people with diabetes are often unaware of the link between diabetes and periodontitis and may not be having regular oral health reviews. To address this, the committee recommended routinely discussing the risk of periodontitis at annual reviews, alongside eye disease and foot problems.\n\nThe evidence also showed that periodontal treatment is cost effective for people with type\xa01 diabetes, assuming improvements in HbA1c are maintained. This was tested with health economic modelling in a range of different scenarios. The only situation in which treatment would not be cost effective is if the analysis only considered up to the first 10\xa0years of periodontal treatment. However, the committee did not think this was realistic, as this excludes the benefits from reducing diabetic complications, which often happen later in life.\n\n## How the recommendations might affect practice\n\nFor oral healthcare professionals, the long-term impact of the recommendations is uncertain. The recommendations specify that people should follow existing NICE guidelines on oral health. However, the recommendations may also increase awareness of periodontitis, leading to a possible short-term increase in the number of oral health reviews. Any increase in the number of oral health reviews will potentially impact on services, as NHS dental services already have capacity issues.\n\nA short-term increase in the number of oral health reviews will also lead to a short-term increase in costs. However, there is likely to be a larger long-term reduction in costs from the improvement to oral health and diabetes control.\n\nOral healthcare and dental teams will need clear advice on what they need to do for people with diabetes. They will need clear care pathways to improve quality of care and service delivery, in line with the NHS England commissioning standard on dental care for people with diabetes.\n\nMany people do not have regular oral health reviews, even if they are eligible for free NHS dental care. People are eligible for free dental care if they are:\n\npregnant\n\nmothers with babies under 1 year old\n\non low income benefits, or under 20 and dependent on someone who is receiving low income benefits\n\nhaving treatment in an NHS hospital by the hospital dentist.\n\nThe recommendations may encourage more people with diabetes to have regular oral health reviews. Combined with proactive engagement and enhanced support for people with diabetes, this may broaden access to dental and oral healthcare and help to reduce oral health inequalities.\n\nReturn to recommendations", 'Context': 'Type\xa01 diabetes affects over 370,000\xa0adults in the UK. It results from destruction of the cells that normally make insulin. Loss of insulin secretion results in high blood glucose and other metabolic and haematological abnormalities, which have both short‑term and long‑term adverse effects on health.\n\nOver years, type\xa01 diabetes causes tissue damage which, if not detected and managed early, can result in disability: blindness, kidney failure, periodontitis, and foot ulceration leading to amputation, as well as premature heart disease, stroke and death. The risk of all of these complications is greatly reduced by treatment that keeps circulating glucose levels to as near normal as possible, reducing tissue damage. Disability from complications that are not avoided can often be prevented by early detection and active management.\n\nType\xa01 diabetes is treated by insulin replacement and supported by active management of other cardiovascular risk factors, such as hypertension and high circulating lipids. Modern insulin replacement therapy aims to recreate normal fluctuations in circulating insulin concentrations. This supports a flexible lifestyle with minimal restrictions and, properly done, can improve blood glucose levels, reducing the risk of both structural complications and episodes of hypoglycaemia.\n\nFlexible insulin therapy usually involves self‑injecting multiple daily doses of insulin, with doses adjusted based on taken or planned exercise, intended food intake and other factors, including current blood glucose, which the insulin user needs to test on a regular basis. This self‑management needs the insulin user to have the skills and confidence to manage the regimen.\n\nOne of the most important roles of healthcare professionals providing diabetes care to adults with type\xa01 diabetes is to ensure that systems are in place to provide informed expert support, education and training for insulin users, as well as a range of other more conventional biomedical services and interventions.\n\nAlthough type\xa01 diabetes in adults is not rare, it is not common enough that all healthcare professionals who deal with it are able to acquire and maintain all the necessary skills for its management. The aim of this guideline is to provide evidence‑based, practical advice on supporting adults with type\xa01 diabetes to live full, largely unrestricted, lives and to avoid the short‑term and long‑term complications of both the disease and of its treatment.'}	https://www.nice.org.uk/guidance/ng17	This guideline covers care and treatment for adults (aged 18 and over) with type 1 diabetes. It includes advice on diagnosis, education and support, blood glucose management, cardiovascular risk, and identifying and managing long-term complications.
288890afd32e01030f81a659e043437e0645fbc5	nice	COVID-19 rapid guideline: delivery of systemic anticancer treatments	COVID-19 rapid guideline: delivery of systemic anticancer treatments The purpose of this guideline is to maximise the safety of patients with cancer and make the best use of NHS resources during the COVID-19 pandemic, while protecting staff from infection. It will also enable services to match the capacity for cancer treatment to patient needs if services become limited because of the COVID-19 pandemic. # Communicating with patients and minimising risk # All patients Communicate with patients and support their mental wellbeing, signposting to charities and support groups where available, to help alleviate any anxiety and fear they may have about COVID‑19. # Patients with symptoms of COVID‑19 at presentation Be aware that patients having systemic anticancer treatments are immunocompromised and may have atypical presentations of COVID‑19. Also, symptoms of COVID‑19, neutropenic sepsis and pneumonitis may be difficult to differentiate at initial presentation. If patients have fever (with or without respiratory symptoms), suspect neutropenic sepsis because this can be rapid and life-threatening, and follow the NICE guideline on neutropenic sepsis, which recommends: referring patients with suspected neutropenic sepsis immediately for assessment in secondary or tertiary care treating suspected neutropenic sepsis as an acute medical emergency and offering empiric antibiotic therapy immediately. # Systemic anticancer treatments # Shared decision making with individual patients Do not routinely delay starting systemic anticancer treatment (SACT), or pause SACT that is already underway, because of the risk of contracting COVID-19. Discuss the risks and benefits of SACT with people with cancer and their family members and carers, taking into account current dominant COVID-19 variants and COVID-19 prevalence. Topics to cover include: that most people who have SACT do not go on to have worse outcomes from COVID-19 infection, should they develop it that the risks of deferring SACT are likely to be greater than the risks of increased COVID-19 severity that people with myeloma or other types of haematological cancer who have immunomodulatory SACT may have worse outcomes from COVID-19 factors that may affect their risk of becoming severely ill with COVID-19, including vaccination status, underlying conditions, increasing age, male sex, ethnicity and cancer symptoms how to reduce the risk of catching COVID-19 while having SACT local access to current treatment options for COVID-19Reach a shared decision with the person about their treatment. Follow relevant national guidance on communication, providing information (including in different formats and languages) and shared decision making, for example, NICE's guideline on shared decision making. For people with myeloma or other types of haematological cancer, discuss treatment strategies with a specialist team (such as, haematology and/or subspecialised myeloma teams) before giving immunomodulatory SACT. If a person who is going to have (or has started) SACT has tested positive for COVID-19: if possible, delay the start of SACT (or pause the treatment if already underway) until any significant COVID-19 symptoms have resolved if delayed or paused, reach a shared decision with the person about when to start or resume SACT (discussions should include the factors described in recommendation 3.2, and take into account any local guidance on testing for SARS-CoV-2) ensure the risk to other patients and healthcare staff is minimised when the person attends hospital for SACT, in line with local policies. # Modifications to usual service # Treatment breaks NHS England are developing a revised treatment break policy. These recommendations will be updated when this is published. It is proposed that the current treatment break policy, which applies to both Cancer Drugs Fund (CDF) and non-CDF treatments, will not be applied during the COVID‑19 outbreak. Where a treatment break is needed, clinicians should complete the approval form to restart treatment, indicating that the patient had a break because of COVID‑19. The request will be approved even if their disease has progressed, providing the clinician indicates there is a reasonable chance that disease control can be regained on restarting treatment. It is expected that the response to treatment will be reviewed 2 or 3 cycles after restarting. If disease control has not been regained treatment should be stopped. # Recommendations for research We have made the following recommendations for research. # Risk of systemic anticancer treatment in people with cancer and COVID-19 Are patients with cancer and COVID-19 who are receiving/have recently received systemic anticancer treatment (SACT) (that is, within the 4 weeks preceding a diagnosis of COVID-19) at increased risk of severe COVID-19 illness or death? It is recommended that this research should also consider: if there are specific types of SACT carrying increased risk of poor outcomes from COVID-19 if there are specific types of cancer for which SACT may carry increased risk of poor outcomes from COVID-19 if there is a difference in any risk of poor outcomes from COVID-19 between people who have received SACT alone, radiotherapy alone, or both SACT and radiotherapy if there is a difference in any risk of poor outcomes from COVID-19 between children and young people who have received SACT and adults who have received SACT. # Duration of risk of systemic anticancer treatment in people with cancer and COVID-19 Are people who have had SACT recently (that is, within the 4 weeks preceding a diagnosis of COVID-19) at increased risk of poor outcomes from COVID-19 compared with those who had SACT less recently?	{'Communicating with patients and minimising risk': '# All patients\n\nCommunicate with patients and support their mental wellbeing, signposting to charities and support groups where available, to help alleviate any anxiety and fear they may have about COVID‑19. ', 'Patients with symptoms of COVID‑19 at presentation': 'Be aware that patients having systemic anticancer treatments are immunocompromised and may have atypical presentations of COVID‑19. Also, symptoms of COVID‑19, neutropenic sepsis and pneumonitis may be difficult to differentiate at initial presentation. \n\nIf patients have fever (with or without respiratory symptoms), suspect neutropenic sepsis because this can be rapid and life-threatening, and follow the NICE guideline on neutropenic sepsis, which recommends:\n\nreferring patients with suspected neutropenic sepsis immediately for assessment in secondary or tertiary care\n\ntreating suspected neutropenic sepsis as an acute medical emergency and offering empiric antibiotic therapy immediately. ', 'Systemic anticancer treatments': "# Shared decision making with individual patients\n\nDo not routinely delay starting systemic anticancer treatment (SACT), or pause SACT that is already underway, because of the risk of contracting COVID-19. \n\nDiscuss the risks and benefits of SACT with people with cancer and their family members and carers, taking into account current dominant COVID-19 variants and COVID-19 prevalence. Topics to cover include:\n\nthat most people who have SACT do not go on to have worse outcomes from COVID-19 infection, should they develop it\n\nthat the risks of deferring SACT are likely to be greater than the risks of increased COVID-19 severity\n\nthat people with myeloma or other types of haematological cancer who have immunomodulatory SACT may have worse outcomes from COVID-19\n\nfactors that may affect their risk of becoming severely ill with COVID-19, including vaccination status, underlying conditions, increasing age, male sex, ethnicity and cancer symptoms\n\nhow to reduce the risk of catching COVID-19 while having SACT\n\nlocal access to current treatment options for COVID-19Reach a shared decision with the person about their treatment. Follow relevant national guidance on communication, providing information (including in different formats and languages) and shared decision making, for example, NICE's guideline on shared decision making. [2021, amended 2022]\n\nFor people with myeloma or other types of haematological cancer, discuss treatment strategies with a specialist team (such as, haematology and/or subspecialised myeloma teams) before giving immunomodulatory SACT. \n\nIf a person who is going to have (or has started) SACT has tested positive for COVID-19:\n\nif possible, delay the start of SACT (or pause the treatment if already underway) until any significant COVID-19 symptoms have resolved\n\nif delayed or paused, reach a shared decision with the person about when to start or resume SACT (discussions should include the factors described in recommendation 3.2, and take into account any local guidance on testing for SARS-CoV-2)\n\nensure the risk to other patients and healthcare staff is minimised when the person attends hospital for SACT, in line with local policies. [2021, amended 2022]", 'Modifications to usual service': '# Treatment breaks\n\nNHS England are developing a revised treatment break policy. These recommendations will be updated when this is published.\n\nIt is proposed that the current treatment break policy, which applies to both Cancer Drugs Fund (CDF) and non-CDF treatments, will not be applied during the COVID‑19 outbreak. \n\nWhere a treatment break is needed, clinicians should complete the approval form to restart treatment, indicating that the patient had a break because of COVID‑19. The request will be approved even if their disease has progressed, providing the clinician indicates there is a reasonable chance that disease control can be regained on restarting treatment. It is expected that the response to treatment will be reviewed 2 or 3 cycles after restarting. If disease control has not been regained treatment should be stopped. ', 'Recommendations for research': 'We have made the following recommendations for research.\n\n# Risk of systemic anticancer treatment in people with cancer and COVID-19\n\nAre patients with cancer and COVID-19 who are receiving/have recently received systemic anticancer treatment (SACT) (that is, within the 4 weeks preceding a diagnosis of COVID-19) at increased risk of severe COVID-19 illness or death? [12 February 2021]\n\nIt is recommended that this research should also consider:\n\nif there are specific types of SACT carrying increased risk of poor outcomes from COVID-19\n\nif there are specific types of cancer for which SACT may carry increased risk of poor outcomes from COVID-19\n\nif there is a difference in any risk of poor outcomes from COVID-19 between people who have received SACT alone, radiotherapy alone, or both SACT and radiotherapy\n\nif there is a difference in any risk of poor outcomes from COVID-19 between children and young people who have received SACT and adults who have received SACT.\n\n# Duration of risk of systemic anticancer treatment in people with cancer and COVID-19\n\nAre people who have had SACT recently (that is, within the 4 weeks preceding a diagnosis of COVID-19) at increased risk of poor outcomes from COVID-19 compared with those who had SACT less recently? [12 February 2021]'}	https://www.nice.org.uk/guidance/ng161	The purpose of this guideline is to maximise the safety of patients with cancer and make the best use of NHS resources during the COVID-19 pandemic, while protecting staff from infection. It will also enable services to match the capacity for cancer treatment to patient needs if services become limited because of the COVID-19 pandemic.
e5386e451f1c4005e5439962069c1cef7f59aed0	nice	Guselkumab for treating active psoriatic arthritis after inadequate response to DMARDs	Guselkumab for treating active psoriatic arthritis after inadequate response to DMARDs Evidence-based recommendations on guselkumab (Tremfya) for active psoriatic arthritis after inadequate response to DMARDs in adults. # Recommendations Guselkumab, alone or with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults whose disease has not responded well enough to disease-modifying antirheumatic drugs (DMARDs) or who cannot tolerate them. It is recommended only if they have had 2 conventional DMARDs and: have had at least 1 biological DMARD, or tumour necrosis factor (TNF)-alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).Guselkumab is recommended only if the company provides it according to the commercial arrangement. Active psoriatic arthritis is defined as peripheral arthritis with 3 or more tender joints and 3 or more swollen joints. Assess the response to guselkumab from 16 weeks. Stop guselkumab at 24 weeks if the psoriatic arthritis has not responded adequately using the Psoriatic Arthritis Response Criteria (PsARC; an adequate response is an improvement in at least 2 of the 4 criteria, 1 of which must be joint tenderness or swelling score, with no worsening in any of the 4 criteria). If the PsARC response is not adequate but there is a Psoriasis Area and Severity Index (PASI) 75 response, a dermatologist should decide whether continuing treatment is appropriate based on skin response. Take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the PsARC and make any adjustments needed. Take into account how skin colour could affect the PASI score and make any adjustments needed. These recommendations are not intended to affect treatment with guselkumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations People with active psoriatic arthritis that is not controlled well enough with 2 conventional DMARDs are usually offered biological DMARDs. Many of these are already recommended by NICE for treating psoriatic arthritis. Guselkumab is a biological DMARD. Clinical evidence shows that guselkumab is effective compared with placebo, but it has not been compared directly with other biological DMARDs for treating psoriatic arthritis. An indirect comparison suggests that guselkumab is as effective as the biological DMARDs secukinumab and ixekizumab, particularly for skin symptoms. For people who have had 2 conventional DMARDs and at least 1 biological DMARD, guselkumab's cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources. For people who have had 2 conventional DMARDs and for whom TNF-alpha inhibitors are contraindicated, the costs and benefits are similar to those of other treatments recommended by NICE. So, guselkumab is recommended for both of these groups.# Information about guselkumab # Marketing authorisation indication Guselkumab (Tremfya, Janssen), 'alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis in adult patients who have had an inadequate response or who have been intolerant to a prior disease-modifying antirheumatic drug (DMARD) therapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for guselkumab. # Price The cost of a 100 mg pre-filled disposable injection of guselkumab is £2,250.00 (excluding VAT; BNF online, accessed May 2022). The company has a commercial arrangement. This makes guselkumab available to the NHS with a discount. The size of the simple patient access scheme discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount. In the complex patient access scheme, the 4‑weekly regimen is provided at the same cost as an 8‑weekly regimen. If every 4 weeks dosing is needed, the price will be equalised with every 8 weeks dosing by supplying 2 of the 100 mg pre‑filled disposable injections for the price of 1.# Committee discussion The appraisal committee considered evidence submitted by Janssen, a review of this original submission by the evidence review group (ERG), another submission by Janssen for the rapid review, NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need ## Psoriatic arthritis substantially affects health-related quality of life The patient and clinical experts explained that active psoriatic arthritis (defined as 3 or more tender joints and 3 or more swollen joints) is a lifelong condition that seriously affects people's quality of life. It can develop at a young age, and affects a person's education, career, relationships and family life. The patient experts explained that symptoms such as fatigue, pain and associated comorbidities such as inflammatory bowel disorders, cardiovascular disease and diabetes can have a substantial physical and psychological effect. The clinical and patient experts explained that psoriatic arthritis symptoms range from mild, non-destructive disease to erosive and deforming arthritis that substantially affects daily life. Symptoms can include swollen fingers and toes, inflammation of larger joints such as elbows, knees, and back, and tendonitis. Skin and nail psoriasis also affect quality of life. The committee concluded that active psoriatic arthritis substantially affects health-related quality of life. # Clinical management ## Clinicians and people with psoriatic arthritis would welcome additional biological treatments that target different inflammation pathways The clinical experts explained that treatment for active psoriatic arthritis aims to control joint and connective tissue inflammation. This prevents joint damage progressing and the associated pain and disability. People will usually have treatment with non-steroidal anti-inflammatory drugs, corticosteroids, and conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate. In line with NICE's technology appraisal guidance on etanercept, infliximab and adalimumab, people are eligible for biological or small molecule treatments if their disease is poorly controlled after 2 conventional DMARDs. Biological and small molecule treatments include: tumour necrosis factor (TNF)-alpha inhibitors such as etanercept and adalimumab interleukin (IL) inhibitors such as secukinumab and ixekizumab (IL‑17A inhibitors) and ustekinumab (IL‑12 and IL‑23 inhibitor) tofacitinib apremilastThe clinical experts explained that psoriatic arthritis is unpredictable and can flare and change over time. Sometimes it responds to the first conventional DMARD, or to a second or third, or it may not respond at all. The clinical experts highlighted that because flares and periods of disease remission are common, the treatment pathway varies. After conventional DMARDs, people often switch among the different TNF-alpha inhibitors, or to different interleukin inhibitors (ustekinumab, secukinumab and ixekizumab) or to tofacitinib. People with psoriatic arthritis would benefit from an additional class of treatment that targets a different inflammatory mediator if: their disease has not responded (or has stopped responding) to DMARDs and other biologicals or small molecules, or they need to stop a treatment because of side effects.Guselkumab is the first monoclonal antibody specifically targeting IL‑23 to be considered by NICE for use in psoriatic arthritis. The committee concluded that people with psoriatic arthritis and clinicians would welcome a further treatment option that targets a different inflammation pathway. # Clinical evidence ## Guselkumab is clinically effective compared with placebo The efficacy and safety evidence for guselkumab in psoriatic arthritis comes from 2 pivotal trials, DISCOVER‑1 and DISCOVER‑2. These trials randomised people to have 100 mg guselkumab every 8 weeks or every 4 weeks, or to placebo. The guselkumab trial arms both showed statistically significant and clinically important benefits compared with placebo for disease activity, joint and skin symptoms, functional capacity and health-related quality of life. Guselkumab met the primary endpoint; a higher proportion of people had an American College of Rheumatology (ACR) 20 response compared with those on placebo at 24 weeks in both trials. The committee concluded that both doses of guselkumab were clinically effective compared with placebo across a range of clinically important outcomes. ## The populations in the clinical trials are broadly generalisable to NHS clinical practice and are appropriate for decision making In its submission, the company assumed that the baseline characteristics of people in the DISCOVER trials reflected those of people seen in NHS clinical practice. The ERG explained that the DISCOVER trials did not include people from the UK. The trials recruited mainly from eastern Europe, where local health systems may have different treatment provision for psoriatic arthritis. The ERG was concerned about the generalisability of the results of the trials because of key differences in the populations compared with populations in the NHS. The company submission identified 4 subgroups and included analyses for 3 subgroups: people whose disease is not adequately controlled by 2 conventional DMARDs but who have not had a biological DMARD people whose disease is not adequately controlled by 2 conventional DMARDs or by at least 1 biological DMARD people whose disease is not adequately controlled by 2 conventional DMARDs and for whom TNF-alpha inhibitors (class of biological DMARD) are contraindicated.The clinical experts confirmed the ERG's view that guselkumab was unlikely to be used as a first-line biological treatment in the NHS. So in clinical practice, a high proportion of people would have had another biological treatment before starting guselkumab. The proportion of people in the trials who had previously had a biological treatment (31% in DISCOVER‑1, 0% in DISCOVER‑2) did not therefore reflect NHS clinical practice. The ERG further explained that in the trials, less than a third of people had already had 2 or more conventional DMARDs. Also, just under 10% of people had not had a conventional DMARD before. Because NICE recommends that biological DMARDs are offered after 2 conventional DMARDs have been tried (see section 3.2), this further limits the applicability of the trials to the NHS. Another generalisability concern was the baseline Psoriasis Area and Severity Index (PASI) scores of people in the trials. The clinical experts agreed with the ERG that these were high and that it was rare to see people with psoriatic arthritis with PASI scores above 5 in the NHS. Because less than a third of people had 2 conventional DMARDs before starting the DISCOVER trials, it would be reasonable to expect the level of disease at baseline to be higher. The committee recalled that in previous NICE psoriatic arthritis technology appraisals, the clinical experts considered that trial PASI scores were higher than would be seen in clinical practice. The clinical experts confirmed that the populations in the trials and in the NHS were different in terms of prior treatments and disease severity at baseline. But they advised that because psoriatic arthritis is unpredictable and the available treatments do not cure it, both populations represented people with active disease. The committee agreed that: there were differences between the trial populations and people with psoriatic arthritis seen in NHS clinical practice the trial populations were broadly similar to those in comparator trials in the network meta-analyses, and to those in previous NICE psoriatic arthritis technology appraisals.The committee concluded that although there were differences between the populations in the trials and in the NHS, the evidence from the DISCOVER trials was broadly appropriate for including in decision making. ## The low discontinuation rates in DISCOVER-1 and DISCOVER-2 are not likely to be seen in the NHS Discontinuation rates for the 4-weekly dose in the pivotal trials were between 2.3% (DISCOVER‑1) and 3.7% (DISCOVER‑2). In its submission, the company said these low rates were evidence of guselkumab's sustained efficacy, safety and tolerability. The committee recalled the ERG's and clinical experts' opinion about the differences between the trial populations and the people who would have treatment in NHS clinical practice (see section 3.4). The baseline characteristics suggested that people in the countries participating in the trials, mostly eastern Europe, had limited access to the range of treatments available in the NHS. The clinical experts explained that the low discontinuation rates in the trials, including in the placebo groups, might reflect this overall lack of access to other treatments. They added that trial discontinuation rates often do not translate into the actual rates seen in clinical practice. In the UK, people whose disease is not controlled would be expected to move quickly to another active treatment. The ERG considered that the company's justification for guselkumab's very low discontinuation rates was not robust. The ERG felt that the company had not shown an underlying biological mechanism for these low rates. The ERG rejected the company's claim that the low discontinuation rates for guselkumab (and ustekinumab) may partly be because of better skin response with these biological treatments. This was because people with psoriatic arthritis mainly have biological DMARDs to control joint disease rather than psoriasis, which tends to be less severe. Also, most studies used to inform the treatment-specific discontinuation rates for guselkumab and the comparators did not report treatment stopping rules in the maintenance period. So it was possible that people in these trials continued treatment beyond the loss of sustained response. This would therefore not reflect the rate seen in clinical practice, where stopping rules would ensure that people did not remain on treatments that were not adequately controlling their disease. The committee agreed with the clinical experts and ERG that the trial populations and the NHS population were not similar. It also agreed about the uncertainties in the evidence base supporting the use of treatment-specific discontinuation rates. The committee concluded that the low discontinuation rates for guselkumab in DISCOVER‑1 and DISCOVER‑2 were not likely to be the same in the NHS. ## Early escape in the guselkumab trials results in bias 'Early escape' to another treatment is common in clinical trials and stops people staying on a treatment if they have uncontrolled disease. The clinical experts explained that it is important for ensuring people remain in trials, which improves the generalisability of the data. The company had opted to treat early escape as non-response (that is, no change from baseline) in the final analysis at 24 weeks. The ERG explained that early escape, as with treatment switching, always results in the potential for bias. Treating early escape as non-response potentially overestimates the benefit of active treatments because most early escape is expected to be in the placebo arm of trials. Early escape was only allowed after 16 weeks in the DISCOVER trials. The ERG explained that the trial investigators did not have to tell people that they had qualified for early escape. Of those who were eligible, most were in the placebo arms, and less than 50% escaped to another treatment, but the reasons for this were unclear. The ERG explained that it did not agree with the company's method of dealing with early escape in the trials, and suggested an assessment time of 16 weeks. This would mean that the data would be free of bias caused by early escape. The company re-did the network meta-analyses using 16‑week data. The ERG also did an exploratory analysis of the effect on first-line treatment cost of a 16‑week stopping rule. The ERG preferred an alternative approach, to include the full observed response of people who escaped early to another treatment. This would also introduce bias by assigning the benefits of an active treatment to placebo. In contrast to the company's preferred approach, this approach would potentially underestimate guselkumab's benefit and would therefore be a more conservative analysis. The company did not consider that either of the ERG's approaches were appropriate. The company claimed that guselkumab's mechanism of action meant that it continued to be effective, particularly in measures of skin response such as PASI scores, between 16 and 24 weeks. To limit analysis to 16 weeks would therefore not represent guselkumab's full benefits. Also, it claimed that assigning guselkumab's benefits to people in the placebo arm by using the full observed response data from people who escaped early would be clinically implausible. The committee agreed with the ERG that the arguments supporting guselkumab's unique mechanism of action were not convincing and more robust evidence would be needed. The committee agreed that early escape would introduce bias for the 24‑week analysis whether it was treated as non-response or the full observed response was used. The committee noted that analysing the DISCOVER trials at 16 weeks only and including the outcome data for early escape at 24 weeks reduced guselkumab's effectiveness relative to placebo, and that the company's preferred approach may have overestimated guselkumab's benefit. The committee concluded that early escape resulted in bias and that it would consider all approaches in its decision making. ## The assessment time of 24 weeks is appropriate, but clinicians would value the option of assessing response at 16 weeks Guselkumab's summary of product characteristics states that stopping treatment should be considered when disease has not responded after 24 weeks of treatment. The patient experts explained that they welcomed the prospect of a new biological treatment that works on an additional inflammation pathway. But they also explained that people with psoriatic arthritis are frequently frustrated by having ineffective treatments, and that irreversible joint damage can occur very quickly. Many people would therefore find it difficult to accept waiting for 24 weeks to have clinical benefit assessed. The clinical experts commented that a 24‑week assessment time for guselkumab was much longer than the 12‑ to 16‑week assessment times for other biological DMARDs. They noted that continued response beyond 12 to 16 weeks had also been seen for other biological DMARDs and small molecules. The clinical experts would welcome the option to assess response at 16 weeks, to help decide whether to switch treatment or intervene with salvage treatment. The ERG explained that it was not convinced that the evidence for guselkumab's unique mechanism of action would justify waiting until 24 weeks to assess response. It noted that the maximum Psoriatic Arthritis Response Criteria (PsARC), Health Assessment Questionnaire-Disability Index (HAQ-DI) and ACR 50 responses were recorded at week 20 in the DISCOVER trials. The ERG further explained that the company's economic model could misrepresent the quality-adjusted life year (QALY) gains associated with an improved PASI response from 16 to 24 weeks. Therefore, the model was not suitable for exploring the full effect on outcomes of using a 16‑week stopping rule for guselkumab. Also, the ERG explained that it was uncertain whether an improved PASI response between 16 and 24 weeks on guselkumab was confounded by the bias potentially introduced by allowing early escape in the DISCOVER trials. The committee noted that the assessment time for skin response was 16 weeks, in line with guselkumab's marketing authorisation for moderate to severe psoriasis. The committee agreed with the ERG that the evidence for further improvement in joint disease between 16 and 24 weeks was limited. But it noted that 24 weeks was the assessment time in the summary of product characteristics. The committee concluded, however, that clinicians would value the option of assessing response at 16 weeks. ## Clinicians would value the option to continue treatment based on a PASI 75 response Continuing guselkumab treatment depends on whether a person has a PsARC response. The ERG explored the possibility of continuing treatment when there is an inadequate PsARC response but there is a PASI 75 response. The ERG explained that this was particularly relevant for guselkumab, which is likely to produce a comparable PsARC response to other biological DMARDs, but has the highest PASI 75 response. The clinical experts explained that if a person with psoriatic arthritis and mild psoriasis did not have an adequate PsARC response, it would not be appropriate to continue guselkumab just because of a 75% reduction in their mild psoriasis. But the decision could be different for people with moderate to severe psoriasis, which can severely affect quality of life. The committee recalled the patient expert statement that for some people with psoriatic arthritis, psoriasis symptoms in skin and nails can be hugely debilitating (see section 3.1). The patient experts also explained that the person's needs must be considered. For some people, skin and nail psoriasis symptoms can have a greater effect on quality of life than joint symptoms. The clinical experts explained that if there is only a partial PsARC response, but the person has a PASI 75 response for psoriasis that has affected their quality of life, then it may be appropriate to continue treatment while that clinical benefit lasts. Some people in this situation will continue to have slow incremental improvement in their joints over time. Clinical judgement is therefore important in deciding when to continue treatment without a full PsARC response. The clinical experts explained that about 10% to 15% of people with psoriatic arthritis present with moderate to severe psoriasis so this only affects a minority who would have guselkumab. The committee concluded that, when improvement in psoriasis symptoms benefits quality of life but there is only a partial PsARC response, clinicians would value the option to continue treatment based on a PASI 75 response. # Network meta-analyses ## The results of the network meta-analyses are uncertain To evaluate guselkumab's effectiveness compared with comparator treatments the company did network meta-analyses for all main outcomes, for: people who have not had a biological DMARD people who have had a biological DMARD.The analysis for people for whom TNF-alpha inhibitors were contraindicated was handled by removing these treatments from the analyses for people who have not had a biological DMARD before. The committee noted that all included trials were mainly comparisons with placebo, with few head-to-head comparisons of active treatments. Also, most treatments were examined either in a single trial, or a set of closely related trials from the company making the drug. For the population who have not had a biological DMARD before, guselkumab was likely the best treatment for skin symptoms, based on PASI score. But it had more modest results for other outcomes and was generally ranked inferior to TNF-alpha inhibitors, and similar to secukinumab or ixekizumab. For the population who have had a biological DMARD before, guselkumab generally ranked better, because TNF-alpha inhibitors were excluded. But the limited data meant that few comparisons (except with placebo) were conclusive. For the people for whom TNF-alpha inhibitors were contraindicated, guselkumab was the best treatment for PASI outcomes, but not clearly better than secukinumab or ixekizumab. The ERG explained that its main concern with the company's network meta-analyses was that they combined outcomes measured at different times. Comparing outcomes assessed at 24 weeks for guselkumab with outcomes assessed at 16 weeks (or earlier) for other treatments may unfairly bias results in favour of guselkumab. The ERG explained that because of the limited data, most differences in effectiveness across treatments were not conclusive. Also, the network meta-analyses results should be taken as evidence of how guselkumab broadly compares with other treatments, rather than as a robust ranking of treatments. The committee agreed with the ERG that guselkumab appeared to be very similar in effectiveness to other interleukin inhibitors (secukinumab and ixekizumab) for the endpoints included in the indirect comparison. All 3 interleukin inhibitors were ranked higher than TNF-alpha inhibitors for PASI outcomes, but lower on ACR and PsARC outcomes. The committee concluded that the results of the network meta-analyses showed treatment class effects, but the specific treatment rankings were uncertain. # Economic model ## The model does not reflect NHS clinical practice but is appropriate for decision making The committee noted that the company's model was based on that used in NICE's technology appraisal guidance on certolizumab pegol and secukinumab for treating active psoriatic arthritis after inadequate response to DMARDs. Using a Markov structure to capture all costs and outcomes associated with guselkumab and the comparators, the model included up to 3 lines of active treatment before best supportive care. The company stated that this structure was intended to reflect current treatment, where multiple lines of targeted treatment are common. The ERG confirmed that this structure was consistent with previous models used in NICE technology appraisals for psoriatic arthritis. But, using a limited number of active treatment lines does not represent NHS clinical practice. The clinical experts agreed with the ERG that because of the range of treatments and because the disease is varied and unpredictable there is no standard treatment sequence in the NHS. People will almost always start treatment with conventional DMARDs such as methotrexate, and then move onto biological DMARDs if their disease is not adequately controlled. But the exact sequence of treatments is determined by the course of the disease for each person. The committee recalled that people often switch between different biological treatments (see section 3.2). The clinical experts explained that the sequencing of biological treatments is often a mix of clinical and economic considerations. Also, there is no pathway of treatments that would suit everyone. The committee concluded that the model was limited in how well it represents clinical practice. But it agreed that the model was consistent with previous NICE technology appraisals for psoriatic arthritis and was therefore suitable for decision making. ## A 16.5% discontinuation rate should be used for all biological treatments in the economic model The committee recalled the low discontinuation rates in DISCOVER‑1 and DISCOVER‑2, and the ERG and clinical experts' reasons why these may not be seen in NHS clinical practice (see section 3.5). It noted that in psoriatic arthritis appraisals published since NICE's technology appraisal guidance on etanercept, infliximab and adalimumab, a 16.5% treatment discontinuation rate had been used for all biological treatments. The ERG explained that the treatment-specific discontinuation rates used in the company's base case were the largest driver of cost effectiveness. The ERG reiterated that the evidence supporting these different treatment-specific discontinuation rates was not robust. But it noted that even if it were, it was not appropriate to use these rates in the economic model. The ERG explained that the company's economic model allowed up to 3 lines of active treatment before people moved to best supportive care (see section 3.10). It noted that this had implications for using treatment-specific discontinuation rates. The clinical experts agreed with the ERG that people often switched between different TNF-alpha inhibitors, and to different interleukin inhibitors (ustekinumab, secukinumab and ixekizumab) or to tofacitinib. They also agreed that 16.5% was an appropriate discontinuation rate to use in the model to ensure consistency with other psoriatic arthritis technology appraisals. The ERG explained that in the company's model, people remained on treatment with best supportive care for an implausibly long time. Therefore considerable costs accrue and people's health-related quality of life declines, as their condition deteriorates. Treatment-specific discontinuation rates should only be used when the appropriate range of treatment sequences reflecting the full duration of disease are modelled. Because this was not possible in the company's model, using treatment-specific discontinuation rates introduced bias by inaccurately characterising total costs and QALYs for treatments associated with further lines of active treatment. In its response to technical engagement, the company disagreed with the ERG that treatment-specific discontinuation rates in the model could potentially bias the results in favour of longer-acting treatments like guselkumab. The company maintained that the additional time spent on guselkumab relative to other treatments before moving to best supportive care represented a real clinical benefit of guselkumab. The ERG further explained that by restricting the number of lines of treatment, the company's model was overly optimistic in quantifying the benefits of 'displacing' best supportive care. This was because it assumed that this occurred earlier than is expected in clinical practice. It also assumed that the displaced strategy would be best supportive care rather than another more cost-effective active treatment. The committee agreed that because the model could not accurately portray the range of treatment sequences used in clinical practice, using a 16.5% discontinuation rate for all treatments would offset the risk of bias in the economic model. It would also ensure consistency with other psoriatic arthritis technology appraisals. The committee therefore concluded that a 16.5% discontinuation rate should be used for all treatments in the economic model. For the rapid review, the company's revised base case included the committee's preferred treatment discontinuation rate. ## Cost-effectiveness results by psoriasis severity were provided The baseline PASI scores for people in the DISCOVER trials were high compared with those in people having NHS treatment (see section 3.4). The clinical experts explained that only a small proportion of people (10% to 15% of people with psoriatic arthritis; see section 3.8) present with moderate to severe psoriasis symptoms. The committee was aware that in previous psoriatic arthritis appraisals, results were presented by psoriasis subgroup. The ERG considered that this approach was appropriate. It did cost-effectiveness analyses by psoriasis severity using data from the DISCOVER trials. As part of the rapid review, the company replicated the ERG's approach and included results by psoriasis subgroup. ## The results of the comparisons with etanercept and tofacitinib should be included in the fully incremental analysis Etanercept was included as a comparator in the scope because NICE recommends it for psoriatic arthritis, and it is commonly used in UK clinical practice (see section 3.2). After technical engagement, the company asked whether etanercept should be excluded as a comparator in the cost-effectiveness analysis because its market share was small. Also, in NICE's technology appraisal guidance on tofacitinib for treating active psoriatic arthritis, the committee decided that comparisons with best supportive care were more reliable than the fully incremental analysis. The ERG explained that both pairwise and fully incremental analyses were included in that appraisal, but the pairwise comparisons with best supportive care were considered appropriate. This was because the fully incremental analyses were very sensitive to small differences in the estimates of costs and QALYs, given that the total costs and QALYs were similar across all active treatments. The ERG explained that the company also raised several concerns about the clinical data supporting etanercept's effectiveness, but did not provide clear evidence of bias in favour of etanercept. The committee noted that etanercept was a comparator in previous psoriatic arthritis appraisals and agreed that there was no case to support excluding it from the comparison. As part of the rapid review, the company suggested that tofacitinib is a relevant comparator for a narrower population than people who are eligible for guselkumab treatment, because of safety restrictions for JAK inhibitors that emerged during and after the original appraisal. However, the committee considered that tofacitinib is part of established NHS practice and so is a relevant comparator. The committee concluded that the results of the comparisons with etanercept and tofacitinib should be included in the fully incremental analysis. ## Additional benefits of the 4-weekly dose are uncertain, but the complex patient access scheme alleviates concerns The committee recalled that guselkumab's 2 pivotal trials in psoriatic arthritis, DISCOVER‑1 and DISCOVER‑2, randomised people to 100 mg guselkumab every 8 weeks or every 4 weeks or to placebo (see section 3.3). The company's submission considered the clinical effectiveness of both the 4‑weekly and 8‑weekly dose but focused on the 8-weekly dose, which reflected the anticipated marketing authorisation. After technical engagement, the company told NICE that the marketing authorisation would also include a 4‑weekly dose for people at high risk of joint damage. The committee was aware that there was no standard definition of 'high risk of joint damage' and that the clinical effectiveness of the 4‑weekly dose provided by the company was based on its effectiveness in the full trial population, not in a high-risk population. The ERG explained that there was no evidence that effectiveness was different between the 8‑weekly and 4‑weekly doses after 16 weeks. It therefore considered it reasonable to assume that both doses would also have the same effectiveness for people at high risk of joint damage. The committee agreed that it could not reliably evaluate guselkumab's cost effectiveness for people at high risk of joint damage because of the uncertainty in defining the group and in the clinical evidence. However, it concluded that, despite uncertainty associated with the clinical benefit of the 4‑weekly dose, the complex patient access scheme proposed during the rapid review alleviated concerns about the cost effectiveness of the 4‑weekly regimen in the populations in which the 8-weekly regimen was considered cost effective. # Cost-effectiveness estimates ## Guselkumab is cost effective for 2 subgroups The committee considered the cost-effectiveness analyses presented for the rapid review, which incorporated the updated confidential commercial arrangements for guselkumab. Because guselkumab and the comparators have confidential commercial arrangements, the exact incremental cost-effectiveness ratios (ICERs) are confidential and cannot be reported here. The committee considered the fully incremental and pairwise results (compared with best supportive care) for the overall subgroups (see section 3.4) and, if appropriate, further split by psoriasis severity (see section 3.12). Using the committee's preferred assumptions: For people whose disease is not adequately controlled by 2 conventional DMARDs and who have not had a biological DMARD, guselkumab was dominated (that is, was less effective but more costly) when considering the overall subgroup and when split by psoriasis severity. For people whose disease is not adequately controlled by 2 conventional DMARDs or by at least 1 biological DMARD, the fully incremental ICER for guselkumab was lower than £20,000 per QALY gained for the overall subgroup. For people whose disease is not adequately controlled by 2 conventional DMARDs and for whom TNF-alpha inhibitors are contraindicated, the fully incremental ICER was higher than the range normally considered a cost-effective use of NHS resources for the overall subgroup. However, the committee noted very small differences in the point estimates of costs and QALYs between guselkumab and the other treatment options for the overall subgroup. The point estimates are uncertain, and small variations either way could have a large effect on the ICER. The committee also considered the pairwise analysis with best supportive care and the net health benefit analysis in its decision making, and noted that all of the pairwise ICERs were below £30,000 per QALY gained. The committee concluded that guselkumab is cost effective for people who have had 2 conventional DMARDs: and at least 1 biological DMARD, or for whom TNF-alpha inhibitors are contraindicated. # Conclusion ## Guselkumab is recommended for people who have had at least 1 biological DMARD or for whom TNF-alpha inhibitors are contraindicated The committee acknowledged the need for further biological treatment options for people with active psoriatic arthritis. It took into account all commercial discounts for guselkumab and for other treatments in the pathway. For people with psoriatic arthritis who have had 2 conventional DMARDs and at least 1 biological DMARD, it concluded that the most plausible ICERs were within the range that NICE normally considers a cost-effective use of NHS resources. For people with psoriatic arthritis who have had 2 conventional DMARDs and for whom TNF-alpha inhibitors are contraindicated, it concluded that in the fully incremental analysis, the QALYs were similar and the incremental costs were sufficiently small between guselkumab and other biological DMARDs to allow guselkumab to be considered a cost-effective use of NHS resources. Therefore, guselkumab was recommended for people with active psoriatic arthritis who have had 2 conventional DMARDs and have either had at least 1 biological DMARD or for whom TNF-alpha inhibitors are contraindicated but would otherwise be considered, as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis. # Other factors ## Clinicians should take into account factors that may affect the PsARC and PASI and make any clinical adjustments needed The committee considered that the recommendation to stop treatment based on an inadequate PsARC response (in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis) was also appropriate for guselkumab. It noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the PsARC, and concluded that this should be taken into account when using the PsARC. The committee was also aware that the PASI might underestimate disease severity in people with darker skin. The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score and make the clinical adjustments they consider appropriate. The company raised a potential equalities issue, stating that using the PASI may create a barrier to access if clinicians were required to judge comorbid skin symptoms. This is because it obtained clinical expert advice that most rheumatologists do not use the PASI routinely. However, the updated recommendation after the rapid review does not involve using the PASI to determine treatment suitability, and the committee was satisfied that using the PASI should be routine practice and would not create inequality of access.	{'Recommendations': "Guselkumab, alone or with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults whose disease has not responded well enough to disease-modifying antirheumatic drugs (DMARDs) or who cannot tolerate them. It is recommended only if they have had 2\xa0conventional DMARDs and:\n\nhave had at least 1\xa0biological DMARD, or\n\ntumour necrosis factor (TNF)-alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).Guselkumab is recommended only if the company provides it according to the commercial arrangement. Active psoriatic arthritis is defined as peripheral arthritis with 3 or more tender joints and 3 or more swollen joints.\n\nAssess the response to guselkumab from 16\xa0weeks. Stop guselkumab at 24\xa0weeks if the psoriatic arthritis has not responded adequately using the Psoriatic Arthritis Response Criteria (PsARC; an adequate response is an improvement in at least 2 of the 4\xa0criteria, 1 of which must be joint tenderness or swelling score, with no worsening in any of the 4\xa0criteria). If the PsARC response is not adequate but there is a Psoriasis Area and Severity Index (PASI)\xa075 response, a dermatologist should decide whether continuing treatment is appropriate based on skin response.\n\nTake into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the PsARC and make any adjustments needed.\n\nTake into account how skin colour could affect the PASI score and make any adjustments needed.\n\nThese recommendations are not intended to affect treatment with guselkumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPeople with active psoriatic arthritis that is not controlled well enough with 2\xa0conventional DMARDs are usually offered biological DMARDs. Many of these are already recommended by NICE for treating psoriatic arthritis. Guselkumab is a biological DMARD.\n\nClinical evidence shows that guselkumab is effective compared with placebo, but it has not been compared directly with other biological DMARDs for treating psoriatic arthritis. An indirect comparison suggests that guselkumab is as effective as the biological DMARDs secukinumab and ixekizumab, particularly for skin symptoms.\n\nFor people who have had 2\xa0conventional DMARDs and at least 1\xa0biological DMARD, guselkumab's cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources.\n\nFor people who have had 2\xa0conventional DMARDs and for whom TNF-alpha inhibitors are contraindicated, the costs and benefits are similar to those of other treatments recommended by NICE.\n\nSo, guselkumab is recommended for both of these groups.", 'Information about guselkumab': "# Marketing authorisation indication\n\nGuselkumab (Tremfya, Janssen), 'alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis in adult patients who have had an inadequate response or who have been intolerant to a prior disease-modifying antirheumatic drug (DMARD) therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for guselkumab.\n\n# Price\n\nThe cost of a 100\xa0mg pre-filled disposable injection of guselkumab is £2,250.00 (excluding VAT; BNF online, accessed May 2022). The company has a commercial arrangement. This makes guselkumab available to the NHS with a discount. The size of the simple patient access scheme discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount. In the complex patient access scheme, the 4‑weekly regimen is provided at the same cost as an 8‑weekly regimen. If every 4\xa0weeks dosing is needed, the price will be equalised with every 8\xa0weeks dosing by supplying 2\xa0of the 100\xa0mg pre‑filled disposable injections for the price of 1.", 'Committee discussion': "The appraisal committee considered evidence submitted by Janssen, a review of this original submission by the evidence review group (ERG), another submission by Janssen for the rapid review, NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## Psoriatic arthritis substantially affects health-related quality of life\n\nThe patient and clinical experts explained that active psoriatic arthritis (defined as 3 or more tender joints and 3 or more swollen joints) is a lifelong condition that seriously affects people's quality of life. It can develop at a young age, and affects a person's education, career, relationships and family life. The patient experts explained that symptoms such as fatigue, pain and associated comorbidities such as inflammatory bowel disorders, cardiovascular disease and diabetes can have a substantial physical and psychological effect. The clinical and patient experts explained that psoriatic arthritis symptoms range from mild, non-destructive disease to erosive and deforming arthritis that substantially affects daily life. Symptoms can include swollen fingers and toes, inflammation of larger joints such as elbows, knees, and back, and tendonitis. Skin and nail psoriasis also affect quality of life. The committee concluded that active psoriatic arthritis substantially affects health-related quality of life.\n\n# Clinical management\n\n## Clinicians and people with psoriatic arthritis would welcome additional biological treatments that target different inflammation pathways\n\nThe clinical experts explained that treatment for active psoriatic arthritis aims to control joint and connective tissue inflammation. This prevents joint damage progressing and the associated pain and disability. People will usually have treatment with non-steroidal anti-inflammatory drugs, corticosteroids, and conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate. In line with NICE's technology appraisal guidance on etanercept, infliximab and adalimumab, people are eligible for biological or small molecule treatments if their disease is poorly controlled after 2\xa0conventional DMARDs. Biological and small molecule treatments include:\n\ntumour necrosis factor (TNF)-alpha inhibitors such as etanercept and adalimumab\n\ninterleukin (IL) inhibitors such as secukinumab and ixekizumab (IL‑17A inhibitors) and ustekinumab (IL‑12 and IL‑23 inhibitor)\n\ntofacitinib\n\napremilastThe clinical experts explained that psoriatic arthritis is unpredictable and can flare and change over time. Sometimes it responds to the first conventional DMARD, or to a second or third, or it may not respond at all. The clinical experts highlighted that because flares and periods of disease remission are common, the treatment pathway varies. After conventional DMARDs, people often switch among the different TNF-alpha inhibitors, or to different interleukin inhibitors (ustekinumab, secukinumab and ixekizumab) or to tofacitinib. People with psoriatic arthritis would benefit from an additional class of treatment that targets a different inflammatory mediator if:\n\ntheir disease has not responded (or has stopped responding) to DMARDs and other biologicals or small molecules, or\n\nthey need to stop a treatment because of side effects.Guselkumab is the first monoclonal antibody specifically targeting IL‑23 to be considered by NICE for use in psoriatic arthritis. The committee concluded that people with psoriatic arthritis and clinicians would welcome a further treatment option that targets a different inflammation pathway.\n\n# Clinical evidence\n\n## Guselkumab is clinically effective compared with placebo\n\nThe efficacy and safety evidence for guselkumab in psoriatic arthritis comes from 2\xa0pivotal trials, DISCOVER‑1 and DISCOVER‑2. These trials randomised people to have 100\xa0mg guselkumab every 8\xa0weeks or every 4\xa0weeks, or to placebo. The guselkumab trial arms both showed statistically significant and clinically important benefits compared with placebo for disease activity, joint and skin symptoms, functional capacity and health-related quality of life. Guselkumab met the primary endpoint; a higher proportion of people had an American College of Rheumatology (ACR)\xa020 response compared with those on placebo at 24\xa0weeks in both trials. The committee concluded that both doses of guselkumab were clinically effective compared with placebo across a range of clinically important outcomes.\n\n## The populations in the clinical trials are broadly generalisable to NHS clinical practice and are appropriate for decision making\n\nIn its submission, the company assumed that the baseline characteristics of people in the DISCOVER trials reflected those of people seen in NHS clinical practice. The ERG explained that the DISCOVER trials did not include people from the UK. The trials recruited mainly from eastern Europe, where local health systems may have different treatment provision for psoriatic arthritis. The ERG was concerned about the generalisability of the results of the trials because of key differences in the populations compared with populations in the NHS. The company submission identified 4\xa0subgroups and included analyses for 3\xa0subgroups:\n\npeople whose disease is not adequately controlled by 2\xa0conventional DMARDs but who have not had a biological DMARD\n\npeople whose disease is not adequately controlled by 2\xa0conventional DMARDs or by at least 1\xa0biological DMARD\n\npeople whose disease is not adequately controlled by 2\xa0conventional DMARDs and for whom TNF-alpha inhibitors (class of biological DMARD) are contraindicated.The clinical experts confirmed the ERG's view that guselkumab was unlikely to be used as a first-line biological treatment in the NHS. So in clinical practice, a high proportion of people would have had another biological treatment before starting guselkumab. The proportion of people in the trials who had previously had a biological treatment (31% in DISCOVER‑1, 0% in DISCOVER‑2) did not therefore reflect NHS clinical practice. The ERG further explained that in the trials, less than a third of people had already had 2\xa0or more conventional DMARDs. Also, just under 10% of people had not had a conventional DMARD before. Because NICE recommends that biological DMARDs are offered after 2\xa0conventional DMARDs have been tried (see section\xa03.2), this further limits the applicability of the trials to the NHS. Another generalisability concern was the baseline Psoriasis Area and Severity Index (PASI) scores of people in the trials. The clinical experts agreed with the ERG that these were high and that it was rare to see people with psoriatic arthritis with PASI scores above\xa05 in the NHS. Because less than a third of people had 2\xa0conventional DMARDs before starting the DISCOVER trials, it would be reasonable to expect the level of disease at baseline to be higher. The committee recalled that in previous NICE psoriatic arthritis technology appraisals, the clinical experts considered that trial PASI scores were higher than would be seen in clinical practice. The clinical experts confirmed that the populations in the trials and in the NHS were different in terms of prior treatments and disease severity at baseline. But they advised that because psoriatic arthritis is unpredictable and the available treatments do not cure it, both populations represented people with active disease. The committee agreed that:\n\nthere were differences between the trial populations and people with psoriatic arthritis seen in NHS clinical practice\n\nthe trial populations were broadly similar to those in comparator trials in the network meta-analyses, and to those in previous NICE psoriatic arthritis technology appraisals.The committee concluded that although there were differences between the populations in the trials and in the NHS, the evidence from the DISCOVER trials was broadly appropriate for including in decision making.\n\n## The low discontinuation rates in DISCOVER-1 and DISCOVER-2 are not likely to be seen in the NHS\n\nDiscontinuation rates for the 4-weekly dose in the pivotal trials were between 2.3% (DISCOVER‑1) and 3.7% (DISCOVER‑2). In its submission, the company said these low rates were evidence of guselkumab's sustained efficacy, safety and tolerability. The committee recalled the ERG's and clinical experts' opinion about the differences between the trial populations and the people who would have treatment in NHS clinical practice (see section\xa03.4). The baseline characteristics suggested that people in the countries participating in the trials, mostly eastern Europe, had limited access to the range of treatments available in the NHS. The clinical experts explained that the low discontinuation rates in the trials, including in the placebo groups, might reflect this overall lack of access to other treatments. They added that trial discontinuation rates often do not translate into the actual rates seen in clinical practice. In the UK, people whose disease is not controlled would be expected to move quickly to another active treatment. The ERG considered that the company's justification for guselkumab's very low discontinuation rates was not robust. The ERG felt that the company had not shown an underlying biological mechanism for these low rates. The ERG rejected the company's claim that the low discontinuation rates for guselkumab (and ustekinumab) may partly be because of better skin response with these biological treatments. This was because people with psoriatic arthritis mainly have biological DMARDs to control joint disease rather than psoriasis, which tends to be less severe. Also, most studies used to inform the treatment-specific discontinuation rates for guselkumab and the comparators did not report treatment stopping rules in the maintenance period. So it was possible that people in these trials continued treatment beyond the loss of sustained response. This would therefore not reflect the rate seen in clinical practice, where stopping rules would ensure that people did not remain on treatments that were not adequately controlling their disease. The committee agreed with the clinical experts and ERG that the trial populations and the NHS population were not similar. It also agreed about the uncertainties in the evidence base supporting the use of treatment-specific discontinuation rates. The committee concluded that the low discontinuation rates for guselkumab in DISCOVER‑1 and DISCOVER‑2 were not likely to be the same in the NHS.\n\n## Early escape in the guselkumab trials results in bias\n\n'Early escape' to another treatment is common in clinical trials and stops people staying on a treatment if they have uncontrolled disease. The clinical experts explained that it is important for ensuring people remain in trials, which improves the generalisability of the data. The company had opted to treat early escape as non-response (that is, no change from baseline) in the final analysis at 24\xa0weeks. The ERG explained that early escape, as with treatment switching, always results in the potential for bias. Treating early escape as non-response potentially overestimates the benefit of active treatments because most early escape is expected to be in the placebo arm of trials. Early escape was only allowed after 16\xa0weeks in the DISCOVER trials. The ERG explained that the trial investigators did not have to tell people that they had qualified for early escape. Of those who were eligible, most were in the placebo arms, and less than 50% escaped to another treatment, but the reasons for this were unclear. The ERG explained that it did not agree with the company's method of dealing with early escape in the trials, and suggested an assessment time of 16\xa0weeks. This would mean that the data would be free of bias caused by early escape. The company re-did the network meta-analyses using 16‑week data. The ERG also did an exploratory analysis of the effect on first-line treatment cost of a 16‑week stopping rule. The ERG preferred an alternative approach, to include the full observed response of people who escaped early to another treatment. This would also introduce bias by assigning the benefits of an active treatment to placebo. In contrast to the company's preferred approach, this approach would potentially underestimate guselkumab's benefit and would therefore be a more conservative analysis. The company did not consider that either of the ERG's approaches were appropriate. The company claimed that guselkumab's mechanism of action meant that it continued to be effective, particularly in measures of skin response such as PASI scores, between 16 and 24\xa0weeks. To limit analysis to 16\xa0weeks would therefore not represent guselkumab's full benefits. Also, it claimed that assigning guselkumab's benefits to people in the placebo arm by using the full observed response data from people who escaped early would be clinically implausible. The committee agreed with the ERG that the arguments supporting guselkumab's unique mechanism of action were not convincing and more robust evidence would be needed. The committee agreed that early escape would introduce bias for the 24‑week analysis whether it was treated as non-response or the full observed response was used. The committee noted that analysing the DISCOVER trials at 16\xa0weeks only and including the outcome data for early escape at 24\xa0weeks reduced guselkumab's effectiveness relative to placebo, and that the company's preferred approach may have overestimated guselkumab's benefit. The committee concluded that early escape resulted in bias and that it would consider all approaches in its decision making.\n\n## The assessment time of 24\xa0weeks is appropriate, but clinicians would value the option of assessing response at 16\xa0weeks\n\nGuselkumab's summary of product characteristics states that stopping treatment should be considered when disease has not responded after 24\xa0weeks of treatment. The patient experts explained that they welcomed the prospect of a new biological treatment that works on an additional inflammation pathway. But they also explained that people with psoriatic arthritis are frequently frustrated by having ineffective treatments, and that irreversible joint damage can occur very quickly. Many people would therefore find it difficult to accept waiting for 24\xa0weeks to have clinical benefit assessed. The clinical experts commented that a 24‑week assessment time for guselkumab was much longer than the 12‑ to 16‑week assessment times for other biological DMARDs. They noted that continued response beyond 12 to 16\xa0weeks had also been seen for other biological DMARDs and small molecules. The clinical experts would welcome the option to assess response at 16\xa0weeks, to help decide whether to switch treatment or intervene with salvage treatment. The ERG explained that it was not convinced that the evidence for guselkumab's unique mechanism of action would justify waiting until 24\xa0weeks to assess response. It noted that the maximum Psoriatic Arthritis Response Criteria (PsARC), Health Assessment Questionnaire-Disability Index (HAQ-DI) and ACR\xa050 responses were recorded at week\xa020 in the DISCOVER trials. The ERG further explained that the company's economic model could misrepresent the quality-adjusted life year (QALY) gains associated with an improved PASI response from 16 to 24\xa0weeks. Therefore, the model was not suitable for exploring the full effect on outcomes of using a 16‑week stopping rule for guselkumab. Also, the ERG explained that it was uncertain whether an improved PASI response between 16 and 24\xa0weeks on guselkumab was confounded by the bias potentially introduced by allowing early escape in the DISCOVER trials. The committee noted that the assessment time for skin response was 16\xa0weeks, in line with guselkumab's marketing authorisation for moderate to severe psoriasis. The committee agreed with the ERG that the evidence for further improvement in joint disease between 16 and 24\xa0weeks was limited. But it noted that 24\xa0weeks was the assessment time in the summary of product characteristics. The committee concluded, however, that clinicians would value the option of assessing response at 16\xa0weeks.\n\n## Clinicians would value the option to continue treatment based on a PASI\xa075 response\n\nContinuing guselkumab treatment depends on whether a person has a PsARC response. The ERG explored the possibility of continuing treatment when there is an inadequate PsARC response but there is a PASI\xa075 response. The ERG explained that this was particularly relevant for guselkumab, which is likely to produce a comparable PsARC response to other biological DMARDs, but has the highest PASI\xa075 response. The clinical experts explained that if a person with psoriatic arthritis and mild psoriasis did not have an adequate PsARC response, it would not be appropriate to continue guselkumab just because of a 75% reduction in their mild psoriasis. But the decision could be different for people with moderate to severe psoriasis, which can severely affect quality of life. The committee recalled the patient expert statement that for some people with psoriatic arthritis, psoriasis symptoms in skin and nails can be hugely debilitating (see section\xa03.1). The patient experts also explained that the person's needs must be considered. For some people, skin and nail psoriasis symptoms can have a greater effect on quality of life than joint symptoms. The clinical experts explained that if there is only a partial PsARC response, but the person has a PASI\xa075 response for psoriasis that has affected their quality of life, then it may be appropriate to continue treatment while that clinical benefit lasts. Some people in this situation will continue to have slow incremental improvement in their joints over time. Clinical judgement is therefore important in deciding when to continue treatment without a full PsARC response. The clinical experts explained that about 10% to 15% of people with psoriatic arthritis present with moderate to severe psoriasis so this only affects a minority who would have guselkumab. The committee concluded that, when improvement in psoriasis symptoms benefits quality of life but there is only a partial PsARC response, clinicians would value the option to continue treatment based on a PASI\xa075 response.\n\n# Network meta-analyses\n\n## The results of the network meta-analyses are uncertain\n\nTo evaluate guselkumab's effectiveness compared with comparator treatments the company did network meta-analyses for all main outcomes, for:\n\npeople who have not had a biological DMARD\n\npeople who have had a biological DMARD.The analysis for people for whom TNF-alpha inhibitors were contraindicated was handled by removing these treatments from the analyses for people who have not had a biological DMARD before. The committee noted that all included trials were mainly comparisons with placebo, with few head-to-head comparisons of active treatments. Also, most treatments were examined either in a single trial, or a set of closely related trials from the company making the drug. For the population who have not had a biological DMARD before, guselkumab was likely the best treatment for skin symptoms, based on PASI score. But it had more modest results for other outcomes and was generally ranked inferior to TNF-alpha inhibitors, and similar to secukinumab or ixekizumab. For the population who have had a biological DMARD before, guselkumab generally ranked better, because TNF-alpha inhibitors were excluded. But the limited data meant that few comparisons (except with placebo) were conclusive. For the people for whom TNF-alpha inhibitors were contraindicated, guselkumab was the best treatment for PASI outcomes, but not clearly better than secukinumab or ixekizumab. The ERG explained that its main concern with the company's network meta-analyses was that they combined outcomes measured at different times. Comparing outcomes assessed at 24\xa0weeks for guselkumab with outcomes assessed at 16\xa0weeks (or earlier) for other treatments may unfairly bias results in favour of guselkumab. The ERG explained that because of the limited data, most differences in effectiveness across treatments were not conclusive. Also, the network meta-analyses results should be taken as evidence of how guselkumab broadly compares with other treatments, rather than as a robust ranking of treatments. The committee agreed with the ERG that guselkumab appeared to be very similar in effectiveness to other interleukin inhibitors (secukinumab and ixekizumab) for the endpoints included in the indirect comparison. All 3\xa0interleukin inhibitors were ranked higher than TNF-alpha inhibitors for PASI outcomes, but lower on ACR and PsARC outcomes. The committee concluded that the results of the network meta-analyses showed treatment class effects, but the specific treatment rankings were uncertain.\n\n# Economic model\n\n## The model does not reflect NHS clinical practice but is appropriate for decision making\n\nThe committee noted that the company's model was based on that used in NICE's technology appraisal guidance on certolizumab pegol and secukinumab for treating active psoriatic arthritis after inadequate response to DMARDs. Using a Markov structure to capture all costs and outcomes associated with guselkumab and the comparators, the model included up to 3\xa0lines of active treatment before best supportive care. The company stated that this structure was intended to reflect current treatment, where multiple lines of targeted treatment are common. The ERG confirmed that this structure was consistent with previous models used in NICE technology appraisals for psoriatic arthritis. But, using a limited number of active treatment lines does not represent NHS clinical practice. The clinical experts agreed with the ERG that because of the range of treatments and because the disease is varied and unpredictable there is no standard treatment sequence in the NHS. People will almost always start treatment with conventional DMARDs such as methotrexate, and then move onto biological DMARDs if their disease is not adequately controlled. But the exact sequence of treatments is determined by the course of the disease for each person. The committee recalled that people often switch between different biological treatments (see section\xa03.2). The clinical experts explained that the sequencing of biological treatments is often a mix of clinical and economic considerations. Also, there is no pathway of treatments that would suit everyone. The committee concluded that the model was limited in how well it represents clinical practice. But it agreed that the model was consistent with previous NICE technology appraisals for psoriatic arthritis and was therefore suitable for decision making.\n\n## A 16.5% discontinuation rate should be used for all biological treatments in the economic model\n\nThe committee recalled the low discontinuation rates in DISCOVER‑1 and DISCOVER‑2, and the ERG and clinical experts' reasons why these may not be seen in NHS clinical practice (see section\xa03.5). It noted that in psoriatic arthritis appraisals published since NICE's technology appraisal guidance on etanercept, infliximab and adalimumab, a 16.5% treatment discontinuation rate had been used for all biological treatments. The ERG explained that the treatment-specific discontinuation rates used in the company's base case were the largest driver of cost effectiveness. The ERG reiterated that the evidence supporting these different treatment-specific discontinuation rates was not robust. But it noted that even if it were, it was not appropriate to use these rates in the economic model. The ERG explained that the company's economic model allowed up to 3\xa0lines of active treatment before people moved to best supportive care (see section\xa03.10). It noted that this had implications for using treatment-specific discontinuation rates. The clinical experts agreed with the ERG that people often switched between different TNF-alpha inhibitors, and to different interleukin inhibitors (ustekinumab, secukinumab and ixekizumab) or to tofacitinib. They also agreed that 16.5% was an appropriate discontinuation rate to use in the model to ensure consistency with other psoriatic arthritis technology appraisals. The ERG explained that in the company's model, people remained on treatment with best supportive care for an implausibly long time. Therefore considerable costs accrue and people's health-related quality of life declines, as their condition deteriorates. Treatment-specific discontinuation rates should only be used when the appropriate range of treatment sequences reflecting the full duration of disease are modelled. Because this was not possible in the company's model, using treatment-specific discontinuation rates introduced bias by inaccurately characterising total costs and QALYs for treatments associated with further lines of active treatment. In its response to technical engagement, the company disagreed with the ERG that treatment-specific discontinuation rates in the model could potentially bias the results in favour of longer-acting treatments like guselkumab. The company maintained that the additional time spent on guselkumab relative to other treatments before moving to best supportive care represented a real clinical benefit of guselkumab. The ERG further explained that by restricting the number of lines of treatment, the company's model was overly optimistic in quantifying the benefits of 'displacing' best supportive care. This was because it assumed that this occurred earlier than is expected in clinical practice. It also assumed that the displaced strategy would be best supportive care rather than another more cost-effective active treatment. The committee agreed that because the model could not accurately portray the range of treatment sequences used in clinical practice, using a 16.5% discontinuation rate for all treatments would offset the risk of bias in the economic model. It would also ensure consistency with other psoriatic arthritis technology appraisals. The committee therefore concluded that a 16.5% discontinuation rate should be used for all treatments in the economic model. For the rapid review, the company's revised base case included the committee's preferred treatment discontinuation rate.\n\n## Cost-effectiveness results by psoriasis severity were provided\n\nThe baseline PASI scores for people in the DISCOVER trials were high compared with those in people having NHS treatment (see section\xa03.4). The clinical experts explained that only a small proportion of people (10% to 15% of people with psoriatic arthritis; see section\xa03.8) present with moderate to severe psoriasis symptoms. The committee was aware that in previous psoriatic arthritis appraisals, results were presented by psoriasis subgroup. The ERG considered that this approach was appropriate. It did cost-effectiveness analyses by psoriasis severity using data from the DISCOVER trials. As part of the rapid review, the company replicated the ERG's approach and included results by psoriasis subgroup.\n\n## The results of the comparisons with etanercept and tofacitinib should be included in the fully incremental analysis\n\nEtanercept was included as a comparator in the scope because NICE recommends it for psoriatic arthritis, and it is commonly used in UK clinical practice (see section\xa03.2). After technical engagement, the company asked whether etanercept should be excluded as a comparator in the cost-effectiveness analysis because its market share was small. Also, in NICE's technology appraisal guidance on tofacitinib for treating active psoriatic arthritis, the committee decided that comparisons with best supportive care were more reliable than the fully incremental analysis. The ERG explained that both pairwise and fully incremental analyses were included in that appraisal, but the pairwise comparisons with best supportive care were considered appropriate. This was because the fully incremental analyses were very sensitive to small differences in the estimates of costs and QALYs, given that the total costs and QALYs were similar across all active treatments. The ERG explained that the company also raised several concerns about the clinical data supporting etanercept's effectiveness, but did not provide clear evidence of bias in favour of etanercept. The committee noted that etanercept was a comparator in previous psoriatic arthritis appraisals and agreed that there was no case to support excluding it from the comparison. As part of the rapid review, the company suggested that tofacitinib is a relevant comparator for a narrower population than people who are eligible for guselkumab treatment, because of safety restrictions for JAK inhibitors that emerged during and after the original appraisal. However, the committee considered that tofacitinib is part of established NHS practice and so is a relevant comparator. The committee concluded that the results of the comparisons with etanercept and tofacitinib should be included in the fully incremental analysis.\n\n## Additional benefits of the 4-weekly dose are uncertain, but the complex patient access scheme alleviates concerns\n\nThe committee recalled that guselkumab's 2\xa0pivotal trials in psoriatic arthritis, DISCOVER‑1 and DISCOVER‑2, randomised people to 100\xa0mg guselkumab every 8\xa0weeks or every 4\xa0weeks or to placebo (see section\xa03.3). The company's submission considered the clinical effectiveness of both the 4‑weekly and 8‑weekly dose but focused on the 8-weekly dose, which reflected the anticipated marketing authorisation. After technical engagement, the company told NICE that the marketing authorisation would also include a 4‑weekly dose for people at high risk of joint damage. The committee was aware that there was no standard definition of 'high risk of joint damage' and that the clinical effectiveness of the 4‑weekly dose provided by the company was based on its effectiveness in the full trial population, not in a high-risk population. The ERG explained that there was no evidence that effectiveness was different between the 8‑weekly and 4‑weekly doses after 16\xa0weeks. It therefore considered it reasonable to assume that both doses would also have the same effectiveness for people at high risk of joint damage. The committee agreed that it could not reliably evaluate guselkumab's cost effectiveness for people at high risk of joint damage because of the uncertainty in defining the group and in the clinical evidence. However, it concluded that, despite uncertainty associated with the clinical benefit of the 4‑weekly dose, the complex patient access scheme proposed during the rapid review alleviated concerns about the cost effectiveness of the 4‑weekly regimen in the populations in which the 8-weekly regimen was considered cost effective.\n\n# Cost-effectiveness estimates\n\n## Guselkumab is cost effective for 2\xa0subgroups\n\nThe committee considered the cost-effectiveness analyses presented for the rapid review, which incorporated the updated confidential commercial arrangements for guselkumab. Because guselkumab and the comparators have confidential commercial arrangements, the exact incremental cost-effectiveness ratios (ICERs) are confidential and cannot be reported here. The committee considered the fully incremental and pairwise results (compared with best supportive care) for the overall subgroups (see section\xa03.4) and, if appropriate, further split by psoriasis severity (see section\xa03.12). Using the committee's preferred assumptions:\n\nFor people whose disease is not adequately controlled by 2\xa0conventional DMARDs and who have not had a biological DMARD, guselkumab was dominated (that is, was less effective but more costly) when considering the overall subgroup and when split by psoriasis severity.\n\nFor people whose disease is not adequately controlled by 2\xa0conventional DMARDs or by at least 1\xa0biological DMARD, the fully incremental ICER for guselkumab was lower than £20,000 per QALY gained for the overall subgroup.\n\nFor people whose disease is not adequately controlled by 2\xa0conventional DMARDs and for whom TNF-alpha inhibitors are contraindicated, the fully incremental ICER was higher than the range normally considered a cost-effective use of NHS resources for the overall subgroup. However, the committee noted very small differences in the point estimates of costs and QALYs between guselkumab and the other treatment options for the overall subgroup. The point estimates are uncertain, and small variations either way could have a large effect on the ICER. The committee also considered the pairwise analysis with best supportive care and the net health benefit analysis in its decision making, and noted that all of the pairwise ICERs were below £30,000 per QALY gained. The committee concluded that guselkumab is cost effective for people who have had 2\xa0conventional DMARDs:\n\nand at least 1\xa0biological DMARD, or\n\nfor whom TNF-alpha inhibitors are contraindicated.\n\n# Conclusion\n\n## Guselkumab is recommended for people who have had at least 1\xa0biological DMARD or for whom TNF-alpha inhibitors are contraindicated\n\nThe committee acknowledged the need for further biological treatment options for people with active psoriatic arthritis. It took into account all commercial discounts for guselkumab and for other treatments in the pathway. For people with psoriatic arthritis who have had 2\xa0conventional DMARDs and at least 1\xa0biological DMARD, it concluded that the most plausible ICERs were within the range that NICE normally considers a cost-effective use of NHS resources. For people with psoriatic arthritis who have had 2\xa0conventional DMARDs and for whom TNF-alpha inhibitors are contraindicated, it concluded that in the fully incremental analysis, the QALYs were similar and the incremental costs were sufficiently small between guselkumab and other biological DMARDs to allow guselkumab to be considered a cost-effective use of NHS resources. Therefore, guselkumab was recommended for people with active psoriatic arthritis who have had 2\xa0conventional DMARDs and have either had at least 1\xa0biological DMARD or for whom TNF-alpha inhibitors are contraindicated but would otherwise be considered, as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis.\n\n# Other factors\n\n## Clinicians should take into account factors that may affect the PsARC and PASI and make any clinical adjustments needed\n\nThe committee considered that the recommendation to stop treatment based on an inadequate PsARC response (in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis) was also appropriate for guselkumab. It noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the PsARC, and concluded that this should be taken into account when using the PsARC. The committee was also aware that the PASI might underestimate disease severity in people with darker skin. The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score and make the clinical adjustments they consider appropriate. The company raised a potential equalities issue, stating that using the PASI may create a barrier to access if clinicians were required to judge comorbid skin symptoms. This is because it obtained clinical expert advice that most rheumatologists do not use the PASI routinely. However, the updated recommendation after the rapid review does not involve using the PASI to determine treatment suitability, and the committee was satisfied that using the PASI should be routine practice and would not create inequality of access."}	https://www.nice.org.uk/guidance/ta815	Evidence-based recommendations on guselkumab (Tremfya) for active psoriatic arthritis after inadequate response to DMARDs in adults.
45160b6e0dc0d3b9fbcd0cd796b742a55be1f6e5	nice	Alpelisib with fulvestrant for treating hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer	Alpelisib with fulvestrant for treating hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer Evidence-based recommendations on alpelisib (Piqray) with fulvestrant for treating hormone receptor-positive, HER2-negative, PIK3CA-mutated, locally advanced or metastatic breast cancer in adults. # Recommendations Alpelisib plus fulvestrant is recommended as an option for treating hormone receptor-positive, HER2-negative, PIK3CA-mutated, locally advanced or metastatic breast cancer in adults, only if: their cancer has progressed after a CDK4/6 inhibitor plus an aromatase inhibitor and the company provides alpelisib according to the commercial arrangement). This recommendation is not intended to affect treatment with alpelisib plus fulvestrant that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Current treatment for hormone receptor-positive, HER2-negative, PIK3CA-mutated, locally advanced or metastatic breast cancer after endocrine-based therapy with a CDK4/6 inhibitor plus an aromatase inhibitor includes everolimus with exemestane. Alpelisib with fulvestrant is a new treatment for this condition. The company has positioned alpelisib with fulvestrant after a CDK4/6 inhibitor plus an aromatase inhibitor, which is narrower than its marketing authorisation (licence). Clinical evidence from indirect comparisons suggests that alpelisib plus fulvestrant is more effective than everolimus plus exemestane, but the analyses are uncertain. The clinical trial evidence presented only included a small number of people who would be eligible for alpelisib with fulvestrant in clinical practice. Alpelisib plus fulvestrant meets NICE's criteria to be a life-extending treatment at the end of life. The most likely cost-effectiveness estimates are uncertain but within the range that NICE considers an acceptable use of NHS resources. So, alpelisib plus fulvestrant is recommended.# Information about alpelisib # Marketing authorisation indication Alpelisib (Piqray, Novartis Pharmaceuticals UK) has a marketing authorisation for use 'in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression following endocrine-based therapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for alpelisib. # Price The company's list price is £4,082.14 per 56‑pack of 150 mg film-coated tablets (excluding VAT; BNF online, accessed May 2022). The average cost of a course of combination treatment at list price is £6,170.70 for the loading dose and £5,126.42 for the following cycles. The company has a commercial arrangement. This makes alpelisib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), responses from stakeholders and comments on the appraisal consultation document. See the committee papers for full details of the evidence. # Clinical need and treatment pathway ## There is a population who could benefit from alpelisib plus fulvestrant Advanced breast cancer is incurable and the aim of treatment is to delay progression and extend survival. Patient experts explained that being diagnosed with advanced breast cancer is extremely difficult for people and their family and friends. It can cause considerable anxiety and fear. These feelings can negatively affect mental health. Women who have been through the menopause, and men, who do not need urgent chemotherapy treatment are offered 1 of 3 CDK4/6 inhibitor treatments (abemaciclib, ribociclib or palbociclib), each with an aromatase inhibitor, as initial treatment. This is in line with NICE's guideline on advanced breast cancer. See NICE's technology appraisal guidance on abemaciclib, ribociclib or palbociclib. Clinical experts noted that women with hormone receptor-positive, HER2-negative advanced breast cancer who have not been through menopause, or who are going through perimenopause, will be offered ovarian suppression. This is to mimic a natural menopause, so they are also eligible for a CDK4/6 inhibitor plus an aromatase inhibitor. After initial treatment with a CDK4/6 inhibitor plus an aromatase inhibitor, current treatment options are limited. People without symptomatic visceral disease can have exemestane plus everolimus (see NICE's technology appraisal guidance on everolimus with exemestane for treating advanced breast cancer after endocrine therapy), but clinical experts noted that adverse events associated with everolimus limit its use. Because of this, capecitabine chemotherapy is sometimes used instead. However, clinical experts noted that people and clinicians are looking for options to delay the need for cytotoxic chemotherapy. They noted that people who have had previous treatment with a CDK4/6 inhibitor plus fulvestrant would not be eligible for alpelisib. The committee concluded that an additional treatment option for this population would be welcome. ## Targeted treatment options are valued by people with advanced breast cancer and clinicians The PIK3CA gene is involved in protein production. It is an important part of the phosphatidylinositol-3-kinase (PI3K) enzyme pathway that drives cancer cell growth. Mutations of PIK3CA are found in around 30% to 40% of oestrogen receptor-positive, HER2-negative breast cancers. The company noted that PIK3CA-mutated breast cancer may be more resistant to endocrine therapy. Clinical experts explained that they are keen to offer targeted treatments for people with advanced breast cancer, but these options have been limited except for drugs acting on hormone receptors. They noted that alpelisib, which is used with fulvestrant, is the first targeted treatment option for advanced breast cancer that has a PIK3CA mutation. Clinical experts stated that the toxicity profile of alpelisib plus fulvestrant is notably worse than that seen with a CDK4/6 inhibitor. However, for people who can tolerate it, alpelisib plus fulvestrant is another step in delaying cytotoxic chemotherapy, which has worse adverse events. They explained that this allows people to stay well for longer, for themselves and as carers for others. Patient experts noted that for people with PIK3CA-mutated advanced breast cancer, knowing a drug was targeted to their mutation was very important and had a positive emotional impact. The Cancer Drugs Fund clinical lead stated that genomic testing for PIK3CA mutation is now included in the National Genomic Test Directory and so should be funded in the NHS, as long as there are no implementation issues. Patient experts noted in their consultation response for this appraisal that telling people they have this mutation but not allowing access to the drug does not make sense. They described a patient's experience where PIK3CA mutation may have directly contributed to their endocrine resistance, resulting in recurrence and a prognosis of incurable breast cancer. The clinical experts noted that PIK3CA testing can be done at any point in the treatment pathway for breast cancer, so if it is not done or available at diagnosis it could be done later when exploring treatment options. The committee noted that, while PIK3CA mutation testing had not been routinely available, this situation is changing and PIK3CA mutation status will soon be routinely identified in clinical practice. It concluded that targeted treatment options for identifiable mutations are valued by people with advanced breast cancer and clinicians. ## The relevant place in the treatment pathway is second line after disease progression on a CDK4/6 inhibitor plus an aromatase inhibitor The company positioned alpelisib plus fulvestrant 'after disease progression following a CDK4/6 inhibitor' in its base case. This is narrower than the marketing authorisation for alpelisib plus fulvestrant, which is 'after disease progression following endocrine-based therapy'. Clinical experts stated that a CDK4/6 inhibitor plus an aromatase inhibitor, with or without chemotherapy, is standard practice for the first-line treatment of hormone receptor-positive, HER2-negative advanced breast cancer, with or without a PIK3CA mutation (see section 3.1). They noted that this would be offered to most people except those who are unable to tolerate treatment with a CDK4/6 inhibitor. It is more appropriate for these people to have endocrine monotherapy, with or without chemotherapy. Therefore, the clinical experts considered that the company's positioning of alpelisib plus fulvestrant was in line with expected clinical use. The committee concluded that the company's positioning of alpelisib with fulvestrant as second line after disease progression on a CDK4/6 inhibitor plus an aromatase inhibitor was appropriate. ## The relevant comparator is everolimus plus exemestane The company used everolimus plus exemestane (see section 3.1) as its base-case comparator. Clinical experts noted that because of tolerability issues with everolimus plus exemestane, some people have oral, single-agent chemotherapy with capecitabine instead. This has a lower toxicity burden than other chemotherapies. The committee noted that some people with advanced breast cancer may have oral capecitabine or more cytotoxic chemotherapy, instead of everolimus plus exemestane, as second-line treatment after a CDK4/6 inhibitor and an aromatase inhibitor. The Cancer Drugs Fund clinical lead noted that most people who are potentially likely to have alpelisib plus fulvestrant currently have everolimus plus exemestane in NHS practice. The committee concluded that everolimus plus exemestane is the most relevant comparator for this appraisal. # Clinical evidence ## Alpelisib with fulvestrant was investigated in 2 studies, BYLieve and SOLAR-1, but only BYLieve is generalisable to UK clinical practice Alpelisib with fulvestrant was studied in 1 phase 2 non-randomised, open label, non-comparative study (BYLieve) and 1 phase 3 randomised controlled trial (SOLAR‑1). The evidence from these studies submitted by the company is in people with hormone receptor-positive, HER2-negative, advanced breast cancer that has a confirmed PIK3CA mutation. The clinical experts noted that almost everyone had stage 4 breast cancer on entry to the studies. BYLieve included 121 people with breast cancer progression on or after a CDK4/6 inhibitor with an aromatase inhibitor. People had treatment with alpelisib plus fulvestrant as first-, second-, third- or later-line treatment for advanced disease. Clinical experts noted that BYLieve is relevant to UK clinical practice because it studied alpelisib plus fulvestrant in advanced breast cancer that had progressed on or after a CDK4/6 inhibitor with an aromatase inhibitor, which is standard care. The committee concluded that the population of BYLieve was generalisable to the NHS. ## Clinical evidence for alpelisib plus fulvestrant after a CDK4/6 inhibitor plus an aromatase inhibitor is uncertain because it is based on 1 single-arm study The primary outcome of BYLieve is progression-free survival. Secondary outcomes include overall survival, objective response rate, clinical benefit rate and duration of response. BYLieve included 121 people who had treatment with alpelisib plus fulvestrant after a CDK4/6 inhibitor plus an aromatase inhibitor. Some of these people had alpelisib plus fulvestrant second line (see section 3.5). The median duration of follow up was 11.7 months. BYLieve met its primary end point, with 50.4% of people alive without disease progression at 6 months (95% confidence interval 41.2 to 59.6; lower bound of the 95% CI exceeding 30%, which was the protocol-defined clinically meaningful threshold) for all lines of treatment (n=121). In people who had alpelisib plus fulvestrant second line, the results suggest it could be clinically effective. The company considers that the data is confidential so it cannot be reported here. However, the relative effectiveness is uncertain because of the lack of comparative data to assess alpelisib plus fulvestrant effectiveness with other treatment options. The committee concluded that evidence from BYLieve suggests that alpelisib plus fulvestrant may be clinically effective, but this evidence was highly uncertain because of the lack of comparative data. ## SOLAR-1 was limited because it only included a small number of people relevant to this appraisal SOLAR‑1 included 341 people with PIK3CA-mutated breast cancer that recurred or progressed on or after treatment with an aromatase inhibitor. It compared alpelisib plus fulvestrant with placebo plus fulvestrant. But clinical experts noted that fulvestrant monotherapy is not used in NHS practice and does not reflect standard care for second-line treatment of hormone receptor-positive, HER2-negative, advanced breast cancer (see section 3.1). Most people had treatment with alpelisib plus fulvestrant as first- or second-line treatment for advanced disease. People who had alpelisib plus fulvestrant or placebo plus fulvestrant as second-line treatment after an aromatase inhibitor from now are called the second-line proxy population. Clinical experts noted that for most people in SOLAR‑1, overall and in the second-line proxy population, the data was not relevant to UK clinical practice. This is because very few people had an aromatase inhibitor with a CDK4/6 inhibitor before treatment with alpelisib plus fulvestrant or placebo plus fulvestrant. The committee noted that only 20 people had a CDK4/6 inhibitor with an aromatase inhibitor, and so only these 20 people are relevant to this appraisal. In SOLAR‑1, median duration of follow up was 42.4 months for the final data-cut point. The results suggested that alpelisib plus fulvestrant may be more effective than placebo plus fulvestrant when given as second-line treatment. Data is considered confidential by the company and cannot be reported here. The committee concluded that this study was limited because it only included 20 people relevant to this appraisal. # Adverse effects ## Alpelisib plus fulvestrant is associated with grade 3 or higher adverse events that need additional monitoring Not everyone will be able to tolerate treatment with alpelisib plus fulvestrant (see section 3.2). In BYLieve and SOLAR‑1, more than 60% of people who had alpelisib plus fulvestrant had a treatment-emergent adverse event of grade 3 or higher. Clinical experts noted that a grade 3 or 4 rash is a rash that covers more than half the body, seen in 9% to 10% of people who had alpelisib plus fulvestrant. They also noted that grade 3 or 4 diarrhoea, seen in 6% to 7% of people who had alpelisib plus fulvestrant, is difficult for people to tolerate. Clinical experts explained that grade 3 or higher hyperglycaemia means that older people or those with a high body mass index or obesity might need weekly testing and follow up during initial treatment. This was seen in around 30% of people who had alpelisib plus fulvestrant. The experts noted that these adverse events and the need for additional monitoring is a burden to both patients and clinicians. The patient expert noted that they were aware that someone who had treatment with alpelisib plus fulvestrant had reported struggling with diarrhoea and having blood sugars monitored weekly. However, this person felt that the benefits of treatment outweighed any discomfort they were experiencing. The ERG noted that 14% of people in BYLieve stopped treatment because of adverse events (based on the full analysis set, n=127). Also, 23% of the alpelisib plus fulvestrant group and 4% of the placebo plus fulvestrant group stopped treatment in SOLAR‑1 because of treatment-related adverse events (based on safety set, n=571). Clinical experts stated that alpelisib with fulvestrant could be difficult for some people to tolerate. However, over time clinicians are developing ways to mitigate toxic effects and are limiting who has treatment or stopping treatment if adverse events are not manageable. The committee concluded that alpelisib plus fulvestrant is associated with grade 3 or higher adverse events that may need additional monitoring. # Indirect treatment comparison ## The company did an indirect treatment comparison using the Bucher method There were no trials directly comparing alpelisib plus fulvestrant with everolimus plus exemestane. So, the company presented an indirect treatment comparison using the Bucher method (used in the company base case) for outcomes including overall survival and progression-free survival. The Bucher analysis included publicly available data from 4 trials. It took known hazard ratios for alpelisib plus fulvestrant compared with placebo plus fulvestrant from SOLAR‑1. It then linked these to the BOLERO‑2 study of everolimus plus exemestane compared with exemestane monotherapy via 2 other trials, CONFIRM and SoFEA. The ERG explained that this approach is a 'reverse' Bucher method when known hazard ratios for the treatment being studied are used to calculate hazard ratios for the comparator group. It is more usual to know the comparator hazard ratios and use these to calculate hazard ratios for the treatment being studied. The company stated that the Bucher analysis showed that alpelisib plus fulvestrant was associated with better efficacy in terms of both progression-free survival and overall survival compared with everolimus plus exemestane. The results of the analysis are confidential and cannot be reported here. The ERG and committee noted that the confidence intervals of the hazard ratios presented for these comparisons were very wide, which makes them unreliable. The committee questioned the internal validity of the Bucher results because when comparing placebo plus fulvestrant with everolimus plus exemestane, 1 treatment group was favoured for progression-free survival and the other group was favoured for overall survival. Clinical experts noted that there is a lack of robust data for treatments used after first line. Some of the comparisons that would help validate the analysis have not been done in trials. ## The results of the Bucher analysis are highly uncertain for several reasons The ERG noted that, of the 4 trials of hormone receptor-positive advanced breast cancer included in the Bucher indirect treatment comparison, only SOLAR‑1 prospectively enrolled people with PIK3CA-mutated breast cancer. It noted that the company restricted the dataset of BOLERO‑2 used in the analysis to the second-line population with a PIK3CA mutation based on tumour tissue samples. This led to 92% of people being excluded from the analysis. The committee noted that if PIK3CA mutation based on plasma sampling was included it may be possible to increase the number of people included in the analysis. In its consultation response, the company noted that it restricted the dataset of BOLERO‑2 for consistency with the sampling method used in BYLieve and SOLAR‑1. It stated that this was to avoid introducing potential bias. It noted that plasma testing was also done in SOLAR‑1, but this data was not used because it would have broken the randomisation of the study. The clinical expert noted that they would prefer that the population of BOLERO‑2 was not restricted. They advised that using plasma to test for PIK3CA mutation is helpful because it means it is more likely that the test is being done for a metastatic tumour sample. The ERG understood the company's rationale for restricting the population of BOLERO‑2. But it noted that this increases uncertainty in the Bucher analysis and contributes to the wide confidence intervals seen for the hazard ratios. The ERG noted that the patient populations of the trials included in the Bucher analysis also had other differences including line of treatment and HER2 status. Almost no one had previously had a CDK4/6 inhibitor with an aromatase inhibitor. The ERG's clinical expert commented that HER2 status may be an important effect modifier for alpelisib plus fulvestrant compared with everolimus plus exemestane. At the request of the ERG, the company did the same Bucher analysis but used a subpopulation of SoFEA that included people with known HER2-negative status. The committee noted that in this subset analysis a treatment effect in favour of alpelisib plus fulvestrant was seen, but this was reduced compared with the overall analysis and was uncertain (see section 3.9). The company explained that it preferred not to restrict the population from SoFEA in this way so as not to reduce the patient numbers. It also noted that there is insufficient data to know whether HER2 status is an effect modifier for alpelisib plus fulvestrant compared with everolimus plus exemestane. In its consultation response, the company noted that technology appraisals of a CDK4/6 inhibitor plus an aromatase inhibitor did not restrict analyses to a HER2‑negative population. The ERG noted that committee papers of these previous appraisals state that not restricting the dataset of SoFEA to people with HER2‑negative breast cancer is a source of heterogeneity and may impact outcomes. The clinical expert noted that people with HER2‑positive breast cancer should not be included when possible, because they have a completely different treatment regimen. The ERG noted that the HER2‑negative subgroup of SoFEA was a reasonably sized group (n=283), 60% of the total study population. It noted that the influence on the Bucher analysis of not restricting the population of SoFEA is unclear, which leads to uncertainty. The committee concluded that the results of the Bucher analysis are highly uncertain for several reasons: Hazard ratios for the indirect comparison of alpelisib plus fulvestrant with everolimus plus exemestane had very wide confidence intervals (see section 3.9). Hazard ratios for the indirect comparison of placebo plus fulvestrant with everolimus plus exemestane may lack face validity (see section 3.9). There is heterogeneity between the 4 trials and some have a lack of generalisability. Patient populations differed, including in terms of PIK3CA-mutation status and HER2 status, and there was a lack of previous treatment with a CDK4/6 inhibitor plus an aromatase inhibitor. There is a potential for HER2 status to be an effect modifier. ## Alpelisib plus fulvestrant may be more effective than everolimus plus exemestane, but the results of the indirect analyses are highly uncertain As noted in section 3.11, the indirect treatment comparison was highly uncertain. The company stated that favourable results for alpelisib plus fulvestrant were supported by real-world evidence. It noted that data from the Flatiron database supports progression-free survival with alpelisib plus fulvestrant in BYLieve being better than that with standard care after a CDK4/6 inhibitor. To support this, the company presented a matching/weighting analysis of BYLieve compared with standard care. The ERG noted that the Flatiron database is a real-world dataset from the US where standard care may differ from that in England. The committee concluded that alpelisib plus fulvestrant may be more effective than everolimus plus exemestane, but the results of the indirect analyses are highly uncertain. # The company's economic model ## The company's economic model is suitable for decision making The company submitted a partitioned survival model to estimate the cost effectiveness of alpelisib plus fulvestrant compared with everolimus plus exemestane. It had 3 health states: progression-free, progressed, and dead. The model had a lifetime time horizon (40 years). The committee considered that the partitioned survival model is a standard approach to estimate the cost effectiveness of cancer drugs and is suitable for decision making. ## The modelling of overall survival and progression-free survival is plausible but highly uncertain The company's model linked progression-free survival distributions to overall survival by using an indirect treatment comparison. The company selected a log-logistic function to extrapolate overall survival and a log-normal function to extrapolate progression-free survival for alpelisib plus fulvestrant from the second-line population in BYLieve. For everolimus plus exemestane, the hazard ratio for overall survival and progression-free survival from the Bucher analysis was applied to the alpelisib plus fulvestrant model. The company and ERG noted that their clinical experts thought that the projections for overall survival and progression-free survival in the model were plausible. The experts noted that a long tail to the modelled overall survival might be expected in breast cancer. The ERG noted that the projections were based on the company's deterministic model (see section 3.18), including data on PIK3CA mutation from tumour samples in BOLERO‑2 (see section 3.10) and the overall population of SoFEA (see section 3.10). It was generally satisfied with the survival functions used, but noted that the Gompertz and Weibull provided slightly better model fit than log-logistic for overall survival. The ERG also explained that the log-logistic model appears to overestimate overall survival for the alpelisib plus fulvestrant group after around 1.5 years, although very few events happen after this. The ERG explored the impact of alternative extrapolations for overall survival and progression-free survival, which showed that the incremental cost-effectiveness ratio (ICER) was very sensitive to these alternative extrapolations. The committee noted that there were several issues with the data underpinning the survival extrapolations. For the alpelisib plus fulvestrant arm, the clinical data underpinning this was either non-comparative (see section 3.6) or for very few people (see section 3.7). For the everolimus plus exemestane arm, data was taken from the Bucher indirect analysis, which was highly uncertain (see section 3.10). The committee concluded that the overall survival and progression-free survival estimates were plausible but highly uncertain. ## Modelled relative treatment effects are highly uncertain Relative treatment effects of alpelisib plus fulvestrant and everolimus plus exemestane were derived from a Bucher indirect treatment comparison (see section 3.9). The ERG's clinical experts considered that the relative treatment effects of alpelisib plus fulvestrant compared with everolimus plus exemestane were plausible. The committee and the ERG recalled that alpelisib plus fulvestrant may be more effective than everolimus plus exemestane. However, given the uncertainty in the underpinning data, quantifying the treatment effect and quality-adjusted life year (QALY) estimates would be highly uncertain (see section 3.9 to 3.11). The ERG noted that the Bucher model was similar to a fixed effects model in that it assumes no between-study variation, which might not be reasonable. It noted that in a fixed effect model, confidence intervals can underestimate the true uncertainty. However, if the assumption for no between-study variation was relaxed, confidence intervals would be even wider. The ERG also explained that because the network of the Bucher analysis involves a single chain of evidence (with no closed loops), and each comparison is informed by only 1 trial, it is not possible to assess the consistency of the evidence. The committee concluded that the relative treatment effect of alpelisib plus fulvestrant compared with everolimus plus exemestane was highly uncertain. ## The model assumes a 5-year duration of treatment effect which is uncertain The model has a lifetime time horizon (see section 3.12). In its original base case, the company assumed that the treatment effects of alpelisib plus fulvestrant compared with everolimus plus exemestane were indefinite with no loss of treatment effect over time. The clinical experts stated that it was not reasonable to say there is indefinite treatment effect. The ERG and its own clinical experts considered an indefinite duration of treatment effect to be optimistic. The ERG did additional sensitivity analyses to explore the possibility that the treatment effect of alpelisib plus fulvestrant for progression-free survival and overall survival wanes and switches to that of everolimus plus exemestane at 3 or 5 years. During consultation, the company presented an updated base case in which the treatment effect of alpelisib plus fulvestrant switches to that of everolimus plus exemestane at 5 years. It noted that to assume a 3‑year duration of treatment effect is pessimistic, because in the SOLAR‑1 study that was used in the Bucher analysis people had follow up for longer than this. The committee noted that the assumed duration of treatment effect of 5 years is not based on evidence. The clinical expert stated that assuming a 5‑year treatment effect is reasonable. The committee concluded that the assumption of a 5‑year duration of treatment effect is uncertain. ## The appropriate utility value after disease progression is uncertain and may be overestimated by the company Across the different health states in the model, the company assumed equal utilities for alpelisib plus fulvestrant and everolimus plus exemestane, which the committee concluded was reasonable. The company used SOLAR‑1 to derive utility values in the pre-progression health state and for terminal disease. However, SOLAR‑1 had limited health-related quality-of-life data after disease progression. Therefore, in its base case, the company used a utility value of 0.69 for the modelled health state after disease progression from a publication by Mitra et al. (2016). The ERG noted that the Mitra study is only published as an abstract with very limited methodological details and the EQ‑5D tariffs used to generate the utility estimates are unclear. It explained that the value used from Mitra is likely to overestimate utility after disease progression. This is because it is based on people with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer who are having treatment at third line or later. In its original critique, the ERG preferred to use a 0.51 post-progression utility value from Lloyd et al. (2006) that has been used in previous technology appraisals when suitable data had not been collected in trials. The company noted that Lloyd is outdated and does not reflect the treatment landscape and people having treatment today. It noted that Mitra was used and preferred to Lloyd in the recent NICE technology appraisal guidance on abemaciclib with fulvestrant for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy. It also stated that at technical engagement it did interviews with healthcare professionals. In these interviews Mitra et al. was considered to reflect the utility value of people having third-line treatment in the NHS. The ERG noted that the utility value needs to reflect the entre post-progression health state. The ERG's clinical experts suggested that a utility value around midway between Lloyd and Mitra might be more appropriate for people with a progressed disease state. The ERG did exploratory analyses to consider a value around the midpoint, which led to an increase in the company's base-case ICER. It noted that this value may have greater face validity than available empirical estimates. The ERG's clinical experts noted that in SOLAR‑1, which had a post-progression utility value close to that of Mitra, the value was consistent with people who have radiological progression on 1 to 3 lines of treatment without a significant change in health-related quality of life. The Cancer Drugs Fund clinical lead noted that the post-progression utility value is assumed constant for the duration of the post-progression health state and does not take account of whether people have additional treatments. As such, the Mitra value is optimistic and may overestimate utility for most of the post-progression state. The committee noted that there is no satisfactory utility value for after disease progression. The committee concluded that the appropriate utility value for the modelled health state after disease progression is uncertain and may be overestimated by the company. ## Treatment costs after disease progression are reasonable but uncertain The company assumed a fixed cost of £1,500 per month for 'all future treatment-related costs' for people after disease progression, excluding end of life care. It noted that this is based on NICE's technology appraisal guidance on ribociclib with fulvestrant for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy. The ERG noted that it is unclear whether the company assumption is reasonable. It noted that lower estimated post-progression treatment costs (£1,140 to £1,200) were preferred by the committee in NICE's technology appraisal guidance on ribociclib with an aromatase inhibitor for previously untreated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer. The ERG suggested that it may be more appropriate to apply subsequent-line treatment costs based on observed post-progression treatments in the alpelisib plus fulvestrant clinical studies. Clinical experts noted that it is reasonable to base treatment costs after disease progression on those assumed for ribociclib plus fulvestrant. The ERG had explored alternative costs assumptions (increasing and decreasing costs by £750), which led to minor changes to the ICER. The committee concluded that treatment costs after disease progression are uncertain, but are not unreasonable and not a major driver of cost-effectiveness results. ## The probabilistic version of the model is not working as expected and is not suitable for decision making During the first committee meeting, the ERG noted that the probabilistic estimate of the ICER was substantially higher (by around £10,000 per QALY gained) than its deterministic estimate, which was highly unusual. The ERG and company noted that in the probabilistic analysis, the sampled treatment effect sometimes suggests a considerable and clinically implausible lower effectiveness of alpelisib plus fulvestrant compared with everolimus plus exemestane. The ERG noted that the main driver of the discrepancy between the deterministic and probabilistic modelled cost effectiveness was the wide confidence interval associated with the hazard ratio for overall survival. A wide confidence interval means that the hazard ratio for overall survival is unreliable. Because the Bucher model is similar to a fixed effects model, confidence intervals can underestimate the true uncertainty (see section 3.14). In its consultation response, the company updated its probabilistic base case using a constrained probabilistic analysis following input from clinical experts. It sought opinion from 4 experts to identify the extent of increase in life years for everolimus plus exemestane compared with alpelisib plus fulvestrant that would be deemed to be clinically implausible. As a result, the probabilistic analysis was amended to remove iterations where everolimus plus exemestane was associated with an increase in life years greater than 10%. The company noted that this approach shows the impact of the implausible samples on the probabilistic ICER, which was now aligned with that of the deterministic analysis. The ERG disagreed with the company's approach. It noted that removing samples that do not match expectations gives an arbitrary mean ICER. The committee noted that it is not satisfied with the company's probabilistic analysis where the outputs have been constrained. It noted that it would be more appropriate to constrain the inputs to the probabilistic analysis, such as the confidence intervals of the hazard ratio, based on expert elicitation. It recalled that the company's probabilistic analysis did not work as expected. It concluded that the probabilistic version of the model is not suitable for decision making. # End of life ## End of life criteria are met The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. During the first meeting, the clinical experts considered that people with hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer whose disease had progressed on a CDK4/6 inhibitor with an aromatase inhibitor are unlikely to live longer than 24 months. However, they considered that it was less certain whether alpelisib plus fulvestrant extended life by 3 months or more. Alpelisib plus fulvestrant had not been directly compared with everolimus plus exemestane and the treatment effect estimates for alpelisib plus fulvestrant from the indirect analyses are highly uncertain (see section 3.14). In the second meeting, the company and the ERG noted that end of life criteria are met for the company's updated deterministic base-case model. The committee noted that the model predicted that alpelisib with fulvestrant would prolong life by more than 3 months longer than everolimus plus exemestane. The ERG noted that the end of life criteria were not met using the probabilistic base-case model or if only people with HER2-negative cancer from the SoFEA study were included in the Bucher analysis (deterministic or probabilistic model). The committee was unable to consider the results of the probabilistic model given the problems associated with it (see section 3.18). It concluded that end of life criteria were met. ## Because of the uncertainty, an ICER comfortably under £50,000 per QALY gained would be necessary for this technology to be considered cost effective NICE's guide to the methods of technology appraisals notes that the appraisal committee does not use a precise maximum acceptable ICER above which a technology would automatically be defined as not cost effective, or below which it would. Also, consideration of the cost effectiveness of a technology is necessary, but is not the sole basis for decision making. Therefore, NICE considers that the influence of other factors on the decision to recommend a technology is greater when the ICER is closer to the top of the acceptable range. Judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee had concluded that end of life criteria applied (see section 3.19). However, the committee noted the high level of uncertainty (see section 3.22) and had considered different durations of treatment effect and post-progression utility values. It noted that the most plausible ICER range for decision making was deterministic. It was unable to consider the probabilistic ICER (see section 3.21). The committee agreed that, given the uncertainty, alpelisib plus fulvestrant would only represent a cost-effective use of NHS resources if the range of plausible ICERs was comfortably below £50,000 per QALY gained. # Cost-effectiveness results ## The committee preferred to use the deterministic model for decision making In the first meeting, the committee noted that probabilistic methods are generally considered most appropriate for decision making because they allow for full expression of the uncertainty in model parameters. In contrast, a deterministic model excludes this uncertainty. It stated that using alpelisib plus fulvestrant for the baseline of the overall survival model and the skewness of this baseline (see section 3.13) contributed to the discrepancy between the deterministic and probabilistic estimates. In the second meeting, the committee noted that the probabilistic model was not suitable for decision making (see section 3.18). The ERG noted that interpretation of ICERs from the deterministic model is problematic because median, not mean, hazard ratios were used. The committee concluded that while the deterministic model did not take account of the high uncertainty in the modelling (see section 3.13 to 3.16), it preferred to use it for decision making. ## The most likely cost-effectiveness estimates are highly uncertain NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER and whether the technology meets the criteria for consideration as a 'life-extending treatment at the end of life'. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty in the cost-effectiveness estimate caused by: an uncontrolled single-arm trial as the primary source of clinical evidence (see section 3.6) issues with the Bucher indirect treatment comparison (see section 3.10) including whether alpelisib with fulvestrant is more effective than everolimus plus exemestane (see section 3.11) modelled survival estimates (see section 3.13) modelled treatment effect of alpelisib plus fulvestrant compared with everolimus plus exemestane (see section 3.14) duration of treatment effect (see section 3.15) appropriate utility value after disease progression (see section 3.16) treatment costs after disease progression (see section 3.17) using the deterministic model because the probabilistic model is not suitable for use in decision making (see section 3.19).The committee concluded that the most likely cost-effectiveness estimates are highly uncertain. ## Alpelisib combination is recommended for routine use Using the deterministic model and considering different durations of treatment effect and likely post-progression utility values, the plausible ICER range calculated by the ERG was, on balance, judged to be comfortably below £50,000 per QALY gained (see section 3.21). The committee concluded that alpelisib plus fulvestrant is a cost-effective use of NHS resources. Therefore, it can be recommended as an option for treating hormone receptor-positive, HER2-negative, PIK3CA-mutated, advanced breast cancer that has progressed after a CDK4/6 inhibitor plus an aromatase inhibitor. # Other factors ## There are no equality issues No equality or social value judgement issues were identified. The committee noted that a person can go through the menopause but not identify as a woman. Gender reassignment is a protected characteristic under the Equality Act 2010. ## All benefits associated with alpelisib plus fulvestrant are captured in the modelling NICE's guide to the methods of technology appraisal notes that a technology may be considered innovative in nature if the innovation adds demonstrable and distinctive benefits of a substantial nature which may not have been adequately captured in the modelling. The company noted that alpelisib is the first licensed PI3K inhibitor that is highly selective for the catalytic subunit alpha of PI3K. When used with fulvestrant it is the first targeted treatment option for hormone receptor-positive, HER2‑negative, PIK3CA-mutated, advanced breast cancer that has progressed on a CDK4/6 inhibitor plus an aromatase inhibitor. Targeted treatment options are valued by people with advanced breast cancer and clinicians (section 3.2). However, the committee noted that while alpelisib plus fulvestrant may be more effective than everolimus plus exemestane, the results of the indirect analyses are highly uncertain. The clinical expert also advised that although alpelisib is effective, it was associated with tolerability issues. The committee concluded that it did not think there were any additional benefits associated with alpelisib plus fulvestrant that had not been captured in the economic analysis.	{'Recommendations': "Alpelisib plus fulvestrant is recommended as an option for treating hormone receptor-positive, HER2-negative, PIK3CA-mutated, locally advanced or metastatic breast cancer in adults, only if:\n\ntheir cancer has progressed after a CDK4/6 inhibitor plus an aromatase inhibitor and\n\nthe company provides alpelisib according to the commercial arrangement).\n\nThis recommendation is not intended to affect treatment with alpelisib plus fulvestrant that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatment for hormone receptor-positive, HER2-negative, PIK3CA-mutated, locally advanced or metastatic breast cancer after endocrine-based therapy with a CDK4/6 inhibitor plus an aromatase inhibitor includes everolimus with exemestane. Alpelisib with fulvestrant is a new treatment for this condition. The company has positioned alpelisib with fulvestrant after a CDK4/6 inhibitor plus an aromatase inhibitor, which is narrower than its marketing authorisation (licence).\n\nClinical evidence from indirect comparisons suggests that alpelisib plus fulvestrant is more effective than everolimus plus exemestane, but the analyses are uncertain. The clinical trial evidence presented only included a small number of people who would be eligible for alpelisib with fulvestrant in clinical practice.\n\nAlpelisib plus fulvestrant meets NICE's criteria to be a life-extending treatment at the end of life. The most likely cost-effectiveness estimates are uncertain but within the range that NICE considers an acceptable use of NHS resources. So, alpelisib plus fulvestrant is recommended.", 'Information about alpelisib': "# Marketing authorisation indication\n\nAlpelisib (Piqray, Novartis Pharmaceuticals UK) has a marketing authorisation for use 'in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression following endocrine-based therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for alpelisib.\n\n# Price\n\nThe company's list price is £4,082.14 per 56‑pack of 150\xa0mg film-coated tablets (excluding VAT; BNF online, accessed May 2022). The average cost of a course of combination treatment at list price is £6,170.70 for the loading dose and £5,126.42 for the following cycles.\n\nThe company has a commercial arrangement. This makes alpelisib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), responses from stakeholders and comments on the appraisal consultation document. See the committee papers for full details of the evidence.\n\n# Clinical need and treatment pathway\n\n## There is a population who could benefit from alpelisib plus fulvestrant\n\nAdvanced breast cancer is incurable and the aim of treatment is to delay progression and extend survival. Patient experts explained that being diagnosed with advanced breast cancer is extremely difficult for people and their family and friends. It can cause considerable anxiety and fear. These feelings can negatively affect mental health. Women who have been through the menopause, and men, who do not need urgent chemotherapy treatment are offered 1 of 3 CDK4/6 inhibitor treatments (abemaciclib, ribociclib or palbociclib), each with an aromatase inhibitor, as initial treatment. This is in line with NICE's guideline on advanced breast cancer. See NICE's technology appraisal guidance on abemaciclib, ribociclib or palbociclib. Clinical experts noted that women with hormone receptor-positive, HER2-negative advanced breast cancer who have not been through menopause, or who are going through perimenopause, will be offered ovarian suppression. This is to mimic a natural menopause, so they are also eligible for a CDK4/6 inhibitor plus an aromatase inhibitor. After initial treatment with a CDK4/6 inhibitor plus an aromatase inhibitor, current treatment options are limited. People without symptomatic visceral disease can have exemestane plus everolimus (see NICE's technology appraisal guidance on everolimus with exemestane for treating advanced breast cancer after endocrine therapy), but clinical experts noted that adverse events associated with everolimus limit its use. Because of this, capecitabine chemotherapy is sometimes used instead. However, clinical experts noted that people and clinicians are looking for options to delay the need for cytotoxic chemotherapy. They noted that people who have had previous treatment with a CDK4/6 inhibitor plus fulvestrant would not be eligible for alpelisib. The committee concluded that an additional treatment option for this population would be welcome.\n\n## Targeted treatment options are valued by people with advanced breast cancer and clinicians\n\nThe PIK3CA gene is involved in protein production. It is an important part of the phosphatidylinositol-3-kinase (PI3K) enzyme pathway that drives cancer cell growth. Mutations of PIK3CA are found in around 30% to 40% of oestrogen receptor-positive, HER2-negative breast cancers. The company noted that PIK3CA-mutated breast cancer may be more resistant to endocrine therapy. Clinical experts explained that they are keen to offer targeted treatments for people with advanced breast cancer, but these options have been limited except for drugs acting on hormone receptors. They noted that alpelisib, which is used with fulvestrant, is the first targeted treatment option for advanced breast cancer that has a PIK3CA mutation. Clinical experts stated that the toxicity profile of alpelisib plus fulvestrant is notably worse than that seen with a CDK4/6 inhibitor. However, for people who can tolerate it, alpelisib plus fulvestrant is another step in delaying cytotoxic chemotherapy, which has worse adverse events. They explained that this allows people to stay well for longer, for themselves and as carers for others. Patient experts noted that for people with PIK3CA-mutated advanced breast cancer, knowing a drug was targeted to their mutation was very important and had a positive emotional impact. The Cancer Drugs Fund clinical lead stated that genomic testing for PIK3CA mutation is now included in the National Genomic Test Directory and so should be funded in the NHS, as long as there are no implementation issues. Patient experts noted in their consultation response for this appraisal that telling people they have this mutation but not allowing access to the drug does not make sense. They described a patient's experience where PIK3CA mutation may have directly contributed to their endocrine resistance, resulting in recurrence and a prognosis of incurable breast cancer. The clinical experts noted that PIK3CA testing can be done at any point in the treatment pathway for breast cancer, so if it is not done or available at diagnosis it could be done later when exploring treatment options. The committee noted that, while PIK3CA mutation testing had not been routinely available, this situation is changing and PIK3CA mutation status will soon be routinely identified in clinical practice. It concluded that targeted treatment options for identifiable mutations are valued by people with advanced breast cancer and clinicians.\n\n## The relevant place in the treatment pathway is second line after disease progression on a CDK4/6 inhibitor plus an aromatase inhibitor\n\nThe company positioned alpelisib plus fulvestrant 'after disease progression following a CDK4/6 inhibitor' in its base case. This is narrower than the marketing authorisation for alpelisib plus fulvestrant, which is 'after disease progression following endocrine-based therapy'. Clinical experts stated that a CDK4/6 inhibitor plus an aromatase inhibitor, with or without chemotherapy, is standard practice for the first-line treatment of hormone receptor-positive, HER2-negative advanced breast cancer, with or without a PIK3CA mutation (see section\xa03.1). They noted that this would be offered to most people except those who are unable to tolerate treatment with a CDK4/6 inhibitor. It is more appropriate for these people to have endocrine monotherapy, with or without chemotherapy. Therefore, the clinical experts considered that the company's positioning of alpelisib plus fulvestrant was in line with expected clinical use. The committee concluded that the company's positioning of alpelisib with fulvestrant as second line after disease progression on a CDK4/6 inhibitor plus an aromatase inhibitor was appropriate.\n\n## The relevant comparator is everolimus plus exemestane\n\nThe company used everolimus plus exemestane (see section\xa03.1) as its base-case comparator. Clinical experts noted that because of tolerability issues with everolimus plus exemestane, some people have oral, single-agent chemotherapy with capecitabine instead. This has a lower toxicity burden than other chemotherapies. The committee noted that some people with advanced breast cancer may have oral capecitabine or more cytotoxic chemotherapy, instead of everolimus plus exemestane, as second-line treatment after a CDK4/6 inhibitor and an aromatase inhibitor. The Cancer Drugs Fund clinical lead noted that most people who are potentially likely to have alpelisib plus fulvestrant currently have everolimus plus exemestane in NHS practice. The committee concluded that everolimus plus exemestane is the most relevant comparator for this appraisal.\n\n# Clinical evidence\n\n## Alpelisib with fulvestrant was investigated in 2 studies, BYLieve and SOLAR-1, but only BYLieve is generalisable to UK clinical practice\n\nAlpelisib with fulvestrant was studied in 1 phase\xa02 non-randomised, open label, non-comparative study (BYLieve) and 1 phase\xa03 randomised controlled trial (SOLAR‑1). The evidence from these studies submitted by the company is in people with hormone receptor-positive, HER2-negative, advanced breast cancer that has a confirmed PIK3CA mutation. The clinical experts noted that almost everyone had stage\xa04 breast cancer on entry to the studies. BYLieve included 121\xa0people with breast cancer progression on or after a CDK4/6 inhibitor with an aromatase inhibitor. People had treatment with alpelisib plus fulvestrant as first-, second-, third- or later-line treatment for advanced disease. Clinical experts noted that BYLieve is relevant to UK clinical practice because it studied alpelisib plus fulvestrant in advanced breast cancer that had progressed on or after a CDK4/6 inhibitor with an aromatase inhibitor, which is standard care. The committee concluded that the population of BYLieve was generalisable to the NHS.\n\n## Clinical evidence for alpelisib plus fulvestrant after a CDK4/6 inhibitor plus an aromatase inhibitor is uncertain because it is based on 1 single-arm study\n\nThe primary outcome of BYLieve is progression-free survival. Secondary outcomes include overall survival, objective response rate, clinical benefit rate and duration of response. BYLieve included 121\xa0people who had treatment with alpelisib plus fulvestrant after a CDK4/6 inhibitor plus an aromatase inhibitor. Some of these people had alpelisib plus fulvestrant second line (see section\xa03.5). The median duration of follow up was 11.7\xa0months. BYLieve met its primary end point, with 50.4% of people alive without disease progression at 6\xa0months (95% confidence interval [CI] 41.2 to 59.6; lower bound of the 95% CI exceeding 30%, which was the protocol-defined clinically meaningful threshold) for all lines of treatment (n=121). In people who had alpelisib plus fulvestrant second line, the results suggest it could be clinically effective. The company considers that the data is confidential so it cannot be reported here. However, the relative effectiveness is uncertain because of the lack of comparative data to assess alpelisib plus fulvestrant effectiveness with other treatment options. The committee concluded that evidence from BYLieve suggests that alpelisib plus fulvestrant may be clinically effective, but this evidence was highly uncertain because of the lack of comparative data.\n\n## SOLAR-1 was limited because it only included a small number of people relevant to this appraisal\n\nSOLAR‑1 included 341\xa0people with PIK3CA-mutated breast cancer that recurred or progressed on or after treatment with an aromatase inhibitor. It compared alpelisib plus fulvestrant with placebo plus fulvestrant. But clinical experts noted that fulvestrant monotherapy is not used in NHS practice and does not reflect standard care for second-line treatment of hormone receptor-positive, HER2-negative, advanced breast cancer (see section\xa03.1). Most people had treatment with alpelisib plus fulvestrant as first- or second-line treatment for advanced disease. People who had alpelisib plus fulvestrant or placebo plus fulvestrant as second-line treatment after an aromatase inhibitor from now are called the second-line proxy population. Clinical experts noted that for most people in SOLAR‑1, overall and in the second-line proxy population, the data was not relevant to UK clinical practice. This is because very few people had an aromatase inhibitor with a CDK4/6 inhibitor before treatment with alpelisib plus fulvestrant or placebo plus fulvestrant. The committee noted that only 20\xa0people had a CDK4/6 inhibitor with an aromatase inhibitor, and so only these 20\xa0people are relevant to this appraisal. In SOLAR‑1, median duration of follow up was 42.4\xa0months for the final data-cut point. The results suggested that alpelisib plus fulvestrant may be more effective than placebo plus fulvestrant when given as second-line treatment. Data is considered confidential by the company and cannot be reported here. The committee concluded that this study was limited because it only included 20\xa0people relevant to this appraisal.\n\n# Adverse effects\n\n## Alpelisib plus fulvestrant is associated with grade 3 or higher adverse events that need additional monitoring\n\nNot everyone will be able to tolerate treatment with alpelisib plus fulvestrant (see section\xa03.2). In BYLieve and SOLAR‑1, more than 60% of people who had alpelisib plus fulvestrant had a treatment-emergent adverse event of grade\xa03 or higher. Clinical experts noted that a grade\xa03 or\xa04 rash is a rash that covers more than half the body, seen in 9% to 10% of people who had alpelisib plus fulvestrant. They also noted that grade\xa03 or\xa04 diarrhoea, seen in 6% to 7% of people who had alpelisib plus fulvestrant, is difficult for people to tolerate. Clinical experts explained that grade\xa03 or higher hyperglycaemia means that older people or those with a high body mass index or obesity might need weekly testing and follow up during initial treatment. This was seen in around 30% of people who had alpelisib plus fulvestrant. The experts noted that these adverse events and the need for additional monitoring is a burden to both patients and clinicians. The patient expert noted that they were aware that someone who had treatment with alpelisib plus fulvestrant had reported struggling with diarrhoea and having blood sugars monitored weekly. However, this person felt that the benefits of treatment outweighed any discomfort they were experiencing. The ERG noted that 14% of people in BYLieve stopped treatment because of adverse events (based on the full analysis set, n=127). Also, 23% of the alpelisib plus fulvestrant group and 4% of the placebo plus fulvestrant group stopped treatment in SOLAR‑1 because of treatment-related adverse events (based on safety set, n=571). Clinical experts stated that alpelisib with fulvestrant could be difficult for some people to tolerate. However, over time clinicians are developing ways to mitigate toxic effects and are limiting who has treatment or stopping treatment if adverse events are not manageable. The committee concluded that alpelisib plus fulvestrant is associated with grade\xa03 or higher adverse events that may need additional monitoring.\n\n# Indirect treatment comparison\n\n## The company did an indirect treatment comparison using the Bucher method\n\nThere were no trials directly comparing alpelisib plus fulvestrant with everolimus plus exemestane. So, the company presented an indirect treatment comparison using the Bucher method (used in the company base case) for outcomes including overall survival and progression-free survival. The Bucher analysis included publicly available data from 4 trials. It took known hazard ratios for alpelisib plus fulvestrant compared with placebo plus fulvestrant from SOLAR‑1. It then linked these to the BOLERO‑2 study of everolimus plus exemestane compared with exemestane monotherapy via 2 other trials, CONFIRM and SoFEA. The ERG explained that this approach is a 'reverse' Bucher method when known hazard ratios for the treatment being studied are used to calculate hazard ratios for the comparator group. It is more usual to know the comparator hazard ratios and use these to calculate hazard ratios for the treatment being studied. The company stated that the Bucher analysis showed that alpelisib plus fulvestrant was associated with better efficacy in terms of both progression-free survival and overall survival compared with everolimus plus exemestane. The results of the analysis are confidential and cannot be reported here. The ERG and committee noted that the confidence intervals of the hazard ratios presented for these comparisons were very wide, which makes them unreliable. The committee questioned the internal validity of the Bucher results because when comparing placebo plus fulvestrant with everolimus plus exemestane, 1 treatment group was favoured for progression-free survival and the other group was favoured for overall survival. Clinical experts noted that there is a lack of robust data for treatments used after first line. Some of the comparisons that would help validate the analysis have not been done in trials.\n\n## The results of the Bucher analysis are highly uncertain for several reasons\n\nThe ERG noted that, of the 4 trials of hormone receptor-positive advanced breast cancer included in the Bucher indirect treatment comparison, only SOLAR‑1 prospectively enrolled people with PIK3CA-mutated breast cancer. It noted that the company restricted the dataset of BOLERO‑2 used in the analysis to the second-line population with a PIK3CA mutation based on tumour tissue samples. This led to 92% of people being excluded from the analysis. The committee noted that if PIK3CA mutation based on plasma sampling was included it may be possible to increase the number of people included in the analysis. In its consultation response, the company noted that it restricted the dataset of BOLERO‑2 for consistency with the sampling method used in BYLieve and SOLAR‑1. It stated that this was to avoid introducing potential bias. It noted that plasma testing was also done in SOLAR‑1, but this data was not used because it would have broken the randomisation of the study. The clinical expert noted that they would prefer that the population of BOLERO‑2 was not restricted. They advised that using plasma to test for PIK3CA mutation is helpful because it means it is more likely that the test is being done for a metastatic tumour sample. The ERG understood the company's rationale for restricting the population of BOLERO‑2. But it noted that this increases uncertainty in the Bucher analysis and contributes to the wide confidence intervals seen for the hazard ratios. The ERG noted that the patient populations of the trials included in the Bucher analysis also had other differences including line of treatment and HER2 status. Almost no one had previously had a CDK4/6 inhibitor with an aromatase inhibitor. The ERG's clinical expert commented that HER2 status may be an important effect modifier for alpelisib plus fulvestrant compared with everolimus plus exemestane. At the request of the ERG, the company did the same Bucher analysis but used a subpopulation of SoFEA that included people with known HER2-negative status. The committee noted that in this subset analysis a treatment effect in favour of alpelisib plus fulvestrant was seen, but this was reduced compared with the overall analysis and was uncertain (see section\xa03.9). The company explained that it preferred not to restrict the population from SoFEA in this way so as not to reduce the patient numbers. It also noted that there is insufficient data to know whether HER2 status is an effect modifier for alpelisib plus fulvestrant compared with everolimus plus exemestane. In its consultation response, the company noted that technology appraisals of a CDK4/6 inhibitor plus an aromatase inhibitor did not restrict analyses to a HER2‑negative population. The ERG noted that committee papers of these previous appraisals state that not restricting the dataset of SoFEA to people with HER2‑negative breast cancer is a source of heterogeneity and may impact outcomes. The clinical expert noted that people with HER2‑positive breast cancer should not be included when possible, because they have a completely different treatment regimen. The ERG noted that the HER2‑negative subgroup of SoFEA was a reasonably sized group (n=283), 60% of the total study population. It noted that the influence on the Bucher analysis of not restricting the population of SoFEA is unclear, which leads to uncertainty. The committee concluded that the results of the Bucher analysis are highly uncertain for several reasons:\n\nHazard ratios for the indirect comparison of alpelisib plus fulvestrant with everolimus plus exemestane had very wide confidence intervals (see section\xa03.9).\n\nHazard ratios for the indirect comparison of placebo plus fulvestrant with everolimus plus exemestane may lack face validity (see section\xa03.9).\n\nThere is heterogeneity between the 4 trials and some have a lack of generalisability. Patient populations differed, including in terms of PIK3CA-mutation status and HER2 status, and there was a lack of previous treatment with a CDK4/6 inhibitor plus an aromatase inhibitor.\n\nThere is a potential for HER2 status to be an effect modifier.\n\n## Alpelisib plus fulvestrant may be more effective than everolimus plus exemestane, but the results of the indirect analyses are highly uncertain\n\nAs noted in section\xa03.11, the indirect treatment comparison was highly uncertain. The company stated that favourable results for alpelisib plus fulvestrant were supported by real-world evidence. It noted that data from the Flatiron database supports progression-free survival with alpelisib plus fulvestrant in BYLieve being better than that with standard care after a CDK4/6 inhibitor. To support this, the company presented a matching/weighting analysis of BYLieve compared with standard care. The ERG noted that the Flatiron database is a real-world dataset from the US where standard care may differ from that in England. The committee concluded that alpelisib plus fulvestrant may be more effective than everolimus plus exemestane, but the results of the indirect analyses are highly uncertain.\n\n# The company's economic model\n\n## The company's economic model is suitable for decision making\n\nThe company submitted a partitioned survival model to estimate the cost effectiveness of alpelisib plus fulvestrant compared with everolimus plus exemestane. It had 3 health states: progression-free, progressed, and dead. The model had a lifetime time horizon (40\xa0years). The committee considered that the partitioned survival model is a standard approach to estimate the cost effectiveness of cancer drugs and is suitable for decision making.\n\n## The modelling of overall survival and progression-free survival is plausible but highly uncertain\n\nThe company's model linked progression-free survival distributions to overall survival by using an indirect treatment comparison. The company selected a log-logistic function to extrapolate overall survival and a log-normal function to extrapolate progression-free survival for alpelisib plus fulvestrant from the second-line population in BYLieve. For everolimus plus exemestane, the hazard ratio for overall survival and progression-free survival from the Bucher analysis was applied to the alpelisib plus fulvestrant model. The company and ERG noted that their clinical experts thought that the projections for overall survival and progression-free survival in the model were plausible. The experts noted that a long tail to the modelled overall survival might be expected in breast cancer. The ERG noted that the projections were based on the company's deterministic model (see section\xa03.18), including data on PIK3CA mutation from tumour samples in BOLERO‑2 (see section\xa03.10) and the overall population of SoFEA (see section\xa03.10). It was generally satisfied with the survival functions used, but noted that the Gompertz and Weibull provided slightly better model fit than log-logistic for overall survival. The ERG also explained that the log-logistic model appears to overestimate overall survival for the alpelisib plus fulvestrant group after around 1.5\xa0years, although very few events happen after this. The ERG explored the impact of alternative extrapolations for overall survival and progression-free survival, which showed that the incremental cost-effectiveness ratio (ICER) was very sensitive to these alternative extrapolations. The committee noted that there were several issues with the data underpinning the survival extrapolations. For the alpelisib plus fulvestrant arm, the clinical data underpinning this was either non-comparative (see section\xa03.6) or for very few people (see section\xa03.7). For the everolimus plus exemestane arm, data was taken from the Bucher indirect analysis, which was highly uncertain (see section\xa03.10). The committee concluded that the overall survival and progression-free survival estimates were plausible but highly uncertain.\n\n## Modelled relative treatment effects are highly uncertain\n\nRelative treatment effects of alpelisib plus fulvestrant and everolimus plus exemestane were derived from a Bucher indirect treatment comparison (see section\xa03.9). The ERG's clinical experts considered that the relative treatment effects of alpelisib plus fulvestrant compared with everolimus plus exemestane were plausible. The committee and the ERG recalled that alpelisib plus fulvestrant may be more effective than everolimus plus exemestane. However, given the uncertainty in the underpinning data, quantifying the treatment effect and quality-adjusted life year (QALY) estimates would be highly uncertain (see section\xa03.9 to\xa03.11). The ERG noted that the Bucher model was similar to a fixed effects model in that it assumes no between-study variation, which might not be reasonable. It noted that in a fixed effect model, confidence intervals can underestimate the true uncertainty. However, if the assumption for no between-study variation was relaxed, confidence intervals would be even wider. The ERG also explained that because the network of the Bucher analysis involves a single chain of evidence (with no closed loops), and each comparison is informed by only 1 trial, it is not possible to assess the consistency of the evidence. The committee concluded that the relative treatment effect of alpelisib plus fulvestrant compared with everolimus plus exemestane was highly uncertain.\n\n## The model assumes a 5-year duration of treatment effect which is uncertain\n\nThe model has a lifetime time horizon (see section\xa03.12). In its original base case, the company assumed that the treatment effects of alpelisib plus fulvestrant compared with everolimus plus exemestane were indefinite with no loss of treatment effect over time. The clinical experts stated that it was not reasonable to say there is indefinite treatment effect. The ERG and its own clinical experts considered an indefinite duration of treatment effect to be optimistic. The ERG did additional sensitivity analyses to explore the possibility that the treatment effect of alpelisib plus fulvestrant for progression-free survival and overall survival wanes and switches to that of everolimus plus exemestane at 3 or 5\xa0years. During consultation, the company presented an updated base case in which the treatment effect of alpelisib plus fulvestrant switches to that of everolimus plus exemestane at 5\xa0years. It noted that to assume a 3‑year duration of treatment effect is pessimistic, because in the SOLAR‑1 study that was used in the Bucher analysis people had follow up for longer than this. The committee noted that the assumed duration of treatment effect of 5\xa0years is not based on evidence. The clinical expert stated that assuming a 5‑year treatment effect is reasonable. The committee concluded that the assumption of a 5‑year duration of treatment effect is uncertain.\n\n## The appropriate utility value after disease progression is uncertain and may be overestimated by the company\n\nAcross the different health states in the model, the company assumed equal utilities for alpelisib plus fulvestrant and everolimus plus exemestane, which the committee concluded was reasonable. The company used SOLAR‑1 to derive utility values in the pre-progression health state and for terminal disease. However, SOLAR‑1 had limited health-related quality-of-life data after disease progression. Therefore, in its base case, the company used a utility value of 0.69 for the modelled health state after disease progression from a publication by Mitra et al. (2016). The ERG noted that the Mitra study is only published as an abstract with very limited methodological details and the EQ‑5D tariffs used to generate the utility estimates are unclear. It explained that the value used from Mitra is likely to overestimate utility after disease progression. This is because it is based on people with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer who are having treatment at third line or later. In its original critique, the ERG preferred to use a 0.51 post-progression utility value from Lloyd et al. (2006) that has been used in previous technology appraisals when suitable data had not been collected in trials. The company noted that Lloyd is outdated and does not reflect the treatment landscape and people having treatment today. It noted that Mitra was used and preferred to Lloyd in the recent NICE technology appraisal guidance on abemaciclib with fulvestrant for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy. It also stated that at technical engagement it did interviews with healthcare professionals. In these interviews Mitra et al. was considered to reflect the utility value of people having third-line treatment in the NHS. The ERG noted that the utility value needs to reflect the entre post-progression health state. The ERG's clinical experts suggested that a utility value around midway between Lloyd and Mitra might be more appropriate for people with a progressed disease state. The ERG did exploratory analyses to consider a value around the midpoint, which led to an increase in the company's base-case ICER. It noted that this value may have greater face validity than available empirical estimates. The ERG's clinical experts noted that in SOLAR‑1, which had a post-progression utility value close to that of Mitra, the value was consistent with people who have radiological progression on 1 to 3 lines of treatment without a significant change in health-related quality of life. The Cancer Drugs Fund clinical lead noted that the post-progression utility value is assumed constant for the duration of the post-progression health state and does not take account of whether people have additional treatments. As such, the Mitra value is optimistic and may overestimate utility for most of the post-progression state. The committee noted that there is no satisfactory utility value for after disease progression. The committee concluded that the appropriate utility value for the modelled health state after disease progression is uncertain and may be overestimated by the company.\n\n## Treatment costs after disease progression are reasonable but uncertain\n\nThe company assumed a fixed cost of £1,500 per month for 'all future treatment-related costs' for people after disease progression, excluding end of life care. It noted that this is based on NICE's technology appraisal guidance on ribociclib with fulvestrant for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy. The ERG noted that it is unclear whether the company assumption is reasonable. It noted that lower estimated post-progression treatment costs (£1,140 to £1,200) were preferred by the committee in NICE's technology appraisal guidance on ribociclib with an aromatase inhibitor for previously untreated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer. The ERG suggested that it may be more appropriate to apply subsequent-line treatment costs based on observed post-progression treatments in the alpelisib plus fulvestrant clinical studies. Clinical experts noted that it is reasonable to base treatment costs after disease progression on those assumed for ribociclib plus fulvestrant. The ERG had explored alternative costs assumptions (increasing and decreasing costs by £750), which led to minor changes to the ICER. The committee concluded that treatment costs after disease progression are uncertain, but are not unreasonable and not a major driver of cost-effectiveness results.\n\n## The probabilistic version of the model is not working as expected and is not suitable for decision making\n\nDuring the first committee meeting, the ERG noted that the probabilistic estimate of the ICER was substantially higher (by around £10,000 per QALY gained) than its deterministic estimate, which was highly unusual. The ERG and company noted that in the probabilistic analysis, the sampled treatment effect sometimes suggests a considerable and clinically implausible lower effectiveness of alpelisib plus fulvestrant compared with everolimus plus exemestane. The ERG noted that the main driver of the discrepancy between the deterministic and probabilistic modelled cost effectiveness was the wide confidence interval associated with the hazard ratio for overall survival. A wide confidence interval means that the hazard ratio for overall survival is unreliable. Because the Bucher model is similar to a fixed effects model, confidence intervals can underestimate the true uncertainty (see section\xa03.14). In its consultation response, the company updated its probabilistic base case using a constrained probabilistic analysis following input from clinical experts. It sought opinion from 4 experts to identify the extent of increase in life years for everolimus plus exemestane compared with alpelisib plus fulvestrant that would be deemed to be clinically implausible. As a result, the probabilistic analysis was amended to remove iterations where everolimus plus exemestane was associated with an increase in life years greater than 10%. The company noted that this approach shows the impact of the implausible samples on the probabilistic ICER, which was now aligned with that of the deterministic analysis. The ERG disagreed with the company's approach. It noted that removing samples that do not match expectations gives an arbitrary mean ICER. The committee noted that it is not satisfied with the company's probabilistic analysis where the outputs have been constrained. It noted that it would be more appropriate to constrain the inputs to the probabilistic analysis, such as the confidence intervals of the hazard ratio, based on expert elicitation. It recalled that the company's probabilistic analysis did not work as expected. It concluded that the probabilistic version of the model is not suitable for decision making.\n\n# End of life\n\n## End of life criteria are met\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. During the first meeting, the clinical experts considered that people with hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer whose disease had progressed on a CDK4/6 inhibitor with an aromatase inhibitor are unlikely to live longer than 24\xa0months. However, they considered that it was less certain whether alpelisib plus fulvestrant extended life by 3\xa0months or more. Alpelisib plus fulvestrant had not been directly compared with everolimus plus exemestane and the treatment effect estimates for alpelisib plus fulvestrant from the indirect analyses are highly uncertain (see section\xa03.14). In the second meeting, the company and the ERG noted that end of life criteria are met for the company's updated deterministic base-case model. The committee noted that the model predicted that alpelisib with fulvestrant would prolong life by more than 3\xa0months longer than everolimus plus exemestane. The ERG noted that the end of life criteria were not met using the probabilistic base-case model or if only people with HER2-negative cancer from the SoFEA study were included in the Bucher analysis (deterministic or probabilistic model). The committee was unable to consider the results of the probabilistic model given the problems associated with it (see section\xa03.18). It concluded that end of life criteria were met.\n\n## Because of the uncertainty, an ICER comfortably under £50,000 per QALY gained would be necessary for this technology to be considered cost effective\n\nNICE's guide to the methods of technology appraisals notes that the appraisal committee does not use a precise maximum acceptable ICER above which a technology would automatically be defined as not cost effective, or below which it would. Also, consideration of the cost effectiveness of a technology is necessary, but is not the sole basis for decision making. Therefore, NICE considers that the influence of other factors on the decision to recommend a technology is greater when the ICER is closer to the top of the acceptable range. Judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee had concluded that end of life criteria applied (see section\xa03.19). However, the committee noted the high level of uncertainty (see section\xa03.22) and had considered different durations of treatment effect and post-progression utility values. It noted that the most plausible ICER range for decision making was deterministic. It was unable to consider the probabilistic ICER (see section\xa03.21). The committee agreed that, given the uncertainty, alpelisib plus fulvestrant would only represent a cost-effective use of NHS resources if the range of plausible ICERs was comfortably below £50,000 per QALY gained.\n\n# Cost-effectiveness results\n\n## The committee preferred to use the deterministic model for decision making\n\nIn the first meeting, the committee noted that probabilistic methods are generally considered most appropriate for decision making because they allow for full expression of the uncertainty in model parameters. In contrast, a deterministic model excludes this uncertainty. It stated that using alpelisib plus fulvestrant for the baseline of the overall survival model and the skewness of this baseline (see section\xa03.13) contributed to the discrepancy between the deterministic and probabilistic estimates. In the second meeting, the committee noted that the probabilistic model was not suitable for decision making (see section\xa03.18). The ERG noted that interpretation of ICERs from the deterministic model is problematic because median, not mean, hazard ratios were used. The committee concluded that while the deterministic model did not take account of the high uncertainty in the modelling (see section\xa03.13 to\xa03.16), it preferred to use it for decision making.\n\n## The most likely cost-effectiveness estimates are highly uncertain\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER and whether the technology meets the criteria for consideration as a 'life-extending treatment at the end of life'. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty in the cost-effectiveness estimate caused by:\n\nan uncontrolled single-arm trial as the primary source of clinical evidence (see section\xa03.6)\n\nissues with the Bucher indirect treatment comparison (see section\xa03.10) including whether alpelisib with fulvestrant is more effective than everolimus plus exemestane (see section\xa03.11)\n\nmodelled survival estimates (see section\xa03.13)\n\nmodelled treatment effect of alpelisib plus fulvestrant compared with everolimus plus exemestane (see section\xa03.14)\n\nduration of treatment effect (see section\xa03.15)\n\nappropriate utility value after disease progression (see section\xa03.16)\n\ntreatment costs after disease progression (see section\xa03.17)\n\nusing the deterministic model because the probabilistic model is not suitable for use in decision making (see section\xa03.19).The committee concluded that the most likely cost-effectiveness estimates are highly uncertain.\n\n## Alpelisib combination is recommended for routine use\n\nUsing the deterministic model and considering different durations of treatment effect and likely post-progression utility values, the plausible ICER range calculated by the ERG was, on balance, judged to be comfortably below £50,000 per QALY gained (see section\xa03.21). The committee concluded that alpelisib plus fulvestrant is a cost-effective use of NHS resources. Therefore, it can be recommended as an option for treating hormone receptor-positive, HER2-negative, PIK3CA-mutated, advanced breast cancer that has progressed after a CDK4/6 inhibitor plus an aromatase inhibitor.\n\n# Other factors\n\n## There are no equality issues\n\nNo equality or social value judgement issues were identified. The committee noted that a person can go through the menopause but not identify as a woman. Gender reassignment is a protected characteristic under the Equality Act 2010.\n\n## All benefits associated with alpelisib plus fulvestrant are captured in the modelling\n\nNICE's guide to the methods of technology appraisal notes that a technology may be considered innovative in nature if the innovation adds demonstrable and distinctive benefits of a substantial nature which may not have been adequately captured in the modelling. The company noted that alpelisib is the first licensed PI3K inhibitor that is highly selective for the catalytic subunit alpha of PI3K. When used with fulvestrant it is the first targeted treatment option for hormone receptor-positive, HER2‑negative, PIK3CA-mutated, advanced breast cancer that has progressed on a CDK4/6 inhibitor plus an aromatase inhibitor. Targeted treatment options are valued by people with advanced breast cancer and clinicians (section\xa03.2). However, the committee noted that while alpelisib plus fulvestrant may be more effective than everolimus plus exemestane, the results of the indirect analyses are highly uncertain. The clinical expert also advised that although alpelisib is effective, it was associated with tolerability issues. The committee concluded that it did not think there were any additional benefits associated with alpelisib plus fulvestrant that had not been captured in the economic analysis."}	https://www.nice.org.uk/guidance/ta816	Evidence-based recommendations on alpelisib (Piqray) with fulvestrant for treating hormone receptor-positive, HER2-negative, PIK3CA-mutated, locally advanced or metastatic breast cancer in adults.
990ba0d997dda25800b9050edf4e3251d5e4efa0	nice	Nivolumab for adjuvant treatment of invasive urothelial cancer at high risk of recurrence	Nivolumab for adjuvant treatment of invasive urothelial cancer at high risk of recurrence Evidence-based recommendations on nivolumab (Opdivo) for adjuvant treatment of invasive urothelial cancer at high risk of recurrence. # Recommendations Nivolumab is recommended as an option for the adjuvant treatment of muscle-invasive urothelial cancer that is at high risk of recurrence after radical resection in adults whose tumours express PD-L1 at a level of 1% or more. It is recommended only if: adjuvant treatment with platinum‑based chemotherapy is unsuitable, and the company provides nivolumab according to the commercial arrangement. This recommendation is not intended to affect treatment with nivolumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Radical resection (surgery) aims to remove all traces of the cancer. Adjuvant treatment aims to reduce the risk of the cancer returning after resection. Standard care for muscle-invasive urothelial cancer that is at high risk of recurrence after radical resection is adjuvant treatment with platinum‑based chemotherapy or best supportive care. Clinical trial evidence shows that adjuvant treatment with nivolumab reduces the risk of the cancer coming back compared with placebo. However, it is uncertain whether nivolumab increases how long people live because this data is not available yet. An indirect treatment comparison of nivolumab with platinum‑based chemotherapy is also highly uncertain. The company did not provide cost-effectiveness estimates comparing nivolumab with platinum‑based chemotherapy. The most likely cost-effectiveness estimates for nivolumab compared with best supportive care are uncertain. But, these estimates are within what NICE usually considers an acceptable use of NHS resources when platinum‑based chemotherapy is not a suitable option. So, adjuvant treatment with nivolumab is recommended only if platinum‑based adjuvant chemotherapy is not suitable.# Information about nivolumab # Marketing authorisation indication Nivolumab (Opdivo, Bristol Myers Squibb) has a UK marketing authorisation 'for the adjuvant treatment of adults with muscle invasive urothelial carcinoma (MIUC) with tumour cell PD-L1 expression ≥ 1%, who are at high risk of recurrence after undergoing radical resection of MIUC'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for nivolumab. # Price The list price of nivolumab is £2,633 per 240 mg per 24‑ml vial (excluding VAT; BNF online, accessed May 2022). The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Bristol Myers Squibb, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # New treatment option ## Nivolumab is a valued adjuvant treatment option for people with resected high-risk muscle-invasive urothelial cancer Muscle-invasive urothelial cancer can have a significant impact on people and their families and carers. Standard care after radical resection is platinum‑based chemotherapy (adjuvant treatment) or best supportive care. Some people have platinum‑based chemotherapy before the surgery (neoadjuvant treatment) and would not be eligible for adjuvant treatment with platinum‑based chemotherapy. Despite resection, the disease can recur. High risk is defined by the MIUC pathologic staging criteria in section 5.1 of nivolumab's summary of product characteristics. The patient experts explained that there is a high unmet need in this area and a new treatment option at this part of the pathway was welcomed. They explained that for some people platinum‑based chemotherapy is not suitable or tolerated, and some people are unwilling to have it. The patient experts explained that extending the duration of disease-free survival is important to patients. This is because it allows them to spend more time with their families and enjoy a good quality of life, and relieves stress on carers. The clinical and patient experts noted that nivolumab was generally well tolerated and that the short infusion time of the treatment compared with chemotherapy was an advantage. The clinical experts explained that immunotherapy at an early stage has the potential to significantly improve outcomes and increase the number of people whose cancer is cured. The committee considered that adjuvant treatment with nivolumab after radical resection may address an unmet need. The committee acknowledged that nivolumab is the first adjuvant immunotherapy available for resected high-risk muscle-invasive urothelial cancer. It concluded that nivolumab is a valued treatment option for people with resected high-risk muscle-invasive urothelial cancer. # Treatment pathway ## Adjuvant platinum-based chemotherapy and best supportive care are the relevant comparators The final NICE scope included adjuvant chemotherapy and best supportive care (active monitoring) as comparators. The CheckMate 274 trial only included a placebo (best supportive care) comparator arm. The company provided cost-effectiveness estimates for nivolumab compared with best supportive care but did not provide cost-effectiveness estimates comparing nivolumab with adjuvant chemotherapy. The company explained that this was because adjuvant chemotherapy use is low in current NHS practice. It explained that this is because of a lack of evidence of clinical benefits and people may refuse chemotherapy because of toxicity concerns. The clinical experts agreed that the use of adjuvant platinum‑based chemotherapy was low for people with bladder cancer. This is because some people have neoadjuvant platinum‑based chemotherapy, and some people are not fit enough to have platinum‑based chemotherapy or they have toxicity concerns. The experts explained that the evidence base for adjuvant platinum‑based chemotherapy was not robust for bladder cancer. The Cancer Drugs Fund clinical lead and the clinical experts explained that for people with urothelial carcinomas of the upper urinary tract, adjuvant platinum‑based chemotherapy was likely to be standard of care. This was because clinical trial evidence from the POUT trial showed an increase in disease‑free survival when platinum‑based adjuvant chemotherapy was given within 90 days of resection (Birtle et al. 2020). In addition, neoadjuvant platinum‑based chemotherapy is usually not suitable for treating urothelial carcinomas of the upper urinary tract. The committee considered that there are several reasons why adjuvant platinum‑based chemotherapy may not be suitable. These reasons included: the lack of robust randomised controlled trial evidence on adjuvant platinum‑based chemotherapy for treating bladder cancer previous neoadjuvant platinum‑based chemotherapy the toxicity profile of platinum‑based chemotherapy in people who have just had major surgery the refusal by a person to have adjuvant treatment with platinum‑based chemotherapy after discussing the benefits and risks with their oncologist. The committee considered that platinum‑based chemotherapy was likely to be a suitable treatment option for people with urothelial carcinomas of the upper urinary tract. The committee concluded that adjuvant platinum‑based chemotherapy, when suitable, and best supportive care are the relevant comparators. ## Retreatment with immunotherapy would be offered to some people who have disease recurrence after adjuvant treatment with nivolumab The company's scenario analysis assumed that only people who had best supportive care after resection would have the option of immunotherapy (atezolizumab) if disease recurrence occurred. This treatment option was based on NICE's technology appraisal guidance on atezolizumab for untreated PD-L1-positive advanced urothelial cancer when cisplatin is unsuitable. The Cancer Drugs Fund clinical lead explained that people who have nivolumab after resection may have immunotherapy again after disease recurrence if enough time has passed since nivolumab treatment had stopped (approximately 12 months). The ERG provided a scenario in which atezolizumab was a treatment option for both the nivolumab and best supportive care groups after disease recurrence. The committee concluded that retreatment with immunotherapy would be offered to some people who have disease recurrence after adjuvant treatment with nivolumab. # Clinical evidence ## The clinical evidence for nivolumab is from Checkmate 274, a randomised controlled trial comparing nivolumab with placebo CheckMate 274 is an ongoing phase 3 randomised controlled trial comparing nivolumab with placebo in people with resected muscle-invasive urothelial cancer at high risk of disease recurrence. People had nivolumab for up to 1 year. The trial included 353 people in the nivolumab arm, of whom 140 had tumours expressing PD‑L1 at a level of 1% or more. The trial included 356 people in the placebo arm, of whom 142 had tumours expressing PD‑L1 at a level of 1% or more. CheckMate 274 included people who were eligible to have adjuvant cisplatin (platinum‑based chemotherapy). However, they were only allowed to enrol in the trial if they had documented reasons for refusing adjuvant cisplatin. Disease‑free survival was the primary outcome measure. Median disease‑free survival was not reached in the nivolumab arm in the currently available data (95% confidence interval , 22.1 months to not estimable). Median disease‑free survival in the placebo arm was 8.4 months (95% CI, 5.6 months to 20.0 months). At 6 and 12 months, 74.5% and 67.6% of people in the nivolumab arm were disease-free, respectively. This compared with 55.7% and 46.3% being disease-free in the best supportive care arm. The committee noted that in CheckMate 274, evidence for nivolumab was less encouraging for people with upper tract urothelial cancer compared with the intention‑to‑treat population (hazard ratios: renal pelvis tumour origin, 1.25, 95% CI 0.70 to 2.25; ureter tumour origin, 1.54, 95% CI 0.69 to 3.44). The committee concluded that the currently available data showed that nivolumab increased disease‑free survival compared with placebo in people whose tumours express PD‑L1 at 1% or more. ## It is not certain to what extent a benefit in disease-free survival translates into a benefit in overall survival The committee noted that because overall survival data from CheckMate 274 was event driven, the currently available data did not provide information on survival. The committee was aware that some published evidence suggested that disease‑free survival gains may not necessarily lead to overall survival gains (Sternberg et al. 2015). The clinical and patient experts emphasised the importance of disease-free survival in the adjuvant treatment setting. A clinical expert explained that the Sternberg et al. study may not be a reliable predictor of overall survival gains with nivolumab. This is because the study recruited over a long period of time, and many participants were enrolled a long time after having surgery. The Cancer Drugs Fund clinical lead highlighted that nivolumab has a different mechanism of action to platinum‑based chemotherapy and therefore the extension in disease‑free survival with nivolumab might translate into improved survival. The committee acknowledged these comments but considered that the lack of overall survival data was a key uncertainty in the analysis. But, it noted that it would take several years for the trial to show this data because nivolumab is positioned at a less severe part of the treatment pathway. The committee concluded that it is not certain to what extent a benefit in disease‑free survival translates into a benefit in overall survival. # Indirect treatment comparison ## The company's indirect treatment comparison is highly uncertain and does not include a comparison for upper tract urothelial cancer CheckMate 274 did not compare nivolumab with platinum‑based chemotherapy (see section 3.4), so the company provided an indirect treatment comparison. One comparison included people in CheckMate 274, in both the nivolumab and placebo groups, who refused cisplatin. Another comparison compared the CheckMate 274 nivolumab group with evidence from published studies of platinum‑based chemotherapy. In both comparisons, the results showed that outcomes associated with nivolumab and platinum‑based chemotherapy were not statistically significantly different. The exact results of the indirect treatment comparisons are considered academic in confidence and cannot be reported here. The company excluded studies that included upper tract urothelial cancer from its indirect comparison. The committee recalled that adjuvant chemotherapy was a relevant treatment option for this group (see section 3.2). The company explained that CheckMate 274 was not powered to detect differences for upper tract disease, and that providing this indirect comparison would reduce the number of patients that would inform the analysis. The committee noted the company's reasons but considered that an indirect treatment comparison for upper tract urothelial cancer would have been informative. The committee concluded that the company's indirect treatment comparison is highly uncertain. It also concluded that a comparison including only upper tract urothelial cancer would have been the most relevant comparison because of the treatment pathway for upper tract disease. # Economic model ## The company's economic model is appropriate for decision making but does not model disease recurrence robustly The company's model was a Markov model with 4 health states: disease‑free survival, long‑term disease-free, recurred disease and death. In the recurred disease state, the company's base case included 1 line of treatment which was assumed to be either cisplatin or carboplatin. The ERG noted that it was assumed this treatment would be continued until death, which it did not consider to be appropriate. The committee noted that the model assumed equal efficacy in both treatment arms in the recurred disease state. This meant that increases to disease-free survival would translate to overall survival improvements. The committee recalled that the extent to which an increase in disease‑free survival translated to an increased overall survival was a key uncertainty (see section 3.5). The company also used a simplified approach to model survival in the recurred disease health state by applying an exponential function (assuming constant hazards) to overall survival using median values from the literature. The committee noted this did not allow survival rates to vary over time. The committee was also aware that there were further treatment lines available which the company's model did not account for. In particular, it did not include NICE's technology appraisal guidance on atezolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy or avelumab for maintenance treatment of locally advanced or metastatic urothelial cancer after platinum-based chemotherapy. The company did include a scenario which included atezolizumab for untreated PD-L1-positive advanced urothelial cancer when cisplatin is unsuitable, but only for people who had not had nivolumab. The committee expressed concern that the company could have modelled post‑recurrence outcomes more robustly, for example, using tunnel states to allow transition rates to vary over time. The committee also highlighted that the model did not include all treatments currently considered standard care in NHS practice, although it understood avelumab had only recently been recommended by NICE, which limited the generalisability of results. However, the committee was reassured by the ERG that the omission of these treatments was unlikely to bias the cost‑effectiveness estimates in favour of nivolumab. This was because the cost‑effectiveness estimates for nivolumab would likely improve if these treatments were included because nivolumab was predicted to cure a higher proportion of people than best supportive care, therefore avoiding less cost‑effective treatments (see section 3.9). The committee concluded that the company's economic model is appropriate for decision making but does not model disease recurrence robustly. ## Both the generalised gamma and Gompertz distributions are potentially appropriate for estimating disease-free survival The economic model provided by the company uses a generalised gamma distribution to model disease‑free survival for both treatment arms. This distribution was deemed appropriate by the company because it had the best fit to the data. It also allows for a better accounting of the protocol-induced features of the hazard profiles, in particular the steep decline seen at 3 months which coincided with tumour assessments. The ERG agreed that this distribution was potentially appropriate. But, it may not have a desirable fit if the patterns of events observed in the trial, which may be influenced by the timing of data collection, are not reflective of what would happen in clinical practice. Additionally, the ERG noted that the generalised gamma distribution produces a higher risk for disease‑free survival events at 5 years than the general population hazard of mortality. This did not match the company's 5‑year cure assumption (see section 3.9). The ERG advised that the Gompertz distribution is also informative but results in a cure point earlier than 5 years. But, it noted that the choice between these 2 potentially appropriate distributions has only a minimal impact on the cost‑effectiveness estimates. The committee agreed that the choice of distribution is unlikely to affect decision making. It concluded that both the generalised gamma and Gompertz distributions are potentially appropriate for estimating disease‑free survival. ## There is uncertainty about the company's cure assumption The company's base‑case model assumes a cure point at 5 years. This means that there will not be a disease recurrence after 5 years in a disease‑free survival state. The company highlighted that evidence from CheckMate 274 demonstrates that risk of death approaches that of the general population at 5 years. Clinical and patient experts agree that after 5 years in a disease‑free state the risk of disease recurrence is low; however, there was some evidence to show that disease recurrence can happen after 5 years in a small number of cases. The ERG provided an exploratory analysis using a 10‑year cure point. It cited evidence from Sternberg et al. (2015) which demonstrated an increased mortality risk for people with resected urothelial cancer compared with the general population, even after 5 years in a disease‑free state. The committee noted that there is uncertainty surrounding which of these points in time is the most accurate. But, it agreed that the exploratory analyses provided by the ERG had a minimal impact on the cost‑effectiveness results. The committee concluded that there is evidence that disease recurrence may take place after 5 years and mortality risks remain elevated. But, it remains uncertain at what point it is reasonable to assume that people are cured. # Utility values in the economic model ## Disease-free utility values may be overestimated in the company's analysis The model provided by the company assumed that people in the disease‑free survival state after radical surgery have the same health utility as age- and sex‑matched people from the general population. The company highlighted that people in CheckMate 274, who were disease‑free, had higher utility values than those of the age- and sex‑matched general population. Clinical and patient experts agreed that, after a period of adjustment, people with resected urothelial cancer often adapt very well to post‑surgical changes and often achieve a good quality of life with a fully functional lifestyle. They accepted that quality of life for this population is likely to be impacted in the first 1 or 2 years after surgery. The clinical experts noted that while a good quality of life is likely, there is potential for reduced quality of life. This is because of the increased presence of comorbidities in this population, the potential for some persistent effects from radical surgery (such as those impacting on sexual function) and persisting adverse events of treatment. Clinical advice to the ERG also suggested that a reduced quality of life compared with the general population was to be expected. Without evidence to inform a specific disutility value in this population, the ERG applied a disutility of 0.02 to their analyses to test the impact of disutility on the cost effectiveness of nivolumab. This was up until the time at which the cure point is applied. The committee agreed that there was likely to be a health disutility for this population. But, it noted that there was not enough evidence to inform what value this disutility should be, and that the ERG's exploratory analyses had a minimal impact on the cost‑effectiveness results. The committee concluded that disease‑free utility values may be overestimated in the company's analysis. # Assumptions in the economic model ## The company's assumption about life expectancy for people in the long-term disease-free health state is optimistic The company's model assumed that people in the disease‑free survival state for 5 years have the same life expectancy as the general population. Clinical experts agreed that the risk of disease recurrence is low after 5 years and noted that discharge from follow‑up is typical at this point (see section 3.9). The ERG advised that there is some evidence of an increased risk of death, even after being disease‑free for 5 years. It noted that the generalised gamma distribution used in the company model also indicated a mortality risk greater than the general population. It therefore provided a scenario analysis in which an increased risk of mortality is applied between years 5 and 10 in the model. The committee had concerns with the modelling provided by the company but agreed that there is a lack of definitive evidence in this area. It also agreed that the ERG's analyses did not have a substantial impact on the cost‑effectiveness estimates. The committee concluded that the company's assumption that people in the long-term disease-free health state have the same life expectancy as the general population is optimistic. # Cost-effectiveness estimates ## The cost-effectiveness results only apply when platinum-based chemotherapy is unsuitable The company provided an indirect comparison of nivolumab with adjuvant chemotherapy (see section 3.6). However, the company did not provide any cost‑effectiveness analysis comparing nivolumab with adjuvant platinum‑based chemotherapy. The company explained that this was because of the limitations of the indirect treatment comparison. The ERG considered that the cost‑effectiveness results provided by the company were only relevant in circumstances in which platinum‑based chemotherapy was not suitable (see section 3.2). However, the committee also recalled that for some people, particularly those with upper tract urothelial cancer, adjuvant platinum‑based chemotherapy would be an appropriate treatment option (see section 3.2). This included carboplatin for people with renal impairment. The committee recalled that in CheckMate 274, the evidence for nivolumab was less encouraging for people with upper tract urothelial cancer compared with the intention‑to‑treat population (see section 3.4). The ERG stated that it was unlikely that nivolumab would be considered cost effective compared with adjuvant platinum‑based chemotherapy, in people for whom it is suitable. This is because the indirect comparison results showed no overall statistically significant difference in treatment effect and the cost of nivolumab is higher. The committee concluded that because it had not been presented with any cost‑effectiveness results comparing nivolumab with platinum‑based chemotherapy, the cost‑effectiveness results only apply when adjuvant platinum‑based chemotherapy is unsuitable. ## Nivolumab is cost effective only when adjuvant platinum-based chemotherapy is unsuitable The company's base‑case incremental cost‑effectiveness ratio (ICER) for nivolumab was £11,361 per quality‑adjusted life year (QALY) gained compared with best supportive care. The company's base‑case analysis included the following key assumptions: using a generalised gamma distribution to estimate disease-free survival (see section 3.8) the disease will not recur after 5 years in the disease‑free health state (see section 3.9) people in the long‑term disease‑free health state have the same risk of death as that of the general population (see section 3.11).The ERG provided alternative scenarios which explored: using a Gompertz distribution to estimate disease‑free survival increasing the time point in the disease‑free survival health state when it is assumed disease recurrence would not occur applying a higher mortality rate to the long‑term disease‑free survival health state including subsequent atezolizumab treatment in the recurred disease health state in both the nivolumab and best supportive care arm (see section 3.7).The ICERs for nivolumab from the ERG's alternative analysis ranged from £11,259 to £13,758 per QALY gained.The ICERs reported here do not include confidential discounts for subsequent treatments, but including these discounts reduced the ICER for nivolumab. The committee noted that the analysis included the following uncertainties: to what extent disease‑free survival translates to overall survival gains (see section 3.5) the company's model applied a simplified approach to estimate outcomes in the recurred disease health state and did not include all available lines of treatment (see section 3.7).The committee considered that the cost‑effectiveness analysis was only relevant for situations when platinum‑based chemotherapy was unsuitable (see section 3.2 and section 3.12). The committee concluded that, despite these uncertainties, the cost‑effectiveness estimates for nivolumab were likely to be within the range that NICE normally considered a cost‑effective use of NHS resources. This is when platinum‑based adjuvant chemotherapy was not appropriate. # Other factors A patient submission suggested that urothelial cancer is more likely to be diagnosed at a later timepoint in women than men and that women have a lower expected survival rate. The committee considered that the recommendations would be applied to everyone with the condition and was satisfied that no additional considerations were needed in relation to this issue. NICE's advice about life‑extending treatments for people with a short life expectancy did not apply. The committee considered that nivolumab was an innovative treatment in the adjuvant setting. The committee noted that all relevant health benefits for people with the condition had been captured in the economic model. But, it noted that the impact on caregiver quality of life had not been captured and no data on caregiver quality of life had been presented. # Conclusion ## Nivolumab is recommended when platinum-based chemotherapy is not suitable The committee considered that nivolumab is a promising new adjuvant treatment for people with muscle‑invasive urothelial cancer at high risk of recurrence after radical resection and whose tumours express PD‑L1 at a level of 1% or more. However, there are uncertainties in the extent that improved disease‑free survival translates into overall survival gains. The committee was not presented with any cost‑effectiveness analyses comparing nivolumab with platinum‑based chemotherapy. It therefore considered that the cost‑effectiveness results were only relevant to situations when platinum‑based chemotherapy was not suitable. These situations included: the lack of evidence of effect in people with bladder cancer in the adjuvant treatment setting; use of neoadjuvant platinum‑based chemotherapy; when platinum‑based chemotherapy is not suitable for the person or will not be tolerated; or if the person refuses platinum‑based chemotherapy after discussing the benefits and risks with their oncologist. The committee considered that platinum‑based chemotherapy was likely to be an appropriate treatment option for people with urothelial carcinomas of the upper urinary tract, given the POUT trial evidence available. Compared with best supportive care, the ICERs for nivolumab were considered a cost‑effective use of NHS resources when platinum‑based chemotherapy is not suitable. Therefore, the committee recommended nivolumab for routine commissioning, but only if platinum‑based chemotherapy is unsuitable.	{'Recommendations': 'Nivolumab is recommended as an option for the adjuvant treatment of muscle-invasive urothelial cancer that is at high risk of recurrence after radical resection in adults whose tumours express PD-L1 at a level of 1% or more. It is recommended only if:\n\nadjuvant treatment with platinum‑based chemotherapy is unsuitable, and\n\nthe company provides nivolumab according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with nivolumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nRadical resection (surgery) aims to remove all traces of the cancer. Adjuvant treatment aims to reduce the risk of the cancer returning after resection. Standard care for muscle-invasive urothelial cancer that is at high risk of recurrence after radical resection is adjuvant treatment with platinum‑based chemotherapy or best supportive care.\n\nClinical trial evidence shows that adjuvant treatment with nivolumab reduces the risk of the cancer coming back compared with placebo. However, it is uncertain whether nivolumab increases how long people live because this data is not available yet. An indirect treatment comparison of nivolumab with platinum‑based chemotherapy is also highly uncertain.\n\nThe company did not provide cost-effectiveness estimates comparing nivolumab with platinum‑based chemotherapy. The most likely cost-effectiveness estimates for nivolumab compared with best supportive care are uncertain. But, these estimates are within what NICE usually considers an acceptable use of NHS resources when platinum‑based chemotherapy is not a suitable option. So, adjuvant treatment with nivolumab is recommended only if platinum‑based adjuvant chemotherapy is not suitable.', 'Information about nivolumab': "# Marketing authorisation indication\n\nNivolumab (Opdivo, Bristol Myers Squibb) has a UK marketing authorisation 'for the adjuvant treatment of adults with muscle invasive urothelial carcinoma (MIUC) with tumour cell PD-L1 expression ≥ 1%, who are at high risk of recurrence after undergoing radical resection of MIUC'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for nivolumab.\n\n# Price\n\nThe list price of nivolumab is £2,633 per 240\xa0mg per 24‑ml vial (excluding VAT; BNF online, accessed May 2022). The company has a\xa0commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bristol Myers Squibb, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## Nivolumab is a valued adjuvant treatment option for people with resected high-risk muscle-invasive urothelial cancer\n\nMuscle-invasive urothelial cancer can have a significant impact on people and their families and carers. Standard care after radical resection is platinum‑based chemotherapy (adjuvant treatment) or best supportive care. Some people have platinum‑based chemotherapy before the surgery (neoadjuvant treatment) and would not be eligible for adjuvant treatment with platinum‑based chemotherapy. Despite resection, the disease can recur. High risk is defined by the MIUC pathologic staging criteria in section\xa05.1 of nivolumab's summary of product characteristics. The patient experts explained that there is a high unmet need in this area and a new treatment option at this part of the pathway was welcomed. They explained that for some people platinum‑based chemotherapy is not suitable or tolerated, and some people are unwilling to have it. The patient experts explained that extending the duration of disease-free survival is important to patients. This is because it allows them to spend more time with their families and enjoy a good quality of life, and relieves stress on carers. The clinical and patient experts noted that nivolumab was generally well tolerated and that the short infusion time of the treatment compared with chemotherapy was an advantage. The clinical experts explained that immunotherapy at an early stage has the potential to significantly improve outcomes and increase the number of people whose cancer is cured. The committee considered that adjuvant treatment with nivolumab after radical resection may address an unmet need. The committee acknowledged that nivolumab is the first adjuvant immunotherapy available for resected high-risk muscle-invasive urothelial cancer. It concluded that nivolumab is a valued treatment option for people with resected high-risk muscle-invasive urothelial cancer.\n\n# Treatment pathway\n\n## Adjuvant platinum-based chemotherapy and best supportive care are the relevant comparators\n\nThe final NICE scope included adjuvant chemotherapy and best supportive care (active monitoring) as comparators. The CheckMate\xa0274 trial only included a placebo (best supportive care) comparator arm. The company provided cost-effectiveness estimates for nivolumab compared with best supportive care but did not provide cost-effectiveness estimates comparing nivolumab with adjuvant chemotherapy. The company explained that this was because adjuvant chemotherapy use is low in current NHS practice. It explained that this is because of a lack of evidence of clinical benefits and people may refuse chemotherapy because of toxicity concerns. The clinical experts agreed that the use of adjuvant platinum‑based chemotherapy was low for people with bladder cancer. This is because some people have neoadjuvant platinum‑based chemotherapy, and some people are not fit enough to have platinum‑based chemotherapy or they have toxicity concerns. The experts explained that the evidence base for adjuvant platinum‑based chemotherapy was not robust for bladder cancer. The Cancer Drugs Fund clinical lead and the clinical experts explained that for people with urothelial carcinomas of the upper urinary tract, adjuvant platinum‑based chemotherapy was likely to be standard of care. This was because clinical trial evidence from the POUT trial showed an increase in disease‑free survival when platinum‑based adjuvant chemotherapy was given within 90\xa0days of resection (Birtle et al. 2020). In addition, neoadjuvant platinum‑based chemotherapy is usually not suitable for treating urothelial carcinomas of the upper urinary tract. The committee considered that there are several reasons why adjuvant platinum‑based chemotherapy may not be suitable. These reasons included:\n\nthe lack of robust randomised controlled trial evidence on adjuvant platinum‑based chemotherapy for treating bladder cancer\n\nprevious neoadjuvant platinum‑based chemotherapy\n\nthe toxicity profile of platinum‑based chemotherapy in people who have just had major surgery\n\nthe refusal by a person to have adjuvant treatment with platinum‑based chemotherapy after discussing the benefits and risks with their oncologist. The committee considered that platinum‑based chemotherapy was likely to be a suitable treatment option for people with urothelial carcinomas of the upper urinary tract. The committee concluded that adjuvant platinum‑based chemotherapy, when suitable, and best supportive care are the relevant comparators.\n\n## Retreatment with immunotherapy would be offered to some people who have disease recurrence after adjuvant treatment with nivolumab\n\nThe company's scenario analysis assumed that only people who had best supportive care after resection would have the option of immunotherapy (atezolizumab) if disease recurrence occurred. This treatment option was based on NICE's technology appraisal guidance on atezolizumab for untreated PD-L1-positive advanced urothelial cancer when cisplatin is unsuitable. The Cancer Drugs Fund clinical lead explained that people who have nivolumab after resection may have immunotherapy again after disease recurrence if enough time has passed since nivolumab treatment had stopped (approximately 12\xa0months). The ERG provided a scenario in which atezolizumab was a treatment option for both the nivolumab and best supportive care groups after disease recurrence. The committee concluded that retreatment with immunotherapy would be offered to some people who have disease recurrence after adjuvant treatment with nivolumab.\n\n# Clinical evidence\n\n## The clinical evidence for nivolumab is from Checkmate\xa0274, a randomised controlled trial comparing nivolumab with placebo\n\nCheckMate\xa0274 is an ongoing phase\xa03 randomised controlled trial comparing nivolumab with placebo in people with resected muscle-invasive urothelial cancer at high risk of disease recurrence. People had nivolumab for up to 1\xa0year. The trial included 353\xa0people in the nivolumab arm, of whom 140 had tumours expressing PD‑L1 at a level of 1% or more. The trial included 356\xa0people in the placebo arm, of whom 142 had tumours expressing PD‑L1 at a level of 1% or more. CheckMate\xa0274 included people who were eligible to have adjuvant cisplatin (platinum‑based chemotherapy). However, they were only allowed to enrol in the trial if they had documented reasons for refusing adjuvant cisplatin. Disease‑free survival was the primary outcome measure. Median disease‑free survival was not reached in the nivolumab arm in the currently available data (95% confidence interval [CI], 22.1\xa0months to not estimable). Median disease‑free survival in the placebo arm was 8.4\xa0months (95% CI, 5.6\xa0months to 20.0\xa0months). At 6 and 12\xa0months, 74.5% and 67.6% of people in the nivolumab arm were disease-free, respectively. This compared with 55.7% and 46.3% being disease-free in the best supportive care arm. The committee noted that in CheckMate\xa0274, evidence for nivolumab was less encouraging for people with upper tract urothelial cancer compared with the intention‑to‑treat population (hazard ratios: renal pelvis tumour origin, 1.25, 95% CI 0.70 to 2.25; ureter tumour origin, 1.54, 95% CI 0.69 to 3.44). The committee concluded that the currently available data showed that nivolumab increased disease‑free survival compared with placebo in people whose tumours express PD‑L1 at 1% or more.\n\n## It is not certain to what extent a benefit in disease-free survival translates into a benefit in overall survival\n\nThe committee noted that because overall survival data from CheckMate\xa0274 was event driven, the currently available data did not provide information on survival. The committee was aware that some published evidence suggested that disease‑free survival gains may not necessarily lead to overall survival gains (Sternberg et al. 2015). The clinical and patient experts emphasised the importance of disease-free survival in the adjuvant treatment setting. A clinical expert explained that the Sternberg et al. study may not be a reliable predictor of overall survival gains with nivolumab. This is because the study recruited over a long period of time, and many participants were enrolled a long time after having surgery. The Cancer Drugs Fund clinical lead highlighted that nivolumab has a different mechanism of action to platinum‑based chemotherapy and therefore the extension in disease‑free survival with nivolumab might translate into improved survival. The committee acknowledged these comments but considered that the lack of overall survival data was a key uncertainty in the analysis. But, it noted that it would take several years for the trial to show this data because nivolumab is positioned at a less severe part of the treatment pathway. The committee concluded that it is not certain to what extent a benefit in disease‑free survival translates into a benefit in overall survival.\n\n# Indirect treatment comparison\n\n## The company's indirect treatment comparison is highly uncertain and does not include a comparison for upper tract urothelial cancer\n\nCheckMate\xa0274 did not compare nivolumab with platinum‑based chemotherapy (see section\xa03.4), so the company provided an indirect treatment comparison. One comparison included people in CheckMate\xa0274, in both the nivolumab and placebo groups, who refused cisplatin. Another comparison compared the CheckMate\xa0274 nivolumab group with evidence from published studies of platinum‑based chemotherapy. In both comparisons, the results showed that outcomes associated with nivolumab and platinum‑based chemotherapy were not statistically significantly different. The exact results of the indirect treatment comparisons are considered academic in confidence and cannot be reported here. The company excluded studies that included upper tract urothelial cancer from its indirect comparison. The committee recalled that adjuvant chemotherapy was a relevant treatment option for this group (see section\xa03.2). The company explained that CheckMate\xa0274 was not powered to detect differences for upper tract disease, and that providing this indirect comparison would reduce the number of patients that would inform the analysis. The committee noted the company's reasons but considered that an indirect treatment comparison for upper tract urothelial cancer would have been informative. The committee concluded that the company's indirect treatment comparison is highly uncertain. It also concluded that a comparison including only upper tract urothelial cancer would have been the most relevant comparison because of the treatment pathway for upper tract disease.\n\n# Economic model\n\n## The company's economic model is appropriate for decision making but does not model disease recurrence robustly\n\nThe company's model was a Markov model with 4\xa0health states: disease‑free survival, long‑term disease-free, recurred disease and death. In the recurred disease state, the company's base case included 1\xa0line of treatment which was assumed to be either cisplatin or carboplatin. The ERG noted that it was assumed this treatment would be continued until death, which it did not consider to be appropriate. The committee noted that the model assumed equal efficacy in both treatment arms in the recurred disease state. This meant that increases to disease-free survival would translate to overall survival improvements. The committee recalled that the extent to which an increase in disease‑free survival translated to an increased overall survival was a key uncertainty (see section\xa03.5). The company also used a simplified approach to model survival in the recurred disease health state by applying an exponential function (assuming constant hazards) to overall survival using median values from the literature. The committee noted this did not allow survival rates to vary over time. The committee was also aware that there were further treatment lines available which the company's model did not account for. In particular, it did not include NICE's technology appraisal guidance on atezolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy or avelumab for maintenance treatment of locally advanced or metastatic urothelial cancer after platinum-based chemotherapy. The company did include a scenario which included atezolizumab for untreated PD-L1-positive advanced urothelial cancer when cisplatin is unsuitable, but only for people who had not had nivolumab. The committee expressed concern that the company could have modelled post‑recurrence outcomes more robustly, for example, using tunnel states to allow transition rates to vary over time. The committee also highlighted that the model did not include all treatments currently considered standard care in NHS practice, although it understood avelumab had only recently been recommended by NICE, which limited the generalisability of results. However, the committee was reassured by the ERG that the omission of these treatments was unlikely to bias the cost‑effectiveness estimates in favour of nivolumab. This was because the cost‑effectiveness estimates for nivolumab would likely improve if these treatments were included because nivolumab was predicted to cure a higher proportion of people than best supportive care, therefore avoiding less cost‑effective treatments (see section\xa03.9). The committee concluded that the company's economic model is appropriate for decision making but does not model disease recurrence robustly.\n\n## Both the generalised gamma and Gompertz distributions are potentially appropriate for estimating disease-free survival\n\nThe economic model provided by the company uses a generalised gamma distribution to model disease‑free survival for both treatment arms. This distribution was deemed appropriate by the company because it had the best fit to the data. It also allows for a better accounting of the protocol-induced features of the hazard profiles, in particular the steep decline seen at 3\xa0months which coincided with tumour assessments. The ERG agreed that this distribution was potentially appropriate. But, it may not have a desirable fit if the patterns of events observed in the trial, which may be influenced by the timing of data collection, are not reflective of what would happen in clinical practice. Additionally, the ERG noted that the generalised gamma distribution produces a higher risk for disease‑free survival events at 5\xa0years than the general population hazard of mortality. This did not match the company's 5‑year cure assumption (see section\xa03.9). The ERG advised that the Gompertz distribution is also informative but results in a cure point earlier than 5\xa0years. But, it noted that the choice between these 2 potentially appropriate distributions has only a minimal impact on the cost‑effectiveness estimates. The committee agreed that the choice of distribution is unlikely to affect decision making. It concluded that both the generalised gamma and Gompertz distributions are potentially appropriate for estimating disease‑free survival.\n\n## There is uncertainty about the company's cure assumption\n\nThe company's base‑case model assumes a cure point at 5\xa0years. This means that there will not be a disease recurrence after 5\xa0years in a disease‑free survival state. The company highlighted that evidence from CheckMate\xa0274 demonstrates that risk of death approaches that of the general population at 5\xa0years. Clinical and patient experts agree that after 5\xa0years in a disease‑free state the risk of disease recurrence is low; however, there was some evidence to show that disease recurrence can happen after 5\xa0years in a small number of cases. The ERG provided an exploratory analysis using a 10‑year cure point. It cited evidence from Sternberg et al. (2015) which demonstrated an increased mortality risk for people with resected urothelial cancer compared with the general population, even after 5\xa0years in a disease‑free state. The committee noted that there is uncertainty surrounding which of these points in time is the most accurate. But, it agreed that the exploratory analyses provided by the ERG had a minimal impact on the cost‑effectiveness results. The committee concluded that there is evidence that disease recurrence may take place after 5\xa0years and mortality risks remain elevated. But, it remains uncertain at what point it is reasonable to assume that people are cured.\n\n# Utility values in the economic model\n\n## Disease-free utility values may be overestimated in the company's analysis\n\nThe model provided by the company assumed that people in the disease‑free survival state after radical surgery have the same health utility as age- and sex‑matched people from the general population. The company highlighted that people in CheckMate\xa0274, who were disease‑free, had higher utility values than those of the age- and sex‑matched general population. Clinical and patient experts agreed that, after a period of adjustment, people with resected urothelial cancer often adapt very well to post‑surgical changes and often achieve a good quality of life with a fully functional lifestyle. They accepted that quality of life for this population is likely to be impacted in the first 1 or 2\xa0years after surgery. The clinical experts noted that while a good quality of life is likely, there is potential for reduced quality of life. This is because of the increased presence of comorbidities in this population, the potential for some persistent effects from radical surgery (such as those impacting on sexual function) and persisting adverse events of treatment. Clinical advice to the ERG also suggested that a reduced quality of life compared with the general population was to be expected. Without evidence to inform a specific disutility value in this population, the ERG applied a disutility of 0.02 to their analyses to test the impact of disutility on the cost effectiveness of nivolumab. This was up until the time at which the cure point is applied. The committee agreed that there was likely to be a health disutility for this population. But, it noted that there was not enough evidence to inform what value this disutility should be, and that the ERG's exploratory analyses had a minimal impact on the cost‑effectiveness results. The committee concluded that disease‑free utility values may be overestimated in the company's analysis.\n\n# Assumptions in the economic model\n\n## The company's assumption about life expectancy for people in the long-term disease-free health state is optimistic\n\nThe company's model assumed that people in the disease‑free survival state for 5\xa0years have the same life expectancy as the general population. Clinical experts agreed that the risk of disease recurrence is low after 5\xa0years and noted that discharge from follow‑up is typical at this point (see section\xa03.9). The ERG advised that there is some evidence of an increased risk of death, even after being disease‑free for 5\xa0years. It noted that the generalised gamma distribution used in the company model also indicated a mortality risk greater than the general population. It therefore provided a scenario analysis in which an increased risk of mortality is applied between years\xa05 and 10 in the model. The committee had concerns with the modelling provided by the company but agreed that there is a lack of definitive evidence in this area. It also agreed that the ERG's analyses did not have a substantial impact on the cost‑effectiveness estimates. The committee concluded that the company's assumption that people in the long-term disease-free health state have the same life expectancy as the general population is optimistic.\n\n# Cost-effectiveness estimates\n\n## The cost-effectiveness results only apply when platinum-based chemotherapy is unsuitable\n\nThe company provided an indirect comparison of nivolumab with adjuvant chemotherapy (see section\xa03.6). However, the company did not provide any cost‑effectiveness analysis comparing nivolumab with adjuvant platinum‑based chemotherapy. The company explained that this was because of the limitations of the indirect treatment comparison. The ERG considered that the cost‑effectiveness results provided by the company were only relevant in circumstances in which platinum‑based chemotherapy was not suitable (see section\xa03.2). However, the committee also recalled that for some people, particularly those with upper tract urothelial cancer, adjuvant platinum‑based chemotherapy would be an appropriate treatment option (see section\xa03.2). This included carboplatin for people with renal impairment. The committee recalled that in CheckMate\xa0274, the evidence for nivolumab was less encouraging for people with upper tract urothelial cancer compared with the intention‑to‑treat population (see section\xa03.4). The ERG stated that it was unlikely that nivolumab would be considered cost effective compared with adjuvant platinum‑based chemotherapy, in people for whom it is suitable. This is because the indirect comparison results showed no overall statistically significant difference in treatment effect and the cost of nivolumab is higher. The committee concluded that because it had not been presented with any cost‑effectiveness results comparing nivolumab with platinum‑based chemotherapy, the cost‑effectiveness results only apply when adjuvant platinum‑based chemotherapy is unsuitable.\n\n## Nivolumab is cost effective only when adjuvant platinum-based chemotherapy is unsuitable\n\nThe company's base‑case incremental cost‑effectiveness ratio (ICER) for nivolumab was £11,361 per quality‑adjusted life year (QALY) gained compared with best supportive care. The company's base‑case analysis included the following key assumptions:\n\nusing a generalised gamma distribution to estimate disease-free survival (see section\xa03.8)\n\nthe disease will not recur after 5\xa0years in the disease‑free health state (see section\xa03.9)\n\npeople in the long‑term disease‑free health state have the same risk of death as that of the general population (see section\xa03.11).The ERG provided alternative scenarios which explored:\n\nusing a Gompertz distribution to estimate disease‑free survival\n\nincreasing the time point in the disease‑free survival health state when it is assumed disease recurrence would not occur\n\napplying a higher mortality rate to the long‑term disease‑free survival health state\n\nincluding subsequent atezolizumab treatment in the recurred disease health state in both the nivolumab and best supportive care arm (see section\xa03.7).The ICERs for nivolumab from the ERG's alternative analysis ranged from £11,259 to £13,758 per QALY gained.The ICERs reported here do not include confidential discounts for subsequent treatments, but including these discounts reduced the ICER for nivolumab. The committee noted that the analysis included the following uncertainties:\n\nto what extent disease‑free survival translates to overall survival gains (see section\xa03.5)\n\nthe company's model applied a simplified approach to estimate outcomes in the recurred disease health state and did not include all available lines of treatment (see section\xa03.7).The committee considered that the cost‑effectiveness analysis was only relevant for situations when platinum‑based chemotherapy was unsuitable (see section\xa03.2 and\xa0section\xa03.12). The committee concluded that, despite these uncertainties, the cost‑effectiveness estimates for nivolumab were likely to be within the range that NICE normally considered a cost‑effective use of NHS resources. This is when platinum‑based adjuvant chemotherapy was not appropriate.\n\n# Other factors\n\nA patient submission suggested that urothelial cancer is more likely to be diagnosed at a later timepoint in women than men and that women have a lower expected survival rate. The committee considered that the recommendations would be applied to everyone with the condition and was satisfied that no additional considerations were needed in relation to this issue.\n\nNICE's advice about life‑extending treatments for people with a short life expectancy did not apply.\n\nThe committee considered that nivolumab was an innovative treatment in the adjuvant setting. The committee noted that all relevant health benefits for people with the condition had been captured in the economic model. But, it noted that the impact on caregiver quality of life had not been captured and no data on caregiver quality of life had been presented.\n\n# Conclusion\n\n## Nivolumab is recommended when platinum-based chemotherapy is not suitable\n\nThe committee considered that nivolumab is a promising new adjuvant treatment for people with muscle‑invasive urothelial cancer at high risk of recurrence after radical resection and whose tumours express PD‑L1 at a level of 1% or more. However, there are uncertainties in the extent that improved disease‑free survival translates into overall survival gains. The committee was not presented with any cost‑effectiveness analyses comparing nivolumab with platinum‑based chemotherapy. It therefore considered that the cost‑effectiveness results were only relevant to situations when platinum‑based chemotherapy was not suitable. These situations included: the lack of evidence of effect in people with bladder cancer in the adjuvant treatment setting; use of neoadjuvant platinum‑based chemotherapy; when platinum‑based chemotherapy is not suitable for the person or will not be tolerated; or if the person refuses platinum‑based chemotherapy after discussing the benefits and risks with their oncologist. The committee considered that platinum‑based chemotherapy was likely to be an appropriate treatment option for people with urothelial carcinomas of the upper urinary tract, given the POUT trial evidence available. Compared with best supportive care, the ICERs for nivolumab were considered a cost‑effective use of NHS resources when platinum‑based chemotherapy is not suitable. Therefore, the committee recommended nivolumab for routine commissioning, but only if platinum‑based chemotherapy is unsuitable."}	https://www.nice.org.uk/guidance/ta817	Evidence-based recommendations on nivolumab (Opdivo) for adjuvant treatment of invasive urothelial cancer at high risk of recurrence.
35976b51c12e303119769a7202ee6bdb7a19fa2d	nice	SecurAcath for securing percutaneous catheters	SecurAcath for securing percutaneous catheters Evidence-based recommendations on SecurAcath for securing percutaneous catheters. # Recommendations SecurAcath is recommended as a cost-saving option for securing peripherally inserted central catheters (PICCs) with an anticipated medium- to long-term dwell time. Why the committee made these recommendations The evidence shows that SecurAcath is at least as good as other devices for securing PICCs. It also has the benefit of not needing to be replaced at weekly dressing changes. It has a high rate of successful device placement and a low incidence of catheter-related complications. Cost modelling shows that SecurAcath is cost saving compared with adhesive securement devices if the PICC remains in place for 21 days or longer. Cost savings result from shorter maintenance times and less need for device replacement when using SecurAcath.# The technology # Description of the technology SecurAcath (Interrad Medical) is a single-use device to secure percutaneous catheters in position on the skin. It is intended for use in adults and children who need a central venous catheter (CVC), a long, thin, flexible tube that is inserted into a vein through the skin. It is positioned so that the distal tip lies in a large central vein, usually the superior vena cava, right atrium or inferior vena cava. CVCs are inserted using various access sites, including veins in the arm, chest, neck or groin; the choice in individual patients depends on a variety of factors such as anticipated duration of access needed (dwell time), reason for insertion and the quality and patency of venous sites available. There are 4 types of CVCs (Dougherty et al. 2015): Peripherally inserted central catheters (PICCs): CVCs inserted into a peripheral vein in the arm, rather than in the neck or chest. PICCs may be used for short-term access (7 to 10 days), but are more typically used in people needing intravenous access for several weeks or months. They are used in inpatient and outpatient settings. Non-tunnelled CVCs (referred to in this guidance as 'CVCs'): Short-term CVCs placed into a large vein near the neck, chest, or groin. Non-tunnelled CVCs are indicated for short-term access (usually 7 to 10 days) when peripheral access is impractical or in acute, urgent situations. Non-tunnelled CVCs need securing at the site of insertion. Tunnelled CVCs (also called Hickman lines): CVCs that are passed under the skin (tunnelled) from an insertion site near the neck or chest to a separate exit site, which helps to prevent infection and provides stability. Tunnelled CVCs are indicated for long-term access (more than 30 days). These long-term CVCs need securement for the first 2 to 4 weeks until tissue granulation around the 'cuff' of the tunnel, but after this, do not need additional securing. Implanted ports: CVCs placed completely under the skin, which are used for long-term therapies. Implanted ports have few complications, have minimal risk of infection and do not need securing. SecurAcath has 2 parts, a base and cover. The base is made up of 2 foldable metal legs and 2 securement feet. The feet are placed under the skin at the catheter insertion site, and unfolded to make a subcutaneous anchor. The cover attaches to the catheter shaft and holds it in place when it is clipped onto the base. The device stays in place as long as the catheter is needed and can be lifted off the skin to allow cleaning of the insertion site. SecurAcath is a class IIB device first CE marked in 2012. It is available in 6 different sizes (3 F to 8 F). The SecurAcath device is size-specific and the choice of device should be matched to the size of the catheter. The current size range for SecurAcath is not suitable for use with most renal dialysis catheters (a specific type of long-term tunnelled CVC). However, larger sizes (up to 12 F) are planned to be available in late 2017, which may be suitable for use with these type of CVCs. The list price of SecurAcath stated in the company's submission is £16.00 excluding VAT. During development of the guidance, the company updated the UK list price of SecurAcath to £20.00. The cost of SecurAcath has been updated in the revised cost model to £18.00 excluding VAT. The claimed benefits of SecurAcath in the case for adoption presented by the company are: no interruptions or delays in therapy because of improved catheter securement fewer repeat procedures by improving vessel preservation and reducing reinsertions fewer catheter complications (dislodgements, migration, thrombosis and infection) a decrease in catheter replacement costs a reduction in overall treatment costs because of fewer delays and complications. # Current management Current options for catheter securement include adhesive devices (such as StatLock and Grip-Lok), steri-strips, tape and sutures (stitches). NICE has not produced guidance on securing catheters for central venous access. The NICE guideline on healthcare-associated infections recommends that the skin at and around the catheter insertion site is cleaned with chlorhexidine gluconate in 70% alcohol and allowed to air dry during dressing changes. The insertion site should be covered by a sterile transparent semipermeable membrane dressing which should be changed every 7 days or sooner if the dressing is no longer intact or moisture collects under it. British Committee for Standards in Haematology on the insertion and management of central venous access devices in adults (Bishop et al. 2007) recommend using securing devices such as StatLock rather than sutures, and discourage the suturing of catheters to the skin. Several NHS trusts have produced local guidance on using catheter securement devices including SecurAcath. The US Infusion Nursing Society's Infusion Standards of Practice (2016) refers to engineered stabilisation devices such as SecurAcath and StatLock. It suggests that these types of devices should be considered for securing catheters. It also says that engineered stabilisation devices promote consistent practice among clinicians, reduce catheter movement that can lead to complications, reduce the number of interruptions needed for infusion therapy, and may lower costs of care. The document suggests that tape or sutures should be avoided because they are not as effective as engineered stabilisation devices, based on good quality evidence from randomised controlled trials. The document also states that users should be aware of the risk of medical adhesive-related skin injury with the use of adhesive-based engineered stabilisation devices.# Clinical evidence # Summary of clinical evidence The key clinical outcomes for SecurAcath given in the decision problem were: rates of catheter migration and dislodgement rates of catheter-related infection, including catheter-related bloodstream infection, local infection or inflammation and thrombophlebitis number of unplanned catheter removals and reinsertions time taken to secure the catheter patient and clinician satisfaction scores pain while in position and on insertion and removal quality-of-life measures device-related adverse events, for example catheter malfunction, thrombosis and vessel erosion. The external assessment centre assessed 11 studies on SecurAcath, 9 submitted by the company and 2 identified independently. Three SecurAcath studies were published as peer-reviewed journal articles (Cordovani and Cooper 2013; Egan et al. 2013; Hughes et al. 2014), the remaining 8 studies were unpublished manuscripts, poster presentations, audit reports or conference abstracts (Janssens et al. 2016b; Djurcic-Jovan et al. 2016; Dougherty et al. 2013; Hill et al. 2014; Misericordia et al. 2015; Zerla et al. 2016; Stone et al. 2013; McParlan et al. 2016). The external assessment centre also identified 6 studies on a comparator, StatLock (Fang et al. 2011; Teichgräber et al. 2011; McMahon et al. 2002; Yamamoto et al. 2002; Zerla et al. 2016; Venturini et al. 2011). During the evaluation, Zerla et al. 2016 was published as a peer-reviewed article (Zerla et al. 2017). ## Published studies with SecurAcath Cordovani and Cooper (2013) is a prospective multicentre cohort study done in Canada, which investigated 74 adults who had central venous catheters (CVCs) secured with SecurAcath. The primary outcome was device securement success, which was reported in 72 patients (97%). Mean catheter securement time was 62.5 seconds and the mean dwell time was 3.1 days. Discomfort was measured on a 1 to 10 scale (with 10 being most discomfort): mean scores were 0.9 in situ and 1.6 at removal. Of the 15 patients who had previously had a sutured catheter, 14 found SecurAcath 'as or more comfortable'. Six out of 8 healthcare professionals found maintenance 'somewhat' or 'much easier' than sutures. Egan et al. (2013, and its earlier iteration Sansivero ) investigated peripherally inserted central catheters (PICCs) secured with SecurAcath in 68 adults in intensive care units, transplant units or outpatient clinics at 3 centres in the US. The primary end point was device securement success, defined by the absence of device-related malfunctions and adverse events. Secondary end points included securement time, patient comfort and ease of maintenance. Mean dwell time was 22.6 days and mean securement time was 31 seconds. Securement-related malfunctions were seen in 6 patients (8.8%), with 20 (22.1%) adverse events reported. Pain scores were measured on a 0 to 10 scale: immediately after device removal, the mean pain score was 1.5. In situ mean pain score was 0.7 and 91.2% of patients were either neutral, satisfied or very satisfied with SecurAcath. Use of SecurAcath did not influence placement or maintenance techniques. The authors concluded that SecurAcath performed favourably when compared with StatLock (on the basis of historical data for StatLock reported by Yamamoto et al. : respective rates of migration and dislodgement of 2.9% and 0% for SecurAcath and 6% and 12% for StatLock). Hughes et al. (2014) prospectively evaluated PICCs with SecurAcath in 31 adults at a single UK centre. Mean dwell time was over 30 days in 45% of patients. The study reported 100% successful device placement; 11% were placed with 'difficulty' and 19% with 'slight difficulty'. Staff reported difficulty with removal 'fairly frequently'. One patient experienced catheter migration of 1 cm. Pain scores were measured on a 0 to 10 scale. At placement, pain scores were 0 in all patients; in situ, 5 patients' scores were over 5, and at removal over half of patients' scores were over 3. PICCs were removed in 3 patients because of severe or unresolved pain. The study reported a PICC-related infection rate of 12% (n=31), which was reduced to 2% in a subsequent cohort (n=100). Zerla et al. (2017; and the earlier unpublished extract Zerla et al. 2016) is a single-centre prospective study done in Italy without a comparator. It investigated 30 adults needing chemotherapy who had a PICC in place for over 2 months, secured with SecurAcath. The median dwell time was 145 days. Skin integrity issues were reported in 32.2% of patients. Pain scores were measured on a 0 to 10 scale: at placement, pain scores were less than or equal to 2 in 90% of patients, in situ they were less than or equal to 2 in 95% of patients and at removal they were less than or equal to 2 in 43.33% of patients. The authors report a median insertion site maintenance time of 10 minutes for SecurAcath, which compared favourably with a median of 20 minutes maintenance time for an adhesive device in a historical cohort of patients. No cases of dislodgment, infection and thrombotic episodes were reported. There were 2 unplanned catheter removals. The authors concluded that, after effective training, SecurAcath is comfortable for the patient, reduces catheter movements, and is more effective in comparison to adhesive devices in oncology patients with long-term catheterisation and ambulatory maintenance. ## Unpublished studies and conference abstracts with SecurAcath Janssens (2016b) is a Belgian-based, single-centre, prospective, unblinded, randomised controlled trial comparing PICCs secured with SecurAcath and PICCs secured with StatLock in adults. The outcomes included time spent on dressing changes, catheter migration, accidental dislodgement and laboratory-confirmed catheter-related bloodstream infection. The study was submitted as an unpublished manuscript which was available to the committee as academic in confidence. Djurcic-Jovan et al. (2016) is a single-centre retrospective, observational, comparative, longitudinal study done in Canada comparing PICCs placed with and without SecurAcath in 54 patients needing complex continuing care. The primary outcome measure was unplanned catheter reinsertion. Mean dwell time was over 31 days. There were 60 unplanned catheter reinsertions reported without using SecurAcath compared with 3 unplanned reinsertions with SecurAcath. There was no catheter migration reported. The authors saw substantial time savings for nurses and clinicians after the introduction of SecurAcath. Qualitative outcomes were collected retrospectively. For SecurAcath, catheter migration was rated 'very good' or 'good' in 88% of cases, and catheter stability while doing insertion site maintenance, ease of dressing, and overall use of the device were rated as 'very good' or 'good' in 95% of cases. Dougherty et al. (2013) is a UK-based single-centre prospective study without a comparator which evaluated PICCs secured with SecurAcath over 1 month in 30 patients. Qualitative data were gathered from nurses and patients. There was a reduction in malposition and catheter damage compared with previous practice and no skin reactions were seen. Nurses reported increased confidence in doing insertion site maintenance but also reported some difficulty removing the device. Patients reported pain at insertion ('if incorrectly placed and the anchor was too superficial') and pain at removal. Hill (2014) is a Canadian-based single-centre pilot evaluation of PICCs secured with SecurAcath in 60 patients without a comparator. The author reported no malpositions but accidental dislodgement in 2 agitated patients. The author described dressing changes as being done by 'general unit staff, not IV team staff': SecurAcath gave staff increased confidence, fewer anxieties and increased efficiencies. The author described the successful use of SecurAcath in patients with skin integrity issues, when the device was used without adhesive dressing. The author concluded that overall patient satisfaction was achieved. Misericordia et al. (2015, reported as Anonymous 2015 in the assessment report) is an unpublished report provided by the company. This is a retrospective, comparative audit done by the parenteral therapy team at the Misericordia Community hospital in Canada which evaluated 164 unanchored PICCs placed during 2013 and 542 PICCs placed during 2014 and secured with SecurAcath. The average dwell time was 29 days. The report also evaluated using a PICC designed to reduce catheter-related thrombosis. Six different operators took part in the evaluation. The primary outcomes were catheter-related thrombosis, PICC occlusion, catheter malposition, local infection and catheter-related bloodstream infection. In the SecurAcath cohort, there were no confirmed catheter-related bloodstream infections. From 2013 to 2014, the rate of catheter-related thrombosis decreased from 3.75% to 3.69%, PICC occlusion increased from 14.35% to 16.97%, and malposition decreased from 10.98% to 1.66%. The authors concluded that without using SecurAcath, around 60 of the 542 patients would have otherwise needed catheter replacements. Stone et al. (2013) is a prospective, single-centre study done in the US which included PICCs secured with SecurAcath in 42 children with previous skin problems, irritation or allergic reactions to standard dressings. The authors compared outcomes with historical data on 17 patients with catheter migration in the same centre (undefined cohort). In the SecurAcath cohort, there were no catheter migrations, complications or unplanned catheter removals. The authors concluded that further research was needed to optimise dressings in patients with skin integrity issues. McParlan et al. (2016) is a single-centre, UK prospective cohort study comparing PICCs secured with SecurAcath and with StatLock in haematology and oncology patients, published as a conference abstract. The full study was submitted as an unpublished poster which was available to the committee as academic in confidence. The abstract states that, during the study, there were no reported incidences of migration or PICC removal. This was associated with a reduction in chest X-rays to verify the location of migrated catheter tips (and therefore decreased exposure to radiation). There was also a reduced need for reinsertions, and reduced delays to therapy. The study reported significant financial benefits because of fewer PICC reinsertions and more efficient dressing changes. Additional benefits include reduced skin reactions, improved cleaning of the catheter site and greater user satisfaction. The abstract authors concluded that using SecurAcath had prevented PICC migration and improved patient outcomes. ## Additional work by the external assessment centre The external assessment centre noted the lack of comparative published evidence between SecurAcath and its comparators. It considered the unpublished randomised controlled trial (Janssens et al. 2016b) to be the most relevant evidence to inform the decision problem. The external assessment centre did a meta-analysis using data from 16 studies on 5 clinical outcomes that it considered appropriate: migration, dislodgement, catheter-related infection, catheter-related bloodstream infection and unplanned removals/reinsertions. Because of the limited evidence base, there was significant uncertainty in the results, reflected in wide 95% confidence intervals (95% CI). The meta-analysis reported the following results comparing SecurAcath with StatLock: migration: 4.00% (95% CI: 1.48 to 8.50) and 4.72% (95% CI: 2.28 to 8.50); dislodgment: 0.59% (95% CI: 0.3 to 1.03) and 4.07% (95% CI: 3.29 to 4.97); catheter-related infection: 0.77% (95% CI: 0.28 to 1.66) and 1.64% (95% CI: 1.10 to 2.35); catheter-related bloodstream infection: 1.68% (95% CI: 0.20 to 5.94) and 1.47% (95% CI: 0.18 to 5.21). The external assessment centre considered the meta-analysis to be supportive of the results of Janssens et al. 2016b (except dislodgement, where the meta-analysis showed a difference in dislodgement rates), with similar clinical outcomes between devices. The external assessment centre concluded that there is not enough evidence to show that SecurAcath is clinically superior in effectiveness and adverse events to StatLock, but there is some evidence that SecurAcath is non-inferior to StatLock. ## Committee considerations The committee considered that the available evidence, despite its limitations, was enough to conclude that SecurAcath was associated with a high rate of successful device placement, a low incidence of catheter-related complications and does not usually need replacing while the catheter is in place. The committee also considered that the emerging comparative evidence suggested that SecurAcath is at least as effective as other devices for securing PICCs, with the added benefit of not needing to be replaced at weekly dressing changes. The committee received advice from experts who use SecurAcath to secure PICCs in haematology and oncology patients in both inpatient and outpatient settings. The experts highlighted that PICCs in these patients have long dwell times of at least 6 months, and can be in place for up to 1 year. The committee was advised by the experts that SecurAcath is well tolerated by patients when placed by an experienced healthcare professional. Pain on insertion is rare, because local anaesthetic is used anyway during the initial PICC placement. Pain is also rare while the device is in place, as long as it has been placed correctly. SecurAcath removal involves using scissors to cut the device in half and local anaesthetic administration is rarely needed. One expert stated that any discomfort patients experienced with using SecurAcath was countered by a reduction in anxiety linked with a lower likelihood of catheter displacement during dressing changes. The committee was told by the experts that it is routine practice to anticipate the likely dwell time of PICCs at the time of insertion, based on the individual patient and clinical circumstances. It is possible that this consideration would inform the securement method selected in normal clinical practice. Although PICCs are sometimes in place for less time than anticipated, this is usually because of unexpected complications that necessitate early removal or replacement.# NHS considerations # System impact The company claimed that SecurAcath could lower costs by avoiding delays in treatment and reducing catheter-related complications. Experts considered that specialist training was needed for the insertion, maintenance and removal of SecurAcath. Removal of the device was identified as the most challenging element in its use, but this becomes easier with more experience. NICE has produced an adoption resource about using SecurAcath for the securement of peripherally inserted central catheters (PICCs). ## Committee considerations The committee was advised by the experts that dressing changes are needed at the catheter insertion site on a weekly basis. They also said that a considerable amount of time is saved by using SecurAcath compared with StatLock for the maintenance of long-term PICCs. Dressing changes are much quicker and easier and there is a reduced risk of catheter dislodgement with SecurAcath. The committee concluded that training was essential for the correct insertion, maintenance and removal of SecurAcath. Experts advised that proficiency improves quickly with experience and that there is a short learning curve. Training is provided free of charge by the company. This includes face-to-face instruction by clinical nurse advisers as well as online support from a downloadable mobile application. SecurAcath is contraindicated in people with nickel allergy. One expert stated that, in their experience, true nickel allergy is rare and they had not encountered an allergic reaction to SecurAcath in their practice. It was also stated by the experts that patients may experience sensitivity to adhesive dressings. The experts stated that they had no experience of using SecurAcath in young children (who tend to have tunnelled central venous catheters), but 1 had used it successfully with older children (aged 12 years and over) having chemotherapy. One expert stated that bleeding can occur after SecurAcath placement, so more dressings may be needed.# Cost considerations # Cost evidence The company identified 3 published economic studies, but the external assessment centre considered them to be outside the scope. It did not identify any further economic studies. The company presented a de novo cost model that compared the cost consequences of using SecurAcath in people with peripherally inserted central catheters (PICCs) compared with StatLock, and in people with central venous catheters (CVCs) compared with sutures. The model used a decision-tree structure where people entered the model at the point of having a securement device (either SecurAcath, StatLock or sutures). Both trees contained 5 outcomes after securement: no complications; catheter migration; catheter malposition; catheter occlusion; or catheter-related infection (catheter-related bloodstream infection or catheter-related thrombosis). There was an additional outcome of needlestick injuries for health professionals in the suture group. The model was constructed with a time horizon of 25 days for PICCs and 3 days for CVCs. Other clinical parameters such as the probability of migration, malposition, occlusion, infection and thrombosis were derived from published and unpublished literature. Device and resource costs relating to the cost of placement (such as nurse time) and complications were also from published and unpublished sources. The results of the company's base case found cost savings with SecurAcath of £41.40 per patient for PICCs compared with StatLock and £1,005.60 per patient for SecurAcath with other CVCs compared with sutures. The main reasons for StatLock's greater costs as compared with SecurAcath were device costs and differences in catheter migration rates. For sutures, the main reasons for the greater costs were differences in the rates of catheter-related bloodstream infection or catheter-related thrombosis. The company did a 1-way deterministic sensitivity analysis, increasing SecurAcath device costs by up to 200%. It also did multiway deterministic sensitivity analyses, changing the values for each economic and clinical parameter simultaneously by ±20%. In all cases, SecurAcath remained cost saving compared with its comparator. When PICC dwell time was increased to 6 months (reflecting a typical clinical situation of a patient having cancer treatment), the cost saving with SecurAcath increased to £115.00 per patient. During the evaluation, a new peer-reviewed article was published that provided a simple cost analysis (Zerla et al. 2017). The published cost comparison of SecurAcath with StatLock only included the cost of the devices. Few details on the analysis are given, but the 30 patients having SecurAcath were compared with a historic control population (Zerla et al. 2015) of 793 patients who had PICCs secured with StatLock. Devices were assumed to cost €30 for SecurAcath and €6 for StatLock, giving a total device cost of €900 for SecurAcath and €4,254 for StatLock. The authors concluded that SecurAcath is cost saving. The authors also report no dislodgments with SecurAcath and compare this with results from Zerla et al. (2015) in which 63 dislodgements were seen. An overall cost for reinsertion for all 63 dislodgements is estimated to be €18,710. The NICE adoption and impact scoping report (included in the assessment report overview) describes a single centre's experience of real-world total cost savings of up to £59,000 with SecurAcath when compared with StatLock when placing 1,100 PICCs over 6 months. NICE has published a resource impact template on SecurAcath, which can be used to calculate the local resource impact of implementing the guidance. ## Additional work by the external assessment centre Overall, the external assessment centre considered the company's model to be appropriate given the limited evidence base available, but noted some errors in the model. These included figures wrongly quoted, applying probabilities as rates and a lack of clarity on some sources of evidence. It queried several assumptions in the model: dwell times; the differential impact of securement device placement by nurses or doctors; that no extra resources are needed to place securement devices and the clinical outcomes chosen. It also queried the significant assumption in the model that outcomes were independent of time and were collected over similar dwell times. It noted there was a risk of study heterogeneity and uncertainty about variations in clinical practice and outcome measurements. The external assessment centre regarded Yamamoto et al. (2002) as the best evidence available on the incidence of complications, because it reported rates rather than probabilities. Yamamoto et al. (2002) is a single-centre, US-based, prospective randomised controlled trial, comparing StatLock with sutures in patients with PICCs (n=170). The primary end point was catheter-related complications. Mean dwell times were 33 days for StatLock and 35 days for sutures. The risk of total complications was 49.4% and 71.7% for StatLock and sutures, respectively (p=not significant). There was no statistically significant difference in dislodgement or migration rates between the 2 groups, but a significant reduction in infections with StatLock was seen (p=0.032). Using this evidence and the updated list price of SecurAcath, the external assessment centre revised the model base case. It assumed clinical equivalence for all outcomes between SecurAcath and comparators, except for needlestick injury, where a reduced risk without sutures was highly likely. Therefore, base-case costs related to placement and maintenance costs over the relevant dwell time only, with needlestick injury costs included where relevant. It also considered 3 dwell times for both CVCs and PICCs: 5 days (short), 25 days (medium), and 120 days (long). Other amendments included: adding StatLock as a comparator for CVCs; varying placement and maintenance times; suturing being done by a band 6 nurse; sutures remaining throughout the dwell time and updating resource costs. The revised base case found that StatLock was the cheapest option for PICCs for short dwell times (5 days), but that SecurAcath was cost saving for medium to long dwell times (25 days and over). For CVCs, StatLock was the cheapest securement option for short dwell times and sutures was the cheapest for medium to long dwell times. After the increase in the SecurAcath list price to £20, the external assessment centre reran the model, which increased SecurAcath costs in all analyses by £4 (see table 1 for a summary of external assessment centre results). The external assessment centre concluded that the impact of the list price change was minimal. StatLock remained the cheapest option for dwell times of 5 days and SecurAcath remained cheaper than StatLock for dwell times of 25 days and 120 days. A one-way sensitivity analysis, reducing SecurAcath placement time to 30 seconds (as reported by the company), made SecurAcath slightly more cost saving and sutures slightly less cost saving, but did not change the base-case results (see table 1 for a summary of external assessment centre results). Another one-way sensitivity analysis assumed an insertion site maintenance time of 7.3 minutes for sutures, equivalent to the time reported for StatLock in Janssens (2016b). This changed the results for CVCs such that SecurAcath was cheaper than sutures for both PICCs and CVCs with a medium and long dwell time (see table 1). The external assessment centre did a multivariate sensitivity analysis including differential risks of migration, dislodgement and catheter-related bloodstream infections, based on the figures reported in Yamamoto et al. (2002) and its meta-analysis. This found that StatLock was the cheapest option for short dwell times for both PICCs and CVCs, but for medium and long dwell times, SecurAcath was the most cost saving (see table 1). Scenario CVC (central venous catheter): 5 days StatLock (£5) StatLock (£5) StatLock (£5) StatLock(£15) StatLock (£5) PICC (peripherally inserted central catheter): 5 days StatLock (£16) StatLock (£11) StatLock (£16) StatLock (£18) StatLock (£16) CVC: 25 days Sutures (£11) Sutures (£6) SecurAcath (£8) SecurAcath (£21) Sutures (£6) PICC: 25 days SecurAcath (£13) SecurAcath (£18) SecurAcath (£13) SecurAcath (£9) SecurAcath (£13) CVC: 120 days (not clinically relevant: non-tunnelled CVCs only used short term) Sutures (£11) Sutures (£6) SecurAcath (£90) SecurAcath (£112) Sutures (£6) PICC: 120 days SecurAcath (£90) SecurAcath (£95) SecurAcath (£90) SecurAcath (£64) SecurAcath (£90) Scenarios: . Base case (placement and maintenance costs only; no differences in complication rates across devices). . One-way sensitivity analysis: assumes a SecurAcath placement time of 30 seconds. . One-way sensitivity analysis: assumes a suture maintenance time of 7.3 minutes. . Multiway sensitivity analysis including complication rates. . Suturing done by a consultant anaesthetist. A threshold sensitivity analysis for dwell times using the base case indicated that SecurAcath was the cheapest option for securing PICCs for 15 days or more. For CVCs, the costs of sutures dropped below those of StatLock for dwell times of 8 days or more, but SecurAcath remained more expensive than sutures for securing CVCs over any dwell time. The increased list price of SecurAcath did not affect the threshold analysis. For PICCs, the external assessment centre agreed with the company's conclusion that SecurAcath appears to be cheaper than StatLock over medium and long dwell times (25 days and over). Cost savings arise from shorter maintenance times with SecurAcath and the need to replace StatLock weekly. It concluded that these cost savings were robust: it found smaller savings in the base case excluding complications, but similar results in sensitivity analyses including complications. For CVCs, the external assessment centre agreed with the company's conclusion that SecurAcath was cost saving compared with sutures over short dwell times, but disagreed with the exclusion of StatLock as a comparator. Additional analysis including StatLock concluded that it was the cheapest for CVCs with short dwell times in all scenarios. For medium to long dwell times, suturing was cheaper than SecurAcath or StatLock in the base case (excluding complications). However, evidence suggested an increased risk of infection with suturing. Sensitivity analyses including complications found SecurAcath to be cheaper than suturing and StatLock over 25- and 120-day dwell times. This led the external assessment centre to conclude that SecurAcath is likely to be the cheapest option for securing CVCs over medium and long dwell times. The external assessment centre reviewed the cost analysis in Zerla et al. (2017). The authors report shorter maintenance time for SecurAcath than StatLock, but do not include this in the cost comparison. They report median maintenance times of 10 minutes for SecurAcath and 20 minutes for StatLock, but the methodology for these estimates is unclear. Although the times reported are longer than the estimates of 4.3 minutes for SecurAcath and 7.3 minutes for StatLock reported by Janssen et al. (2016b; used in the external assessment centre cost analysis), they were in about the same ratio (that is, 1:2). The external assessment centre noted that the estimated cost of PICC reinsertion is similar to the cost of PICC dislodgement used in its cost analysis. In summary, the external assessment centre concluded that this study does not significantly change the findings of its cost analysis. The external assessment centre used the increased maintenance times from Zerla et al. (2017) in an updated threshold analysis. The results reduced the cost-saving threshold for SecurAcath to a dwell time of 8 days or more. The external assessment centre noted that the use of maintenance times from this study instead of Janssen et al. (2016b) would not change the conclusions of its cost comparison (that is, StatLock is cheaper than SecurAcath over short dwell times and SecurAcath is cheaper than StatLock over medium and long dwell times). The external assessment centre highlighted that Janssen et al. (2016b) provides higher quality evidence than Zerla et al. (2017) on maintenance times. ## Committee considerations The committee noted that the experts disagreed with the external assessment centre's assumption that nurses would place sutures in the NHS, because they considered it would usually be done by a doctor in an operating theatre environment. Furthermore, the committee noted that when the external assessment centre had recalculated the CVC costs for using a consultant anaesthetist to place sutures, there were only minor differences in the results of the cost modelling (see table 1), with sutures becoming slightly less cost saving compared with SecurAcath in the base case. The committee was advised by the experts that a 25-day dwell time for PICCs was an underestimate of routine clinical practice, because haematology and oncology patients usually have PICCs in place for 4 to 6 months, and even up to 1 year. The committee concluded that while SecurAcath may take a few minutes longer than StatLock to place and remove (although the experts indicated that this difference reduces with increased experience), maintenance times with SecurAcath are a lot shorter than with StatLock. The committee concluded that SecurAcath would not usually be used for tunnelled (Hickman) CVCs or implanted ports, but may be used for non-tunnelled CVCs. However, the committee also noted that non-tunnelled CVCs are used for short-term vascular access (usually less than 10 days). Furthermore, if SecurAcath is used for non-tunnelled CVCs, experts advised that in their experience, an adhesive device would also be placed on top of SecurAcath as an additional measure to prevent potential dislodgement. For all these reasons, the committee concluded that the cost-modelling results for non-PICC CVCs (with dwell times for up to 120 days) are unlikely to be clinically relevant. ## guidance review For the guidance review, the EAC revised the model to reflect 2021 costs. Further details of the revised model are in the cost update in the review decision from July 2022. During the review, the original economic model was corrected so that the model accounted for the weekly replacement of StatLock devices. This meant that in the original guidance, SecurAcath should have been cost saving by £12.60 to £148.54 for PICCs with medium- to long-term dwell times, respectively. Based on the 2022 guidance review updated cost model, the EAC updated the costs included in the original model. It found that SecurAcath was still cost saving for medium- and long-term dwell times of PICC lines but that the extent of cost saving was reduced compared with the original guidance. Cost savings result from shorter maintenance times and less need for device replacement with SecurAcath.# Conclusions The committee concluded that there is evidence that SecurAcath is effective for securing peripherally inserted central catheters (PICCs). Using SecurAcath avoids the need for securement device replacement and is associated with a low incidence of catheter-associated complications, such as migration, occlusion, thrombosis and infection. The committee concluded that SecurAcath is easy to use and is well tolerated by people with PICCs, provided that device placement is done by staff with appropriate training and experience. The committee concluded that the adoption of SecurAcath for the securement of PICCs is likely to be cost saving compared with StatLock, with cost savings resulting from a reduction in the time taken during weekly dressing changes and from avoiding securement device replacement. Cost savings are greater with longer PICC dwell times, with cost modelling indicating that using SecurAcath becomes cost saving when the catheter is expected to be in place for 15 days or more.	{'Recommendations': 'SecurAcath is recommended as a cost-saving option for securing peripherally inserted central catheters (PICCs) with an anticipated medium- to long-term dwell time.\n\nWhy the committee made these recommendations\n\nThe evidence shows that SecurAcath is at least as good as other devices for securing PICCs. It also has the benefit of not needing to be replaced at weekly dressing changes. It has a high rate of successful device placement and a low incidence of catheter-related complications.\n\nCost modelling shows that SecurAcath is cost saving compared with adhesive securement devices if the PICC remains in place for 21\xa0days or longer. Cost savings result from shorter maintenance times and less need for device replacement when using SecurAcath.', 'The technology': "# Description of the technology\n\nSecurAcath (Interrad Medical) is a single-use device to secure percutaneous catheters in position on the skin. It is intended for use in adults and children who need a central venous catheter (CVC), a long, thin, flexible tube that is inserted into a vein through the skin. It is positioned so that the distal tip lies in a large central vein, usually the superior vena cava, right atrium or inferior vena cava.\n\nCVCs are inserted using various access sites, including veins in the arm, chest, neck or groin; the choice in individual patients depends on a variety of factors such as anticipated duration of access needed (dwell time), reason for insertion and the quality and patency of venous sites available. There are 4 types of CVCs (Dougherty et al. 2015):\n\nPeripherally inserted central catheters (PICCs): CVCs inserted into a peripheral vein in the arm, rather than in the neck or chest. PICCs may be used for short-term access (7 to 10\xa0days), but are more typically used in people needing intravenous access for several weeks or months. They are used in inpatient and outpatient settings.\n\nNon-tunnelled CVCs (referred to in this guidance as 'CVCs'): Short-term CVCs placed into a large vein near the neck, chest, or groin. Non-tunnelled CVCs are indicated for short-term access (usually 7 to 10\xa0days) when peripheral access is impractical or in acute, urgent situations. Non-tunnelled CVCs need securing at the site of insertion.\n\nTunnelled CVCs (also called Hickman lines): CVCs that are passed under the skin (tunnelled) from an insertion site near the neck or chest to a separate exit site, which helps to prevent infection and provides stability. Tunnelled CVCs are indicated for long-term access (more than 30\xa0days). These long-term CVCs need securement for the first 2 to 4\xa0weeks until tissue granulation around the 'cuff' of the tunnel, but after this, do not need additional securing.\n\nImplanted ports: CVCs placed completely under the skin, which are used for long-term therapies. Implanted ports have few complications, have minimal risk of infection and do not need securing.\n\nSecurAcath has 2\xa0parts, a base and cover. The base is made up of 2 foldable metal legs and 2 securement feet. The feet are placed under the skin at the catheter insertion site, and unfolded to make a subcutaneous anchor. The cover attaches to the catheter shaft and holds it in place when it is clipped onto the base. The device stays in place as long as the catheter is needed and can be lifted off the skin to allow cleaning of the insertion site.\n\nSecurAcath is a class IIB device first CE marked in 2012. It is available in 6 different sizes (3\xa0F to 8\xa0F). The SecurAcath device is size-specific and the choice of device should be matched to the size of the catheter. The current size range for SecurAcath is not suitable for use with most renal dialysis catheters (a specific type of long-term tunnelled CVC). However, larger sizes (up to 12\xa0F) are planned to be available in late 2017, which may be suitable for use with these type of CVCs.\n\nThe list price of SecurAcath stated in the company's submission is £16.00 excluding VAT. During development of the guidance, the company updated the UK list price of SecurAcath to £20.00. The cost of SecurAcath has been updated in the revised cost model to £18.00 excluding VAT. \n\nThe claimed benefits of SecurAcath in the case for adoption presented by the company are:\n\nno interruptions or delays in therapy because of improved catheter securement\n\nfewer repeat procedures by improving vessel preservation and reducing reinsertions\n\nfewer catheter complications (dislodgements, migration, thrombosis and infection)\n\na decrease in catheter replacement costs\n\na reduction in overall treatment costs because of fewer delays and complications.\n\n# Current management\n\nCurrent options for catheter securement include adhesive devices (such as StatLock and Grip-Lok), steri-strips, tape and sutures (stitches).\n\nNICE has not produced guidance on securing catheters for central venous access. The NICE guideline on healthcare-associated infections recommends that the skin at and around the catheter insertion site is cleaned with chlorhexidine gluconate in 70% alcohol and allowed to air dry during dressing changes. The insertion site should be covered by a sterile transparent semipermeable membrane dressing which should be changed every 7\xa0days or sooner if the dressing is no longer intact or moisture collects under it.\n\nBritish Committee for Standards in Haematology on the insertion and management of central venous access devices in adults (Bishop et al. 2007) recommend using securing devices such as StatLock rather than sutures, and discourage the suturing of catheters to the skin. Several NHS trusts have produced local guidance on using catheter securement devices including SecurAcath.\n\nThe US Infusion Nursing Society's Infusion Standards of Practice (2016) refers to engineered stabilisation devices such as SecurAcath and StatLock. It suggests that these types of devices should be considered for securing catheters. It also says that engineered stabilisation devices promote consistent practice among clinicians, reduce catheter movement that can lead to complications, reduce the number of interruptions needed for infusion therapy, and may lower costs of care. The document suggests that tape or sutures should be avoided because they are not as effective as engineered stabilisation devices, based on good quality evidence from randomised controlled trials. The document also states that users should be aware of the risk of medical adhesive-related skin injury with the use of adhesive-based engineered stabilisation devices.", 'Clinical evidence': "# Summary of clinical evidence\n\nThe key clinical outcomes for SecurAcath given in the decision problem were:\n\nrates of catheter migration and dislodgement\n\nrates of catheter-related infection, including catheter-related bloodstream infection, local infection or inflammation and thrombophlebitis\n\nnumber of unplanned catheter removals and reinsertions\n\ntime taken to secure the catheter\n\npatient and clinician satisfaction scores\n\npain while in position and on insertion and removal\n\nquality-of-life measures\n\ndevice-related adverse events, for example catheter malfunction, thrombosis and vessel erosion.\n\nThe external assessment centre assessed 11\xa0studies on SecurAcath, 9 submitted by the company and 2 identified independently. Three SecurAcath studies were published as peer-reviewed journal articles (Cordovani and Cooper 2013; Egan et al. 2013; Hughes et al. 2014), the remaining 8\xa0studies were unpublished manuscripts, poster presentations, audit reports or conference abstracts (Janssens et al. 2016b; Djurcic-Jovan et al. 2016; Dougherty et al. 2013; Hill et al. 2014; Misericordia et al. 2015; Zerla et al. 2016; Stone et al. 2013; McParlan et al. 2016). The external assessment centre also identified 6\xa0studies on a comparator, StatLock (Fang et al. 2011; Teichgräber et al. 2011; McMahon et al. 2002; Yamamoto et al. 2002; Zerla et al. 2016; Venturini et al. 2011). During the evaluation, Zerla et al. 2016 was published as a peer-reviewed article (Zerla et al. 2017).\n\n## Published studies with SecurAcath\n\nCordovani and Cooper (2013) is a prospective multicentre cohort study done in Canada, which investigated 74\xa0adults who had central venous catheters (CVCs) secured with SecurAcath. The primary outcome was device securement success, which was reported in 72\xa0patients (97%). Mean catheter securement time was 62.5\xa0seconds and the mean dwell time was 3.1\xa0days. Discomfort was measured on a 1 to 10 scale (with 10 being most discomfort): mean scores were 0.9 in situ and 1.6 at removal. Of the 15\xa0patients who had previously had a sutured catheter, 14 found SecurAcath 'as or more comfortable'. Six out of 8 healthcare professionals found maintenance 'somewhat' or 'much easier' than sutures.\n\nEgan et al. (2013, and its earlier iteration Sansivero ) investigated peripherally inserted central catheters (PICCs) secured with SecurAcath in 68\xa0adults in intensive care units, transplant units or outpatient clinics at 3\xa0centres in the US. The primary end point was device securement success, defined by the absence of device-related malfunctions and adverse events. Secondary end points included securement time, patient comfort and ease of maintenance. Mean dwell time was 22.6\xa0days and mean securement time was 31\xa0seconds. Securement-related malfunctions were seen in 6\xa0patients (8.8%), with 20 (22.1%) adverse events reported. Pain scores were measured on a 0 to 10 scale: immediately after device removal, the mean pain score was 1.5. In situ mean pain score was 0.7 and 91.2% of patients were either neutral, satisfied or very satisfied with SecurAcath. Use of SecurAcath did not influence placement or maintenance techniques. The authors concluded that SecurAcath performed favourably when compared with StatLock (on the basis of historical data for StatLock reported by Yamamoto et al. : respective rates of migration and dislodgement of 2.9% and 0% for SecurAcath and 6% and 12% for StatLock).\n\nHughes et al. (2014) prospectively evaluated PICCs with SecurAcath in 31\xa0adults at a single UK centre. Mean dwell time was over 30\xa0days in 45% of patients. The study reported 100% successful device placement; 11% were placed with 'difficulty' and 19% with 'slight difficulty'. Staff reported difficulty with removal 'fairly frequently'. One patient experienced catheter migration of 1\xa0cm. Pain scores were measured on a 0 to 10 scale. At placement, pain scores were 0 in all patients; in situ, 5 patients' scores were over 5, and at removal over half of patients' scores were over 3. PICCs were removed in 3\xa0patients because of severe or unresolved pain. The study reported a PICC-related infection rate of 12% (n=31), which was reduced to 2% in a subsequent cohort (n=100).\n\nZerla et al. (2017; and the earlier unpublished extract Zerla et al. 2016) is a single-centre prospective study done in Italy without a comparator. It investigated 30\xa0adults needing chemotherapy who had a PICC in place for over 2\xa0months, secured with SecurAcath. The median dwell time was 145\xa0days. Skin integrity issues were reported in 32.2% of patients. Pain scores were measured on a 0 to 10 scale: at placement, pain scores were less than or equal to 2 in 90% of patients, in situ they were less than or equal to 2 in 95% of patients and at removal they were less than or equal to 2 in 43.33% of patients. The authors report a median insertion site maintenance time of 10\xa0minutes for SecurAcath, which compared favourably with a median of 20\xa0minutes maintenance time for an adhesive device in a historical cohort of patients. No cases of dislodgment, infection and thrombotic episodes were reported. There were 2 unplanned catheter removals. The authors concluded that, after effective training, SecurAcath is comfortable for the patient, reduces catheter movements, and is more effective in comparison to adhesive devices in oncology patients with long-term catheterisation and ambulatory maintenance.\n\n## Unpublished studies and conference abstracts with SecurAcath\n\nJanssens (2016b) is a Belgian-based, single-centre, prospective, unblinded, randomised controlled trial comparing PICCs secured with SecurAcath and PICCs secured with StatLock in adults. The outcomes included time spent on dressing changes, catheter migration, accidental dislodgement and laboratory-confirmed catheter-related bloodstream infection. The study was submitted as an unpublished manuscript which was available to the committee as academic in confidence.\n\nDjurcic-Jovan et al. (2016) is a single-centre retrospective, observational, comparative, longitudinal study done in Canada comparing PICCs placed with and without SecurAcath in 54\xa0patients needing complex continuing care. The primary outcome measure was unplanned catheter reinsertion. Mean dwell time was over 31\xa0days. There were 60\xa0unplanned catheter reinsertions reported without using SecurAcath compared with 3\xa0unplanned reinsertions with SecurAcath. There was no catheter migration reported. The authors saw substantial time savings for nurses and clinicians after the introduction of SecurAcath. Qualitative outcomes were collected retrospectively. For SecurAcath, catheter migration was rated 'very good' or 'good' in 88% of cases, and catheter stability while doing insertion site maintenance, ease of dressing, and overall use of the device were rated as 'very good' or 'good' in 95% of cases.\n\nDougherty et al. (2013) is a UK-based single-centre prospective study without a comparator which evaluated PICCs secured with SecurAcath over 1\xa0month in 30\xa0patients. Qualitative data were gathered from nurses and patients. There was a reduction in malposition and catheter damage compared with previous practice and no skin reactions were seen. Nurses reported increased confidence in doing insertion site maintenance but also reported some difficulty removing the device. Patients reported pain at insertion ('if incorrectly placed and the anchor was too superficial') and pain at removal.\n\nHill (2014) is a Canadian-based single-centre pilot evaluation of PICCs secured with SecurAcath in 60\xa0patients without a comparator. The author reported no malpositions but accidental dislodgement in 2\xa0agitated patients. The author described dressing changes as being done by 'general unit staff, not IV team staff': SecurAcath gave staff increased confidence, fewer anxieties and increased efficiencies. The author described the successful use of SecurAcath in patients with skin integrity issues, when the device was used without adhesive dressing. The author concluded that overall patient satisfaction was achieved.\n\nMisericordia et al. (2015, reported as Anonymous 2015 in the assessment report) is an unpublished report provided by the company. This is a retrospective, comparative audit done by the parenteral therapy team at the Misericordia Community hospital in Canada which evaluated 164\xa0unanchored PICCs placed during 2013 and 542\xa0PICCs placed during 2014 and secured with SecurAcath. The average dwell time was 29\xa0days. The report also evaluated using a PICC designed to reduce catheter-related thrombosis. Six different operators took part in the evaluation. The primary outcomes were catheter-related thrombosis, PICC occlusion, catheter malposition, local infection and catheter-related bloodstream infection. In the SecurAcath cohort, there were no confirmed catheter-related bloodstream infections. From 2013 to 2014, the rate of catheter-related thrombosis decreased from 3.75% to 3.69%, PICC occlusion increased from 14.35% to 16.97%, and malposition decreased from 10.98% to 1.66%. The authors concluded that without using SecurAcath, around 60 of the 542\xa0patients would have otherwise needed catheter replacements.\n\nStone et al. (2013) is a prospective, single-centre study done in the US which included PICCs secured with SecurAcath in 42\xa0children with previous skin problems, irritation or allergic reactions to standard dressings. The authors compared outcomes with historical data on 17\xa0patients with catheter migration in the same centre (undefined cohort). In the SecurAcath cohort, there were no catheter migrations, complications or unplanned catheter removals. The authors concluded that further research was needed to optimise dressings in patients with skin integrity issues.\n\nMcParlan et al. (2016) is a single-centre, UK prospective cohort study comparing PICCs secured with SecurAcath and with StatLock in haematology and oncology patients, published as a conference abstract. The full study was submitted as an unpublished poster which was available to the committee as academic in confidence. The abstract states that, during the study, there were no reported incidences of migration or PICC removal. This was associated with a reduction in chest X-rays to verify the location of migrated catheter tips (and therefore decreased exposure to radiation). There was also a reduced need for reinsertions, and reduced delays to therapy. The study reported significant financial benefits because of fewer PICC reinsertions and more efficient dressing changes. Additional benefits include reduced skin reactions, improved cleaning of the catheter site and greater user satisfaction. The abstract authors concluded that using SecurAcath had prevented PICC migration and improved patient outcomes.\n\n## Additional work by the external assessment centre\n\nThe external assessment centre noted the lack of comparative published evidence between SecurAcath and its comparators. It considered the unpublished randomised controlled trial (Janssens et al. 2016b) to be the most relevant evidence to inform the decision problem.\n\nThe external assessment centre did a meta-analysis using data from 16\xa0studies on 5\xa0clinical outcomes that it considered appropriate: migration, dislodgement, catheter-related infection, catheter-related bloodstream infection and unplanned removals/reinsertions. Because of the limited evidence base, there was significant uncertainty in the results, reflected in wide 95% confidence intervals (95% CI). The meta-analysis reported the following results comparing SecurAcath with StatLock: migration: 4.00% (95% CI: 1.48 to 8.50) and 4.72% (95% CI: 2.28 to 8.50); dislodgment: 0.59% (95% CI: 0.3 to 1.03) and 4.07% (95% CI: 3.29 to 4.97); catheter-related infection: 0.77% (95% CI: 0.28 to 1.66) and 1.64% (95% CI: 1.10 to 2.35); catheter-related bloodstream infection: 1.68% (95% CI: 0.20 to 5.94) and 1.47% (95% CI: 0.18 to 5.21). The external assessment centre considered the meta-analysis to be supportive of the results of Janssens et al. 2016b (except dislodgement, where the meta-analysis showed a difference in dislodgement rates), with similar clinical outcomes between devices. The external assessment centre concluded that there is not enough evidence to show that SecurAcath is clinically superior in effectiveness and adverse events to StatLock, but there is some evidence that SecurAcath is non-inferior to StatLock.\n\n## Committee considerations\n\nThe committee considered that the available evidence, despite its limitations, was enough to conclude that SecurAcath was associated with a high rate of successful device placement, a low incidence of catheter-related complications and does not usually need replacing while the catheter is in place. The committee also considered that the emerging comparative evidence suggested that SecurAcath is at least as effective as other devices for securing PICCs, with the added benefit of not needing to be replaced at weekly dressing changes.\n\nThe committee received advice from experts who use SecurAcath to secure PICCs in haematology and oncology patients in both inpatient and outpatient settings. The experts highlighted that PICCs in these patients have long dwell times of at least 6\xa0months, and can be in place for up to 1\xa0year.\n\nThe committee was advised by the experts that SecurAcath is well tolerated by patients when placed by an experienced healthcare professional. Pain on insertion is rare, because local anaesthetic is used anyway during the initial PICC placement. Pain is also rare while the device is in place, as long as it has been placed correctly. SecurAcath removal involves using scissors to cut the device in half and local anaesthetic administration is rarely needed. One expert stated that any discomfort patients experienced with using SecurAcath was countered by a reduction in anxiety linked with a lower likelihood of catheter displacement during dressing changes.\n\nThe committee was told by the experts that it is routine practice to anticipate the likely dwell time of PICCs at the time of insertion, based on the individual patient and clinical circumstances. It is possible that this consideration would inform the securement method selected in normal clinical practice. Although PICCs are sometimes in place for less time than anticipated, this is usually because of unexpected complications that necessitate early removal or replacement.", 'NHS considerations': '# System impact\n\nThe company claimed that SecurAcath could lower costs by avoiding delays in treatment and reducing catheter-related complications.\n\nExperts considered that specialist training was needed for the insertion, maintenance and removal of SecurAcath. Removal of the device was identified as the most challenging element in its use, but this becomes easier with more experience.\n\nNICE has produced an adoption resource about using SecurAcath for the securement of peripherally inserted central catheters (PICCs).\n\n## Committee considerations\n\nThe committee was advised by the experts that dressing changes are needed at the catheter insertion site on a weekly basis. They also said that a considerable amount of time is saved by using SecurAcath compared with StatLock for the maintenance of long-term PICCs. Dressing changes are much quicker and easier and there is a reduced risk of catheter dislodgement with SecurAcath.\n\nThe committee concluded that training was essential for the correct insertion, maintenance and removal of SecurAcath. Experts advised that proficiency improves quickly with experience and that there is a short learning curve. Training is provided free of charge by the company. This includes face-to-face instruction by clinical nurse advisers as well as online support from a downloadable mobile application.\n\nSecurAcath is contraindicated in people with nickel allergy. One expert stated that, in their experience, true nickel allergy is rare and they had not encountered an allergic reaction to SecurAcath in their practice. It was also stated by the experts that patients may experience sensitivity to adhesive dressings.\n\nThe experts stated that they had no experience of using SecurAcath in young children (who tend to have tunnelled central venous catheters), but\xa01 had used it successfully with older children (aged 12\xa0years and over) having chemotherapy.\n\nOne expert stated that bleeding can occur after SecurAcath placement, so more dressings may be needed.', 'Cost considerations': "# Cost evidence\n\nThe company identified 3\xa0published economic studies, but the external assessment centre considered them to be outside the scope. It did not identify any further economic studies.\n\nThe company presented a de novo cost model that compared the cost consequences of using SecurAcath in people with peripherally inserted central catheters (PICCs) compared with StatLock, and in people with central venous catheters (CVCs) compared with sutures.\n\nThe model used a decision-tree structure where people entered the model at the point of having a securement device (either SecurAcath, StatLock or sutures). Both trees contained 5\xa0outcomes after securement: no complications; catheter migration; catheter malposition; catheter occlusion; or catheter-related infection (catheter-related bloodstream infection or catheter-related thrombosis). There was an additional outcome of needlestick injuries for health professionals in the suture group.\n\nThe model was constructed with a time horizon of 25\xa0days for PICCs and 3\xa0days for CVCs. Other clinical parameters such as the probability of migration, malposition, occlusion, infection and thrombosis were derived from published and unpublished literature. Device and resource costs relating to the cost of placement (such as nurse time) and complications were also from published and unpublished sources.\n\nThe results of the company's base case found cost savings with SecurAcath of £41.40 per patient for PICCs compared with StatLock and £1,005.60 per patient for SecurAcath with other CVCs compared with sutures. The main reasons for StatLock's greater costs as compared with SecurAcath were device costs and differences in catheter migration rates. For sutures, the main reasons for the greater costs were differences in the rates of catheter-related bloodstream infection or catheter-related thrombosis.\n\nThe company did a 1-way deterministic sensitivity analysis, increasing SecurAcath device costs by up to 200%. It also did multiway deterministic sensitivity analyses, changing the values for each economic and clinical parameter simultaneously by ±20%. In all cases, SecurAcath remained cost saving compared with its comparator. When PICC dwell time was increased to 6\xa0months (reflecting a typical clinical situation of a patient having cancer treatment), the cost saving with SecurAcath increased to £115.00 per patient.\n\nDuring the evaluation, a new peer-reviewed article was published that provided a simple cost analysis (Zerla et al. 2017). The published cost comparison of SecurAcath with StatLock only included the cost of the devices. Few details on the analysis are given, but the 30\xa0patients having SecurAcath were compared with a historic control population (Zerla et al. 2015) of 793\xa0patients who had PICCs secured with StatLock. Devices were assumed to cost €30 for SecurAcath and €6 for StatLock, giving a total device cost of €900 for SecurAcath and €4,254 for StatLock. The authors concluded that SecurAcath is cost saving. The authors also report no dislodgments with SecurAcath and compare this with results from Zerla et al. (2015) in which 63\xa0dislodgements were seen. An overall cost for reinsertion for all 63\xa0dislodgements is estimated to be €18,710.\n\nThe NICE adoption and impact scoping report (included in the assessment report overview) describes a single centre's experience of real-world total cost savings of up to £59,000 with SecurAcath when compared with StatLock when placing 1,100\xa0PICCs over 6 months.\n\nNICE has published a resource impact template on SecurAcath, which can be used to calculate the local resource impact of implementing the guidance.\n\n## Additional work by the external assessment centre\n\nOverall, the external assessment centre considered the company's model to be appropriate given the limited evidence base available, but noted some errors in the model. These included figures wrongly quoted, applying probabilities as rates and a lack of clarity on some sources of evidence. It queried several assumptions in the model: dwell times; the differential impact of securement device placement by nurses or doctors; that no extra resources are needed to place securement devices and the clinical outcomes chosen. It also queried the significant assumption in the model that outcomes were independent of time and were collected over similar dwell times. It noted there was a risk of study heterogeneity and uncertainty about variations in clinical practice and outcome measurements.\n\nThe external assessment centre regarded Yamamoto et al. (2002) as the best evidence available on the incidence of complications, because it reported rates rather than probabilities. Yamamoto et al. (2002) is a single-centre, US-based, prospective randomised controlled trial, comparing StatLock with sutures in patients with PICCs (n=170). The primary end point was catheter-related complications. Mean dwell times were 33\xa0days for StatLock and 35\xa0days for sutures. The risk of total complications was 49.4% and 71.7% for StatLock and sutures, respectively (p=not significant). There was no statistically significant difference in dislodgement or migration rates between the 2 groups, but a significant reduction in infections with StatLock was seen (p=0.032).\n\nUsing this evidence and the updated list price of SecurAcath, the external assessment centre revised the model base case. It assumed clinical equivalence for all outcomes between SecurAcath and comparators, except for needlestick injury, where a reduced risk without sutures was highly likely. Therefore, base-case costs related to placement and maintenance costs over the relevant dwell time only, with needlestick injury costs included where relevant. It also considered 3 dwell times for both CVCs and PICCs: 5\xa0days (short), 25\xa0days (medium), and 120\xa0days (long). Other amendments included: adding StatLock as a comparator for CVCs; varying placement and maintenance times; suturing being done by a band\xa06 nurse; sutures remaining throughout the dwell time and updating resource costs.\n\nThe revised base case found that StatLock was the cheapest option for PICCs for short dwell times (5\xa0days), but that SecurAcath was cost saving for medium to long dwell times (25\xa0days and over). For CVCs, StatLock was the cheapest securement option for short dwell times and sutures was the cheapest for medium to long dwell times. After the increase in the SecurAcath list price to £20, the external assessment centre reran the model, which increased SecurAcath costs in all analyses by £4 (see table\xa01 for a summary of external assessment centre results). The external assessment centre concluded that the impact of the list price change was minimal. StatLock remained the cheapest option for dwell times of 5\xa0days and SecurAcath remained cheaper than StatLock for dwell times of 25\xa0days and 120\xa0days.\n\nA one-way sensitivity analysis, reducing SecurAcath placement time to 30\xa0seconds (as reported by the company), made SecurAcath slightly more cost saving and sutures slightly less cost saving, but did not change the base-case results (see table\xa01 for a summary of external assessment centre results). Another one-way sensitivity analysis assumed an insertion site maintenance time of 7.3\xa0minutes for sutures, equivalent to the time reported for StatLock in Janssens (2016b). This changed the results for CVCs such that SecurAcath was cheaper than sutures for both PICCs and CVCs with a medium and long dwell time (see table\xa01).\n\nThe external assessment centre did a multivariate sensitivity analysis including differential risks of migration, dislodgement and catheter-related bloodstream infections, based on the figures reported in Yamamoto et al. (2002) and its meta-analysis. This found that StatLock was the cheapest option for short dwell times for both PICCs and CVCs, but for medium and long dwell times, SecurAcath was the most cost saving (see table\xa01).\n\nScenario\n\n\n\n\n\n\n\n\n\n\n\nCVC (central venous catheter): 5 days\n\nStatLock (£5)\n\nStatLock (£5)\n\nStatLock (£5)\n\nStatLock(£15)\n\nStatLock (£5)\n\nPICC (peripherally inserted central catheter): 5 days\n\nStatLock (£16)\n\nStatLock (£11)\n\nStatLock (£16)\n\nStatLock (£18)\n\nStatLock (£16)\n\nCVC: 25 days\n\nSutures (£11)\n\nSutures (£6)\n\nSecurAcath (£8)\n\nSecurAcath (£21)\n\nSutures (£6)\n\nPICC: 25 days\n\nSecurAcath (£13)\n\nSecurAcath (£18)\n\nSecurAcath (£13)\n\nSecurAcath (£9)\n\nSecurAcath (£13)\n\nCVC: 120 days (not clinically relevant: non-tunnelled CVCs only used short term)\n\nSutures (£11)\n\nSutures (£6)\n\nSecurAcath (£90)\n\nSecurAcath (£112)\n\nSutures (£6)\n\nPICC: 120 days\n\nSecurAcath (£90)\n\nSecurAcath (£95)\n\nSecurAcath (£90)\n\nSecurAcath (£64)\n\nSecurAcath (£90)\n\nScenarios:\n\n. Base case (placement and maintenance costs only; no differences in complication rates across devices).\n\n. One-way sensitivity analysis: assumes a SecurAcath placement time of 30\xa0seconds.\n\n. One-way sensitivity analysis: assumes a suture maintenance time of 7.3\xa0minutes.\n\n. Multiway sensitivity analysis including complication rates.\n\n. Suturing done by a consultant anaesthetist.\n\nA threshold sensitivity analysis for dwell times using the base case indicated that SecurAcath was the cheapest option for securing PICCs for 15\xa0days or more. For CVCs, the costs of sutures dropped below those of StatLock for dwell times of 8\xa0days or more, but SecurAcath remained more expensive than sutures for securing CVCs over any dwell time. The increased list price of SecurAcath did not affect the threshold analysis.\n\nFor PICCs, the external assessment centre agreed with the company's conclusion that SecurAcath appears to be cheaper than StatLock over medium and long dwell times (25\xa0days and over). Cost savings arise from shorter maintenance times with SecurAcath and the need to replace StatLock weekly. It concluded that these cost savings were robust: it found smaller savings in the base case excluding complications, but similar results in sensitivity analyses including complications.\n\nFor CVCs, the external assessment centre agreed with the company's conclusion that SecurAcath was cost saving compared with sutures over short dwell times, but disagreed with the exclusion of StatLock as a comparator. Additional analysis including StatLock concluded that it was the cheapest for CVCs with short dwell times in all scenarios. For medium to long dwell times, suturing was cheaper than SecurAcath or StatLock in the base case (excluding complications). However, evidence suggested an increased risk of infection with suturing. Sensitivity analyses including complications found SecurAcath to be cheaper than suturing and StatLock over 25- and 120-day dwell times. This led the external assessment centre to conclude that SecurAcath is likely to be the cheapest option for securing CVCs over medium and long dwell times.\n\nThe external assessment centre reviewed the cost analysis in Zerla et al. (2017). The authors report shorter maintenance time for SecurAcath than StatLock, but do not include this in the cost comparison. They report median maintenance times of 10\xa0minutes for SecurAcath and 20\xa0minutes for StatLock, but the methodology for these estimates is unclear. Although the times reported are longer than the estimates of 4.3\xa0minutes for SecurAcath and 7.3\xa0minutes for StatLock reported by Janssen et al. (2016b; used in the external assessment centre cost analysis), they were in about the same ratio (that is, 1:2). The external assessment centre noted that the estimated cost of PICC reinsertion is similar to the cost of PICC dislodgement used in its cost analysis. In summary, the external assessment centre concluded that this study does not significantly change the findings of its cost analysis.\n\nThe external assessment centre used the increased maintenance times from Zerla et al. (2017) in an updated threshold analysis. The results reduced the cost-saving threshold for SecurAcath to a dwell time of 8\xa0days or more. The external assessment centre noted that the use of maintenance times from this study instead of Janssen et al. (2016b) would not change the conclusions of its cost comparison (that is, StatLock is cheaper than SecurAcath over short dwell times and SecurAcath is cheaper than StatLock over medium and long dwell times). The external assessment centre highlighted that Janssen et al. (2016b) provides higher quality evidence than Zerla et al. (2017) on maintenance times.\n\n## Committee considerations\n\nThe committee noted that the experts disagreed with the external assessment centre's assumption that nurses would place sutures in the NHS, because they considered it would usually be done by a doctor in an operating theatre environment. Furthermore, the committee noted that when the external assessment centre had recalculated the CVC costs for using a consultant anaesthetist to place sutures, there were only minor differences in the results of the cost modelling (see table\xa01), with sutures becoming slightly less cost saving compared with SecurAcath in the base case.\n\nThe committee was advised by the experts that a 25-day dwell time for PICCs was an underestimate of routine clinical practice, because haematology and oncology patients usually have PICCs in place for 4 to 6\xa0months, and even up to 1\xa0year.\n\nThe committee concluded that while SecurAcath may take a few minutes longer than StatLock to place and remove (although the experts indicated that this difference reduces with increased experience), maintenance times with SecurAcath are a lot shorter than with StatLock.\n\nThe committee concluded that SecurAcath would not usually be used for tunnelled (Hickman) CVCs or implanted ports, but may be used for non-tunnelled CVCs. However, the committee also noted that non-tunnelled CVCs are used for short-term vascular access (usually less than 10\xa0days). Furthermore, if SecurAcath is used for non-tunnelled CVCs, experts advised that in their experience, an adhesive device would also be placed on top of SecurAcath as an additional measure to prevent potential dislodgement. For all these reasons, the committee concluded that the cost-modelling results for non-PICC CVCs (with dwell times for up to 120\xa0days) are unlikely to be clinically relevant.\n\n## guidance review\n\nFor the guidance review, the EAC revised the model to reflect 2021 costs. Further details of the revised model are in the cost update in the review decision from July 2022.\n\nDuring the review, the original economic model was corrected so that the model accounted for the weekly replacement of StatLock devices. This meant that in the original guidance, SecurAcath should have been cost saving by £12.60 to £148.54 for PICCs with medium- to long-term dwell times, respectively.\n\nBased on the 2022 guidance review updated cost model, the EAC updated the costs included in the original model. It found that SecurAcath was still cost saving for medium- and long-term dwell times of PICC lines but that the extent of cost saving was reduced compared with the original guidance. Cost savings result from shorter maintenance times and less need for device replacement with SecurAcath.", 'Conclusions': 'The committee concluded that there is evidence that SecurAcath is effective for securing peripherally inserted central catheters (PICCs). Using SecurAcath avoids the need for securement device replacement and is associated with a low incidence of catheter-associated complications, such as migration, occlusion, thrombosis and infection.\n\nThe committee concluded that SecurAcath is easy to use and is well tolerated by people with PICCs, provided that device placement is done by staff with appropriate training and experience.\n\nThe committee concluded that the adoption of SecurAcath for the securement of PICCs is likely to be cost saving compared with StatLock, with cost savings resulting from a reduction in the time taken during weekly dressing changes and from avoiding securement device replacement. Cost savings are greater with longer PICC dwell times, with cost modelling indicating that using SecurAcath becomes cost saving when the catheter is expected to be in place for 15\xa0days or more.'}	https://www.nice.org.uk/guidance/mtg34	Evidence-based recommendations on SecurAcath for securing percutaneous catheters.
d7e4813547ff29f14f3a02b63197d37419ff4665	nice	Asciminib for treating chronic myeloid leukaemia after 2 or more tyrosine kinase inhibitors	Asciminib for treating chronic myeloid leukaemia after 2 or more tyrosine kinase inhibitors Evidence-based recommendations on asciminib (Scemblix) for chronic myeloid leukaemia after 2 or more tyrosine kinase inhibitors. # Recommendations Asciminib is recommended, within its marketing authorisation, as an option for treating chronic-phase Philadelphia chromosome-positive chronic myeloid leukaemia without a T315I mutation after 2 or more tyrosine kinase inhibitors in adults. It is recommended only if the company provides asciminib according to the commercial arrangement. Why the committee made these recommendations Usual treatment for chronic-phase Philadelphia chromosome-positive chronic myeloid leukaemia without a known T315I mutation after 2 or more tyrosine kinase inhibitors is tyrosine kinase inhibitors such as bosutinib, ponatinib, dasatinib or nilotinib. Although an allogeneic stem cell transplant can be a cure, it is not an option for many people. Asciminib is another tyrosine kinase inhibitor. Clinical trial evidence shows that asciminib works better than bosutinib in people without a T315I mutation who have had 2 or more tyrosine kinase inhibitors, but it is uncertain how much longer people having asciminib live. It is unclear how well asciminib works compared with the other tyrosine kinase inhibitors when compared indirectly. This makes the clinical and cost-effectiveness results uncertain. Despite the uncertainties, the cost-effectiveness estimates are likely to be within the range NICE considers an acceptable use of NHS resources. So, asciminib is recommended.# Information about asciminib # Marketing authorisation indication Asciminib (Scemblix, Novartis) is indicated for the 'treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukaemia (Ph + CML) in chronic phase (CP), previously treated with two or more tyrosine kinase inhibitors, and without a known T315I mutation'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for asciminib. # Price The list price for asciminib is £4,050.37 for a 60‑tablet pack of 40‑mg tablets (excluding VAT; company submission). The company has a commercial arrangement. This makes asciminib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need and treatment pathway ## Chronic myeloid leukaemia has a substantial impact on quality of life Symptoms of chronic myeloid leukaemia (CML) include weight loss, loss of appetite, splenomegaly (increased spleen size), skin rash, anaemia, sweating, drowsiness, abdominal fullness, sleep disturbances, muscle soreness, muscle cramping and memory loss. As well as physical symptoms, the patient experts explained that being diagnosed with CML can have a major psychological impact. They described how the physical symptoms and the psychological impact of CML, as well as the side effects of current tyrosine kinase inhibitors (TKIs), can affect everyday life. They explained that this can have a considerable impact on family life, education and work, with many people diagnosed with CML having to stop work or reduce their hours. The committee concluded that CML has a substantial impact on the quality of life of patients and their families and carers. ## People with CML who have had 2 or more TKIs would welcome a new treatment option The clinical experts explained that decisions about which TKI to prescribe are individual and depend on many factors, including comorbidities, age and resistance to a previously tried TKI. A dose reduction would be tried for people whose disease was responding to treatment but who could not tolerate it. They confirmed most people with CML have imatinib as first-line treatment, with dasatinib or nilotinib also available as first-line options. At second line or later, the choice of TKI depends on tolerance to treatment and resistance to previous TKIs. If a person was not able to tolerate a previous TKI, the choice of treatment is a TKI that is tolerable and effective, allowing them to remain on that treatment long term. If the disease is resistant, the choice of treatment depends on the potency of the TKIs that have been tried previously. If the disease is resistant to the less-potent first-generation TKI, imatinib, then a more potent TKI such as nilotinib, dasatinib or bosutinib may be tried. If the disease is resistant to a more potent TKI, or the T315I mutation is present, ponatinib may be an option. The clinical and patient experts explained that ponatinib is associated with potentially serious adverse events that may have a substantial effect on quality of life for some people. They considered that although most CML responds to first-line TKI therapy, there remains an unmet need for CML that is resistant to existing TKIs and for people who cannot tolerate them. They advised the main aim of treatment is to balance clinical effectiveness with side effects, and that many people have tried at least 2 previous TKIs. Although allogeneic stem cell transplant is potentially curative, it is only an option for a minority of people and is associated with a considerable risk of mortality and long-term issues with graft-versus-host disease. The NHS England Cancer Drugs Fund clinical lead confirmed that the treatment pathway is complicated and individualised. They explained there is a benefit to having alternative treatment options that are effective and tolerated. The committee recognised that people who are not eligible for allogeneic stem cell transplant and who cannot tolerate current TKIs or whose disease is resistant to them have limited treatment options. It also noted that asciminib works by inhibiting breakpoint cluster region protein‑ABL1 and therefore may have a different mechanism of action compared with other TKIs. It concluded that asciminib would be an important option for people with chronic-phase Philadelphia chromosome-positive CML who have had 2 or more TKIs and do not have a T315I mutation. ## Bosutinib and ponatinib are the main comparators The clinical experts explained that the choice of TKI at third line and later varies on a case-by-case basis. They confirmed that once the 3 primary TKIs (imatinib, dasatinib and nilotinib) have been tried and are no longer tolerable, or the disease becomes resistant, the choice will normally be between bosutinib and ponatinib. The committee recognised that most people will have imatinib as their first-line treatment and therefore it is not an appropriate comparator. It also noted that nilotinib and dasatinib are most commonly used earlier in the treatment pathway than at asciminib's proposed positioning (see section 3.2). The committee was aware that most people having third-line and later treatment would have bosutinib. But ponatinib would be appropriate for people whose disease is resistant to bosutinib. It therefore concluded that although all of the TKIs except for imatinib are potential comparators, bosutinib and ponatinib are the main comparators for asciminib. # Clinical evidence ## Asciminib is clinically effective compared with bosutinib, but the survival benefit is unclear The clinical-effectiveness evidence was based on ASCEMBL: a randomised, controlled, open-label trial that compared asciminib with bosutinib. ASCEMBL included people with chronic-phase Philadelphia chromosome-positive CML after 2 or more TKIs who did not have a T315I mutation. The primary outcome was major molecular response rate at 24 weeks. Secondary outcomes included complete cytogenic response, time to treatment discontinuation (TTD), progression-free survival and overall survival. The company also reported some of the outcomes at 48 and 60 weeks. Major molecular response and complete cytogenic response were higher in the asciminib arm than in the bosutinib arm at each reported time point. At 24 weeks, 25.48% of people in the asciminib arm had a major molecular response compared with 13.16% in the bosutinib arm. At 24 weeks, 40.78% of people in the asciminib arm had a complete cytogenic response, compared with 24.19% in the bosutinib arm. The results for all outcomes at 48 weeks and 60 weeks are considered confidential by the company, so they cannot be reported here. The committee noted that data for overall survival and progression-free survival from ASCEMBL was immature, so the survival benefit of asciminib was unclear. It concluded that asciminib is clinically effective compared with bosutinib for molecular and cytogenic response rates, but that the difference in survival outcomes is unclear. ## The company did indirect treatment comparisons Because ASCEMBL compared asciminib with bosutinib, there is no head-to-head evidence for asciminib against the remaining comparators. The company provided a series of unanchored matching-adjusted indirect comparisons (MAICs) to compare the TTD of asciminib with those of ponatinib, nilotinib and dasatinib. It explained that an unanchored MAIC was needed because the studies included did not share a common comparator arm. At technical engagement, the ERG highlighted concerns with the company MAICs. These included comparator studies being excluded inappropriately, a lack of comparison with Haematological Malignancy Research Network (HMRN) data, adjustment for limited variables, and limited reporting of survival outcomes and relative estimates of effectiveness. At technical engagement, the ERG also requested MAICs for major molecular response outcomes, and for the MAICs to be compared with the HMRN data. In response, the company explained that it was not possible to adjust for all variables. It said that the survival data in ASCEMBL was too immature to support a comparison of survival data with other published studies. The company did provide further information about why certain trials were excluded from the MAICs. These included the small sizes of the trials, inappropriate comparators, different populations, and lack of baseline data for the relevant subpopulations. It also provided MAICs for major molecular response, and comparing outcomes for asciminib and bosutinib from ASCEMBL with outcomes for dasatinib, nilotinib and bosutinib from the HMRN data. ## The indirect treatment comparisons are appropriate but should be interpreted with caution The company noted that the comparison with HMRN data had several limitations, including non-randomisation, but that the results supported the original MAIC using the clinical trial comparator data. The committee noted that no MAIC for ponatinib was done because of the limited number of people who had ponatinib in the HMRN data. The ERG accepted that the trials in the company's MAIC analyses were likely to be the only trials for which a robust MAIC could be done. However, it had concerns about the differences between naive, unanchored and anchored analyses of TTD and the inconsistency between results for TTD and major molecular response. The ERG explained that this suggests that TTD is not an appropriate surrogate for survival outcomes. The ERG preferred the MAIC of major molecular response for the comparison of asciminib with other TKIs from the HMRN data. It thought that the MAIC analyses against HMRN showed no clear evidence of any difference between asciminib and dasatinib or nilotinib. The committee recognised the uncertainty in the MAIC analyses, in particular the use of TTD, there being only 1 study per comparator, and the limited set of variables adjusted for. It concluded that the MAICs comparing asciminib with ponatinib, nilotinib and dasatinib were appropriate, but that the results should be interpreted with caution. # Economic model ## The surrogate survival model structure is most appropriate The company's economic model used a cumulative survival approach to estimate survival based on TTD. The company explained that this is because survival data from ASCEMBL is immature (see section 3.4). The cumulative survival model uses TTD parametric curves for each arm. Total survival time is estimated as the sum of treatment-specific TTD and a fixed, treatment-independent survival period post-discontinuation, which includes fixed periods in the accelerated phase and blast phase. The committee noted this model structure was used for decision making in NICE's technology appraisal guidance on bosutinib for previously treated chronic myeloid leukaemia (TA401). At clarification, the ERG asked the company to provide a surrogate survival modelling approach using a response-based model. This was broadly based on the model used in NICE's technology appraisal guidance on ponatinib for treating chronic myeloid leukaemia and acute lymphoblastic leukaemia (TA451). Using the surrogate survival model, duration of progression-free survival is modelled as a function of cytogenic and haematological response. People are grouped into different response categories and assumed to follow response-dependent progression-free survival curves based on patient-level data digitised from TA451. The ERG was concerned with the cumulative survival model because it used TTD as a surrogate for survival outcomes. It explained that treatment decisions that impact TTD may be subjective, and therefore there are concerns about the validity of comparing TTD across trials. It also explained that there is a lack of evidence to link TTD with survival outcomes. Therefore, it was concerned that TTD was confounded as a clinical outcome and less suitable for modelling. The company explained that using TTD as a surrogate for survival was validated by a clinician. It considered TTD a good surrogate outcome for survival because when people continue treatment it shows that they are able to tolerate it and that their condition is responding. The clinical experts agreed, but explained that previous surrogates used for survival in CML have been cytogenic or molecular response. They advised that both modelling approaches would be reasonable. The ERG preferred to use cytogenic or molecular response as a surrogate for survival based on the model used in TA451. It explained that this approach is supported by literature, and cytogenic or molecular response has clearer value as a clinical outcome than TTD. The ERG highlighted that this approach is not without limitations and explained that the progression-free survival curves used to estimate overall survival came from a second-line population and therefore may be an optimistic estimate in a third-line population. The committee recognised that because of the nature of the condition, there is currently no direct trial data to suggest a survival benefit for asciminib, and therefore a surrogate outcome must be used to estimate survival. It recognised the limitations of both approaches but was reassured that the cost-effectiveness results were broadly similar for both model types. It considered that a response-based approach using cytogenic or molecular response to estimate survival was more clinically appropriate and less subjective than using TTD. It therefore concluded that the surrogate survival model structure is the most appropriate for decision making. ## Survival for 10.1 years after stopping treatment is clinically plausible In the company-preferred cumulative survival model (see section 3.7), there is a fixed, treatment-independent survival period after stopping treatment. In its original submission, the company assumed 7 years survival after stopping treatment, based on estimates of mean overall survival from TA401. The ERG preferred a longer survival after stopping treatment because the company survival estimate was in people who did not have a stem cell transplant or TKIs after imatinib was stopped. It was also concerned that the subsequent treatments used in TA401 no longer represent current NHS clinical practice. It therefore believed that the company estimate of 7 years survival after stopping treatment was pessimistic given changes in the treatment pathway and improvements in care. The ERG also highlighted that the mean survival from the HMRN data is likely to be greater than 7 years, and median survival in PACE, a single-arm, phase 2 clinical trial of ponatinib, is likely to be greater than 5 years. The ERG provided an alternative scenario of 10.1 years survival after stopping treatment. It explained that this was generated by extrapolating evidence from the PACE trial, assuming a mean overall survival of 167 months and a mean TTD of 46.3 months. It then subtracted the mean TTD from overall survival, resulting in an estimated post-discontinuation survival of 120.7 months (10.1 years). The clinical experts agreed with the ERG that a survival of 10.1 years after stopping treatment is a reasonable assumption. The committee noted that this assumption only applies to the company's cumulative survival model. It concluded that in the cumulative survival model, an assumption of 10.1 years survival after stopping treatment is clinically plausible. # End of life ## Asciminib does not meet the end of life criteria The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The life expectancy of people with chronic-phase Philadelphia chromosome-positive CML after 2 or more TKIs who do not have a T315I mutation is estimated to be substantially greater than 2 years. And the evidence for a survival benefit is uncertain. Therefore, the committee concluded that asciminib does not meet the end of life criteria. # Cost-effectiveness results ## The company's updated base case reflects the committee's preferred assumptions except for the model structure The company used the cumulative survival approach in its base case. The committee preferred the surrogate survival model, using cytogenic or molecular response as a surrogate outcome to estimate survival. It noted that apart from the model structure (see section 3.7) its preferred assumptions aligned with the updated company base case: Removing retreatment with the same drug. Using the log-logistic curve to extrapolate TTD. Using Niederwieser (2021) for stem cell transplant survival outcomes. Using a multiplicative approach to adjust utilities for age. Ponatinib comparator dosing based on people having a major cytogenic response is assumed to reduce to a 15‑mg dose and the cost is halved. People in chronic phase without a major cytogenic response and all people whose disease has progressed to the accelerated and blast phases are assumed to have the higher 45‑mg or 30‑mg dose. All dose reductions occur at 12 months. ## An acceptable ICER would be within the range normally considered a cost-effective use of NHS resources NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted that although its preferred assumptions aligned with the company base case, it favoured a different model structure. It recognised the uncertainty with the model structure, but was reassured that the cost-effectiveness results were broadly similar for the 2 different model structures. Therefore, the committee agreed that an acceptable ICER for asciminib would be between £20,000 and £30,000 per QALY gained. ## The ICERs are below £30,000 per QALY gained for asciminib compared with bosutinib, nilotinib and dasatinib There are confidential discounts for asciminib, bosutinib, nilotinib and dasatinib so the exact ICERs are confidential and cannot be reported here. Using the confidential discounts, the company base case ICERs were below £30,000 per QALY gained for all 3 comparisons. Using the committee's preferred model structure and all confidential discounts, the ICERs were below £30,000 per QALY gained for all 3 comparisons. The committee also considered scenario analyses varying the effectiveness of the comparator treatments, for which the ICERs were still all below £30,000 per QALY gained. Overall, the committee concluded that asciminib was a cost-effective treatment option compared with bosutinib, nilotinib and dasatinib. ## Asciminib is cost saving compared with ponatinib Using the confidential discounts, the company base case resulted in asciminib having an overall lower cost of treatment and a small loss in QALYs when compared with ponatinib. When an ICER for a technology is less effective and less costly than its comparator, the rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment becomes. The committee-preferred ICER, including all confidential discounts, resulted in asciminib still being associated with cost savings per QALY lost with an ICER above £30,000 saved per QALY lost. Overall, the committee concluded that asciminib was a cost-saving treatment option and was cost effective compared with ponatinib. ## Other factors No equality or social value judgement issues were identified. # Conclusion ## Asciminib is recommended for routine commissioning Using the committee's preferred assumptions (see section 3.10) and including all commercial arrangements resulted in an ICER below £30,000 per QALY gained for each pairwise comparison of asciminib with bosutinib, nilotinib and dasatinib. The ICER for asciminib compared with ponatinib showed that asciminib is associated with sufficiently high cost savings per QALY lost. The exact ICERs are confidential and cannot be reported here. The committee acknowledged uncertainty with the model structure, but was reassured that the cost-effectiveness results were broadly similar for the 2 different model structures (see section 3.7). Based on the evidence presented, the committee concluded that, with the discount agreed in the commercial arrangement, the most plausible ICERs were within the range that NICE normally considers an acceptable use of NHS resources. Therefore, it recommended asciminib as an option for treating chronic-phase Philadelphia chromosome-positive CML after 2 or more TKIs in adults without a T315I mutation.	{'Recommendations': 'Asciminib is recommended, within its marketing authorisation, as an option for treating chronic-phase Philadelphia chromosome-positive chronic myeloid leukaemia without a T315I mutation after 2 or more tyrosine kinase inhibitors in adults. It is recommended only if the company provides asciminib according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nUsual treatment for chronic-phase Philadelphia chromosome-positive chronic myeloid leukaemia without a known T315I mutation after 2 or more tyrosine kinase inhibitors is tyrosine kinase inhibitors such as bosutinib, ponatinib, dasatinib or nilotinib. Although an allogeneic stem cell transplant can be a cure, it is not an option for many people. Asciminib is another tyrosine kinase inhibitor.\n\nClinical trial evidence shows that asciminib works better than bosutinib in people without a T315I mutation who have had 2 or more tyrosine kinase inhibitors, but it is uncertain how much longer people having asciminib live. It is unclear how well asciminib works compared with the other tyrosine kinase inhibitors when compared indirectly. This makes the clinical and cost-effectiveness results uncertain.\n\nDespite the uncertainties, the cost-effectiveness estimates are likely to be within the range NICE considers an acceptable use of NHS resources. So, asciminib is recommended.', 'Information about asciminib': "# Marketing authorisation indication\n\nAsciminib (Scemblix, Novartis) is indicated for the 'treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukaemia (Ph + CML) in chronic phase (CP), previously treated with two or more tyrosine kinase inhibitors, and without a known T315I mutation'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for asciminib.\n\n# Price\n\nThe list price for asciminib is £4,050.37 for a 60‑tablet pack of 40‑mg tablets (excluding VAT; company submission).\n\nThe company has a commercial arrangement. This makes asciminib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need and treatment pathway\n\n## Chronic myeloid leukaemia has a substantial impact on quality of life\n\nSymptoms of chronic myeloid leukaemia (CML) include weight loss, loss of appetite, splenomegaly (increased spleen size), skin rash, anaemia, sweating, drowsiness, abdominal fullness, sleep disturbances, muscle soreness, muscle cramping and memory loss. As well as physical symptoms, the patient experts explained that being diagnosed with CML can have a major psychological impact. They described how the physical symptoms and the psychological impact of CML, as well as the side effects of current tyrosine kinase inhibitors (TKIs), can affect everyday life. They explained that this can have a considerable impact on family life, education and work, with many people diagnosed with CML having to stop work or reduce their hours. The committee concluded that CML has a substantial impact on the quality of life of patients and their families and carers.\n\n## People with CML who have had 2 or more TKIs would welcome a new treatment option\n\nThe clinical experts explained that decisions about which TKI to prescribe are individual and depend on many factors, including comorbidities, age and resistance to a previously tried TKI. A dose reduction would be tried for people whose disease was responding to treatment but who could not tolerate it. They confirmed most people with CML have imatinib as first-line treatment, with dasatinib or nilotinib also available as first-line options. At second line or later, the choice of TKI depends on tolerance to treatment and resistance to previous TKIs. If a person was not able to tolerate a previous TKI, the choice of treatment is a TKI that is tolerable and effective, allowing them to remain on that treatment long term. If the disease is resistant, the choice of treatment depends on the potency of the TKIs that have been tried previously. If the disease is resistant to the less-potent first-generation TKI, imatinib, then a more potent TKI such as nilotinib, dasatinib or bosutinib may be tried. If the disease is resistant to a more potent TKI, or the T315I mutation is present, ponatinib may be an option. The clinical and patient experts explained that ponatinib is associated with potentially serious adverse events that may have a substantial effect on quality of life for some people. They considered that although most CML responds to first-line TKI therapy, there remains an unmet need for CML that is resistant to existing TKIs and for people who cannot tolerate them. They advised the main aim of treatment is to balance clinical effectiveness with side effects, and that many people have tried at least 2\xa0previous TKIs. Although allogeneic stem cell transplant is potentially curative, it is only an option for a minority of people and is associated with a considerable risk of mortality and long-term issues with graft-versus-host disease. The NHS England Cancer Drugs Fund clinical lead confirmed that the treatment pathway is complicated and individualised. They explained there is a benefit to having alternative treatment options that are effective and tolerated. The committee recognised that people who are not eligible for allogeneic stem cell transplant and who cannot tolerate current TKIs or whose disease is resistant to them have limited treatment options. It also noted that asciminib works by inhibiting breakpoint cluster region protein‑ABL1 and therefore may have a different mechanism of action compared with other TKIs. It concluded that asciminib would be an important option for people with chronic-phase Philadelphia chromosome-positive CML who have had 2 or more TKIs and do not have a T315I mutation.\n\n## Bosutinib and ponatinib are the main comparators\n\nThe clinical experts explained that the choice of TKI at third line and later varies on a case-by-case basis. They confirmed that once the 3\xa0primary TKIs (imatinib, dasatinib and nilotinib) have been tried and are no longer tolerable, or the disease becomes resistant, the choice will normally be between bosutinib and ponatinib. The committee recognised that most people will have imatinib as their first-line treatment and therefore it is not an appropriate comparator. It also noted that nilotinib and dasatinib are most commonly used earlier in the treatment pathway than at asciminib's proposed positioning (see section 3.2). The committee was aware that most people having third-line and later treatment would have bosutinib. But ponatinib would be appropriate for people whose disease is resistant to bosutinib. It therefore concluded that although all of the TKIs except for imatinib are potential comparators, bosutinib and ponatinib are the main comparators for asciminib.\n\n# Clinical evidence\n\n## Asciminib is clinically effective compared with bosutinib, but the survival benefit is unclear\n\nThe clinical-effectiveness evidence was based on ASCEMBL: a randomised, controlled, open-label trial that compared asciminib with bosutinib. ASCEMBL included people with chronic-phase Philadelphia chromosome-positive CML after 2 or more TKIs who did not have a T315I mutation. The primary outcome was major molecular response rate at 24\xa0weeks. Secondary outcomes included complete cytogenic response, time to treatment discontinuation (TTD), progression-free survival and overall survival. The company also reported some of the outcomes at 48 and 60\xa0weeks. Major molecular response and complete cytogenic response were higher in the asciminib arm than in the bosutinib arm at each reported time point. At 24\xa0weeks, 25.48% of people in the asciminib arm had a major molecular response compared with 13.16% in the bosutinib arm. At 24\xa0weeks, 40.78% of people in the asciminib arm had a complete cytogenic response, compared with 24.19% in the bosutinib arm. The results for all outcomes at 48\xa0weeks and 60\xa0weeks are considered confidential by the company, so they cannot be reported here. The committee noted that data for overall survival and progression-free survival from ASCEMBL was immature, so the survival benefit of asciminib was unclear. It concluded that asciminib is clinically effective compared with bosutinib for molecular and cytogenic response rates, but that the difference in survival outcomes is unclear.\n\n## The company did indirect treatment comparisons\n\nBecause ASCEMBL compared asciminib with bosutinib, there is no head-to-head evidence for asciminib against the remaining comparators. The company provided a series of unanchored matching-adjusted indirect comparisons (MAICs) to compare the TTD of asciminib with those of ponatinib, nilotinib and dasatinib. It explained that an unanchored MAIC was needed because the studies included did not share a common comparator arm. At technical engagement, the ERG highlighted concerns with the company MAICs. These included comparator studies being excluded inappropriately, a lack of comparison with Haematological Malignancy Research Network (HMRN) data, adjustment for limited variables, and limited reporting of survival outcomes and relative estimates of effectiveness. At technical engagement, the ERG also requested MAICs for major molecular response outcomes, and for the MAICs to be compared with the HMRN data. In response, the company explained that it was not possible to adjust for all variables. It said that the survival data in ASCEMBL was too immature to support a comparison of survival data with other published studies. The company did provide further information about why certain trials were excluded from the MAICs. These included the small sizes of the trials, inappropriate comparators, different populations, and lack of baseline data for the relevant subpopulations. It also provided MAICs for major molecular response, and comparing outcomes for asciminib and bosutinib from ASCEMBL with outcomes for dasatinib, nilotinib and bosutinib from the HMRN data.\n\n## The indirect treatment comparisons are appropriate but should be interpreted with caution\n\nThe company noted that the comparison with HMRN data had several limitations, including non-randomisation, but that the results supported the original MAIC using the clinical trial comparator data. The committee noted that no MAIC for ponatinib was done because of the limited number of people who had ponatinib in the HMRN data. The ERG accepted that the trials in the company's MAIC analyses were likely to be the only trials for which a robust MAIC could be done. However, it had concerns about the differences between naive, unanchored and anchored analyses of TTD and the inconsistency between results for TTD and major molecular response. The ERG explained that this suggests that TTD is not an appropriate surrogate for survival outcomes. The ERG preferred the MAIC of major molecular response for the comparison of asciminib with other TKIs from the HMRN data. It thought that the MAIC analyses against HMRN showed no clear evidence of any difference between asciminib and dasatinib or nilotinib. The committee recognised the uncertainty in the MAIC analyses, in particular the use of TTD, there being only 1\xa0study per comparator, and the limited set of variables adjusted for. It concluded that the MAICs comparing asciminib with ponatinib, nilotinib and dasatinib were appropriate, but that the results should be interpreted with caution.\n\n# Economic model\n\n## The surrogate survival model structure is most appropriate\n\nThe company's economic model used a cumulative survival approach to estimate survival based on TTD. The company explained that this is because survival data from ASCEMBL is immature (see section 3.4). The cumulative survival model uses TTD parametric curves for each arm. Total survival time is estimated as the sum of treatment-specific TTD and a fixed, treatment-independent survival period post-discontinuation, which includes fixed periods in the accelerated phase and blast phase. The committee noted this model structure was used for decision making in NICE's technology appraisal guidance on bosutinib for previously treated chronic myeloid leukaemia (TA401). At clarification, the ERG asked the company to provide a surrogate survival modelling approach using a response-based model. This was broadly based on the model used in NICE's technology appraisal guidance on ponatinib for treating chronic myeloid leukaemia and acute lymphoblastic leukaemia (TA451). Using the surrogate survival model, duration of progression-free survival is modelled as a function of cytogenic and haematological response. People are grouped into different response categories and assumed to follow response-dependent progression-free survival curves based on patient-level data digitised from TA451. The ERG was concerned with the cumulative survival model because it used TTD as a surrogate for survival outcomes. It explained that treatment decisions that impact TTD may be subjective, and therefore there are concerns about the validity of comparing TTD across trials. It also explained that there is a lack of evidence to link TTD with survival outcomes. Therefore, it was concerned that TTD was confounded as a clinical outcome and less suitable for modelling. The company explained that using TTD as a surrogate for survival was validated by a clinician. It considered TTD a good surrogate outcome for survival because when people continue treatment it shows that they are able to tolerate it and that their condition is responding. The clinical experts agreed, but explained that previous surrogates used for survival in CML have been cytogenic or molecular response. They advised that both modelling approaches would be reasonable. The ERG preferred to use cytogenic or molecular response as a surrogate for survival based on the model used in TA451. It explained that this approach is supported by literature, and cytogenic or molecular response has clearer value as a clinical outcome than TTD. The ERG highlighted that this approach is not without limitations and explained that the progression-free survival curves used to estimate overall survival came from a second-line population and therefore may be an optimistic estimate in a third-line population. The committee recognised that because of the nature of the condition, there is currently no direct trial data to suggest a survival benefit for asciminib, and therefore a surrogate outcome must be used to estimate survival. It recognised the limitations of both approaches but was reassured that the cost-effectiveness results were broadly similar for both model types. It considered that a response-based approach using cytogenic or molecular response to estimate survival was more clinically appropriate and less subjective than using TTD. It therefore concluded that the surrogate survival model structure is the most appropriate for decision making.\n\n## Survival for 10.1\xa0years after stopping treatment is clinically plausible\n\nIn the company-preferred cumulative survival model (see section 3.7), there is a fixed, treatment-independent survival period after stopping treatment. In its original submission, the company assumed 7\xa0years survival after stopping treatment, based on estimates of mean overall survival from TA401. The ERG preferred a longer survival after stopping treatment because the company survival estimate was in people who did not have a stem cell transplant or TKIs after imatinib was stopped. It was also concerned that the subsequent treatments used in TA401 no longer represent current NHS clinical practice. It therefore believed that the company estimate of 7\xa0years survival after stopping treatment was pessimistic given changes in the treatment pathway and improvements in care. The ERG also highlighted that the mean survival from the HMRN data is likely to be greater than 7\xa0years, and median survival in PACE, a single-arm, phase\xa02 clinical trial of ponatinib, is likely to be greater than 5\xa0years. The ERG provided an alternative scenario of 10.1\xa0years survival after stopping treatment. It explained that this was generated by extrapolating evidence from the PACE trial, assuming a mean overall survival of 167\xa0months and a mean TTD of 46.3\xa0months. It then subtracted the mean TTD from overall survival, resulting in an estimated post-discontinuation survival of 120.7\xa0months (10.1\xa0years). The clinical experts agreed with the ERG that a survival of 10.1\xa0years after stopping treatment is a reasonable assumption. The committee noted that this assumption only applies to the company's cumulative survival model. It concluded that in the cumulative survival model, an assumption of 10.1\xa0years survival after stopping treatment is clinically plausible.\n\n# End of life\n\n## Asciminib does not meet the end\xa0of\xa0life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The life expectancy of people with chronic-phase Philadelphia chromosome-positive CML after 2 or more TKIs who do not have a T315I mutation is estimated to be substantially greater than 2\xa0years. And the evidence for a survival benefit is uncertain. Therefore, the committee concluded that asciminib does not meet the end\xa0of\xa0life criteria.\n\n# Cost-effectiveness results\n\n## The company's updated base case reflects the committee's preferred assumptions except for the model structure\n\nThe company used the cumulative survival approach in its base case. The committee preferred the surrogate survival model, using cytogenic or molecular response as a surrogate outcome to estimate survival. It noted that apart from the model structure (see section 3.7) its preferred assumptions aligned with the updated company base case:\n\nRemoving retreatment with the same drug.\n\nUsing the log-logistic curve to extrapolate TTD.\n\nUsing Niederwieser (2021) for stem cell transplant survival outcomes.\n\nUsing a multiplicative approach to adjust utilities for age.\n\nPonatinib comparator dosing based on people having a major cytogenic response is assumed to reduce to a 15‑mg dose and the cost is halved. People in chronic phase without a major cytogenic response and all people whose disease has progressed to the accelerated and blast phases are assumed to have the higher 45‑mg or 30‑mg dose. All dose reductions occur at 12\xa0months.\n\n## An acceptable ICER would be within the range normally considered a cost-effective use of NHS resources\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted that although its preferred assumptions aligned with the company base case, it favoured a different model structure. It recognised the uncertainty with the model structure, but was reassured that the cost-effectiveness results were broadly similar for the 2\xa0different model structures. Therefore, the committee agreed that an acceptable ICER for asciminib would be between £20,000 and £30,000 per QALY gained.\n\n## The ICERs are below £30,000 per QALY gained for asciminib compared with bosutinib, nilotinib and dasatinib\n\nThere are confidential discounts for asciminib, bosutinib, nilotinib and dasatinib so the exact ICERs are confidential and cannot be reported here. Using the confidential discounts, the company base case ICERs were below £30,000 per QALY gained for all 3\xa0comparisons. Using the committee's preferred model structure and all confidential discounts, the ICERs were below £30,000 per QALY gained for all 3\xa0comparisons. The committee also considered scenario analyses varying the effectiveness of the comparator treatments, for which the ICERs were still all below £30,000 per QALY gained. Overall, the committee concluded that asciminib was a cost-effective treatment option compared with bosutinib, nilotinib and dasatinib.\n\n## Asciminib is cost saving compared with ponatinib\n\nUsing the confidential discounts, the company base case resulted in asciminib having an overall lower cost of treatment and a small loss in QALYs when compared with ponatinib. When an ICER for a technology is less effective and less costly than its comparator, the rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment becomes. The committee-preferred ICER, including all confidential discounts, resulted in asciminib still being associated with cost savings per QALY lost with an ICER above £30,000 saved per QALY lost. Overall, the committee concluded that asciminib was a cost-saving treatment option and was cost effective compared with ponatinib.\n\n## Other factors\n\nNo equality or social value judgement issues were identified.\n\n# Conclusion\n\n## Asciminib is recommended for routine commissioning\n\nUsing the committee's preferred assumptions (see section 3.10) and including all commercial arrangements resulted in an ICER below £30,000 per QALY gained for each pairwise comparison of asciminib with bosutinib, nilotinib and dasatinib. The ICER for asciminib compared with ponatinib showed that asciminib is associated with sufficiently high cost savings per QALY lost. The exact ICERs are confidential and cannot be reported here. The committee acknowledged uncertainty with the model structure, but was reassured that the cost-effectiveness results were broadly similar for the 2\xa0different model structures (see section 3.7). Based on the evidence presented, the committee concluded that, with the discount agreed in the commercial arrangement, the most plausible ICERs were within the range that NICE normally considers an acceptable use of NHS resources. Therefore, it recommended asciminib as an option for treating chronic-phase Philadelphia chromosome-positive CML after 2\xa0or more TKIs in adults without a T315I mutation."}	https://www.nice.org.uk/guidance/ta813	Evidence-based recommendations on asciminib (Scemblix) for chronic myeloid leukaemia after 2 or more tyrosine kinase inhibitors.
2f799e95f576d78dbca635589e232cc3a9b7fb7b	nice	Abrocitinib, tralokinumab or upadacitinib for treating moderate to severe atopic dermatitis	Abrocitinib, tralokinumab or upadacitinib for treating moderate to severe atopic dermatitis Evidence-based recommendations on abrocitinib (Cibinqo), tralokinumab (Adtralza) or upadacitinib (Rinvoq) for treating moderate to severe atopic dermatitis. # Recommendations Abrocitinib and upadacitinib are recommended as options for treating moderate to severe atopic dermatitis that is suitable for systemic treatment in adults and young people 12 years and over, only if: the disease has not responded to at least 1 systemic immunosuppressant, or these are not suitable the companies provide abrocitinib and upadacitinib according to the commercial arrangement. Tralokinumab is recommended as an option for treating moderate to severe atopic dermatitis that is suitable for systemic treatment in adults, only if: the disease has not responded to at least 1 systemic immunosuppressant, or these are not suitable the company provides tralokinumab according to the commercial arrangement. Stop abrocitinib, upadacitinib or tralokinumab at 16 weeks if the atopic dermatitis has not responded adequately. An adequate response is: at least a 50% reduction in the Eczema Area and Severity Index score (EASI 50) from when treatment started and at least a 4‑point reduction in the Dermatology Life Quality Index (DLQI) from when treatment started. Take into account how skin colour could affect the EASI score, and make any appropriate adjustments. Take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI, and make any appropriate adjustments. These recommendations are not intended to affect treatment with abrocitinib, upadacitinib or tralokinumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. In young people this decision should be made jointly by them, their clinician, and their parents or carers. Why the committee made these recommendations Standard treatment for moderate to severe atopic dermatitis (eczema) includes topical treatments such as emollients and corticosteroids. If these treatments are not effective, systemic immunosuppressants such as methotrexate and ciclosporin can be added. Dupilumab and baricitinib are used if systemic immunosuppressants are not effective. The clinical trial evidence shows that abrocitinib, tralokinumab and upadacitinib all reduce symptoms of atopic dermatitis compared with placebo. Abrocitinib and upadacitinib were indirectly compared with ciclosporin, but the results are highly uncertain. Abrocitinib, upadacitinib and tralokinumab were each directly or indirectly compared with dupilumab and baricitinib for use after systemic immunosuppressants, but the results are uncertain. Despite the uncertainty the most likely cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources. Therefore, abrocitinib, upadacitinib or tralokinumab are recommended as options for moderate to severe atopic dermatitis that has not responded to at least 1 systemic immunosuppressant.# Information about abrocitinib, tralokinumab, upadacitinib # Marketing authorisation indication Abrocitinib (Cibinqo, Pfizer) is 'indicated for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy'. Tralokinumab (Adtralza, Leo) is 'indicated for the treatment of moderate-to-severe atopic dermatitis in adult patients who are candidates for systemic therapy'. Upadacitinib (Rinvoq, AbbVie) is 'indicated for the treatment of moderate to severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy'. # Dosage in the marketing authorisation The dosage schedule for abrocitinib is available in the summary of product characteristics for abrocitinib. The dosage schedule for tralokinumab is available in the summary of product characteristics for tralokinumab. The dosage schedule for upadacitinib is available in the summary of product characteristics for upadacitinib. # Price The list price of abrocitinib is £893.76 for a 28‑pack of 100 mg or 200 mg tablets (excluding VAT, BNF online, accessed March 2022). The company has a commercial arrangement. This makes abrocitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount. The list price of tralokinumab is £1,070 for a 4‑pack of 150 mg per 1 ml pre-filled syringes (excluding VAT, BNF online, accessed March 2022). The company has a commercial arrangement. This makes tralokinumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount. The list price of upadacitinib is £805.56 for a 28‑pack of 15 mg modified-release tablets or £1,611.12 for a 28‑pack of 30 mg modified-release tablets (excluding VAT, BNF online, accessed March 2022). The company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence from a number of sources. See the committee papers for full details of the evidence. # Experience of people with atopic dermatitis ## Atopic dermatitis affects all aspects of a person's life Atopic dermatitis is a chronic, recurrently flaring, generalised skin condition that often starts in childhood. People with severe atopic dermatitis may need treatment in hospital. Feedback from patient and professional organisations highlighted that the condition is life-limiting, debilitating, and isolating, and affects all aspects of life (physical, psychological, social, and financial). They emphasised that severe disease is associated with intolerable itch that disrupts sleep, and a higher risk of depression and suicide. The committee noted that having a choice of treatments that improve the condition and which are associated with few, or manageable adverse effects is important to people with atopic dermatitis. # Assessing the severity of atopic dermatitis ## Symptom burden and quality of life are used to determine the severity of atopic dermatitis The clinical experts explained that there is variability in how clinicians assess the severity of atopic dermatitis. They assess severity based on clinical assessment of signs of the disease and the areas of the body that are affected. They also assess patient-reported symptoms including their effect on sleep and work, and how much people need to use topical corticosteroids or systemic therapy. The committee understood that clinical trials in this disease area routinely use the Eczema Area and Severity Index (EASI) to assess clinical signs (for example, skin lesions) and the Dermatology Life Quality Index (DLQI) to assess quality of life. Moderate to severe atopic dermatitis in published trials is defined by an EASI score of 16 or more. Additional tools such as the investigator's global assessment (IGA) are also used to assess severity of the condition. People with an IGA score of 3 or more, or whose body surface area is 10% or more affected are considered to have moderate to severe atopic dermatitis. The consensus-based Harmonising Outcome Measures for Eczema (HOME) initiative also recommends using the Patient Oriented Eczema Measure (POEM) to assess symptoms (for example, itch) in clinical practice. It recommends that clinical signs of severity are assessed using the EASI score. The committee did not consider there to be substantial variation in classification of moderate to severe severity. # Clinical management ## There is an unmet need for people whose dermatitis does not respond to treatment or who are unable to tolerate existing treatment The committee understood that treatment for atopic dermatitis is variable for each person. Initial treatment involves emollients, topical corticosteroids and topical calcineurin inhibitors. Some people may also try phototherapy, although the clinical experts explained that this treatment is not uniformly available and is used variably in the NHS. The patient experts also noted variability in practice with lack of access to phototherapy and considered that there is insufficient guidance on topical corticosteroids. They also explained that many people prefer not to use topical corticosteroids because of their potential to sting, the increased burden of administration and their fear of systemic side effects and steroid withdrawal effects. If there is an inadequate response to topical treatments and phototherapy, systemic immunosuppressants are considered. This includes treatment with ciclosporin, methotrexate, prednisolone, azathioprine or mycophenolate mofetil. The clinical experts explained that frequent blood tests are needed during treatment with most systemic immunosuppressants and that people who take them can experience serious adverse effects. Although ciclosporin is the only licensed treatment, it is used for only short periods because of toxicity concerns and many clinicians now prefer to consider methotrexate first. If there is inadequate response, intolerance, or contraindication to at least 1 systemic treatment, dupilumab and baricitinib are recommended as alternative options for moderate to severe atopic dermatitis that has not responded to at least 1 other systemic therapy. Exacerbations (flares) in atopic dermatitis are managed using short-term high-potency topical corticosteroids, oral corticosteroids and other systemic treatments. The committee concluded that there is an unmet need for well-tolerated treatments for people with moderate to severe atopic dermatitis. # Positioning in the treatment pathway, comparators and sequencing ## Abrocitinib, tralokinumab or upadacitinib would likely be used after systemic immunosuppressants The marketing authorisations for abrocitinib and upadacitinib are 'for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy'. Tralokinumab currently has a marketing authorisation only in adults with moderate to severe atopic dermatitis who are candidates for systemic therapy. The committee considered that the marketing authorisation wording is broad and could refer to first-line treatment, but all the companies positioned their treatments after at least 1 systemic immunosuppressant, as alternatives to dupilumab and baricitinib. One of the clinical experts considered this positioning to be appropriate. The companies also proposed that upadacitinib and abrocitinib could be used as alternatives to systemic immunosuppressants, before dupilumab and baricitinib. One of the clinical experts considered that this positioning was less appropriate. They explained that methotrexate and other systemic immunosuppressants are clinically effective and well tolerated, although there is limited randomised trial evidence to show this effect. They also have substantially lower costs and are therefore likely to be more cost-effective to try as first-line treatment for people whose dermatitis is suitable for systemic therapy. The committee noted that all available JAK inhibitors used in inflammatory disorders (including abrocitinib, baricitinib and upadacitinib) are currently under a European Medicines Agency (EMA) safety review. This is because of a potential class effect of increased risk of major cardiovascular events and higher risk of developing cancer. The committee concluded that in clinical practice, systemic immunosuppressants such as methotrexate would normally be considered first, so the companies' additional positioning of upadacitinib and abrocitinib is less appropriate. ## Abrocitinib, tralokinumab or upadacitinib are likely to be used at the same time as topical treatments, as combination therapy All the companies provided evidence for their treatments both as monotherapy (used alone) and in combination with topical treatments (combination therapy). The clinical experts explained that all the treatments are likely to be offered alongside topical corticosteroids in clinical practice. The committee noted that monotherapy trials are used for regulatory endpoints and do not represent how these treatments would be used in clinical practice. Therefore, it agreed to focus on the evidence for combination therapy as the most relevant evidence for decision making. ## Treatments would likely be used in sequences, but cost-effectiveness analysis of sequences would be uncertain because of limited clinical data The clinical experts explained that there is no typical treatment journey and there is variation in prescribing practices. Atopic dermatitis is a lifelong disease, and in practice people who have treatment, such as dupilumab, may have an inadequate response and switch to baricitinib or retry other systemic immunotherapies. The treatment choice would likely be based on previous responses to treatment, expected differences in how they work, and potential adverse effects. New treatment options are therefore also likely to be used in sequence with existing treatments but there would likely be no 'standard' sequence. The committee considered that cost-effectiveness analyses for sequences should ideally be taken into account in decision making. But it acknowledged that there is no clinical data on sequential effectiveness and the clinical rationale for using various sequences of treatments would be personalised to each person. Therefore, the committee concluded that analysis of treatment sequences would be uncertain. # Clinical evidence ## The JADE-COMPARE and JADE-DARE trials provide the key clinical evidence for abrocitinib The evidence for abrocitinib came from 6 trials, including 2 trials (JADE-DARE, JADE-COMPARE) that compared abrocitinib plus background topical corticosteroids with dupilumab in adults. JADE-COMPARE was a randomised double-blind trial that included 837 adults who had moderate to severe atopic dermatitis for at least 12 months and had an inadequate response to medicated topical treatment or systemic treatment. People in the trial could use more than 1 topical treatment. The trial compared 2 doses of abrocitinib (200 mg and 100 mg, both once daily) with dupilumab 300 mg every 2 weeks or placebo. The primary endpoints were assessed at the end of the 'induction period' (that is, 12 weeks after starting treatment): at least a 75% reduction in the EASI score from when treatment started (EASI 75) a rating of 'clear' (score of 0) or 'almost clear' (score of 1) on the IGA, and at least a 2‑point improvement from baseline.JADE-DARE is an ongoing trial. It compared abrocitinib 200 mg with dupilumab, each used with topical corticosteroids. Initial response data for JADE-DARE was provided by the company and included in the analysis after consultation. The committee considered that these trials provided the key clinical evidence for abrocitinib. The JADE-TEEN trial also compared abrocitinib with placebo in combination with topical corticosteroids in young people aged 12 to 18. ## The AD-UP trial provides the key clinical evidence for upadacitinib The evidence for upadacitinib came from 6 trials including 2 trials on upadacitinib plus background topical corticosteroids (AD-UP and RISING-UP). RISING-UP was a randomised controlled trial carried out in Japan but data is not yet available, and its results were not included in the analysis. AD-UP was a randomised double-blind trial that included 901 people (aged 12 to 75) who had moderate to severe atopic dermatitis and had an inadequate response to medicated topical therapy or systemic therapies. The trial compared 2 doses of upadacitinib (15 mg or 30 mg once daily) with a placebo. The primary endpoints were assessed at 16 weeks after the 'induction' period: AD-UP: at least a 75% reduction in the EASI score from when treatment started (EASI 75) AD-UP: a rating of 'clear' (score of 0) or 'almost clear' (score of 1) on the IGA, and at least a 2‑point improvement from baseline.People in AD-UP had an additional 120‑week blinded extension period that was not included in the analysis. A subgroup of people who were eligible for systemic therapy in UK clinical practice were identified and included in the main analysis. ## The ECZTRA 3 and ECZTRA 7 trials provide the key clinical evidence for tralokinumab The evidence for tralokinumab came from 6 trials including 2 trials on tralokinumab plus background topical corticosteroids (ECZTRA 3 and ECZTRA 7). Both were randomised double-blind trials that included adults who had moderate to severe atopic dermatitis for at least 12 months and had an inadequate response to medicated topical treatment or systemic treatment. The trials compared tralokinumab (300 mg every 2 weeks) with a placebo. The primary endpoints were assessed at 16 weeks after the 'induction' period: ECZTRA 3 and ECZTRA 7: at least a 75% reduction in the EASI score from when treatment started (EASI 75) ECZTRA 3: a rating of 'clear' (score of 0) or 'almost clear' (score of 1) on the IGA, and at least a 2‑point improvement from baseline. ## Abrocitinib, tralokinumab and upadacitinib are clinically effective treatments compared with placebo For all people who had treatment in the key clinical evidence studies (see sections 3.7 to 3.9), the results showed a greater chance of reaching a 50% reduction in EASI score (EASI 50) plus an improvement of at least 4 in the DLQI score at week 12 or 16, than people who had a placebo. These results were statistically significant for abrocitinib and upadacitinib. More people who had tralokinumab also achieved EASI 50 than those who had placebo, but the results were not statistically significant. Significantly more people who had tralokinumab achieved EASI 75 compared with people who had placebo. However, the committee noted that substantial heterogeneity in trial design and placebo response rates may have contributed to these results. This may have affected the comparison of these studies (see section 3.13 for discussion of the network meta-analysis). The committee concluded that abrocitinib, tralokinumab or upadacitinib are clinically effective treatments compared with placebo. ## A composite end point of EASI 50 plus an improvement in the DLQI score of at least 4 is the most relevant end point for decision making Common outcomes in clinical trials are relative reductions in EASI scores from baseline by 50% and 75% (EASI 50 and EASI 75). The clinical experts considered that these outcomes were appropriate for measuring response to treatment, but ideal outcomes would be an absolute reduction to no symptoms or mild symptoms. A consultee also commented that the use of EASI 50 may not capture additional benefits measured by EASI 75 or above. One of the clinical experts noted that EASI 75 was commonly used in clinical trials for assessing improvement in atopic dermatitis. The committee understood that using EASI 75 alone is not adequate to capture a quality of life improvement and it may not capture clinically meaningful improvements. The committee agreed to use a composite end point of EASI 50 plus an improvement in the DLQI of at least 4 in the analysis. It included patient-reported quality of life and was consistent with NICE's technology appraisal guidance on dupilumab for treating moderate to severe atopic dermatitis (TA534) and baricitinib for treating moderate to severe atopic dermatitis (TA681). Therefore, the committee considered that the EASI 50 combined with DLQI of at least 4 is the most relevant end point for decision making and should be used to define treatment response. The external assessment group (EAG) used this composite outcome as the basis for assessing relative response, but also considered the EASI 75 outcome when data was not available for the composite outcome. ## Results for adults who have tried systemic immunotherapy are likely to be generalisable to young people Both the abrocitinib and upadacitinib marketing authorisations include young people aged 12 to 18 with atopic dermatitis. At the first committee meeting the clinical experts explained that the current treatment pathways for adults and young people with atopic dermatitis are similar. The feedback from consultees agreed that young people were treated the same as adults and the results of the trials for adults would be generalisable to young people. However, baricitinib is currently licensed for adults only. For young people, the only data available that allowed for indirect comparison with other treatments was using EASI 75 outcome measurements. The EAG also noted the very small numbers of people in the treatment arms, leading to high uncertainty. The EAG initially did separate analyses for the adult and young people populations, but after the first committee meeting an updated analysis was done for the adult population. The committee considered that because of the likely similarity in treatment for young people and adults, and limited available evidence for young people, it had not seen sufficient justification for considering young people as a separate subgroup. The committee concluded that the results of the 'combination therapy' analysis for adults who had tried systemic immunotherapy would likely be generalisable to young people. # Indirect treatment comparisons ## The network meta-analysis with dupilumab or baricitinib is appropriate for decision making There was no direct evidence comparing tralokinumab or upadacitinib used in combination with topical treatments ('combination therapy') with dupilumab or baricitinib for atopic dermatitis in adults. So data from the relevant trials was analysed to compare treatments indirectly through a network meta-analysis: abrocitinib: a subgroup of the JADE-COMPARE trial who would be eligible for systemic therapy in UK practice tralokinumab: ECZTRA 7 plus the ECZTRA 7‑like subgroup from ECZTRA 3 upadacitinib: a subgroup of the AD-UP trial who would be eligible for systemic therapy in UK practice dupilumab: the CAFÉ trial and a subgroup of people from the CHRONOS trial for whom ciclosporin was contraindicated or not tolerated, or whose disease was uncontrolled on ciclosporin (the 'CAFÉ‑like' subgroup) baricitinib: BREEZE‑AD4 and BREEZE‑AD7.All trials included a placebo arm, so placebo was the common comparator for all trials in the network analysis. The EAG explained that 2 trials comparing abrocitinib doses with dupilumab were included in the network of indirect comparisons to improve consistency. The EAG considered that only people whose dermatitis had not responded to systemic treatments were included in the analysis, but noted that: ECZTRA 7 and CAFÉ only included people who had either not had ciclosporin or could not have it, or who had it before but had an inadequate response. Baseline characteristics for the full trial populations are comparable, but ECZTRA 7 and CAFÉ included a blended population, and clinical data to inform the comparisons was from post-hoc subgroups.The committee concluded that, despite their limitations, the indirect treatment comparisons with dupilumab or baricitinib used the most appropriate clinical evidence. ## The indirect comparisons of treatments with ciclosporin are highly uncertain For people who have not previously had systemic treatment, the EAG presented results for first-line treatments from a network analysis using results from the trials for upadacitinib and abrocitinib. The clinical experts explained that randomised trial evidence for currently used systemic treatments is limited because of the off-label use of systemic immunosuppressants (see section 3.4). The EAG considered the most appropriate evidence to include in the network was a small observational study (Ariens et al. 2019). The study compared individual person data from a clinical trial for dupilumab against individual patient data from ciclosporin use in daily clinical practice in a treatment centre in the Netherlands (n=57). The clinical experts considered this appropriate although noted that methotrexate is now the most commonly used treatment in people who have not had systemic immunotherapies before (see section 3.4). One consultee noted the TREAT trial which compared ciclosporin with methotrexate in young people, but its results have not been published yet. There is also additional published evidence regarding methotrexate compared with ciclosporin in adults. The committee considered that including the comparison of ciclosporin and methotrexate in the network analysis would introduce uncertainties because of ciclosporin's limited evidence base. The committee also noted that, in order to compare ciclosporin with upadacitinib and abrocitinib, the comparison had to be done indirectly through both dupilumab and placebo, which increased uncertainty of the comparison. It also noted that there are likely to be substantial differences between daily clinical practice and clinical trial evidence in this disease area, including adherence to topical treatments. It also considered that upadacitinib would be used for longer periods of time in clinical practice than ciclosporin, which is only indicated for a short time frame. The committee concluded that the indirect comparison with ciclosporin was highly uncertain. ## Results of fixed-effects and random-effects network meta-analyses are comparable The committee considered that there was substantial clinical heterogeneity in the trial design which may have contributed to very wide credibility intervals of the results of the network meta-analyses. The EAG considered that these included: use of post-hoc subgroups to define people who were eligible for systemic therapy, and would break randomisation methodological heterogeneity across studies in the washout period before starting the treatment in the trial the type and potency of concomitant topical corticosteroids and other relevant optimisation of baseline care used in the trial heterogeneity in how rescue therapy was implemented or allowed in the trial.The EAG considered that this substantial between-trial heterogeneity would best be accounted for using a random-effects model with an informed prior for the between-trial heterogeneity. This would otherwise be ignored using a fixed-effect model that assumes all placebo arms are estimating the same treatment effect. The EAG explained that adjusting the placebo effect for each trial was not possible for some analyses and may have overfitted the data in other analyses. The committee noted the substantial heterogeneity in the treatment arms but also noted the very wide confidence intervals. It considered that the random-effects model approach taken by the EAG may not be appropriate because the small number of trials for each treatment arm of the analyses may be inflating the heterogeneity in the network. After consultation, the EAG also presented a fixed-effects model. The committee considered that the results were very similar but the random-effects model had slightly wider credibility intervals. It considered that the wide credibility intervals indicated substantial uncertainty around the point estimates of the results used in the deterministic base-case analysis. However, the results of the analyses were comparable when fixed-effects or random-effects models were applied. # Adverse events ## Trial evidence shows low adverse event rates but more safety data on JAK inhibitors would be valuable The number of adverse events reported in the trials was generally small. Upper respiratory tract infections (URTIs) were one of the most frequent adverse events in the abrocitinib trials. URTI, conjunctivitis (allergic and infectious), and injection-site reactions were commonly reported in people using tralokinumab. Upadacitinib was associated with slightly higher rates of acne, oral herpes, and URTI compared with placebo. The committee understood that the EMA has started a safety review of JAK inhibitors including baricitinib, abrocitinib and upadacitinib. Preliminary findings suggest that using JAK inhibitors may be associated with an increased risk of cardiovascular problems such as heart attack and developing cancer. The clinical experts considered it was too early to conclude the impact of JAK inhibitors on developing cardiovascular problems or cancer because of limited available safety data. The committee noted that the increased cancer risk would be a particularly important outcome for people with atopic dermatitis, because of an already increased risk of some skin cancers. The committee agreed that more safety data on JAK inhibitors would be valuable. # The economic model ## The structure of the economic model is appropriate for decision making The economic model for this appraisal was produced by the EAG. The model structure was informed by a systematic literature review, the companies' submissions, and previous technology appraisals in the disease area. The economic model is a short-term (52 week) decision tree model that feeds into a long-term Markov model for the rest of the lifetime horizon. People in the economic model start in the baseline health state and are assigned to active treatment. At 16 weeks, people are assigned to health states based on response to treatment, informed by the results of the network meta-analysis (see section 3.13). People whose dermatitis does not respond will stop treatment and progress to the best supportive care health state. People whose dermatitis does respond continue treatment in the responder health state. People enter the Markov model in different maintenance health states depending on initial response to treatment and discontinuation up until week 52. People then transition to the best supportive care health state based on annual discontinuation and treatment effect waning assumptions agreed upon in a previous appraisal (TA534). The committee noted that this represented a simplification of clinical practice, in which further sequential treatments would be trialled (see section 3.6). However, it considered that this simplification could be appropriate in the context of a chronic recurrent disease modelled over a lifetime horizon. The committee concluded that the model structure was similar to models previously seen in atopic dermatitis appraisals and was appropriate for decision making. # Assumptions in the economic model ## Comparison with systemic immunosuppressants does not represent clinical practice The EAG explained that for the first-line treatment comparison with ciclosporin in the economic model, it was assumed that people would only have ciclosporin for 1 year and then have best supportive care for the rest of the modelled time horizon. The committee considered that this did not represent clinical practice because it would involve sequential treatment. It also did not represent ciclosporin's marketing authorisation indication, nor how methotrexate or other systemic immunosuppressants would be used as a first-line treatment. The committee also recalled the substantial limitations of the comparative efficacy evidence (see section 3.14). Therefore, the committee concluded that the analysis comparing treatments with first-line systemic immunosuppressants was limited in value and further evidence is needed for this comparison. ## Cost effectiveness of different dosing options is explored through pooling Abrocitinib and upadacitinib each have 2 daily dose options (low dose treatment or high dose treatment). The choice of dose would depend on individual patient presentation and response. The clinical evidence was assessed as individual daily doses in the network meta-analysis, and this was maintained in the economic model as different treatment options. This approach was informed by the companies' submissions. The committee considered that in clinical practice, the decision to start treatment would be based on the overall effectiveness of the drug and not on efficacy evidence of individual doses. Therefore, it considered that modelling individual doses in the economic model would not represent expected use in clinical practice and that it added difficulties to the decision-making process. After consultation, the EAG provided a scenario analysis which pooled the cost-effectiveness results of the high and low doses, assuming an equal split of high and low dose distribution. This was because there was no robust data on which to base this distribution. An alternative dose distribution for abrocitinib was provided by the company, based on its use in an early access programme. The company consider this distribution to be confidential. The clinical experts considered this dose distribution was likely to reflect expected use in clinical practice of abrocitinib and upadacitinib. The committee concluded that in the absence of further evidence, it was appropriate to pool the doses using the distribution provided for abrocitinib. ## It is appropriate to consider tralokinumab's alternative dosing schedule but its use in clinical practice is uncertain The committee noted an alternative dosing schedule for tralokinumab which allowed for dosing every 4 weeks for people whose dermatitis is clear or almost clear after 16 weeks of treatment. The EAG included an option in the economic model for a proportion of people taking tralokinumab to switch to the less frequent dosing schedule, based on evidence from ECZTRA 3. The committee considered that some people would switch to less frequent dosing, but others may stay on the more frequent dose if they tolerate the treatment and the dermatitis responds well to it. However, the committee considered that the proportion of those who would switch to the 4‑weekly dosing is uncertain outside of a clinical trial context. The committee therefore considered a range of results. These ranged from assuming the same number of people use the alternative dosing schedule as in the ECZTRA 3 trial, to assuming all people continue on the 2-weekly dosing schedule. # Utility values in the economic model ## Utility values used in the economic model are derived from the clinical trials Health-related quality of life data was collected in all the key clinical trials using the 5‑level EQ‑5D (EQ‑5D‑5L) and the data was then mapped to the 3-level EQ‑5D (EQ‑5D‑3L), using the van Hout crosswalk method. At the first committee meeting, the EAG separated the treatments into 3 treatment-specific groups: high dose JAK inhibitors (abrocitinib 200 mg, upadacitinib 30 mg, and baricitinib 4 mg), low dose JAK inhibitors (abrocitinib 100 mg, upadacitinib 15 mg, and baricitinib 4 mg), and monoclonal antibodies (dupilumab and tralokinumab). The EAG presented analyses with both high and low dose utility values for baricitinib. For adult second-line 'combination therapy' analysis, the JAK inhibitor low dose and high dose utility values were derived from the AD-UP trial. The monoclonal antibody utility values were derived from ECZTRA 7 and the ECZTRA 7‑like subgroup in ECZTRA 3. After the first committee meeting, the EAG provided a scenario using data from the AD‑UP trial to create a response-based health-state utility value, that was applied to all treatments regardless of drug class. ## Response-based utility values are more appropriate than treatment-specific utility values At the first committee meeting, the EAG explained that treatment-specific utility values were used to better represent potential treatment-specific differences. This included differences in baseline utility values for people whose condition responds to treatment at 16 weeks. The committee considered that there is no rationale for differences in baseline utility values, and this would likely only represent heterogeneity between the clinical trials. It considered it plausible that there may be some differences in utility values based on response to treatment. But the size of the difference between the different treatments was likely to be because of trial design and reporting methodology, rather than true differences in quality of life. It considered that the use of different baseline utility values and treatment-specific utility values introduced unnecessary complexity to the economic model. The committee preferred a single response-based utility value for baseline and response, or ideally a single synthesis of relative difference in utility, similar to the network meta-analysis. After the first committee meeting, the EAG provided a scenario using health-state utility values based on data from the AD‑UP trial only. One consultee considered that removal of treatment-specific utility values would not capture all the benefits of treatment. Therefore they proposed an alternative approach of applying a common baseline utility value and a responder utility value associated with having an EASI 50 response plus a DLQI of at least 4, for all treatments. Additional utility benefits were applied based on the proportion of people achieving EASI 75 and EASI 90 within the trials. The EAG considered this approach may not be appropriate because it bases longer-term utility increments on trials measured at a single time point after a few months. The EAG also considered that larger reductions in EASI score may not be maintained outside of a trial setting for longer time periods, but this is unclear. The committee also noted that the largest gains in quality of life came from achieving good response on the DLQI's measure of health-related quality of life. It considered the proposed approach could increase uncertainty and also highlight further heterogeneity between trials. Therefore, it concluded that there was not enough evidence to justify changing the specified composite outcome of interest in regards to utility data, because it may introduce additional uncertainties. # Best supportive care assumptions ## The utility values for the best supportive care health state are highly uncertain, and have a large impact on the modelled benefit The EAG explained that the utility values for the best supportive care health state were derived using a weighted average of the utility values for responders and non-responders at week 16. This method was used to capture the waxing and waning nature of response to best supportive care and was also used in NICE's technology appraisal guidance on baricitinib for treating moderate to severe atopic dermatitis (TA681). The EAG explained that the utility value for non-responders was significantly higher than the baseline health state utility values because it included people whose dermatitis had partially responded to treatment but did not reach the EASI 50 or DLQI of at least 4 threshold, or who later lost response but still maintained some residual effect. In addition, the baseline utility values were elicited after a 'washout' period in the trials, when previous treatment with standard care was stopped. This included stopping use of topical corticosteroids in the AD‑UP trial. The clinical experts noted that the 'washout' period does not reflect clinical practice in the NHS because people would always be having some treatment. The committee considered that the utility values for best supportive care are highly uncertain using this approach because they represent most of the modelled time over a lifetime horizon. After the first committee meeting, the committee requested further exploration of best supportive care utility through time using a best supportive care waning assumption. ## Best supportive care waning assumptions are highly uncertain Previous appraisals have also modelled best supportive care waning effects, when response to treatment wanes towards that seen in the baseline of the trial over time. The clinical experts considered this waning effect to plausibly represent a reduction over time for those who do not have further treatment and who have reduced benefit from topical corticosteroids. The committee considered that the best supportive care health state may wane to some extent over time, but in clinical practice, people would have further treatments as part of a sequence (see section 3.6) and some could improve over time. After the first committee meeting consultation, the EAG updated the analyses and included a scenario with best supportive care waning. The analysis applied the accepted best supportive care waning assumptions for dupilumab from TA534. The scenario assumed that by year 5, 97% of people had returned to baseline utility, and none of them had topical corticosteroids. The committee acknowledged that the EAG's approach represented different people in the model moving in and out of disease control over time. The committee considered this may simplify the effect of people having best supportive care because their quality of life could vary because of other factors such as treatment sequence. The committee concluded that there was significant uncertainty with attempting to model best supportive care waning without evidence of the natural history of the disease, or use of further sequential treatments. # Cost-effectiveness estimates ## Abrocitinib, tralokinumab and upadacitinib are cost effective compared with dupilumab or baricitinib based on the ICERs for the committee's preferred scenarios The committee considered that the cost-effectiveness estimates for abrocitinib and upadacitinib for first-line treatment compared with ciclosporin were highly uncertain and did not represent clinical practice. Therefore the committee concluded that it was inappropriate to consider the economic model outputs for these comparisons and could not make a recommendation for first-line treatment. The committee considered second-line treatment for people whose disease has not responded to at least 1 systemic immunosuppressant, or when systemic immunosuppressants are not suitable. For second-line treatment, the incremental cost-effectiveness ratios (ICERs) were calculated for abrocitinib, tralokinumab and upadacitinib plus topical corticosteroids compared with dupilumab or baricitinib. The exact ICERs are confidential and cannot be reported here. The committee noted their preferred assumptions to: consider clinical effectiveness data from adults to be generalisable to young people (see section 3.12) use specific dose and dose scheduling assumptions for each treatment (see sections 3.19 and 3.20) use utility values derived from a single baseline and response to treatment data (see section 3.22).The committee noted substantial uncertainty with the relative clinical effectiveness of each treatment in the network meta-analysis and effectiveness of sequential treatments and best supportive care over the full time horizon. It considered that taking into account these uncertainties, the ICERs for each treatment suggested that abrocitinib, upadacitinib and tralokinumab are likely to be an effective use of NHS resources compared with current treatments. # Other factors ## Head-to-head trials and real-world data may help future decision making The EAG noted that there are limited head-to-head comparative studies which evaluate the efficacy of treatment options for atopic dermatitis. Feedback from consultees highlighted that real-world data such as the A-STAR registry (UK-Irish Atopic Eczema Systemic Therapy Register) could potentially improve the current evidence base. The registry is an independent research data platform and collects both clinical and cost data to help treatment decisions for people with atopic eczema. The committee understood that real-world evidence could improve the current evidence base and help inform decision making, and may also help inform understanding of sequential treatments in NHS clinical practice. ## EASI and DLQI may not be appropriate for all people with atopic dermatitis The committee noted the following potential equality issues: the EASI might underestimate the severity of atopic dermatitis in people with brown or black skin the DLQI may not account for anxiety and depression.The committee concluded that, when using the EASI, healthcare professionals should take into account skin colour and how this could affect the EASI score. Also, it concluded that when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or difficulties in communication that could affect a person's response to the DLQI.	{'Recommendations': 'Abrocitinib and upadacitinib are recommended as options for treating moderate to severe atopic dermatitis that is suitable for systemic treatment in adults and young people 12\xa0years and over, only if:\n\nthe disease has not responded to at least 1 systemic immunosuppressant, or these are not suitable\n\nthe companies provide abrocitinib and upadacitinib according to the commercial arrangement.\n\nTralokinumab is recommended as an option for treating moderate to severe atopic dermatitis that is suitable for systemic treatment in adults, only if:\n\nthe disease has not responded to at least 1 systemic immunosuppressant, or these are not suitable\n\nthe company provides tralokinumab according to the commercial arrangement.\n\nStop abrocitinib, upadacitinib or tralokinumab at 16\xa0weeks if the atopic dermatitis has not responded adequately. An adequate response is:\n\nat least a 50% reduction in the Eczema Area and Severity Index score (EASI\xa050) from when treatment started and\n\nat least a 4‑point reduction in the Dermatology Life Quality Index (DLQI) from when treatment started.\n\nTake into account how skin colour could affect the EASI score, and make any appropriate adjustments.\n\nTake into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI, and make any appropriate adjustments.\n\nThese recommendations are not intended to affect treatment with abrocitinib, upadacitinib or tralokinumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. In young people this decision should be made jointly by them, their clinician, and their parents or carers.\n\nWhy the committee made these recommendations\n\nStandard treatment for moderate to severe atopic dermatitis (eczema) includes topical treatments such as emollients and corticosteroids. If these treatments are not effective, systemic immunosuppressants such as methotrexate and ciclosporin can be added. Dupilumab and baricitinib are used if systemic immunosuppressants are not effective.\n\nThe clinical trial evidence shows that abrocitinib, tralokinumab and upadacitinib all reduce symptoms of atopic dermatitis compared with placebo. Abrocitinib and upadacitinib were indirectly compared with ciclosporin, but the results are highly uncertain.\n\nAbrocitinib, upadacitinib and tralokinumab were each directly or indirectly compared with dupilumab and baricitinib for use after systemic immunosuppressants, but the results are uncertain.\n\nDespite the uncertainty the most likely cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources. Therefore, abrocitinib, upadacitinib or tralokinumab are recommended as options for moderate to severe atopic dermatitis that has not responded to at least 1 systemic immunosuppressant.', 'Information about abrocitinib, tralokinumab, upadacitinib': "# Marketing authorisation indication\n\nAbrocitinib (Cibinqo, Pfizer) is 'indicated for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents 12\xa0years and older who are candidates for systemic therapy'.\n\nTralokinumab (Adtralza, Leo) is 'indicated for the treatment of moderate-to-severe atopic dermatitis in adult patients who are candidates for systemic therapy'.\n\nUpadacitinib (Rinvoq, AbbVie) is 'indicated for the treatment of moderate to severe atopic dermatitis in adults and adolescents 12\xa0years and older who are candidates for systemic therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule for abrocitinib is available in the summary of product characteristics for abrocitinib.\n\nThe dosage schedule for tralokinumab is available in the summary of product characteristics for tralokinumab.\n\nThe dosage schedule for upadacitinib is available in the summary of product characteristics for upadacitinib.\n\n# Price\n\nThe list price of abrocitinib is £893.76 for a 28‑pack of 100\xa0mg or 200\xa0mg tablets (excluding VAT, BNF online, accessed March 2022). The company has a commercial arrangement. This makes abrocitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.\n\nThe list price of tralokinumab is £1,070 for a 4‑pack of 150\xa0mg per 1\xa0ml pre-filled syringes (excluding VAT, BNF online, accessed March 2022). The company has a commercial arrangement. This makes tralokinumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.\n\nThe list price of upadacitinib is £805.56 for a 28‑pack of 15\xa0mg modified-release tablets or £1,611.12 for a 28‑pack of 30\xa0mg modified-release tablets (excluding VAT, BNF online, accessed March 2022). The company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# Experience of people with atopic dermatitis\n\n## Atopic dermatitis affects all aspects of a person's life\n\nAtopic dermatitis is a chronic, recurrently flaring, generalised skin condition that often starts in childhood. People with severe atopic dermatitis may need treatment in hospital. Feedback from patient and professional organisations highlighted that the condition is life-limiting, debilitating, and isolating, and affects all aspects of life (physical, psychological, social, and financial). They emphasised that severe disease is associated with intolerable itch that disrupts sleep, and a higher risk of depression and suicide. The committee noted that having a choice of treatments that improve the condition and which are associated with few, or manageable adverse effects is important to people with atopic dermatitis.\n\n# Assessing the severity of atopic dermatitis\n\n## Symptom burden and quality of life are used to determine the severity of atopic dermatitis\n\nThe clinical experts explained that there is variability in how clinicians assess the severity of atopic dermatitis. They assess severity based on clinical assessment of signs of the disease and the areas of the body that are affected. They also assess patient-reported symptoms including their effect on sleep and work, and how much people need to use topical corticosteroids or systemic therapy. The committee understood that clinical trials in this disease area routinely use the Eczema Area and Severity Index (EASI) to assess clinical signs (for example, skin lesions) and the Dermatology Life Quality Index (DLQI) to assess quality of life. Moderate to severe atopic dermatitis in published trials is defined by an EASI score of 16 or more. Additional tools such as the investigator's global assessment (IGA) are also used to assess severity of the condition. People with an IGA score of 3 or more, or whose body surface area is 10% or more affected are considered to have moderate to severe atopic dermatitis. The consensus-based Harmonising Outcome Measures for Eczema (HOME) initiative also recommends using the Patient Oriented Eczema Measure (POEM) to assess symptoms (for example, itch) in clinical practice. It recommends that clinical signs of severity are assessed using the EASI score. The committee did not consider there to be substantial variation in classification of moderate to severe severity.\n\n# Clinical management\n\n## There is an unmet need for people whose dermatitis does not respond to treatment or who are unable to tolerate existing treatment\n\nThe committee understood that treatment for atopic dermatitis is variable for each person. Initial treatment involves emollients, topical corticosteroids and topical calcineurin inhibitors. Some people may also try phototherapy, although the clinical experts explained that this treatment is not uniformly available and is used variably in the NHS. The patient experts also noted variability in practice with lack of access to phototherapy and considered that there is insufficient guidance on topical corticosteroids. They also explained that many people prefer not to use topical corticosteroids because of their potential to sting, the increased burden of administration and their fear of systemic side effects and steroid withdrawal effects. If there is an inadequate response to topical treatments and phototherapy, systemic immunosuppressants are considered. This includes treatment with ciclosporin, methotrexate, prednisolone, azathioprine or mycophenolate mofetil. The clinical experts explained that frequent blood tests are needed during treatment with most systemic immunosuppressants and that people who take them can experience serious adverse effects. Although ciclosporin is the only licensed treatment, it is used for only short periods because of toxicity concerns and many clinicians now prefer to consider methotrexate first. If there is inadequate response, intolerance, or contraindication to at least 1 systemic treatment, dupilumab and baricitinib are recommended as alternative options for moderate to severe atopic dermatitis that has not responded to at least 1 other systemic therapy. Exacerbations (flares) in atopic dermatitis are managed using short-term high-potency topical corticosteroids, oral corticosteroids and other systemic treatments. The committee concluded that there is an unmet need for well-tolerated treatments for people with moderate to severe atopic dermatitis.\n\n# Positioning in the treatment pathway, comparators and sequencing\n\n## Abrocitinib, tralokinumab or upadacitinib would likely be used after systemic immunosuppressants\n\nThe marketing authorisations for abrocitinib and upadacitinib are 'for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents 12\xa0years and older who are candidates for systemic therapy'. Tralokinumab currently has a marketing authorisation only in adults with moderate to severe atopic dermatitis who are candidates for systemic therapy. The committee considered that the marketing authorisation wording is broad and could refer to first-line treatment, but all the companies positioned their treatments after at least 1 systemic immunosuppressant, as alternatives to dupilumab and baricitinib. One of the clinical experts considered this positioning to be appropriate. The companies also proposed that upadacitinib and abrocitinib could be used as alternatives to systemic immunosuppressants, before dupilumab and baricitinib. One of the clinical experts considered that this positioning was less appropriate. They explained that methotrexate and other systemic immunosuppressants are clinically effective and well tolerated, although there is limited randomised trial evidence to show this effect. They also have substantially lower costs and are therefore likely to be more cost-effective to try as first-line treatment for people whose dermatitis is suitable for systemic therapy. The committee noted that all available JAK inhibitors used in inflammatory disorders (including abrocitinib, baricitinib and upadacitinib) are currently under a European Medicines Agency (EMA) safety review. This is because of a potential class effect of increased risk of major cardiovascular events and higher risk of developing cancer. The committee concluded that in clinical practice, systemic immunosuppressants such as methotrexate would normally be considered first, so the companies' additional positioning of upadacitinib and abrocitinib is less appropriate.\n\n## Abrocitinib, tralokinumab or upadacitinib are likely to be used at the same time as topical treatments, as combination therapy\n\nAll the companies provided evidence for their treatments both as monotherapy (used alone) and in combination with topical treatments (combination therapy). The clinical experts explained that all the treatments are likely to be offered alongside topical corticosteroids in clinical practice. The committee noted that monotherapy trials are used for regulatory endpoints and do not represent how these treatments would be used in clinical practice. Therefore, it agreed to focus on the evidence for combination therapy as the most relevant evidence for decision making.\n\n## Treatments would likely be used in sequences, but cost-effectiveness analysis of sequences would be uncertain because of limited clinical data\n\nThe clinical experts explained that there is no typical treatment journey and there is variation in prescribing practices. Atopic dermatitis is a lifelong disease, and in practice people who have treatment, such as dupilumab, may have an inadequate response and switch to baricitinib or retry other systemic immunotherapies. The treatment choice would likely be based on previous responses to treatment, expected differences in how they work, and potential adverse effects. New treatment options are therefore also likely to be used in sequence with existing treatments but there would likely be no 'standard' sequence. The committee considered that cost-effectiveness analyses for sequences should ideally be taken into account in decision making. But it acknowledged that there is no clinical data on sequential effectiveness and the clinical rationale for using various sequences of treatments would be personalised to each person. Therefore, the committee concluded that analysis of treatment sequences would be uncertain.\n\n# Clinical evidence\n\n## The JADE-COMPARE and JADE-DARE trials provide the key clinical evidence for abrocitinib\n\nThe evidence for abrocitinib came from 6\xa0trials, including 2\xa0trials (JADE-DARE, JADE-COMPARE) that compared abrocitinib plus background topical corticosteroids with dupilumab in adults. JADE-COMPARE was a randomised double-blind trial that included 837\xa0adults who had moderate to severe atopic dermatitis for at least 12\xa0months and had an inadequate response to medicated topical treatment or systemic treatment. People in the trial could use more than 1 topical treatment. The trial compared 2 doses of abrocitinib (200\xa0mg and 100\xa0mg, both once daily) with dupilumab 300\xa0mg every 2\xa0weeks or placebo. The primary endpoints were assessed at the end of the 'induction period' (that is, 12\xa0weeks after starting treatment):\n\nat least a 75% reduction in the EASI score from when treatment started (EASI\xa075)\n\na rating of 'clear' (score of 0) or 'almost clear' (score of 1) on the IGA, and at least a 2‑point improvement from baseline.JADE-DARE is an ongoing trial. It compared abrocitinib 200\xa0mg with dupilumab, each used with topical corticosteroids. Initial response data for JADE-DARE was provided by the company and included in the analysis after consultation. The committee considered that these trials provided the key clinical evidence for abrocitinib. The JADE-TEEN trial also compared abrocitinib with placebo in combination with topical corticosteroids in young people aged 12\xa0to\xa018.\n\n## The AD-UP trial provides the key clinical evidence for upadacitinib\n\nThe evidence for upadacitinib came from 6\xa0trials including 2\xa0trials on upadacitinib plus background topical corticosteroids (AD-UP and RISING-UP). RISING-UP was a randomised controlled trial carried out in Japan but data is not yet available, and its results were not included in the analysis. AD-UP was a randomised double-blind trial that included 901\xa0people (aged 12\xa0to\xa075) who had moderate to severe atopic dermatitis and had an inadequate response to medicated topical therapy or systemic therapies. The trial compared 2 doses of upadacitinib (15\xa0mg or 30\xa0mg once daily) with a placebo. The primary endpoints were assessed at 16\xa0weeks after the 'induction' period:\n\nAD-UP: at least a 75% reduction in the EASI score from when treatment started (EASI 75)\n\nAD-UP: a rating of 'clear' (score of 0) or 'almost clear' (score of 1) on the IGA, and at least a 2‑point improvement from baseline.People in AD-UP had an additional 120‑week blinded extension period that was not included in the analysis. A subgroup of people who were eligible for systemic therapy in UK clinical practice were identified and included in the main analysis.\n\n## The ECZTRA\xa03 and ECZTRA\xa07 trials provide the key clinical evidence for tralokinumab\n\nThe evidence for tralokinumab came from 6\xa0trials including 2\xa0trials on tralokinumab plus background topical corticosteroids (ECZTRA\xa03 and ECZTRA\xa07). Both were randomised double-blind trials that included adults who had moderate to severe atopic dermatitis for at least 12\xa0months and had an inadequate response to medicated topical treatment or systemic treatment. The trials compared tralokinumab (300\xa0mg every 2\xa0weeks) with a placebo. The primary endpoints were assessed at 16\xa0weeks after the 'induction' period:\n\nECZTRA\xa03 and ECZTRA\xa07: at least a 75% reduction in the EASI score from when treatment started (EASI 75)\n\nECZTRA\xa03: a rating of 'clear' (score of 0) or 'almost clear' (score of 1) on the IGA, and at least a 2‑point improvement from baseline.\n\n## Abrocitinib, tralokinumab and upadacitinib are clinically effective treatments compared with placebo\n\nFor all people who had treatment in the key clinical evidence studies (see sections 3.7 to 3.9), the results showed a greater chance of reaching a 50% reduction in EASI score (EASI\xa050) plus an improvement of at least 4 in the DLQI score at week 12 or 16, than people who had a placebo. These results were statistically significant for abrocitinib and upadacitinib. More people who had tralokinumab also achieved EASI\xa050 than those who had placebo, but the results were not statistically significant. Significantly more people who had tralokinumab achieved EASI\xa075 compared with people who had placebo. However, the committee noted that substantial heterogeneity in trial design and placebo response rates may have contributed to these results. This may have affected the comparison of these studies (see section 3.13 for discussion of the network meta-analysis). The committee concluded that abrocitinib, tralokinumab or upadacitinib are clinically effective treatments compared with placebo.\n\n## A composite end point of EASI\xa050 plus an improvement in the DLQI score of at least 4 is the most relevant end point for decision making\n\nCommon outcomes in clinical trials are relative reductions in EASI scores from baseline by 50% and 75% (EASI\xa050 and EASI\xa075). The clinical experts considered that these outcomes were appropriate for measuring response to treatment, but ideal outcomes would be an absolute reduction to no symptoms or mild symptoms. A consultee also commented that the use of EASI\xa050 may not capture additional benefits measured by EASI\xa075 or above. One of the clinical experts noted that EASI\xa075 was commonly used in clinical trials for assessing improvement in atopic dermatitis. The committee understood that using EASI\xa075 alone is not adequate to capture a quality of life improvement and it may not capture clinically meaningful improvements. The committee agreed to use a composite end point of EASI\xa050 plus an improvement in the DLQI of at least 4 in the analysis. It included patient-reported quality of life and was consistent with NICE's technology appraisal guidance on dupilumab for treating moderate to severe atopic dermatitis (TA534) and baricitinib for treating moderate to severe atopic dermatitis (TA681). Therefore, the committee considered that the EASI\xa050 combined with DLQI of at least 4 is the most relevant end point for decision making and should be used to define treatment response. The external assessment group (EAG) used this composite outcome as the basis for assessing relative response, but also considered the EASI\xa075 outcome when data was not available for the composite outcome.\n\n## Results for adults who have tried systemic immunotherapy are likely to be generalisable to young people\n\nBoth the abrocitinib and upadacitinib marketing authorisations include young people aged 12\xa0to\xa018 with atopic dermatitis. At the first committee meeting the clinical experts explained that the current treatment pathways for adults and young people with atopic dermatitis are similar. The feedback from consultees agreed that young people were treated the same as adults and the results of the trials for adults would be generalisable to young people. However, baricitinib is currently licensed for adults only. For young people, the only data available that allowed for indirect comparison with other treatments was using EASI\xa075 outcome measurements. The EAG also noted the very small numbers of people in the treatment arms, leading to high uncertainty. The EAG initially did separate analyses for the adult and young people populations, but after the first committee meeting an updated analysis was done for the adult population. The committee considered that because of the likely similarity in treatment for young people and adults, and limited available evidence for young people, it had not seen sufficient justification for considering young people as a separate subgroup. The committee concluded that the results of the 'combination therapy' analysis for adults who had tried systemic immunotherapy would likely be generalisable to young people.\n\n# Indirect treatment comparisons\n\n## The network meta-analysis with dupilumab or baricitinib is appropriate for decision making\n\nThere was no direct evidence comparing tralokinumab or upadacitinib used in combination with topical treatments ('combination therapy') with dupilumab or baricitinib for atopic dermatitis in adults. So data from the relevant trials was analysed to compare treatments indirectly through a network meta-analysis:\n\nabrocitinib: a subgroup of the JADE-COMPARE trial who would be eligible for systemic therapy in UK practice\n\ntralokinumab: ECZTRA\xa07 plus the ECZTRA\xa07‑like subgroup from ECZTRA\xa03\n\nupadacitinib: a subgroup of the AD-UP trial who would be eligible for systemic therapy in UK practice\n\ndupilumab: the CAFÉ trial and a subgroup of people from the CHRONOS trial for whom ciclosporin was contraindicated or not tolerated, or whose disease was uncontrolled on ciclosporin (the 'CAFÉ‑like' subgroup)\n\nbaricitinib: BREEZE‑AD4 and BREEZE‑AD7.All trials included a placebo arm, so placebo was the common comparator for all trials in the network analysis. The EAG explained that 2 trials comparing abrocitinib doses with dupilumab were included in the network of indirect comparisons to improve consistency. The EAG considered that only people whose dermatitis had not responded to systemic treatments were included in the analysis, but noted that:\n\nECZTRA\xa07 and CAFÉ only included people who had either not had ciclosporin or could not have it, or who had it before but had an inadequate response.\n\nBaseline characteristics for the full trial populations are comparable, but ECZTRA\xa07 and CAFÉ included a blended population, and clinical data to inform the comparisons was from post-hoc subgroups.The committee concluded that, despite their limitations, the indirect treatment comparisons with dupilumab or baricitinib used the most appropriate clinical evidence.\n\n## The indirect comparisons of treatments with ciclosporin are highly uncertain\n\nFor people who have not previously had systemic treatment, the EAG presented results for first-line treatments from a network analysis using results from the trials for upadacitinib and abrocitinib. The clinical experts explained that randomised trial evidence for currently used systemic treatments is limited because of the off-label use of systemic immunosuppressants (see section 3.4). The EAG considered the most appropriate evidence to include in the network was a small observational study (Ariens et al. 2019). The study compared individual person data from a clinical trial for dupilumab against individual patient data from ciclosporin use in daily clinical practice in a treatment centre in the Netherlands (n=57). The clinical experts considered this appropriate although noted that methotrexate is now the most commonly used treatment in people who have not had systemic immunotherapies before (see section\xa03.4). One consultee noted the TREAT trial which compared ciclosporin with methotrexate in young people, but its results have not been published yet. There is also additional published evidence regarding methotrexate compared with ciclosporin in adults. The committee considered that including the comparison of ciclosporin and methotrexate in the network analysis would introduce uncertainties because of ciclosporin's limited evidence base. The committee also noted that, in order to compare ciclosporin with upadacitinib and abrocitinib, the comparison had to be done indirectly through both dupilumab and placebo, which increased uncertainty of the comparison. It also noted that there are likely to be substantial differences between daily clinical practice and clinical trial evidence in this disease area, including adherence to topical treatments. It also considered that upadacitinib would be used for longer periods of time in clinical practice than ciclosporin, which is only indicated for a short time frame. The committee concluded that the indirect comparison with ciclosporin was highly uncertain.\n\n## Results of fixed-effects and random-effects network meta-analyses are comparable\n\nThe committee considered that there was substantial clinical heterogeneity in the trial design which may have contributed to very wide credibility intervals of the results of the network meta-analyses. The EAG considered that these included:\n\nuse of post-hoc subgroups to define people who were eligible for systemic therapy, and would break randomisation\n\nmethodological heterogeneity across studies in the washout period before starting the treatment in the trial\n\nthe type and potency of concomitant topical corticosteroids and other relevant optimisation of baseline care used in the trial\n\nheterogeneity in how rescue therapy was implemented or allowed in the trial.The EAG considered that this substantial between-trial heterogeneity would best be accounted for using a random-effects model with an informed prior for the between-trial heterogeneity. This would otherwise be ignored using a fixed-effect model that assumes all placebo arms are estimating the same treatment effect. The EAG explained that adjusting the placebo effect for each trial was not possible for some analyses and may have overfitted the data in other analyses. The committee noted the substantial heterogeneity in the treatment arms but also noted the very wide confidence intervals. It considered that the random-effects model approach taken by the EAG may not be appropriate because the small number of trials for each treatment arm of the analyses may be inflating the heterogeneity in the network. After consultation, the EAG also presented a fixed-effects model. The committee considered that the results were very similar but the random-effects model had slightly wider credibility intervals. It considered that the wide credibility intervals indicated substantial uncertainty around the point estimates of the results used in the deterministic base-case analysis. However, the results of the analyses were comparable when fixed-effects or random-effects models were applied.\n\n# Adverse events\n\n## Trial evidence shows low adverse event rates but more safety data on JAK inhibitors would be valuable\n\nThe number of adverse events reported in the trials was generally small. Upper respiratory tract infections (URTIs) were one of the most frequent adverse events in the abrocitinib trials. URTI, conjunctivitis (allergic and infectious), and injection-site reactions were commonly reported in people using tralokinumab. Upadacitinib was associated with slightly higher rates of acne, oral herpes, and URTI compared with placebo. The committee understood that the EMA has started a safety review of JAK inhibitors including baricitinib, abrocitinib and upadacitinib. Preliminary findings suggest that using JAK inhibitors may be associated with an increased risk of cardiovascular problems such as heart attack and developing cancer. The clinical experts considered it was too early to conclude the impact of JAK inhibitors on developing cardiovascular problems or cancer because of limited available safety data. The committee noted that the increased cancer risk would be a particularly important outcome for people with atopic dermatitis, because of an already increased risk of some skin cancers. The committee agreed that more safety data on JAK inhibitors would be valuable.\n\n# The economic model\n\n## The structure of the economic model is appropriate for decision making\n\nThe economic model for this appraisal was produced by the EAG. The model structure was informed by a systematic literature review, the companies' submissions, and previous technology appraisals in the disease area. The economic model is a short-term (52\xa0week) decision tree model that feeds into a long-term Markov model for the rest of the lifetime horizon. People in the economic model start in the baseline health state and are assigned to active treatment. At 16\xa0weeks, people are assigned to health states based on response to treatment, informed by the results of the network meta-analysis (see section 3.13). People whose dermatitis does not respond will stop treatment and progress to the best supportive care health state. People whose dermatitis does respond continue treatment in the responder health state. People enter the Markov model in different maintenance health states depending on initial response to treatment and discontinuation up until week\xa052. People then transition to the best supportive care health state based on annual discontinuation and treatment effect waning assumptions agreed upon in a previous appraisal (TA534). The committee noted that this represented a simplification of clinical practice, in which further sequential treatments would be trialled (see section 3.6). However, it considered that this simplification could be appropriate in the context of a chronic recurrent disease modelled over a lifetime horizon. The committee concluded that the model structure was similar to models previously seen in atopic dermatitis appraisals and was appropriate for decision making.\n\n# Assumptions in the economic model\n\n## Comparison with systemic immunosuppressants does not represent clinical practice\n\nThe EAG explained that for the first-line treatment comparison with ciclosporin in the economic model, it was assumed that people would only have ciclosporin for 1\xa0year and then have best supportive care for the rest of the modelled time horizon. The committee considered that this did not represent clinical practice because it would involve sequential treatment. It also did not represent ciclosporin's marketing authorisation indication, nor how methotrexate or other systemic immunosuppressants would be used as a first-line treatment. The committee also recalled the substantial limitations of the comparative efficacy evidence (see section 3.14). Therefore, the committee concluded that the analysis comparing treatments with first-line systemic immunosuppressants was limited in value and further evidence is needed for this comparison.\n\n## Cost effectiveness of different dosing options is explored through pooling\n\nAbrocitinib and upadacitinib each have 2\xa0daily dose options (low dose treatment or high dose treatment). The choice of dose would depend on individual patient presentation and response. The clinical evidence was assessed as individual daily doses in the network meta-analysis, and this was maintained in the economic model as different treatment options. This approach was informed by the companies' submissions. The committee considered that in clinical practice, the decision to start treatment would be based on the overall effectiveness of the drug and not on efficacy evidence of individual doses. Therefore, it considered that modelling individual doses in the economic model would not represent expected use in clinical practice and that it added difficulties to the decision-making process. After consultation, the EAG provided a scenario analysis which pooled the cost-effectiveness results of the high and low doses, assuming an equal split of high and low dose distribution. This was because there was no robust data on which to base this distribution. An alternative dose distribution for abrocitinib was provided by the company, based on its use in an early access programme. The company consider this distribution to be confidential. The clinical experts considered this dose distribution was likely to reflect expected use in clinical practice of abrocitinib and upadacitinib. The committee concluded that in the absence of further evidence, it was appropriate to pool the doses using the distribution provided for abrocitinib.\n\n## It is appropriate to consider tralokinumab's alternative dosing schedule but its use in clinical practice is uncertain\n\nThe committee noted an alternative dosing schedule for tralokinumab which allowed for dosing every 4\xa0weeks for people whose dermatitis is clear or almost clear after 16\xa0weeks of treatment. The EAG included an option in the economic model for a proportion of people taking tralokinumab to switch to the less frequent dosing schedule, based on evidence from ECZTRA\xa03. The committee considered that some people would switch to less frequent dosing, but others may stay on the more frequent dose if they tolerate the treatment and the dermatitis responds well to it. However, the committee considered that the proportion of those who would switch to the 4‑weekly dosing is uncertain outside of a clinical trial context. The committee therefore considered a range of results. These ranged from assuming the same number of people use the alternative dosing schedule as in the ECZTRA\xa03 trial, to assuming all people continue on the 2-weekly dosing schedule.\n\n# Utility values in the economic model\n\n## Utility values used in the economic model are derived from the clinical trials\n\nHealth-related quality of life data was collected in all the key clinical trials using the 5‑level EQ‑5D (EQ‑5D‑5L) and the data was then mapped to the 3-level EQ‑5D (EQ‑5D‑3L), using the van Hout crosswalk method. At the first committee meeting, the EAG separated the treatments into 3\xa0treatment-specific groups: high dose JAK inhibitors (abrocitinib 200\xa0mg, upadacitinib 30\xa0mg, and baricitinib 4\xa0mg), low dose JAK inhibitors (abrocitinib 100\xa0mg, upadacitinib 15\xa0mg, and baricitinib 4\xa0mg), and monoclonal antibodies (dupilumab and tralokinumab). The EAG presented analyses with both high and low dose utility values for baricitinib. For adult second-line 'combination therapy' analysis, the JAK inhibitor low dose and high dose utility values were derived from the AD-UP trial. The monoclonal antibody utility values were derived from ECZTRA\xa07 and the ECZTRA\xa07‑like subgroup in ECZTRA\xa03. After the first committee meeting, the EAG provided a scenario using data from the AD‑UP trial to create a response-based health-state utility value, that was applied to all treatments regardless of drug class.\n\n## Response-based utility values are more appropriate than treatment-specific utility values\n\nAt the first committee meeting, the EAG explained that treatment-specific utility values were used to better represent potential treatment-specific differences. This included differences in baseline utility values for people whose condition responds to treatment at 16\xa0weeks. The committee considered that there is no rationale for differences in baseline utility values, and this would likely only represent heterogeneity between the clinical trials. It considered it plausible that there may be some differences in utility values based on response to treatment. But the size of the difference between the different treatments was likely to be because of trial design and reporting methodology, rather than true differences in quality of life. It considered that the use of different baseline utility values and treatment-specific utility values introduced unnecessary complexity to the economic model. The committee preferred a single response-based utility value for baseline and response, or ideally a single synthesis of relative difference in utility, similar to the network meta-analysis. After the first committee meeting, the EAG provided a scenario using health-state utility values based on data from the AD‑UP trial only. One consultee considered that removal of treatment-specific utility values would not capture all the benefits of treatment. Therefore they proposed an alternative approach of applying a common baseline utility value and a responder utility value associated with having an EASI\xa050 response plus a DLQI of at least 4, for all treatments. Additional utility benefits were applied based on the proportion of people achieving EASI\xa075 and EASI\xa090 within the trials. The EAG considered this approach may not be appropriate because it bases longer-term utility increments on trials measured at a single time point after a few months. The EAG also considered that larger reductions in EASI score may not be maintained outside of a trial setting for longer time periods, but this is unclear. The committee also noted that the largest gains in quality of life came from achieving good response on the DLQI's measure of health-related quality of life. It considered the proposed approach could increase uncertainty and also highlight further heterogeneity between trials. Therefore, it concluded that there was not enough evidence to justify changing the specified composite outcome of interest in regards to utility data, because it may introduce additional uncertainties.\n\n# Best supportive care assumptions\n\n## The utility values for the best supportive care health state are highly uncertain, and have a large impact on the modelled benefit\n\nThe EAG explained that the utility values for the best supportive care health state were derived using a weighted average of the utility values for responders and non-responders at week\xa016. This method was used to capture the waxing and waning nature of response to best supportive care and was also used in NICE's technology appraisal guidance on baricitinib for treating moderate to severe atopic dermatitis (TA681). The EAG explained that the utility value for non-responders was significantly higher than the baseline health state utility values because it included people whose dermatitis had partially responded to treatment but did not reach the EASI\xa050 or DLQI of at least 4 threshold, or who later lost response but still maintained some residual effect. In addition, the baseline utility values were elicited after a 'washout' period in the trials, when previous treatment with standard care was stopped. This included stopping use of topical corticosteroids in the AD‑UP trial. The clinical experts noted that the 'washout' period does not reflect clinical practice in the NHS because people would always be having some treatment. The committee considered that the utility values for best supportive care are highly uncertain using this approach because they represent most of the modelled time over a lifetime horizon. After the first committee meeting, the committee requested further exploration of best supportive care utility through time using a best supportive care waning assumption.\n\n## Best supportive care waning assumptions are highly uncertain\n\nPrevious appraisals have also modelled best supportive care waning effects, when response to treatment wanes towards that seen in the baseline of the trial over time. The clinical experts considered this waning effect to plausibly represent a reduction over time for those who do not have further treatment and who have reduced benefit from topical corticosteroids. The committee considered that the best supportive care health state may wane to some extent over time, but in clinical practice, people would have further treatments as part of a sequence (see section 3.6) and some could improve over time. After the first committee meeting consultation, the EAG updated the analyses and included a scenario with best supportive care waning. The analysis applied the accepted best supportive care waning assumptions for dupilumab from TA534. The scenario assumed that by year 5, 97% of people had returned to baseline utility, and none of them had topical corticosteroids. The committee acknowledged that the EAG's approach represented different people in the model moving in and out of disease control over time. The committee considered this may simplify the effect of people having best supportive care because their quality of life could vary because of other factors such as treatment sequence. The committee concluded that there was significant uncertainty with attempting to model best supportive care waning without evidence of the natural history of the disease, or use of further sequential treatments.\n\n# Cost-effectiveness estimates\n\n## Abrocitinib, tralokinumab and upadacitinib are cost effective compared with dupilumab or baricitinib based on the ICERs for the committee's preferred scenarios\n\nThe committee considered that the cost-effectiveness estimates for abrocitinib and upadacitinib for first-line treatment compared with ciclosporin were highly uncertain and did not represent clinical practice. Therefore the committee concluded that it was inappropriate to consider the economic model outputs for these comparisons and could not make a recommendation for first-line treatment. The committee considered second-line treatment for people whose disease has not responded to at least 1\xa0systemic immunosuppressant, or when systemic immunosuppressants are not suitable. For second-line treatment, the incremental cost-effectiveness ratios (ICERs) were calculated for abrocitinib, tralokinumab and upadacitinib plus topical corticosteroids compared with dupilumab or baricitinib. The exact ICERs are confidential and cannot be reported here. The committee noted their preferred assumptions to:\n\nconsider clinical effectiveness data from adults to be generalisable to young people (see section 3.12)\n\nuse specific dose and dose scheduling assumptions for each treatment (see sections 3.19 and 3.20)\n\nuse utility values derived from a single baseline and response to treatment data (see section 3.22).The committee noted substantial uncertainty with the relative clinical effectiveness of each treatment in the network meta-analysis and effectiveness of sequential treatments and best supportive care over the full time horizon. It considered that taking into account these uncertainties, the ICERs for each treatment suggested that abrocitinib, upadacitinib and tralokinumab are likely to be an effective use of NHS resources compared with current treatments.\n\n# Other factors\n\n## Head-to-head trials and real-world data may help future decision making\n\nThe EAG noted that there are limited head-to-head comparative studies which evaluate the efficacy of treatment options for atopic dermatitis. Feedback from consultees highlighted that real-world data such as the A-STAR registry (UK-Irish Atopic Eczema Systemic Therapy Register) could potentially improve the current evidence base. The registry is an independent research data platform and collects both clinical and cost data to help treatment decisions for people with atopic eczema. The committee understood that real-world evidence could improve the current evidence base and help inform decision making, and may also help inform understanding of sequential treatments in NHS clinical practice.\n\n## EASI and DLQI may not be appropriate for all people with atopic dermatitis\n\nThe committee noted the following potential equality issues:\n\nthe EASI might underestimate the severity of atopic dermatitis in people with brown or black skin\n\nthe DLQI may not account for anxiety and depression.The committee concluded that, when using the EASI, healthcare professionals should take into account skin colour and how this could affect the EASI score. Also, it concluded that when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or difficulties in communication that could affect a person's response to the DLQI."}	https://www.nice.org.uk/guidance/ta814	Evidence-based recommendations on abrocitinib (Cibinqo), tralokinumab (Adtralza) or upadacitinib (Rinvoq) for treating moderate to severe atopic dermatitis.
359a838fb09aecacfca28afd9f758401715fd6da	nice	Bioresorbable stent implantation to treat coronary artery disease	Bioresorbable stent implantation to treat coronary artery disease Evidence-based recommendations on bioresorbable stent implantation to treat coronary artery disease in adults. This involves implanting a stent (small tube) into a narrowed artery to widen it. # Recommendations Evidence on the efficacy of bioresorbable stent implantation to treat coronary artery disease is inadequate. Evidence on its safety has shown an increased risk of serious complications in the longer term. This includes an increased risk of myocardial infarction and death with some types of bioresorbable stents. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. Clinicians should enter details about everyone having bioresorbable stent implantation to treat coronary artery disease into the National Institute for Cardiovascular Outcomes Research's National Audit of Percutaneous Coronary Interventions. Contact nicor.auditenquiries@nhs.net for details. Further research should include randomised controlled trials reporting details of patient selection and choice of bioresorbable stent. It should also include long-term outcomes.# The condition, current treatments and procedure # The condition Stenosis of the coronary arteries is usually caused by deposition of atherosclerotic plaque. This reduces blood flow to the heart muscle and is usually progressive. Symptoms of coronary artery disease typically include angina (chest pain that is exacerbated by exertion). A critical reduction of the blood supply to the heart may result in myocardial infarction or death. # Current treatments The symptoms from a stenosed artery may be treated medically. This includes modifying risk factors (for example, smoking, hyperlipidaemia, obesity, hyperglycaemia) and treatment with medicines (for example, beta blockers, nitrates, calcium-channel blockers, antiplatelet agents, statins). If medical management fails or is inappropriate, the usual options are coronary artery bypass grafting, or percutaneous transluminal coronary angioplasty followed by stent insertion to maintain the patency of the coronary artery. # The procedure Bioresorbable stents are designed to be absorbed by the body over time. One aim is to reduce the risk of late complications such as thrombosis, which may happen after using metal stents. The other is to reduce the need for long-term antiplatelet medicines, with their risk of bleeding complications. The procedure is done under local anaesthesia. A guidewire is passed into the target coronary artery, usually from the radial or femoral artery under fluoroscopic image guidance. A balloon angioplasty catheter passed over the guidewire is used to dilate the coronary artery stenosis. A bioresorbable stent mounted on a balloon catheter is passed over the guide wire into the relevant segment of the artery. Then, it is expanded by inflation of the balloon inside it. The balloon is then deflated and removed with the guide wire. The stent acts as a scaffold to hold the vessel open. Additional imaging, such as intravascular ultrasound and optical coherence tomography, is sometimes used to guide the procedure. This is to optimise positioning and deployment of the stent in the target coronary artery. Bioresorbable stents are absorbed over time. Most bioresorbable stents are also drug-eluting, with a view to reducing the risk of restenosis. Antiplatelet medicines such as aspirin and clopidogrel are usually prescribed for at least 6 months after the procedure.	{'Recommendations': "Evidence on the efficacy of bioresorbable stent implantation to treat coronary artery disease is inadequate. Evidence on its safety has shown an increased risk of serious complications in the longer term. This includes an increased risk of myocardial infarction and death with some types of bioresorbable stents. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nClinicians should enter details about everyone having bioresorbable stent implantation to treat coronary artery disease into the National Institute for Cardiovascular Outcomes Research's National Audit of Percutaneous Coronary Interventions. Contact nicor.auditenquiries@nhs.net for details.\n\nFurther research should include randomised controlled trials reporting details of patient selection and choice of bioresorbable stent. It should also include long-term outcomes.", 'The condition, current treatments and procedure': '# The condition\n\nStenosis of the coronary arteries is usually caused by deposition of atherosclerotic plaque. This reduces blood flow to the heart muscle and is usually progressive. Symptoms of coronary artery disease typically include angina (chest pain that is exacerbated by exertion). A critical reduction of the blood supply to the heart may result in myocardial infarction or death.\n\n# Current treatments\n\nThe symptoms from a stenosed artery may be treated medically. This includes modifying risk factors (for example, smoking, hyperlipidaemia, obesity, hyperglycaemia) and treatment with medicines (for example, beta blockers, nitrates, calcium-channel blockers, antiplatelet agents, statins).\n\nIf medical management fails or is inappropriate, the usual options are coronary artery bypass grafting, or percutaneous transluminal coronary angioplasty followed by stent insertion to maintain the patency of the coronary artery.\n\n# The procedure\n\nBioresorbable stents are designed to be absorbed by the body over time. One aim is to reduce the risk of late complications such as thrombosis, which may happen after using metal stents. The other is to reduce the need for long-term antiplatelet medicines, with their risk of bleeding complications.\n\nThe procedure is done under local anaesthesia. A guidewire is passed into the target coronary artery, usually from the radial or femoral artery under fluoroscopic image guidance. A balloon angioplasty catheter passed over the guidewire is used to dilate the coronary artery stenosis. A bioresorbable stent mounted on a balloon catheter is passed over the guide wire into the relevant segment of the artery. Then, it is expanded by inflation of the balloon inside it. The balloon is then deflated and removed with the guide wire. The stent acts as a scaffold to hold the vessel open. Additional imaging, such as intravascular ultrasound and optical coherence tomography, is sometimes used to guide the procedure. This is to optimise positioning and deployment of the stent in the target coronary artery.\n\nBioresorbable stents are absorbed over time. Most bioresorbable stents are also drug-eluting, with a view to reducing the risk of restenosis. Antiplatelet medicines such as aspirin and clopidogrel are usually prescribed for at least 6\xa0months after the procedure.'}	https://www.nice.org.uk/guidance/ipg732	Evidence-based recommendations on bioresorbable stent implantation to treat coronary artery disease in adults. This involves implanting a stent (small tube) into a narrowed artery to widen it.
5bc70e93956442db45c0cb7a4f91d5e13813d8c8	nice	Aortic remodelling hybrid stent insertion during surgical repair of an acute type A aortic dissection	Aortic remodelling hybrid stent insertion during surgical repair of an acute type A aortic dissection Evidence-based recommendations on aortic remodelling hybrid stent insertion for acute type A aortic dissection. This involves inserting a stent with material sewed on one end into part of the aorta. # Recommendations Evidence on the safety and efficacy of aortic remodelling hybrid stent insertion during surgical repair of an acute type A aortic dissection is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do aortic remodelling hybrid stent insertion during surgical repair of an acute type A aortic dissection should: Inform the clinical governance leads in their healthcare organisation. If possible, give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. If possible, ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Enter details about all patients having aortic remodelling hybrid stent insertion during surgical repair of an acute type A aortic dissection into the NICOR Adult Cardiac Surgery Audit. Contact nicor.auditenquiries@nhs.net for details. Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure. Regularly review data on outcomes and safety for this procedure. This procedure should only be done in specialised centres by surgeons experienced in aortic surgery and with special training in this procedure. Further research could include randomised controlled trials or analysis of registry data. It should include details of patient selection and report 30‑day mortality, quality of life, and long-term outcomes including aortic remodelling and complications.# The condition, current treatments and procedure # The condition An aortic dissection is a serious condition in which a tear occurs in the inner layer of the aorta. Blood flows through the tear and into the wall of the aorta. This forces the inner and middle layers of the aorta to split apart (dissect), creating 2 passages (a true lumen and a false lumen). As more blood flows into the new false lumen the dissection extends along the aorta. This can lead to aortic rupture or decreased blood flow (ischaemia or malperfusion) to organs. Aortic dissections are classified into 2 types, depending on which part of the aorta is affected. Type A dissection involves a tear in the ascending part of the aorta. The tear may also occur in the aortic arch, which may extend into the abdomen or back into the ascending aorta. Type B dissection involves a tear in the aorta beyond the arch, usually in the descending thoracic aorta. Dissections can be acute or chronic. # Current treatments Treatments for aortic dissection include medicines (to control hypertension) and surgery (to repair the aorta, and possible replacement of the aortic valve). Type of treatment depends on the chronicity, site location, and whether there are complicating features. Acute type A aortic dissection is life threatening and needs immediate surgery. The goals of surgical repair are to seal the false lumen and resolve malperfusion. # The procedure Insertion of aortic remodelling hybrid stent is incorporated into open hemiarch repair for an acute type A aortic dissection, under general anaesthesia. The device is a self-expanding bare-metal stent with a short felt sewing cuff end. It aims to resolve malperfusion and promote positive remodelling of the aorta. During the hemiarch aortic reconstruction, once circulatory arrest is established, the ascending aorta is transected and resected in the standard manner. A hybrid stent is then inserted until the entire device is inside the true lumen. This is usually done under direct vision, although it can be implanted using a guidewire. The cuff end of the stent is placed level with the edge of the transected aorta and attached with interrupted sutures. The uncovered portion of the stent expands along the aortic arch into the descending aorta. The remainder of the surgical hemiarch aortic reconstruction is completed in the usual way.	{'Recommendations': "Evidence on the safety and efficacy of aortic remodelling hybrid stent insertion during surgical repair of an acute type A aortic dissection is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do aortic remodelling hybrid stent insertion during surgical repair of an acute type A aortic dissection should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nIf possible, give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nIf possible, ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nEnter details about all patients having aortic remodelling hybrid stent insertion during surgical repair of an acute type A aortic dissection into the NICOR Adult Cardiac Surgery Audit. Contact nicor.auditenquiries@nhs.net for details.\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nThis procedure should only be done in specialised centres by surgeons experienced in aortic surgery and with special training in this procedure.\n\nFurther research could include randomised controlled trials or analysis of registry data. It should include details of patient selection and report 30‑day mortality, quality of life, and long-term outcomes including aortic remodelling and complications.", 'The condition, current treatments and procedure': '# The condition\n\nAn aortic dissection is a serious condition in which a tear occurs in the inner layer of the aorta. Blood flows through the tear and into the wall of the aorta. This forces the inner and middle layers of the aorta to split apart (dissect), creating 2\xa0passages (a true lumen and a false lumen). As more blood flows into the new false lumen the dissection extends along the aorta. This can lead to aortic rupture or decreased blood flow (ischaemia or malperfusion) to organs.\n\nAortic dissections are classified into 2\xa0types, depending on which part of the aorta is affected. Type\xa0A dissection involves a tear in the ascending part of the aorta. The tear may also occur in the aortic arch, which may extend into the abdomen or back into the ascending aorta. Type\xa0B dissection involves a tear in the aorta beyond the arch, usually in the descending thoracic aorta. Dissections can be acute or chronic.\n\n# Current treatments\n\nTreatments for aortic dissection include medicines (to control hypertension) and surgery (to repair the aorta, and possible replacement of the aortic valve). Type of treatment depends on the chronicity, site location, and whether there are complicating features. Acute type\xa0A aortic dissection is life threatening and needs immediate surgery. The goals of surgical repair are to seal the false lumen and resolve malperfusion.\n\n# The procedure\n\nInsertion of aortic remodelling hybrid stent is incorporated into open hemiarch repair for an acute type\xa0A aortic dissection, under general anaesthesia. The device is a self-expanding bare-metal stent with a short felt sewing cuff end. It aims to resolve malperfusion and promote positive remodelling of the aorta.\n\nDuring the hemiarch aortic reconstruction, once circulatory arrest is established, the ascending aorta is transected and resected in the standard manner. A hybrid stent is then inserted until the entire device is inside the true lumen. This is usually done under direct vision, although it can be implanted using a guidewire. The cuff end of the stent is placed level with the edge of the transected aorta and attached with interrupted sutures. The uncovered portion of the stent expands along the aortic arch into the descending aorta. The remainder of the surgical hemiarch aortic reconstruction is completed in the usual way.'}	https://www.nice.org.uk/guidance/ipg733	Evidence-based recommendations on aortic remodelling hybrid stent insertion for acute type A aortic dissection. This involves inserting a stent with material sewed on one end into part of the aorta.
4005ce77d38d581c1ea6ac19e88a3a4a8f3893a6	nice	Pralsetinib for treating RET fusion-positive advanced non-small-cell lung cancer	Pralsetinib for treating RET fusion-positive advanced non-small-cell lung cancer Evidence-based recommendations on pralsetinib (Gavreto) for treating RET fusion-positive advanced non-small-cell lung cancer in adults. # Recommendations Pralsetinib is not recommended, within its marketing authorisation, for treating RET fusion-positive advanced non-small-cell lung cancer (NSCLC) in adults who have not had a RET inhibitor before. This recommendation is not intended to affect treatment with pralsetinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Usual treatment for untreated RET fusion-positive advanced NSCLC is pembrolizumab with pemetrexed and chemotherapy, or platinum-based chemotherapy with or without pemetrexed. Usual treatment for previously treated RET fusion-positive advanced NSCLC is docetaxel chemotherapy or docetaxel with nintedanib. The clinical evidence for pralsetinib suggests it could be clinically effective, but its benefit is uncertain because it was not compared directly with any usual NHS treatments. The results from indirectly comparing pralsetinib with some usual treatments suggest that pralsetinib could increase the time before the NSCLC gets worse and how long people live. Pralsetinib meets NICE's criteria to be a life-extending treatment at the end of life for people with previously treated NSCLC, but not for untreated NSCLC. Because of the uncertainty in the clinical evidence, the estimates of cost effectiveness are uncertain and too high to be considered a cost-effective use of NHS resources. So pralsetinib cannot be recommended for routine use. Pralsetinib is a new treatment and more data on its clinical effectiveness is being collected from 1 ongoing trial and 1 new trial. Collecting more data from these trials through a managed access agreement in the Cancer Drugs Fund may resolve some uncertainty in the clinical evidence. But NICE was advised that it was not possible to put a managed access agreement in place, meaning pralsetinib cannot be recommended for use in the Cancer Drugs Fund.# Information about pralsetinib # Marketing authorisation indication Pralsetinib (Gavreto, Roche) is indicated for 'the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced non-small cell lung cancer (NSCLC) not previously treated with a RET inhibitor'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for pralsetinib. # Price The list price for 120 capsules of pralsetinib (100 mg) is £7,044 (excluding VAT, company submission). The company has a commercial arrangement, which would have applied if the technology had been recommended.# Committee discussion The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Treatment pathway and clinical practice ## People with RET fusion-positive advanced non-small-cell lung cancer would welcome a new treatment A clinical expert stated that RET fusion-positive advanced non-small-cell lung cancer (NSCLC) particularly affects young people who do not smoke and who do not typically fit the profile of people with lung cancer. So, people often tend to be diagnosed at a late stage. The patient experts highlighted that people with this condition have a poor prognosis which has a significant impact on family and carers. The illness is characterised by breathlessness, cough and weight loss, which can be difficult to manage without treatment. The clinical experts explained that pralsetinib is a once daily oral pill that has a clear advantage over intravenous treatment, which is normally given in hospital. The committee agreed that there is an unmet need in this patient population. It concluded that people with RET fusion-positive advanced NSCLC would welcome a new oral treatment option. ## RET fusion status is not yet routinely identified in clinical practice The clinical experts stated that there is no treatment pathway specific to RET fusion-positive advanced NSCLC because testing for RET fusion status has not been universally introduced (which is expected to change within 18 months). Also, until recently there were no targeted treatments in the UK. The clinical experts explained that RET fusion status is included in the 2020/2021 National Genomic Test Directory. However, this genetic screening has not yet been implemented at all hospitals and is typically only available at large centres. The experts further explained that test results might not be available at or soon after diagnosis, so decisions about first-line treatment are usually made without knowing RET fusion status. The clinical experts explained that if RET fusion status is unknown, the person will typically be offered pembrolizumab plus pemetrexed and chemotherapy as first-line treatment. If RET fusion status is known, they suggested that people would usually have platinum-based chemotherapy with or without pemetrexed. But the company explained in its consultation response that it had received input from clinical experts that suggested that pembrolizumab plus pemetrexed and chemotherapy may be more likely to be used in clinical practice nationally. A professional organisation noted that immunotherapy is believed to be less effective in cancer with oncogene drivers such as RET fusion than in the broader advanced NSCLC population. Second-line treatment for people whose RET fusion status is known is usually docetaxel monotherapy or docetaxel plus nintedanib. The clinical experts noted that use of docetaxel plus nintedanib is decreasing because of the limited benefit and increased side effects compared with docetaxel alone. The committee concluded that RET fusion status is not routinely identified in the NHS at present, and confirmation of RET fusion status influences which treatments would be considered relevant comparators. # Population and subgroups ## Considering the untreated and treated subgroups separately is appropriate The company submission included data for RET fusion-positive advanced NSCLC categorised in 2 subgroups: untreated, and previously treated (having had systemic treatment before). The committee concluded that the company's approach considering 2 subgroups was appropriate. ## Pralsetinib's clinical evidence is based on non-squamous NSCLC alone The company did not present information for squamous NSCLC. It explained that this was because there is a low incidence of people with RET fusion-positive squamous advanced NSCLC. Also, only a small number of people with squamous NSCLC were included in the clinical trial. Therefore, it chose the comparators for this appraisal using current standard care for this population in NICE's non-squamous treatment pathway. At consultation, the company explained that the marketing authorisation for pralsetinib does not differentiate between non-squamous and squamous NSCLC. The committee concluded that it was aware of the histological difference and determined it had not seen evidence for the squamous population, and that it would factor this into its decision making. # Comparators ## The company's comparators are aligned with NHS practice The company did not compare pralsetinib to all the comparators in the NICE scope. Based on clinical advice, the company refined the list of comparators and categorised them by treatment subgroup: untreated or previously treated. The company had been advised that people only have immunotherapies if they have not had treatment before. Also, it had excluded atezolizumab, bevacizumab, and carboplatin plus paclitaxel because they are used minimally. The clinical expert agreed with the company in excluding immunotherapy in people whose cancer had relapsed. After consultation, the company updated its comparators to better align with NHS practice (see section 3.2). For the untreated subgroup, these were: platinum-based chemotherapy with or without pemetrexed pembrolizumab plus pemetrexed and chemotherapy.For the previously treated subgroup, the company's updated comparators were: docetaxel monotherapy docetaxel plus nintedanib.The committee was satisfied with the company's updated comparators, and considered that they were aligned with NHS practice (see section 3.2). # Clinical effectiveness ## Clinical evidence for pralsetinib's effectiveness is uncertain because it is based on 1 single-arm study The evidence for pralsetinib came from the ARROW clinical trial. This is a single-arm, open-label, non-randomised, multicentre, phase 1 and 2 trial for advanced, unresectable, RET fusion-positive NSCLC and other RET-altered solid tumours. The primary outcome of the trial is objective response rate. Secondary outcomes include duration of response, clinical benefit rate, disease control rate, progression-free survival, and overall survival. The trial recruited people from 79 centres in 13 countries, including 13 patients from the UK. It enrolled 310 people with RET fusion-positive advanced NSCLC, which provided the clinical evidence for the company's base-case cost-effectiveness analysis. Objective response rate using the November 2020 data cut was 69% (95% confidence interval: 62 to 75), and was higher for the untreated subgroup (79%) than the previously treated subgroup (64%). The median progression-free survival and overall survival results are confidential and cannot be shown here. The results suggest pralsetinib could be clinically effective. But this is uncertain because of the lack of comparative data to directly assess pralsetinib's effectiveness compared with other systemic treatment options. Also, the ERG assessed the quality of the ARROW study using the Downs and Black checklist, a scale used to assess the quality of studies. The quality of the trial was marked down in all 4 sections of the scale: reporting, external validity, internal validity, and confounding. The ERG explained that based on the results of the assessment, the trial does not appear to be a well-conducted, non-comparative observational study. The committee concluded that data from the ARROW study is relevant and suggests pralsetinib could be clinically effective, but it is uncertain because it comes from 1 single-arm study. ## The trial population is likely to be generalisable to the NHS population The ERG was concerned about the small number of patients enrolled in the UK centres in the ARROW study. It said this could affect the generalisability of the trial to the population having treatment for RET fusion-positive advanced NSCLC in the NHS. The clinical expert said the trial population did reflect the NHS population for this indication. The committee considered that the ARROW trial population is likely to be generalisable to the NHS population. ## The indirect treatment comparison results are uncertain Because ARROW is a single-arm trial, indirect treatment comparisons were needed to establish the efficacy of pralsetinib compared with other treatments. Because of the lack of available clinical trial evidence about RET fusion-positive tumours, the company used data from people with wild type tumours (that is, tumours without a gene mutation or rearrangement, or of unknown mutation status). However, people with RET fusion-positive tumours have different characteristics to those with wild type tumours. Namely, their cancer is usually non-squamous, they are usually younger and have likely never smoked. So, the company adjusted the data to account for the different characteristics and reduce bias in the results. However, the lack of individual patient data meant some of the comparisons were naive. After consultation, the company updated its comparative analyses with the updated comparators (see section 3.5) using the committee's preferred methodology for the indirect treatment comparison: naive comparison for pembrolizumab plus pemetrexed and chemotherapy (using KEYNOTE‑189, a randomised controlled trial comparing pembrolizumab plus pemetrexed and chemotherapy with placebo plus pemetrexed and chemotherapy) propensity score weighting analysis for platinum-based chemotherapy with or without pemetrexed (using IMpower132, a randomised controlled trial comparing atezolizumab plus platinum-based chemotherapy with chemotherapy alone) propensity score weighting analysis assuming equal efficacy between docetaxel monotherapy and docetaxel plus nintedanib (using the OAK trial, an open-label randomised controlled study comparing atezolizumab with docetaxel in patients with locally advanced or metastatic NSCLC who are having or who have had platinum-based chemotherapy).The ERG noted that there were methodological problems with the systematic literature review, including baseline differences between the studies and the ARROW trial, which was a particular concern for the validity of the naive comparisons. Also, the search methods were not described, no other methods of adjustment were considered, and overlap was not explicitly assessed. So, the ERG considered that the results of the indirect treatment comparison needed to be regarded with caution. The company included an assumption of equal efficacy between docetaxel monotherapy and docetaxel plus nintedanib for the comparison in the previously treated subgroup. The committee acknowledged that the benefit of adding nintedanib to docetaxel is perceived to be limited (see section 3.2) but considered assuming no additional benefit to be implausible. The committee concluded that the results of the indirect treatment comparisons were uncertain. # The company's economic model ## The company's model is appropriate for decision making The company used a partitioned survival model that included 3 health states: progression-free, progressed disease and death. At consultation, the company updated its model in response to the committee's concerns, by: updating its comparators (see section 3.5) updating the model with the committee's preferred methodology for the indirect treatment comparison (see section 3.8) removing the proportional hazards assumption for the lifetime benefit of pralsetinib, except for pembrolizumab plus pemetrexed and chemotherapy using independent curves to model survival (see section 3.11).The committee concluded that the company's revised economic model was suitable for decision making. ## The model assumes a constant treatment benefit which may be implausible The company model assumed that the benefit of pralsetinib compared with standard care could be characterised by a proportional hazards relationship over the full period of the model, which the committee considered implausible. After consultation, the company removed the proportional hazards assumption from the model for the comparisons with platinum-based chemotherapy with or without pemetrexed, docetaxel monotherapy and docetaxel plus nintedanib (see section 3.8). Instead, it fitted independent curves to model overall and progression-free survival for pralsetinib compared with the main comparators in all subgroups. However, it did not remove the proportional hazards assumption for pembrolizumab plus pemetrexed and chemotherapy. The company considered this to be a pragmatic approach to maintain simplicity in the model. The ERG considered that the company's model was improved. But some uncertainty still remained, because a constant treatment effect is still seen throughout the model, the trial data is immature, and the sample size used was small. The committee concluded that the assumption of pralsetinib's constant benefit over time may be implausible, particularly because there is no trial evidence beyond 18 months. ## The overall survival and progression-free survival extrapolations are uncertain, but acceptable for decision making Given that the ARROW trial did not include comparators, the company did an indirect treatment comparison to estimate the relative effectiveness of pralsetinib compared with other treatments (see section 3.8). To estimate survival for pralsetinib beyond the data collection period, the company used parametric models to extrapolate survival for both the untreated and previously treated subgroups. To estimate survival for the main comparators, the company fitted independent curves to model overall survival and progression-free survival, where patient-level data was available. The curve selection aligned with the NICE technical guidance on survival analysis. For the untreated subgroup, the company used exponential curves for overall survival and generalised gamma curves for progression-free survival and time to treatment discontinuation. For the previously treated subgroup, exponential curves were also used to model overall survival. Weibull curves were used for progression-free survival and time to treatment discontinuation. The committee was aware that there is a lack of available clinical trial evidence about RET fusion-positive tumours. It recalled that the company used data from patients with wild type tumours in its indirect treatment comparisons (see section 3.8). Because the overall survival and progression-free survival extrapolations are based on these data, the extrapolations are uncertain. Noting this uncertainty, the committee agreed that, on balance, this approach was reasonable based on the limited data available. The committee concluded that the overall survival and progression-free survival extrapolations were uncertain, but acceptable for decision making. # End of life The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. ## The end of life criteria are met for previously treated RET fusion-positive advanced NSCLC The committee accepted that people with previously treated RET fusion-positive advanced NSCLC are unlikely to live for longer than 24 months. The clinical experts explained that it is likely that pralsetinib will extend life for more than 3 months. In addition, the model estimated an undiscounted mean overall survival gain for pralsetinib compared with the comparators of more than 3 months (the exact results are confidential and cannot be reported here). Despite the uncertainty in the clinical data, and how this was incorporated into the company's economic model, the committee agreed it was likely that this criterion was met. So, the committee concluded that the end of life criteria had been met for this subgroup. ## The end of life criteria are not met for untreated RET fusion-positive advanced NSCLC The committee recalled that treatments in the untreated subgroup are pembrolizumab plus pemetrexed and chemotherapy, and platinum-based chemotherapy with or without pemetrexed (see section 3.5). The committee was aware that, nationally, clinicians may be more likely to prescribe pembrolizumab plus pemetrexed and chemotherapy for untreated RET fusion-positive advanced NSCLC. At consultation, the company acknowledged that people having pembrolizumab plus pemetrexed and chemotherapy tend to live longer than 24 months. On balance, the committee concluded that the end of life criteria were not met for untreated RET fusion-positive advanced NSCLC. # Cost-effectiveness estimates ## An acceptable ICER would be at the lower end of the range normally considered a cost-effective use of NHS resources NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER and whether the technology meets the criteria for consideration as a 'life-extending treatment at the end of life'. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the uncertainties informing the cost-effectiveness estimates, including the primary clinical evidence being from a single-arm trial (see section 3.6), limitations with the indirect treatment comparisons (see section 3.8) and a constant treatment benefit for pralsetinib applied throughout the modelled time horizon (see section 3.10). Because of these uncertainties, the committee considered the maximum acceptable ICER would be at the lower end of the range normally considered a cost-effective use of NHS resources. ## Pralsetinib is not recommended for routine use in the NHS Because of confidential discounts for pralsetinib and its comparators, the cost-effectiveness results are commercial in confidence and cannot be reported here. The committee recalled that the end of life criteria were met in the previously treated group, but not the untreated group (see section 3.13). The committee noted the uncertainties with clinical and cost-effectiveness evidence, and that its preferred cost-effectiveness estimates were above the maximum ICERs considered a cost-effective use of NHS resources for the untreated and treated groups. Therefore, it concluded it could not recommend pralsetinib for routine use in the NHS. # Cancer Drugs Fund ## Data from AcceleRET could address some clinical uncertainties Having concluded that pralsetinib could not be recommended for routine use for either subgroup, the committee considered if it could be recommended for use in the Cancer Drugs Fund. Although the ongoing single-arm ARROW trial would provide further data on progression-free and overall survival for pralsetinib, the committee agreed this will not address the key uncertainties about pralsetinib's relative clinical effectiveness. It was aware that another trial had started. This is AcceleRET, an open-label, randomised, phase 3 study of pralsetinib compared with standard care in untreated RET fusion-positive advanced NSCLC (standard care being platinum-based chemotherapy plus pemetrexed with or without pembrolizumab in non-squamous disease and platinum-based chemotherapy plus gemcitabine in squamous disease). Progression-free survival is the primary outcome, and overall survival is included as a secondary outcome. The committee concluded that data from the AcceleRET trial would resolve some uncertainty for the untreated subgroup by providing direct comparative evidence against other systemic treatments and longer progression-free and overall survival estimates (estimated to be 32 months). ## Pralsetinib is not recommended for use in the Cancer Drugs Fund Having established that data collection could address some of the clinical uncertainty, the committee considered whether there was plausible potential for satisfying the criteria for routine commissioning. It agreed that, based on current data from ARROW and the commercial arrangement submitted as part of the company's consultation response, pralsetinib had the potential to be cost effective. It concluded that pralsetinib met the criteria to be considered for inclusion in the Cancer Drugs Fund. The committee was aware that NHS England's Appraisal and funding of cancer drugs from July 2016 (including the new Cancer Drugs Fund) – A new deal for patients, taxpayers and industry specifies that final acceptance into the Cancer Drugs Fund depends on a managed access agreement being in place. NICE has been informed that it was not possible for a managed access agreement to be finalised by the company and NHS England. So, pralsetinib cannot be recommended for use within the Cancer Drugs Fund for RET fusion-positive NSCLC. # Other factors ## There are no equality issues No equality or social value judgement issues were identified.	{'Recommendations': "Pralsetinib is not recommended, within its marketing authorisation, for treating RET fusion-positive advanced non-small-cell lung cancer (NSCLC) in adults who have not had a RET inhibitor before.\n\nThis recommendation is not intended to affect treatment with pralsetinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nUsual treatment for untreated RET fusion-positive advanced NSCLC is pembrolizumab with pemetrexed and chemotherapy, or platinum-based chemotherapy with or without pemetrexed. Usual treatment for previously treated RET fusion-positive advanced NSCLC is docetaxel chemotherapy or docetaxel with nintedanib.\n\nThe clinical evidence for pralsetinib suggests it could be clinically effective, but its benefit is uncertain because it was not compared directly with any usual NHS treatments. The results from indirectly comparing pralsetinib with some usual treatments suggest that pralsetinib could increase the time before the NSCLC gets worse and how long people live.\n\nPralsetinib meets NICE's criteria to be a life-extending treatment at the end of life for people with previously treated NSCLC, but not for untreated NSCLC. Because of the uncertainty in the clinical evidence, the estimates of cost effectiveness are uncertain and too high to be considered a cost-effective use of NHS resources. So pralsetinib cannot be recommended for routine use.\n\nPralsetinib is a new treatment and more data on its clinical effectiveness is being collected from 1 ongoing trial and 1 new trial. Collecting more data from these trials through a managed access agreement in the Cancer Drugs Fund may resolve some uncertainty in the clinical evidence. But NICE was advised that it was not possible to put a managed access agreement in place, meaning pralsetinib cannot be recommended for use in the Cancer Drugs Fund.", 'Information about pralsetinib': "# Marketing authorisation indication\n\nPralsetinib (Gavreto, Roche) is indicated for 'the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced non-small cell lung cancer (NSCLC) not previously treated with a RET inhibitor'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for pralsetinib.\n\n# Price\n\nThe list price for 120\xa0capsules of pralsetinib (100\xa0mg) is £7,044 (excluding VAT, company submission).\n\nThe company has a commercial arrangement, which would have applied if the technology had been recommended.", 'Committee discussion': "The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway and clinical practice\n\n## People with RET fusion-positive advanced non-small-cell lung cancer would welcome a new treatment\n\nA clinical expert stated that RET fusion-positive advanced non-small-cell lung cancer (NSCLC) particularly affects young people who do not smoke and who do not typically fit the profile of people with lung cancer. So, people often tend to be diagnosed at a late stage. The patient experts highlighted that people with this condition have a poor prognosis which has a significant impact on family and carers. The illness is characterised by breathlessness, cough and weight loss, which can be difficult to manage without treatment. The clinical experts explained that pralsetinib is a once daily oral pill that has a clear advantage over intravenous treatment, which is normally given in hospital. The committee agreed that there is an unmet need in this patient population. It concluded that people with RET fusion-positive advanced NSCLC would welcome a new oral treatment option.\n\n## RET fusion status is not yet routinely identified in clinical practice\n\nThe clinical experts stated that there is no treatment pathway specific to RET fusion-positive advanced NSCLC because testing for RET fusion status has not been universally introduced (which is expected to change within 18\xa0months). Also, until recently there were no targeted treatments in the UK. The clinical experts explained that RET fusion status is included in the 2020/2021 National Genomic Test Directory. However, this genetic screening has not yet been implemented at all hospitals and is typically only available at large centres. The experts further explained that test results might not be available at or soon after diagnosis, so decisions about first-line treatment are usually made without knowing RET fusion status. The clinical experts explained that if RET fusion status is unknown, the person will typically be offered pembrolizumab plus pemetrexed and chemotherapy as first-line treatment. If RET fusion status is known, they suggested that people would usually have platinum-based chemotherapy with or without pemetrexed. But the company explained in its consultation response that it had received input from clinical experts that suggested that pembrolizumab plus pemetrexed and chemotherapy may be more likely to be used in clinical practice nationally. A professional organisation noted that immunotherapy is believed to be less effective in cancer with oncogene drivers such as RET fusion than in the broader advanced NSCLC population. Second-line treatment for people whose RET fusion status is known is usually docetaxel monotherapy or docetaxel plus nintedanib. The clinical experts noted that use of docetaxel plus nintedanib is decreasing because of the limited benefit and increased side effects compared with docetaxel alone. The committee concluded that RET fusion status is not routinely identified in the NHS at present, and confirmation of RET fusion status influences which treatments would be considered relevant comparators.\n\n# Population and subgroups\n\n## Considering the untreated and treated subgroups separately is appropriate\n\nThe company submission included data for RET fusion-positive advanced NSCLC categorised in 2\xa0subgroups: untreated, and previously treated (having had systemic treatment before). The committee concluded that the company's approach considering 2\xa0subgroups was appropriate.\n\n## Pralsetinib's clinical evidence is based on non-squamous NSCLC alone\n\nThe company did not present information for squamous NSCLC. It explained that this was because there is a low incidence of people with RET fusion-positive squamous advanced NSCLC. Also, only a small number of people with squamous NSCLC were included in the clinical trial. Therefore, it chose the comparators for this appraisal using current standard care for this population in NICE's non-squamous treatment pathway. At consultation, the company explained that the marketing authorisation for pralsetinib does not differentiate between non-squamous and squamous NSCLC. The committee concluded that it was aware of the histological difference and determined it had not seen evidence for the squamous population, and that it would factor this into its decision making.\n\n# Comparators\n\n## The company's comparators are aligned with NHS practice\n\nThe company did not compare pralsetinib to all the comparators in the NICE scope. Based on clinical advice, the company refined the list of comparators and categorised them by treatment subgroup: untreated or previously treated. The company had been advised that people only have immunotherapies if they have not had treatment before. Also, it had excluded atezolizumab, bevacizumab, and carboplatin plus paclitaxel because they are used minimally. The clinical expert agreed with the company in excluding immunotherapy in people whose cancer had relapsed. After consultation, the company updated its comparators to better align with NHS practice (see section\xa03.2). For the untreated subgroup, these were:\n\nplatinum-based chemotherapy with or without pemetrexed\n\npembrolizumab plus pemetrexed and chemotherapy.For the previously treated subgroup, the company's updated comparators were:\n\ndocetaxel monotherapy\n\ndocetaxel plus nintedanib.The committee was satisfied with the company's updated comparators, and considered that they were aligned with NHS practice (see section 3.2).\n\n# Clinical effectiveness\n\n## Clinical evidence for pralsetinib's effectiveness is uncertain because it is based on 1 single-arm study\n\nThe evidence for pralsetinib came from the ARROW clinical trial. This is a single-arm, open-label, non-randomised, multicentre, phase 1 and 2 trial for advanced, unresectable, RET fusion-positive NSCLC and other RET-altered solid tumours. The primary outcome of the trial is objective response rate. Secondary outcomes include duration of response, clinical benefit rate, disease control rate, progression-free survival, and overall survival. The trial recruited people from 79\xa0centres in 13\xa0countries, including 13\xa0patients from the UK. It enrolled 310\xa0people with RET fusion-positive advanced NSCLC, which provided the clinical evidence for the company's base-case cost-effectiveness analysis. Objective response rate using the November 2020 data cut was 69% (95% confidence interval: 62 to 75), and was higher for the untreated subgroup (79%) than the previously treated subgroup (64%). The median progression-free survival and overall survival results are confidential and cannot be shown here. The results suggest pralsetinib could be clinically effective. But this is uncertain because of the lack of comparative data to directly assess pralsetinib's effectiveness compared with other systemic treatment options. Also, the ERG assessed the quality of the ARROW study using the Downs and Black checklist, a scale used to assess the quality of studies. The quality of the trial was marked down in all 4\xa0sections of the scale: reporting, external validity, internal validity, and confounding. The ERG explained that based on the results of the assessment, the trial does not appear to be a well-conducted, non-comparative observational study. The committee concluded that data from the ARROW study is relevant and suggests pralsetinib could be clinically effective, but it is uncertain because it comes from 1\xa0single-arm study.\n\n## The trial population is likely to be generalisable to the NHS population\n\nThe ERG was concerned about the small number of patients enrolled in the UK centres in the ARROW study. It said this could affect the generalisability of the trial to the population having treatment for RET fusion-positive advanced NSCLC in the NHS. The clinical expert said the trial population did reflect the NHS population for this indication. The committee considered that the ARROW trial population is likely to be generalisable to the NHS population.\n\n## The indirect treatment comparison results are uncertain\n\nBecause ARROW is a single-arm trial, indirect treatment comparisons were needed to establish the efficacy of pralsetinib compared with other treatments. Because of the lack of available clinical trial evidence about RET fusion-positive tumours, the company used data from people with wild type tumours (that is, tumours without a gene mutation or rearrangement, or of unknown mutation status). However, people with RET fusion-positive tumours have different characteristics to those with wild type tumours. Namely, their cancer is usually non-squamous, they are usually younger and have likely never smoked. So, the company adjusted the data to account for the different characteristics and reduce bias in the results. However, the lack of individual patient data meant some of the comparisons were naive. After consultation, the company updated its comparative analyses with the updated comparators (see section 3.5) using the committee's preferred methodology for the indirect treatment comparison:\n\nnaive comparison for pembrolizumab plus pemetrexed and chemotherapy (using KEYNOTE‑189, a randomised controlled trial comparing pembrolizumab plus pemetrexed and chemotherapy with placebo plus pemetrexed and chemotherapy)\n\npropensity score weighting analysis for platinum-based chemotherapy with or without pemetrexed (using IMpower132, a randomised controlled trial comparing atezolizumab plus platinum-based chemotherapy with chemotherapy alone)\n\npropensity score weighting analysis assuming equal efficacy between docetaxel monotherapy and docetaxel plus nintedanib (using the OAK trial, an open-label randomised controlled study comparing atezolizumab with docetaxel in patients with locally advanced or metastatic NSCLC who are having or who have had platinum-based chemotherapy).The ERG noted that there were methodological problems with the systematic literature review, including baseline differences between the studies and the ARROW trial, which was a particular concern for the validity of the naive comparisons. Also, the search methods were not described, no other methods of adjustment were considered, and overlap was not explicitly assessed. So, the ERG considered that the results of the indirect treatment comparison needed to be regarded with caution. The company included an assumption of equal efficacy between docetaxel monotherapy and docetaxel plus nintedanib for the comparison in the previously treated subgroup. The committee acknowledged that the benefit of adding nintedanib to docetaxel is perceived to be limited (see section 3.2) but considered assuming no additional benefit to be implausible. The committee concluded that the results of the indirect treatment comparisons were uncertain.\n\n# The company's economic model\n\n## The company's model is appropriate for decision making\n\nThe company used a partitioned survival model that included 3\xa0health states: progression-free, progressed disease and death. At consultation, the company updated its model in response to the committee's concerns, by:\n\nupdating its comparators (see section 3.5)\n\nupdating the model with the committee's preferred methodology for the indirect treatment comparison (see section 3.8)\n\nremoving the proportional hazards assumption for the lifetime benefit of pralsetinib, except for pembrolizumab plus pemetrexed and chemotherapy\n\nusing independent curves to model survival (see section 3.11).The committee concluded that the company's revised economic model was suitable for decision making.\n\n## The model assumes a constant treatment benefit which may be implausible\n\nThe company model assumed that the benefit of pralsetinib compared with standard care could be characterised by a proportional hazards relationship over the full period of the model, which the committee considered implausible. After consultation, the company removed the proportional hazards assumption from the model for the comparisons with platinum-based chemotherapy with or without pemetrexed, docetaxel monotherapy and docetaxel plus nintedanib (see section 3.8). Instead, it fitted independent curves to model overall and progression-free survival for pralsetinib compared with the main comparators in all subgroups. However, it did not remove the proportional hazards assumption for pembrolizumab plus pemetrexed and chemotherapy. The company considered this to be a pragmatic approach to maintain simplicity in the model. The ERG considered that the company's model was improved. But some uncertainty still remained, because a constant treatment effect is still seen throughout the model, the trial data is immature, and the sample size used was small. The committee concluded that the assumption of pralsetinib's constant benefit over time may be implausible, particularly because there is no trial evidence beyond 18\xa0months.\n\n## The overall survival and progression-free survival extrapolations are uncertain, but acceptable for decision making\n\nGiven that the ARROW trial did not include comparators, the company did an indirect treatment comparison to estimate the relative effectiveness of pralsetinib compared with other treatments (see section 3.8). To estimate survival for pralsetinib beyond the data collection period, the company used parametric models to extrapolate survival for both the untreated and previously treated subgroups. To estimate survival for the main comparators, the company fitted independent curves to model overall survival and progression-free survival, where patient-level data was available. The curve selection aligned with the NICE technical guidance on survival analysis. For the untreated subgroup, the company used exponential curves for overall survival and generalised gamma curves for progression-free survival and time to treatment discontinuation. For the previously treated subgroup, exponential curves were also used to model overall survival. Weibull curves were used for progression-free survival and time to treatment discontinuation. The committee was aware that there is a lack of available clinical trial evidence about RET fusion-positive tumours. It recalled that the company used data from patients with wild type tumours in its indirect treatment comparisons (see section 3.8). Because the overall survival and progression-free survival extrapolations are based on these data, the extrapolations are uncertain. Noting this uncertainty, the committee agreed that, on balance, this approach was reasonable based on the limited data available. The committee concluded that the overall survival and progression-free survival extrapolations were uncertain, but acceptable for decision making.\n\n# End of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal.\n\n## The end of life criteria are met for previously treated RET fusion-positive advanced NSCLC\n\nThe committee accepted that people with previously treated RET fusion-positive advanced NSCLC are unlikely to live for longer than 24 months. The clinical experts explained that it is likely that pralsetinib will extend life for more than 3\xa0months. In addition, the model estimated an undiscounted mean overall survival gain for pralsetinib compared with the comparators of more than 3\xa0months (the exact results are confidential and cannot be reported here). Despite the uncertainty in the clinical data, and how this was incorporated into the company's economic model, the committee agreed it was likely that this criterion was met. So, the committee concluded that the end of life criteria had been met for this subgroup.\n\n## The end of life criteria are not met for untreated RET fusion-positive advanced NSCLC\n\nThe committee recalled that treatments in the untreated subgroup are pembrolizumab plus pemetrexed and chemotherapy, and platinum-based chemotherapy with or without pemetrexed (see section\xa03.5). The committee was aware that, nationally, clinicians may be more likely to prescribe pembrolizumab plus pemetrexed and chemotherapy for untreated RET fusion-positive advanced NSCLC. At consultation, the company acknowledged that people having pembrolizumab plus pemetrexed and chemotherapy tend to live longer than 24\xa0months. On balance, the committee concluded that the end of life criteria were not met for untreated RET fusion-positive advanced NSCLC.\n\n# Cost-effectiveness estimates\n\n## An acceptable ICER would be at the lower end of the range normally considered a cost-effective use of NHS resources\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER and whether the technology meets the criteria for consideration as a 'life-extending treatment at the end of life'. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the uncertainties informing the cost-effectiveness estimates, including the primary clinical evidence being from a single-arm trial (see section 3.6), limitations with the indirect treatment comparisons (see section 3.8) and a constant treatment benefit for pralsetinib applied throughout the modelled time horizon (see section 3.10). Because of these uncertainties, the committee considered the maximum acceptable ICER would be at the lower end of the range normally considered a cost-effective use of NHS resources.\n\n## Pralsetinib is not recommended for routine use in the NHS\n\nBecause of confidential discounts for pralsetinib and its comparators, the cost-effectiveness results are commercial in confidence and cannot be reported here. The committee recalled that the end of life criteria were met in the previously treated group, but not the untreated group (see section 3.13). The committee noted the uncertainties with clinical and cost-effectiveness evidence, and that its preferred cost-effectiveness estimates were above the maximum ICERs considered a cost-effective use of NHS resources for the untreated and treated groups. Therefore, it concluded it could not recommend pralsetinib for routine use in the NHS.\n\n# Cancer Drugs Fund\n\n## Data from AcceleRET could address some clinical uncertainties\n\nHaving concluded that pralsetinib could not be recommended for routine use for either subgroup, the committee considered if it could be recommended for use in the Cancer Drugs Fund. Although the ongoing single-arm ARROW trial would provide further data on progression-free and overall survival for pralsetinib, the committee agreed this will not address the key uncertainties about pralsetinib's relative clinical effectiveness. It was aware that another trial had started. This is AcceleRET, an open-label, randomised, phase 3 study of pralsetinib compared with standard care in untreated RET fusion-positive advanced NSCLC (standard care being platinum-based chemotherapy plus pemetrexed with or without pembrolizumab in non-squamous disease and platinum-based chemotherapy plus gemcitabine in squamous disease). Progression-free survival is the primary outcome, and overall survival is included as a secondary outcome. The committee concluded that data from the AcceleRET trial would resolve some uncertainty for the untreated subgroup by providing direct comparative evidence against other systemic treatments and longer progression-free and overall survival estimates (estimated to be 32\xa0months).\n\n## Pralsetinib is not recommended for use in the Cancer Drugs Fund\n\nHaving established that data collection could address some of the clinical uncertainty, the committee considered whether there was plausible potential for satisfying the criteria for routine commissioning. It agreed that, based on current data from ARROW and the commercial arrangement submitted as part of the company's consultation response, pralsetinib had the potential to be cost effective. It concluded that pralsetinib met the criteria to be considered for inclusion in the Cancer Drugs Fund. The committee was aware that NHS England's Appraisal and funding of cancer drugs from July 2016 (including the new Cancer Drugs Fund) – A new deal for patients, taxpayers and industry specifies that final acceptance into the Cancer Drugs Fund depends on a managed access agreement being in place. NICE has been informed that it was not possible for a managed access agreement to be finalised by the company and NHS England. So, pralsetinib cannot be recommended for use within the Cancer Drugs Fund for RET fusion-positive NSCLC.\n\n# Other factors\n\n## There are no equality issues\n\nNo equality or social value judgement issues were identified."}	https://www.nice.org.uk/guidance/ta812	Evidence-based recommendations on pralsetinib (Gavreto) for treating RET fusion-positive advanced non-small-cell lung cancer in adults.
3d119361b52b309b51d234d8c90d2767e0a4e02f	nice	PLGF-based testing to help diagnose suspected preterm pre-eclampsia	PLGF-based testing to help diagnose suspected preterm pre-eclampsia Evidence-based recommendations on placental growth factor (PLGF)-based testing to help diagnose suspected preterm pre-eclampsia. The tests are: DELFIA Xpress PLGF 1‑2‑3, DELFIA Xpress sFlt‑1/PLGF 1‑2‑3 ratio, Elecsys immunoassay sFlt‑1/PLGF ratio, Triage PLGF Test. # Recommendations The following placental growth factor (PLGF)-based tests, used with standard clinical assessment, are recommended to help decide on care (to help rule in or rule out pre-eclampsia) for people with suspected preterm (between 20 weeks and 36 weeks and 6 days of pregnancy) pre‑eclampsia: DELFIA Xpress PLGF 1‑2‑3 DELFIA Xpress sFlt‑1/PLGF 1‑2‑3 ratio Elecsys immunoassay sFlt‑1/PLGF ratio Triage PLGF Test.Not all manufacturers indicate their tests for use across the full range of 20 weeks to 36 weeks and 6 days of pregnancy. The tests should be used according to their indications for use (see section 2). PLGF-based testing may particularly benefit groups at higher risk of severe adverse pregnancy outcomes, such as people from African, Caribbean and Asian family backgrounds. Further research is recommended into how well the tests work when people are pregnant with more than 1 baby (see section 4.3). Do not use PLGF-based tests to make decisions about whether to offer a planned early birth to people with preterm pre-eclampsia. The NICE guideline on hypertension in pregnancy has recommendations on timing of birth. Use a PLGF-based test once per episode of suspected preterm pre‑eclampsia. Further research is recommended on repeat testing (see section 4.2). BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio is not recommended for routine use in the NHS. Further research is needed to show the accuracy of this test when using specified thresholds (see section 4.1). Why the committee made these recommendations The DELFIA Xpress PLGF 1‑2‑3 test was not previously recommended by NICE because there was not enough evidence on its accuracy. High-quality evidence now shows that this test, and the DELFIA Xpress sFlt‑1/PLGF 1‑2‑3 ratio assay, have good accuracy for preterm pre-eclampsia. NICE previously recommended the Elecsys immunoassay sFlt‑1/PLGF ratio and Triage PLGF Test to help rule out pre-eclampsia. But they were not recommended to help diagnose (rule in) pre-eclampsia because of concerns that this could result in people being unnecessarily offered early births. Data now shows that this is not the case. Modelling shows that all these tests are cost effective compared with standard assessment when used to help diagnose (rule in) or exclude (rule out) preterm pre‑eclampsia. So these tests are recommended to help plan safe care and a safe birth for people with pre-eclampsia, and also to identify people unlikely to develop pre-eclampsia, and therefore reduce unnecessary hospitalisation. The tests may work differently in people who are pregnant with more than one baby. Therefore, NICE has recommended further research to find out how well the tests work in this group. There is not enough evidence on whether or not the test should be repeated. Therefore, NICE has recommended testing just once when a person presents with possible symptoms of preterm pre-eclampsia (an episode) and recommended further research on if repeat testing improves outcomes. There is new data for BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio, which was originally not recommended. But the data is lower quality than that for the other tests. Data on test sensitivity and specificity is from 2 studies, 1 that was small and 1 that did not specify the test threshold to use in advance. There is not enough good-quality data to assess how well it works and its cost effectiveness. There is also uncertainty about how the company intends the test to be used. So this test is still not recommended.# The diagnostic tests # Clinical need and practice Pre-eclampsia is a potentially serious complication of pregnancy, thought to be related to problems with the development of the placenta. It requires referral to a specialist and hospital admission to monitor the mother and unborn baby, and is only cured by the birth of the baby. Pre-eclampsia is characterised by high blood pressure (hypertension) and proteinuria, which is when the kidneys leak protein into the urine. Either, on its own indicates a risk of developing pre-eclampsia. Other symptoms include headache, visual disturbances, right upper quadrant abdominal (epigastric) pain, oedema (swelling of the hands, face or feet) and oliguria (low urine output). If pre-eclampsia is not diagnosed and closely monitored, it can lead to potentially life-threatening complications including eclampsia, HELLP syndrome (haemolysis, elevated liver enzymes and low platelets), disseminated intravascular coagulation, stroke or organ dysfunction. Women who have hypertension or pre-eclampsia during pregnancy may have a higher risk of placental abruption. Gestational hypertension and pre-eclampsia may also affect the unborn baby by slowing growth or leading to premature birth. This is a full update of NICE's diagnostics guidance on placental growth factor (PLGF)-based testing to help diagnose suspected pre-eclampsia (DG23), which was published in 2016. The original guidance recommended the Triage PLGF Test and the Elecsys immunoassay sFlt‑1/PLGF ratio, used with standard clinical assessment and subsequent clinical follow up, to help rule out pre-eclampsia. Further research was recommended on using these tests to rule in pre-eclampsia. The DELFIA Xpress PLGF 1‑2‑3 test and BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio were not recommended for routine adoption in the NHS. # The diagnostic and care pathway ## Identifying and managing the risk of developing pre-eclampsia Recommendations on management of pre-eclampsia in NICE's guideline on antenatal care include measuring blood pressure and doing urinalysis for protein at each antenatal visit to check for pre-eclampsia. The guideline also recommends determining risk factors for pre-eclampsia at the booking appointment (by 10 weeks of pregnancy). NICE's guideline on hypertension in pregnancy describes risk factors for pre‑eclampsia. It defines pre-eclampsia as new-onset hypertension (over 140 mmHg systolic or over 90 mmHg diastolic) after 20 weeks of pregnancy plus 1 or more new-onset conditions. If a woman presents with some but not all of these criteria, they are considered to have suspected pre-eclampsia. If they are under 37 weeks of pregnancy, this would be suspected preterm pre-eclampsia. ## Managing pregnancy with gestational hypertension with or without pre-eclampsia NICE's guideline on hypertension in pregnancy includes recommendations on managing gestational hypertension and pre-eclampsia in pregnancy, including timing the birth in women with pre-eclampsia. # The interventions ## Triage PLGF Test (Quidel) The Triage PLGF Test can be used at the point of care and in the laboratory. The test is used with other clinical information to help diagnose preterm pre-eclampsia, and as an aid in the prognosis of birth, in women who are between 20 weeks and 35 weeks pregnant with signs and symptoms of pre-eclampsia. The Triage PLGF kit costs £1,000 (excluding VAT) and can do 25 tests. The cost per test used in the economic model (incorporating additional cost components such as machine costs, reagents, service charges, training and staff costs) was £49.58. Result Classification Interpretation Placental growth factor (PLGF) less than 12 pg/ml Test positive – highly abnormal Highly abnormal and suggestive of patients with severe placental dysfunction and at increased risk of preterm birth PLGF between 12 pg/ml and 99 pg/ml Test positive – abnormal Abnormal and suggestive of patients with placental dysfunction and at increased risk of preterm birth PLGF 100 pg/ml or more Test negative – normal Normal and suggestive of patients without placental dysfunction and unlikely to progress to birth within 14 days of the test ## Elecsys immunoassay sFlt‑1/PLGF ratio (Roche) The Elecsys immunoassay sFlt‑1/PLGF ratio is formed by combining the results from 2 electrochemiluminescence immunoassays (the Elecsys PLGF and Elecsys sFlt‑1 assays), which are compatible with the Roche Cobas e automated clinical chemistry analysers. The sFlt‑1/PLGF ratio is intended to help diagnose pre-eclampsia, together with other diagnostic and clinical information. The sFlt‑1/PLGF ratio is also intended to help predict pre-eclampsia in the short term (rule out and rule in) in pregnant women with suspected pre-eclampsia, together with other diagnostic and clinical information. The Elecsys sFlt‑1 reagent kit and the Elecsys PLGF reagent kit cost £3,310.78 each and can do 100 tests. They are intended to be used together, with each sFlt‑1/PLGF ratio test costing £66.21 (excluding VAT). The cost per test used in the economic model (incorporating additional cost components such as machine costs, reagents, service charges, training and staff costs) was £79.23. Intended use Stage of pregnancy Decision rule sFlt‑1/PLGF ratio To help diagnose pre-eclampsia Week 20 to week 33 plus 6 days Rule out cut-off To help diagnose pre-eclampsia Week 20 to week 33 plus 6 days Rule in cut-off To help diagnose pre-eclampsia Week 34 to birth Rule out cut-off To help diagnose pre-eclampsia Week 34 to birth Rule in cut-off Short-term prediction of pre-eclampsia Week 24 to week 36 plus 6 days Rule out pre-eclampsia for 1 week -r less Short-term prediction of pre-eclampsia Week 24 to week 36 plus 6 days Rule in pre-eclampsia within 4 weeks Over 38 ## DELFIA Xpress PLGF 1-2-3 test and DELFIA Xpress sFlt-1 kit (PerkinElmer) The DELFIA Xpress PLGF 1‑2‑3 can be used on its own or with the DELFIA Xpress sFlt‑1 kit. The tests are intended to help diagnose pre‑eclampsia and for short-term prediction of suspected pre-eclampsia together with other biochemical and clinical information. The company specifies threshold values for the DELFIA Xpress PLGF 1‑2‑3 test when used alone (see table 3): Intended use Stage of pregnancy Decision rule PLGF cut-off To help diagnose pre-eclampsia Week 20 to week 33 plus 6 days Week 34 or more Rule in cut-off Less than 50 pg/ml To help diagnose pre-eclampsia Week 20 to week 33 plus 6 days Week 34 or more Rule out cut-off pg/ml or more Short-term prediction of pre-eclampsia Week 20 to week 41 Week 20 to week 33 plus 6 days Week 34 or more Rule out pre-eclampsia within 1 week pg/ml or more Short-term prediction of pre-eclampsia Week 20 to week 41 Week 20 to week 33 plus 6 days Week 34 or more Rule out pre-eclampsia within 4 weeks pg/ml or more The company specifies threshold values for DELFIA Xpress 1‑2‑3 used with the DELFIA Xpress sFlt‑1 (see table 4): Intended use Stage of pregnancy Decision rule sFlt‑1/PLGF ratio To help diagnose pre-eclampsia Week 20 to week 33 plus 6 days Rule in cut-off -r over To help diagnose pre-eclampsia Week 34 or more Rule in cut-off -r over Short-term prediction of pre-eclampsia Week 20 to week 41 Week 20 to week 33 plus 6 days Week 34 or more Rule out pre-eclampsia within 1 week -r less Short-term prediction of pre-eclampsia Week 20 to week 41 Week 20 to week 33 plus 6 days Week 34 or more Rule out pre-eclampsia within 4 weeks -r less The DELFIA Xpress PLGF 1‑2‑3 kit costs £722 (excluding VAT) and the DELFIA Xpress sFlt‑1 kits costs £944 (excluding VAT). Each can do 96 tests (that is 96 PLGF tests alone or 96 sFlt‑1/PLGF ratio tests). The cost per test used in the economic model (incorporating additional cost components such as machine costs, reagents, service charges, training and staff costs) was £37.41 for DELFIA Xpress PLGF 1‑2‑3 and £71.41 for the DELFIA Xpress sFlt‑1/PLGF ratio. ## BRAHMS sFlt-1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio (ThermoFisher) The BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio is formed by combining the results from the BRAHMS sFlt‑1 Kryptor and BRAHMS PLGF plus Kryptor assays. The assays are compatible with the BRAHMS Kryptor compact plus analyser and the Kryptor Gold immunoanalyser. The BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio is intended to be used to confirm or exclude a diagnosis of pre-eclampsia after 20 weeks of pregnancy. The BRAHMS sFlt‑1 Kryptor and BRAHMS PLGF plus Kryptor kits cost £825 each and can do 75 tests. The cost per test used in the economic model (incorporating additional cost components such as machine costs, reagents, service charges, training and staff costs) was £52.28. The company says that a ratio of more than 85 suggests pre-eclampsia and a high-risk pregnancy. At consultation on the draft guidance, it said that updated instructions for use will be released later in 2022 (see section 3.6). # The comparator The comparator is no further assessment beyond clinical assessments already done, such as blood pressure measurement, urinalysis and fetal monitoring, to help diagnose preterm pre-eclampsia and make decisions about care.# Committee discussion The diagnostics advisory committee considered evidence from several sources on the BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio, DELFIA Xpress PLGF 1‑2‑3 test, DELFIA Xpress sFlt‑1/PLGF ratio, Elecsys immunoassay sFlt‑1/PLGF ratio and Triage PLGF Test. Evidence was considered from the diagnostics assessment report and an overview of that report, and the decision support unit's (DSU) report and updated model. Full details of all the evidence are in the project documents for this guidance on the NICE website. # The condition ## PLGF-based tests are likely to substantially benefit women with suspected preterm pre-eclampsia A patient expert explained that pregnancy can be a particularly worrying time for expectant mothers if they had preterm pre-eclampsia or complications from hypertension in a previous pregnancy. Placental growth factor (PLGF)-based testing can reassure pregnant women with hypertension who are anxious about complications and risks to the baby and themselves, and increase their confidence in treatment plans. A patient expert highlighted an Action on Pre-eclampsia report that stated that women from African, Asian or Caribbean family backgrounds have a higher risk of developing pre-eclampsia and that PLGF tests may particularly benefit higher risk groups. Clinical experts said that the tests can improve risk assessment and enable early planning for a safe birth. They said they may also help avoid stressful last-minute medical interventions. Early planning for at-risk pregnancies also means women at centres without facilities for preterm baby care can be safely transferred to a suitably equipped centre in good time. This improves the outcome for the baby and can avoid stressful situations, such as the mother and baby being cared for in different centres. Another benefit of the tests is better identification of women who will not develop preterm pre-eclampsia, reducing unnecessary hospitalisation. The committee considered that this was particularly relevant during the COVID‑19 pandemic to help reduce spread of the virus. Clinical experts also highlighted the benefits of using the tests for shared decision making, with test results helping discussions. # Clinical effectiveness ## PLGF-based test results should be used alongside clinical information for decision making The committee considered the PARROT and INSPIRE trials, which assessed PLGF-based tests as part of a clinical algorithm that included using the tests alongside clinical judgement to make decisions about care. The PARROT trial was a multicentre, pragmatic, stepped wedge cluster randomised controlled trial of 1,023 women with suspected preterm pre‑eclampsia who were between 20 weeks and 36 weeks and 6 days of pregnancy. It was done in 11 maternity units in the UK and used the Triage PLGF Test. The INSPIRE trial was a prospective, interventional, parallel-group, randomised clinical trial of 370 women with suspected pre‑eclampsia who were between 24 weeks and 37 weeks of pregnancy. It was based in a single UK tertiary referral hospital and used the Elecsys immunoassay sFlt1/PLGF ratio. Clinical experts said that the tests are not a substitute for clinical assessment. Instead PLGF-based testing gives the clinician more evidence to help them make an informed decision. Clinical experts also explained that a low PLGF test result does not always mean a woman has pre-eclampsia and can be associated with other conditions affecting the placenta. They did however highlight that PLGF-based test results can be very useful to help with clinical decision making, particularly for women who had hypertension or proteinuria before becoming pregnant. The committee concluded that PLGF-based test results should be used alongside clinical information for decision making. ## PLGF-based testing did not lead to unnecessary early births in UK trials In the original guidance (DG23) published in 2016, the committee was concerned that too much emphasis might be placed on PLGF test results indicating preterm pre-eclampsia, which could result in the unnecessary early birth of the baby. Since this guidance was published, the NICE guideline on hypertension in pregnancy has been updated to include recommendations on deciding the timing of birth in women with pre‑eclampsia. In the PARROT trial, the proportions of births before 37 weeks in the test and control arms of the trial were similar. In the PARROT, PARROT Ireland (a multicentre, pragmatic, stepped wedge cluster randomised controlled trial done in 7 maternity units throughout Ireland) and INSPIRE trials, weeks of pregnancy before birth were also similar in the test and control arms. Clinical experts said that this reflects current practice because the tests are used to help with decisions about hospitalisation and whether to transfer to a specialist unit, not to guide decisions about birth. They also pointed out that about half the centres that participated in the PARROT trial were not specialist centres, which reduced concern about how the tests would be used if they were adopted more widely. The committee concluded that there was evidence that use of the tests did not lead to unnecessary early births. ## Maternal outcomes: evidence from trials suggests potential improvements with PLGF-based testing and better decisions about care The PARROT trial data suggested that using a PLGF test improved maternal outcomes. In PARROT, the number of women with adverse outcomes, defined by the fullPIERS consensus, was lower in the revealed group (4%) than the concealed group (5%), and this difference was statistically significant. Incidence of placental abruption and severe pre‑eclampsia was also lower with test use in the INSPIRE trial but not statistically significantly so. The clinical experts explained that the INSPIRE trial was not powered to detect differences in the adverse maternal outcomes that it assessed. In the INSPIRE trial, the proportion of women who had confirmed pre-eclampsia within 7 days of testing who were admitted to hospital was greater in the test use arm of the trial (100%) than the control arm (83%). At the second committee meeting, the committee considered the PARROT Ireland randomised controlled trial. It found that integrating PLGF testing into routine clinical investigations for women with suspected preterm pre-eclampsia had no significant effect on maternal morbidity. Clinical experts highlighted differences between the PARROT and PARROT Ireland study cohorts. PARROT Ireland had a higher proportion of women with suspected fetal growth restriction (55%) than PARROT (16%). Also, the incidence of pre-eclampsia in PARROT was higher (35%) than in PARROT Ireland (14%). They also noted that PARROT Ireland had only recruited just over half the proposed participants (2,313 out of a planned 4,000; or 58%) and may have been underpowered to detect significant differences. The committee concluded that there was some evidence that PLGF-based test use could improve management decisions and clinical outcomes for women with suspected preterm pre-eclampsia, although there was considerable uncertainty about this. ## Neonatal outcomes: the effect of PLGF-based testing is uncertain but some evidence suggests it may improve decisions about care Incidence of perinatal and neonatal mortality and complications in the test and control arms of the PARROT trial were similar. Clinical experts explained that there was a very low number of these clinical events and that the trial was not powered to show differences. The committee considered that it was uncertain whether the differences were down to test use or chance. Clinical experts explained that intraventricular haemorrhage (IVH) and respiratory distress syndrome (RDS) can be devastating for babies and their families. But because they happen rarely, it is difficult to do trials to assess how tests affect them. A clinical expert said that, in a stratified analysis of the PARROT data, more women with a PLGF test result of less than 12 pg/ml who delivered before 35 weeks of pregnancy were given antenatal corticosteroids 7 days before birth in the revealed group (39%) than the concealed group (16%). They explained that this meant the women who had the PLGF test had better clinical care because antenatal corticosteroids reduce the risk of RDS, IVH and death in preterm babies. A clinical expert also pointed out that the number of nights that babies spent in the intensive care or high-dependency unit was only 15.2 nights in the test arm of PARROT, compared with 24.2 nights in the control arm. The committee concluded that, because of the rarity of IVH, RDS and death, the effect of using PLGF-based tests on neonatal outcomes is uncertain. But it agreed there was some evidence that they influence management decisions that could improve care. ## The DELFIA Xpress tests have established rule in and rule out thresholds, but the BRAHMS Kryptor test does not In the original guidance, the committee did not recommend the DELFIA Xpress PLGF 1‑2‑3 test or BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio test for routine adoption in the NHS. It said that further research should be done by the companies to show their clinical effectiveness, including diagnostic accuracy and analytical validity. No new data was found for how these 2 tests affect management decisions or clinical outcomes (such as maternal or neonatal outcomes). However, there was new evidence on test accuracy. Since the original guidance, rule in and rule out thresholds have been established for the DELFIA Xpress PLGF 1‑2‑3 test based on performance of the test compared with the Triage PLGF and Elecsys immunoassay sFlt‑1/PLGF ratio tests (McCarthy et al. 2018 and Giblin et al. 2020). A prospective study using these preset thresholds was also considered at the second committee meeting (Bremner et al. 2022). A quality assessment of this study indicated a low risk of bias and no applicability concerns. This study also provided accuracy estimates for the DELFIA Xpress sFlt‑1/PLGF 1‑2‑3 ratio assay, using specified thresholds. The external assessment group (EAG) identified 2 studies that compared the BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio with the Elecsys test. One indicated highly correlated results (Salahuddin et al. 2016) but the authors of the other study (Cheng et al. 2019) indicated that results from the different manufacturers' immunoassays were significantly different, and that sFlt‑1/PLGF rule in and rule out criteria are manufacturer-specific, not interchangeable, and require separate clinical validation. At consultation on the draft guidance, the BRAHMS test manufacturer provided detail from updated instructions for use, which it plans to release in the second half of 2022. This included reference to thresholds for the BRAHMS ratio test of 85, which the company already said should be used to rule in pre‑eclampsia (see section 2.13), and 66, based on Andersen et al. (2021; see section 3.13). In the committee meeting, the company said that 66 should be used to rule out pre-eclampsia and 85 to rule it in. However, the committee noted that, although the instructions for use did refer to these 2 thresholds, they did not say whether they should be used as single thresholds or together, or whether they should be used to rule in or rule out pre-eclampsia. Clinical experts said that this could lead to uncertainty in how to interpret test results. The committee concluded that, even based on the information from the updated instructions for use, it is not clear how to interpret the test result. It also noted that the test's accuracy using the threshold of 66 had not been validated in a population independent from the one used to set this threshold (see section 3.13). The committee further concluded that there was now some evidence on the accuracy of the DELFIA Xpress tests, which could address the request for further data in the original guidance. ## Repeat PLGF-based testing evidence is still limited The original guidance made a research recommendation on using repeat PLGF‑based testing. Not much more evidence was found for repeat PLGF testing for this assessment, but the clinical experts pointed out that ongoing work, for example the PARROT 2 trial, will provide further data in the future. The committee concluded that the research recommendation made in DG23 about repeat testing should be retained in this guidance (see section 4.2). # Cost effectiveness ## The DSU model is suitable for decision making At the first committee meeting, the committee was concerned about the EAG's model and approach to modelling. The standard assessment costs and quality-adjusted life years (QALYs) in the EAG's model were different for the Elecsys immunoassay sFlt‑1/PLGF ratio and the Triage PLGF Test. The EAG explained this was because it used data from the control arm of the INSPIRE trial for the Elecsys test and from the PARROT trial for the Triage PLGF Test. But clinical experts said that there were important differences between the 2 trial populations, for example pre‑eclampsia incidence. The committee noted that using different populations to assess standard assessment for different tests made interpreting results more difficult, and could lead to a biased assessment. The level of pre-eclampsia in the test use and non-test use arms of the individual models was also different, particularly for the Elecsys model. This was because the EAG used unadjusted data from the trials, and the pre-eclampsia incidence was higher in the test use arm. A clinical expert said that this was caused by chance allocation to trial arms. There was also uncertainty about whether the populations modelled accurately represented women with suspected preterm pre-eclampsia who would have the PLGF-based tests in the NHS. The committee would have preferred the same model for standard assessment to be used for all tests, and for the model to be based on a population that accurately represents women with suspected preterm pre-eclampsia in the NHS. The committee concluded that more work on the model was needed to address these concerns before any recommendations could be made. As a result of these concerns, NICE commissioned the DSU to carry out further modelling work. For the second committee meeting, the DSU provided an updated model and analyses. The committee said that the DSU's model addressed its previous concerns and concluded that it was suitable for decision making. ## It is appropriate to consider cost-effectiveness estimates of the tests when used to help rule out and rule in preterm pre-eclampsia The DSU provided cost-effectiveness estimates when the PLGF-based tests were used to rule out preterm pre-eclampsia only, and when the tests were used to rule in and rule out preterm pre-eclampsia. The committee recalled that data from recent studies provided reassurance that using positive results from the tests to inform care did not lead to earlier births (see section 3.3). Clinical experts said that training and education on these tests focuses on using them to identify women who have a higher risk of developing preterm pre-eclampsia, rather than as a trigger for offering an early birth. The committee concluded that, provided the tests are used alongside clinical judgement (see section 3.2) and are not used to decide on timing of birth (see section 3.14), it is appropriate to use the tests to help diagnose preterm pre-eclampsia. Therefore, it was appropriate to consider cost-effectiveness results from the DSU's model in which the tests were used to help rule in and rule out preterm pre‑eclampsia. ## The Elecsys and Triage tests used to rule out and rule in preterm pre-eclampsia are cost effective When used for rule in and rule out in the DSU's base-case analysis, testing using the Elecsys immunoassay sFlt‑1/PLGF ratio or Triage PLGF Test typically dominated standard assessment (that is, they led to lower costs and provided more QALYs). Tests were less cost effective when neonatal outcomes were removed from the model, but incremental cost‑effectiveness ratios (ICERs) only increased to above £20,000 per QALY gained when decisions about care based on test results were based on the PreOS trial (a multicentre, prospective, open-label, non‑interventional study in 150 women with suspected pre-eclampsia) and standard assessment was modelled based on the INSPIRE trial. The committee concluded that the Elecsys and Triage tests were cost effective, compared with standard assessment, when used to rule out and rule in preterm pre-eclampsia. ## The DELFIA Xpress PLGF 1-2-3 used to rule out and rule in preterm pre-eclampsia is cost effective Costs-effectiveness estimates for the DELFIA Xpress PLGF 1‑2‑3 used to rule in and rule out preterm pre-eclampsia, compared with standard assessment, from the DSU's model were similar to those for the Elecsys immunoassay sFlt‑1/PLGF ratio and Triage PLGF Test (see section 3.10). The committee recalled that the thresholds for this test were set based on giving the same accuracy as the Triage and Elecsys tests (see section 3.6). The DSU used data from the COMPARE study for the DELFIA Xpress PLGF 1‑2‑3 in its model. COMPARE was a secondary analysis of samples from 3 prospective cohort studies, including 396 women with suspected pre-eclampsia or babies suspected to be small for gestational age, before 35 weeks and between 35 and 36 weeks of pregnancy. The DSU noted that this study had no prespecified threshold, which was a concern. Comments received on the DSU report included reference to a recently published prospective study (Bremner et al. 2022) that provided further diagnostic accuracy evidence for the DELFIA Xpress PLGF 1‑2‑3 test using prespecified cut-offs. The committee was satisfied that there was enough data to show how well the test worked. It concluded that the DELFIA Xpress PLGF 1‑2‑3 was cost effective, compared with standard assessment, when used to rule out and rule in preterm pre-eclampsia. ## The DELFIA Xpress sFlt-1/PLGF 1-2-3 ratio is cost effective when used to rule out and rule in preterm pre-eclampsia The Bremner et al. (2022) study (see section 3.11) also provided accuracy estimates for the DELFIA Xpress sFlt‑1/PLGF ratio. Because this study had accuracy estimates from the DELFIA Xpress PLGF 1‑2‑3 alone from the same population, the DSU was able to include this test in its model. The results for this test, compared with standard assessment, were similar to the DELFIA Xpress PLGF 1‑2‑3 alone. When the DELFIA Xpress sFlt‑1/PLGF ratio and DELFIA Xpress PLGF 1‑2‑3 alone were compared with each other, rather than with standard assessment, the DELFIA Xpress sFlt‑1/PLGF ratio was in general dominated (that is, it had higher costs and produced fewer QALYs). But the committee noted that differences in costs and QALYs were small, and that there was uncertainty about their relative cost effectiveness. The committee also noted that the cost of doing the DELFIA Xpress sFlt‑1/PLGF ratio was higher than the DELFIA Xpress PLGF 1‑2‑3 alone, and questioned whether commissioners would want to use the more expensive test without evidence of benefit. Clinical experts said that there may be some additional benefit to including a measurement of sFlt‑1 because it may improve test performance. The committee concluded that the DELFIA Xpress sFlt‑1/PLGF 1‑2‑3 ratio was cost effective, compared with standard assessment, when used to rule out and rule in preterm pre‑eclampsia. It said that commissioners could make a decision to add the DELFIA Xpress sFlt‑1 assay to the DELFIA Xpress PLGF 1‑2‑3 assay, based on locally available costs. ## There is not enough data to recommend the BRAHMS Kryptor ratio test and it's not clear how the test is intended to be used For the BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio test, the DSU's initial modelling used accuracy estimates from the Simon et al. (2020) study. The committee noted that this study used a threshold of 38 for rule out that was not specified by the manufacturer (see section 3.6). This was also a case-control study that was not done in the UK and included participants from a high-risk population that were already known to have pre-eclampsia or fetal growth restriction, rather than a population with suspected preterm pre-eclampsia. The committee noted that for this reason, the EAG had excluded this study from its original report. The committee said that it had concerns about the size and case‑control design of the Simon et al. study. At consultation, a consultee noted that Andersen et al. (2021) gave further diagnostic accuracy evidence for the BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio test (see section 3.6). This retrospective study included 501 pregnant women with suspected pre-eclampsia. It calculated diagnostic accuracy for previously suggested threshold values of 33 and 85 and determined a further ratio of 66, which the authors described as optimal. They concluded that this single threshold could be used as a simpler alternative to dual thresholds. The committee noted that this was not a prespecified threshold. The DSU did a quality assessment of Anderson et al. using QUADAS‑2, and concluded that this could have biased the study results. The committee highlighted the importance of using separate populations to establish test thresholds and assess accuracy at a given threshold to obtain reliable estimates of performance. It noted that data was available for the DELFIA Xpress tests from studies with prespecified thresholds (see section 3.11 and section 3.12). The committee acknowledged the extra detail from the updated instructions for use for the BRAHMS ratio test but, as previously noted, this did not clear up the uncertainty about how the test should be interpreted (see section 3.6). The committee acknowledged the new evidence from Andersen et al. but concluded that there was still too much uncertainty about the diagnostic performance of the BRAHMS ratio test to recommend routine adoption. A study using a prespecified threshold, or thresholds, done in a population not used to derive these thresholds (external validation) was needed to demonstrate performance (see section 4.1). ## PLGF-based tests should not be used to make decisions about timing of birth in women with preterm pre-eclampsia The committee recalled that data from trials had reassured it that using the tests to help rule in preterm pre-eclampsia had not led to unnecessary early births. Clinical experts emphasised that if the tests were used more widely, it was important that they were not used to make decisions about timing of birth. The committee concluded that it was important to highlight this in the recommendations. # Research considerations ## Research is needed on test cut-offs for women pregnant with more than 1 baby The INSPIRE and PARROT studies only included women pregnant with 1 baby. Clinical experts said that PLGF or sFlt‑1 levels may differ in pregnancies with more than 1 baby because of increased placental mass. Therefore, specialists using the tests in this group would interpret the results with caution and potentially not use the specified cut-offs. They said that research is needed to find out if different cut-offs are needed. ## There is no international standard reference material for PLGF testing The committee noted that there is currently no international standard or reference method procedure for PLGF or sFlt‑1 testing. This is important for the external quality assurance of laboratories offering this testing, and the committee encouraged the development of such standards.# Recommendations for further research A high-quality test accuracy study is needed for the BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio test, using thresholds defined by the company, done in a population independent from that used to establish the test's thresholds, and with the test used as intended in the NHS. Further research is recommended on repeat PLGF (placental growth factor)‑based testing, with standard clinical assessment, in women presenting with suspected preterm pre-eclampsia, who have had a previous PLGF‑based test result (see section 3.7). This should include: exploring the different scenarios in which repeat testing may be indicated the appropriate intervals between PLGF‑based tests the diagnostic accuracy of repeat PLGF‑based testing in women with suspected preterm pre-eclampsia. Further research is recommended into how well the tests work when women are pregnant with more than 1 baby to find out if different cut-offs are needed (see section 3.15).	{'Recommendations': 'The following placental growth factor (PLGF)-based tests, used with standard clinical assessment, are recommended to help decide on care (to help rule in or rule out pre-eclampsia) for people with suspected preterm (between 20\xa0weeks and 36\xa0weeks and 6\xa0days of pregnancy) pre‑eclampsia:\n\nDELFIA Xpress PLGF 1‑2‑3\n\nDELFIA Xpress sFlt‑1/PLGF 1‑2‑3 ratio\n\nElecsys immunoassay sFlt‑1/PLGF ratio\n\nTriage PLGF Test.Not all manufacturers indicate their tests for use across the full range of 20\xa0weeks to 36\xa0weeks and 6\xa0days of pregnancy. The tests should be used according to their indications for use (see section\xa02).\n\nPLGF-based testing may particularly benefit groups at higher risk of severe adverse pregnancy outcomes, such as people from African, Caribbean and Asian family backgrounds.\n\nFurther research is recommended into how well the tests work when people are pregnant with more than 1\xa0baby (see section\xa04.3).\n\nDo not use PLGF-based tests to make decisions about whether to offer a planned early birth to people with preterm pre-eclampsia. The NICE guideline on hypertension in pregnancy has recommendations on timing of birth.\n\nUse a PLGF-based test once per episode of suspected preterm pre‑eclampsia. Further research is recommended on repeat testing (see section\xa04.2).\n\nBRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio is not recommended for routine use in the NHS. Further research is needed to show the accuracy of this test when using specified thresholds (see section\xa04.1).\n\nWhy the committee made these recommendations\n\nThe DELFIA Xpress PLGF 1‑2‑3 test was not previously recommended by NICE because there was not enough evidence on its accuracy. High-quality evidence now shows that this test, and the DELFIA Xpress sFlt‑1/PLGF 1‑2‑3 ratio assay, have good accuracy for preterm pre-eclampsia.\n\nNICE previously recommended the Elecsys immunoassay sFlt‑1/PLGF ratio and Triage PLGF Test to help rule out pre-eclampsia. But they were not recommended to help diagnose (rule in) pre-eclampsia because of concerns that this could result in people being unnecessarily offered early births. Data now shows that this is not the case.\n\nModelling shows that all these tests are cost effective compared with standard assessment when used to help diagnose (rule in) or exclude (rule out) preterm pre‑eclampsia. So these tests are recommended to help plan safe care and a safe birth for people with pre-eclampsia, and also to identify people unlikely to develop pre-eclampsia, and therefore reduce unnecessary hospitalisation. The tests may work differently in people who are pregnant with more than one baby. Therefore, NICE has recommended further research to find out how well the tests work in this group.\n\nThere is not enough evidence on whether or not the test should be repeated. Therefore, NICE has recommended testing just once when a person presents with possible symptoms of preterm pre-eclampsia (an episode) and recommended further research on if repeat testing improves outcomes.\n\nThere is new data for BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio, which was originally not recommended. But the data is lower quality than that for the other tests. Data on test sensitivity and specificity is from 2\xa0studies, 1 that was small and 1 that did not specify the test threshold to use in advance. There is not enough good-quality data to assess how well it works and its cost effectiveness. There is also uncertainty about how the company intends the test to be used. So this test is still not recommended.', 'The diagnostic tests': "# Clinical need and practice\n\nPre-eclampsia is a potentially serious complication of pregnancy, thought to be related to problems with the development of the placenta. It requires referral to a specialist and hospital admission to monitor the mother and unborn baby, and is only cured by the birth of the baby. Pre-eclampsia is characterised by high blood pressure (hypertension) and proteinuria, which is when the kidneys leak protein into the urine. Either, on its own indicates a risk of developing pre-eclampsia. Other symptoms include headache, visual disturbances, right upper quadrant abdominal (epigastric) pain, oedema (swelling of the hands, face or feet) and oliguria (low urine output).\n\nIf pre-eclampsia is not diagnosed and closely monitored, it can lead to potentially life-threatening complications including eclampsia, HELLP syndrome (haemolysis, elevated liver enzymes and low platelets), disseminated intravascular coagulation, stroke or organ dysfunction. Women who have hypertension or pre-eclampsia during pregnancy may have a higher risk of placental abruption. Gestational hypertension and pre-eclampsia may also affect the unborn baby by slowing growth or leading to premature birth.\n\nThis is a full update of NICE's diagnostics guidance on placental growth factor (PLGF)-based testing to help diagnose suspected pre-eclampsia (DG23), which was published in 2016. The original guidance recommended the Triage PLGF Test and the Elecsys immunoassay sFlt‑1/PLGF ratio, used with standard clinical assessment and subsequent clinical follow up, to help rule out pre-eclampsia. Further research was recommended on using these tests to rule in pre-eclampsia. The DELFIA Xpress PLGF 1‑2‑3 test and BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio were not recommended for routine adoption in the NHS.\n\n# The diagnostic and care pathway\n\n## Identifying and managing the risk of developing pre-eclampsia\n\nRecommendations on management of pre-eclampsia in NICE's guideline on antenatal care include measuring blood pressure and doing urinalysis for protein at each antenatal visit to check for pre-eclampsia. The guideline also recommends determining risk factors for pre-eclampsia at the booking appointment (by 10\xa0weeks of pregnancy). NICE's guideline on hypertension in pregnancy describes risk factors for pre‑eclampsia. It defines pre-eclampsia as new-onset hypertension (over 140\xa0mmHg systolic or over 90\xa0mmHg diastolic) after 20\xa0weeks of pregnancy plus 1 or more new-onset conditions. If a woman presents with some but not all of these criteria, they are considered to have suspected pre-eclampsia. If they are under 37\xa0weeks of pregnancy, this would be suspected preterm pre-eclampsia.\n\n## Managing pregnancy with gestational hypertension with or without pre-eclampsia\n\nNICE's guideline on hypertension in pregnancy includes recommendations on managing gestational hypertension and pre-eclampsia in pregnancy, including timing the birth in women with pre-eclampsia.\n\n# The interventions\n\n## Triage PLGF Test (Quidel)\n\nThe Triage PLGF Test can be used at the point of care and in the laboratory. The test is used with other clinical information to help diagnose preterm pre-eclampsia, and as an aid in the prognosis of birth, in women who are between 20\xa0weeks and 35\xa0weeks pregnant with signs and symptoms of pre-eclampsia. The Triage PLGF kit costs £1,000 (excluding VAT) and can do 25\xa0tests. The cost per test used in the economic model (incorporating additional cost components such as machine costs, reagents, service charges, training and staff costs) was £49.58.\n\nResult\n\nClassification\n\nInterpretation\n\nPlacental growth factor (PLGF) less than 12\xa0pg/ml\n\nTest positive – highly abnormal\n\nHighly abnormal and suggestive of patients with severe placental dysfunction and at increased risk of preterm birth\n\nPLGF between 12\xa0pg/ml and 99\xa0pg/ml\n\nTest positive – abnormal\n\nAbnormal and suggestive of patients with placental dysfunction and at increased risk of preterm birth\n\nPLGF 100\xa0pg/ml or more\n\nTest negative – normal\n\nNormal and suggestive of patients without placental dysfunction and unlikely to progress to birth within 14\xa0days of the test\n\n## Elecsys immunoassay sFlt‑1/PLGF ratio (Roche)\n\nThe Elecsys immunoassay sFlt‑1/PLGF ratio is formed by combining the results from 2\xa0electrochemiluminescence immunoassays (the Elecsys PLGF and Elecsys sFlt‑1 assays), which are compatible with the Roche Cobas\xa0e automated clinical chemistry analysers. The sFlt‑1/PLGF ratio is intended to help diagnose pre-eclampsia, together with other diagnostic and clinical information. The sFlt‑1/PLGF ratio is also intended to help predict pre-eclampsia in the short term (rule out and rule in) in pregnant women with suspected pre-eclampsia, together with other diagnostic and clinical information. The Elecsys sFlt‑1 reagent kit and the Elecsys PLGF reagent kit cost £3,310.78 each and can do 100\xa0tests. They are intended to be used together, with each sFlt‑1/PLGF ratio test costing £66.21 (excluding VAT). The cost per test used in the economic model (incorporating additional cost components such as machine costs, reagents, service charges, training and staff costs) was £79.23.\n\nIntended use\n\nStage of pregnancy\n\nDecision rule\n\nsFlt‑1/PLGF ratio\n\nTo help diagnose pre-eclampsia\n\nWeek\xa020 to week\xa033 plus 6\xa0days\n\nRule out cut-off\n\n\n\nTo help diagnose pre-eclampsia\n\nWeek\xa020 to week\xa033 plus 6\xa0days\n\nRule in cut-off\n\n\n\nTo help diagnose pre-eclampsia\n\nWeek\xa034 to birth\n\nRule out cut-off\n\n\n\nTo help diagnose pre-eclampsia\n\nWeek\xa034 to birth\n\nRule in cut-off\n\n\n\nShort-term prediction of pre-eclampsia\n\nWeek\xa024 to week\xa036 plus 6\xa0days\n\nRule out pre-eclampsia for 1\xa0week\n\nor less\n\nShort-term prediction of pre-eclampsia\n\nWeek\xa024 to week\xa036 plus 6\xa0days\n\nRule in pre-eclampsia within 4\xa0weeks\n\nOver 38\n\n## DELFIA Xpress PLGF 1-2-3 test and DELFIA Xpress sFlt-1 kit (PerkinElmer)\n\nThe DELFIA Xpress PLGF 1‑2‑3 can be used on its own or with the DELFIA Xpress sFlt‑1 kit. The tests are intended to help diagnose pre‑eclampsia and for short-term prediction of suspected pre-eclampsia together with other biochemical and clinical information.\n\nThe company specifies threshold values for the DELFIA Xpress PLGF 1‑2‑3 test when used alone (see table\xa03):\n\nIntended use\n\nStage of pregnancy\n\nDecision rule\n\nPLGF cut-off\n\nTo help diagnose pre-eclampsia\n\nWeek\xa020 to week\xa033 plus 6\xa0days\n\nWeek 34 or more\n\nRule in cut-off\n\nLess than 50\xa0pg/ml\n\nTo help diagnose pre-eclampsia\n\nWeek\xa020 to week\xa033 plus 6\xa0days\n\nWeek\xa034 or more\n\nRule out cut-off\n\npg/ml or more\n\nShort-term prediction of pre-eclampsia\n\nWeek\xa020 to week\xa041\n\nWeek\xa020 to week\xa033 plus 6\xa0days\n\nWeek\xa034 or more\n\nRule out pre-eclampsia within 1\xa0week\n\npg/ml or more\n\nShort-term prediction of pre-eclampsia\n\nWeek\xa020 to week\xa041\n\nWeek\xa020 to week\xa033 plus 6\xa0days\n\nWeek\xa034 or more\n\nRule out pre-eclampsia within 4\xa0weeks\n\npg/ml or more\n\nThe company specifies threshold values for DELFIA Xpress 1‑2‑3 used with the DELFIA Xpress sFlt‑1 (see table\xa04):\n\nIntended use\n\nStage of pregnancy\n\nDecision rule\n\nsFlt‑1/PLGF ratio\n\nTo help diagnose pre-eclampsia\n\nWeek\xa020 to week\xa033 plus 6\xa0days\n\nRule in cut-off\n\nor over\n\nTo help diagnose pre-eclampsia\n\nWeek\xa034 or more\n\nRule in cut-off\n\nor over\n\nShort-term prediction of pre-eclampsia\n\nWeek\xa020 to week\xa041\n\nWeek\xa020 to week\xa033 plus 6\xa0days\n\nWeek\xa034 or more\n\nRule out pre-eclampsia within 1\xa0week\n\nor less\n\nShort-term prediction of pre-eclampsia\n\nWeek\xa020 to week\xa041\n\nWeek\xa020 to week\xa033 plus 6\xa0days\n\nWeek\xa034 or more\n\nRule out pre-eclampsia within 4\xa0weeks\n\nor less\n\nThe DELFIA Xpress PLGF 1‑2‑3 kit costs £722 (excluding VAT) and the DELFIA Xpress sFlt‑1 kits costs £944 (excluding VAT). Each can do 96\xa0tests (that is 96\xa0PLGF tests alone or 96\xa0sFlt‑1/PLGF ratio tests). The cost per test used in the economic model (incorporating additional cost components such as machine costs, reagents, service charges, training and staff costs) was £37.41 for DELFIA Xpress PLGF 1‑2‑3 and £71.41 for the DELFIA Xpress sFlt‑1/PLGF ratio.\n\n## BRAHMS sFlt-1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio (ThermoFisher)\n\nThe BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio is formed by combining the results from the BRAHMS sFlt‑1 Kryptor and BRAHMS PLGF plus Kryptor assays. The assays are compatible with the BRAHMS Kryptor compact plus analyser and the Kryptor Gold immunoanalyser. The BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio is intended to be used to confirm or exclude a diagnosis of pre-eclampsia after 20\xa0weeks of pregnancy. The BRAHMS sFlt‑1 Kryptor and BRAHMS PLGF plus Kryptor kits cost £825 each and can do 75\xa0tests. The cost per test used in the economic model (incorporating additional cost components such as machine costs, reagents, service charges, training and staff costs) was £52.28.\n\nThe company says that a ratio of more than 85 suggests pre-eclampsia and a high-risk pregnancy. At consultation on the draft guidance, it said that updated instructions for use will be released later in 2022 (see section\xa03.6).\n\n# The comparator\n\nThe comparator is no further assessment beyond clinical assessments already done, such as blood pressure measurement, urinalysis and fetal monitoring, to help diagnose preterm pre-eclampsia and make decisions about care.", 'Committee discussion': "The diagnostics advisory committee considered evidence from several sources on the BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio, DELFIA Xpress PLGF 1‑2‑3 test, DELFIA Xpress sFlt‑1/PLGF ratio, Elecsys immunoassay sFlt‑1/PLGF ratio and Triage PLGF Test. Evidence was considered from the diagnostics assessment report and an overview of that report, and the decision support unit's (DSU) report and updated model. Full details of all the evidence are in the project documents for this guidance on the NICE website.\n\n# The condition\n\n## PLGF-based tests are likely to substantially benefit women with suspected preterm pre-eclampsia\n\nA patient expert explained that pregnancy can be a particularly worrying time for expectant mothers if they had preterm pre-eclampsia or complications from hypertension in a previous pregnancy. Placental growth factor (PLGF)-based testing can reassure pregnant women with hypertension who are anxious about complications and risks to the baby and themselves, and increase their confidence in treatment plans. A patient expert highlighted an Action on Pre-eclampsia report that stated that women from African, Asian or Caribbean family backgrounds have a higher risk of developing pre-eclampsia and that PLGF tests may particularly benefit higher risk groups. Clinical experts said that the tests can improve risk assessment and enable early planning for a safe birth. They said they may also help avoid stressful last-minute medical interventions. Early planning for at-risk pregnancies also means women at centres without facilities for preterm baby care can be safely transferred to a suitably equipped centre in good time. This improves the outcome for the baby and can avoid stressful situations, such as the mother and baby being cared for in different centres. Another benefit of the tests is better identification of women who will not develop preterm pre-eclampsia, reducing unnecessary hospitalisation. The committee considered that this was particularly relevant during the COVID‑19 pandemic to help reduce spread of the virus. Clinical experts also highlighted the benefits of using the tests for shared decision making, with test results helping discussions.\n\n# Clinical effectiveness\n\n## PLGF-based test results should be used alongside clinical information for decision making\n\nThe committee considered the PARROT and INSPIRE trials, which assessed PLGF-based tests as part of a clinical algorithm that included using the tests alongside clinical judgement to make decisions about care. The PARROT trial was a multicentre, pragmatic, stepped wedge cluster randomised controlled trial of 1,023\xa0women with suspected preterm pre‑eclampsia who were between 20\xa0weeks and 36\xa0weeks and 6\xa0days of pregnancy. It was done in 11\xa0maternity units in the UK and used the Triage PLGF Test. The INSPIRE trial was a prospective, interventional, parallel-group, randomised clinical trial of 370\xa0women with suspected pre‑eclampsia who were between 24\xa0weeks and 37\xa0weeks of pregnancy. It was based in a single UK tertiary referral hospital and used the Elecsys immunoassay sFlt1/PLGF ratio. Clinical experts said that the tests are not a substitute for clinical assessment. Instead PLGF-based testing gives the clinician more evidence to help them make an informed decision. Clinical experts also explained that a low PLGF test result does not always mean a woman has pre-eclampsia and can be associated with other conditions affecting the placenta. They did however highlight that PLGF-based test results can be very useful to help with clinical decision making, particularly for women who had hypertension or proteinuria before becoming pregnant. The committee concluded that PLGF-based test results should be used alongside clinical information for decision making.\n\n## PLGF-based testing did not lead to unnecessary early births in UK trials\n\nIn the original guidance (DG23) published in 2016, the committee was concerned that too much emphasis might be placed on PLGF test results indicating preterm pre-eclampsia, which could result in the unnecessary early birth of the baby. Since this guidance was published, the NICE guideline on hypertension in pregnancy has been updated to include recommendations on deciding the timing of birth in women with pre‑eclampsia. In the PARROT trial, the proportions of births before 37\xa0weeks in the test and control arms of the trial were similar. In the PARROT, PARROT Ireland (a multicentre, pragmatic, stepped wedge cluster randomised controlled trial done in 7\xa0maternity units throughout Ireland) and INSPIRE trials, weeks of pregnancy before birth were also similar in the test and control arms. Clinical experts said that this reflects current practice because the tests are used to help with decisions about hospitalisation and whether to transfer to a specialist unit, not to guide decisions about birth. They also pointed out that about half the centres that participated in the PARROT trial were not specialist centres, which reduced concern about how the tests would be used if they were adopted more widely. The committee concluded that there was evidence that use of the tests did not lead to unnecessary early births.\n\n## Maternal outcomes: evidence from trials suggests potential improvements with PLGF-based testing and better decisions about care\n\nThe PARROT trial data suggested that using a PLGF test improved maternal outcomes. In PARROT, the number of women with adverse outcomes, defined by the fullPIERS consensus, was lower in the revealed group (4%) than the concealed group (5%), and this difference was statistically significant. Incidence of placental abruption and severe pre‑eclampsia was also lower with test use in the INSPIRE trial but not statistically significantly so. The clinical experts explained that the INSPIRE trial was not powered to detect differences in the adverse maternal outcomes that it assessed. In the INSPIRE trial, the proportion of women who had confirmed pre-eclampsia within 7\xa0days of testing who were admitted to hospital was greater in the test use arm of the trial (100%) than the control arm (83%). At the second committee meeting, the committee considered the PARROT Ireland randomised controlled trial. It found that integrating PLGF testing into routine clinical investigations for women with suspected preterm pre-eclampsia had no significant effect on maternal morbidity. Clinical experts highlighted differences between the PARROT and PARROT Ireland study cohorts. PARROT Ireland had a higher proportion of women with suspected fetal growth restriction (55%) than PARROT (16%). Also, the incidence of pre-eclampsia in PARROT was higher (35%) than in PARROT Ireland (14%). They also noted that PARROT Ireland had only recruited just over half the proposed participants (2,313 out of a planned 4,000; or 58%) and may have been underpowered to detect significant differences. The committee concluded that there was some evidence that PLGF-based test use could improve management decisions and clinical outcomes for women with suspected preterm pre-eclampsia, although there was considerable uncertainty about this.\n\n## Neonatal outcomes: the effect of PLGF-based testing is uncertain but some evidence suggests it may improve decisions about care\n\nIncidence of perinatal and neonatal mortality and complications in the test and control arms of the PARROT trial were similar. Clinical experts explained that there was a very low number of these clinical events and that the trial was not powered to show differences. The committee considered that it was uncertain whether the differences were down to test use or chance. Clinical experts explained that intraventricular haemorrhage (IVH) and respiratory distress syndrome (RDS) can be devastating for babies and their families. But because they happen rarely, it is difficult to do trials to assess how tests affect them. A clinical expert said that, in a stratified analysis of the PARROT data, more women with a PLGF test result of less than 12\xa0pg/ml who delivered before 35\xa0weeks of pregnancy were given antenatal corticosteroids 7\xa0days before birth in the revealed group (39%) than the concealed group (16%). They explained that this meant the women who had the PLGF test had better clinical care because antenatal corticosteroids reduce the risk of RDS, IVH and death in preterm babies. A clinical expert also pointed out that the number of nights that babies spent in the intensive care or high-dependency unit was only 15.2\xa0nights in the test arm of PARROT, compared with 24.2\xa0nights in the control arm. The committee concluded that, because of the rarity of IVH, RDS and death, the effect of using PLGF-based tests on neonatal outcomes is uncertain. But it agreed there was some evidence that they influence management decisions that could improve care.\n\n## The DELFIA Xpress tests have established rule in and rule out thresholds, but the BRAHMS Kryptor test does not\n\nIn the original guidance, the committee did not recommend the DELFIA Xpress PLGF 1‑2‑3 test or BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio test for routine adoption in the NHS. It said that further research should be done by the companies to show their clinical effectiveness, including diagnostic accuracy and analytical validity. No new data was found for how these 2\xa0tests affect management decisions or clinical outcomes (such as maternal or neonatal outcomes). However, there was new evidence on test accuracy. Since the original guidance, rule in and rule out thresholds have been established for the DELFIA Xpress PLGF 1‑2‑3 test based on performance of the test compared with the Triage PLGF and Elecsys immunoassay sFlt‑1/PLGF ratio tests (McCarthy et al. 2018 and Giblin et al. 2020). A prospective study using these preset thresholds was also considered at the second committee meeting (Bremner et al. 2022). A quality assessment of this study indicated a low risk of bias and no applicability concerns. This study also provided accuracy estimates for the DELFIA Xpress sFlt‑1/PLGF 1‑2‑3 ratio assay, using specified thresholds. The external assessment group (EAG) identified 2\xa0studies that compared the BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio with the Elecsys test. One indicated highly correlated results (Salahuddin et al. 2016) but the authors of the other study (Cheng et al. 2019) indicated that results from the different manufacturers' immunoassays were significantly different, and that sFlt‑1/PLGF rule in and rule out criteria are manufacturer-specific, not interchangeable, and require separate clinical validation. At consultation on the draft guidance, the BRAHMS test manufacturer provided detail from updated instructions for use, which it plans to release in the second half of 2022. This included reference to thresholds for the BRAHMS ratio test of 85, which the company already said should be used to rule in pre‑eclampsia (see section\xa02.13), and 66, based on Andersen et al. (2021; see section\xa03.13). In the committee meeting, the company said that 66 should be used to rule out pre-eclampsia and 85 to rule it in. However, the committee noted that, although the instructions for use did refer to these 2\xa0thresholds, they did not say whether they should be used as single thresholds or together, or whether they should be used to rule in or rule out pre-eclampsia. Clinical experts said that this could lead to uncertainty in how to interpret test results. The committee concluded that, even based on the information from the updated instructions for use, it is not clear how to interpret the test result. It also noted that the test's accuracy using the threshold of 66 had not been validated in a population independent from the one used to set this threshold (see section\xa03.13). The committee further concluded that there was now some evidence on the accuracy of the DELFIA Xpress tests, which could address the request for further data in the original guidance.\n\n## Repeat PLGF-based testing evidence is still limited\n\nThe original guidance made a research recommendation on using repeat PLGF‑based testing. Not much more evidence was found for repeat PLGF testing for this assessment, but the clinical experts pointed out that ongoing work, for example the PARROT\xa02 trial, will provide further data in the future. The committee concluded that the research recommendation made in DG23 about repeat testing should be retained in this guidance (see section\xa04.2).\n\n# Cost effectiveness\n\n## The DSU model is suitable for decision making\n\nAt the first committee meeting, the committee was concerned about the EAG's model and approach to modelling. The standard assessment costs and quality-adjusted life years (QALYs) in the EAG's model were different for the Elecsys immunoassay sFlt‑1/PLGF ratio and the Triage PLGF Test. The EAG explained this was because it used data from the control arm of the INSPIRE trial for the Elecsys test and from the PARROT trial for the Triage PLGF Test. But clinical experts said that there were important differences between the 2\xa0trial populations, for example pre‑eclampsia incidence. The committee noted that using different populations to assess standard assessment for different tests made interpreting results more difficult, and could lead to a biased assessment. The level of pre-eclampsia in the test use and non-test use arms of the individual models was also different, particularly for the Elecsys model. This was because the EAG used unadjusted data from the trials, and the pre-eclampsia incidence was higher in the test use arm. A clinical expert said that this was caused by chance allocation to trial arms. There was also uncertainty about whether the populations modelled accurately represented women with suspected preterm pre-eclampsia who would have the PLGF-based tests in the NHS. The committee would have preferred the same model for standard assessment to be used for all tests, and for the model to be based on a population that accurately represents women with suspected preterm pre-eclampsia in the NHS. The committee concluded that more work on the model was needed to address these concerns before any recommendations could be made. As a result of these concerns, NICE commissioned the DSU to carry out further modelling work. For the second committee meeting, the DSU provided an updated model and analyses. The committee said that the DSU's model addressed its previous concerns and concluded that it was suitable for decision making.\n\n## It is appropriate to consider cost-effectiveness estimates of the tests when used to help rule out and rule in preterm pre-eclampsia\n\nThe DSU provided cost-effectiveness estimates when the PLGF-based tests were used to rule out preterm pre-eclampsia only, and when the tests were used to rule in and rule out preterm pre-eclampsia. The committee recalled that data from recent studies provided reassurance that using positive results from the tests to inform care did not lead to earlier births (see section\xa03.3). Clinical experts said that training and education on these tests focuses on using them to identify women who have a higher risk of developing preterm pre-eclampsia, rather than as a trigger for offering an early birth. The committee concluded that, provided the tests are used alongside clinical judgement (see section\xa03.2) and are not used to decide on timing of birth (see section\xa03.14), it is appropriate to use the tests to help diagnose preterm pre-eclampsia. Therefore, it was appropriate to consider cost-effectiveness results from the DSU's model in which the tests were used to help rule in and rule out preterm pre‑eclampsia.\n\n## The Elecsys and Triage tests used to rule out and rule in preterm pre-eclampsia are cost effective\n\nWhen used for rule in and rule out in the DSU's base-case analysis, testing using the Elecsys immunoassay sFlt‑1/PLGF ratio or Triage PLGF Test typically dominated standard assessment (that is, they led to lower costs and provided more QALYs). Tests were less cost effective when neonatal outcomes were removed from the model, but incremental cost‑effectiveness ratios (ICERs) only increased to above £20,000 per QALY gained when decisions about care based on test results were based on the PreOS trial (a multicentre, prospective, open-label, non‑interventional study in 150\xa0women with suspected pre-eclampsia) and standard assessment was modelled based on the INSPIRE trial. The committee concluded that the Elecsys and Triage tests were cost effective, compared with standard assessment, when used to rule out and rule in preterm pre-eclampsia.\n\n## The DELFIA Xpress PLGF 1-2-3 used to rule out and rule in preterm pre-eclampsia is cost effective\n\nCosts-effectiveness estimates for the DELFIA Xpress PLGF 1‑2‑3 used to rule in and rule out preterm pre-eclampsia, compared with standard assessment, from the DSU's model were similar to those for the Elecsys immunoassay sFlt‑1/PLGF ratio and Triage PLGF Test (see section\xa03.10). The committee recalled that the thresholds for this test were set based on giving the same accuracy as the Triage and Elecsys tests (see section\xa03.6). The DSU used data from the COMPARE study for the DELFIA Xpress PLGF 1‑2‑3 in its model. COMPARE was a secondary analysis of samples from 3\xa0prospective cohort studies, including 396\xa0women with suspected pre-eclampsia or babies suspected to be small for gestational age, before 35\xa0weeks and between 35\xa0and 36\xa0weeks of pregnancy. The DSU noted that this study had no prespecified threshold, which was a concern. Comments received on the DSU report included reference to a recently published prospective study (Bremner et al. 2022) that provided further diagnostic accuracy evidence for the DELFIA Xpress PLGF 1‑2‑3 test using prespecified cut-offs. The committee was satisfied that there was enough data to show how well the test worked. It concluded that the DELFIA Xpress PLGF 1‑2‑3 was cost effective, compared with standard assessment, when used to rule out and rule in preterm pre-eclampsia.\n\n## The DELFIA Xpress sFlt-1/PLGF 1-2-3 ratio is cost effective when used to rule out and rule in preterm pre-eclampsia\n\nThe Bremner et al. (2022) study (see section\xa03.11) also provided accuracy estimates for the DELFIA Xpress sFlt‑1/PLGF ratio. Because this study had accuracy estimates from the DELFIA Xpress PLGF 1‑2‑3 alone from the same population, the DSU was able to include this test in its model. The results for this test, compared with standard assessment, were similar to the DELFIA Xpress PLGF 1‑2‑3 alone. When the DELFIA Xpress sFlt‑1/PLGF ratio and DELFIA Xpress PLGF 1‑2‑3 alone were compared with each other, rather than with standard assessment, the DELFIA Xpress sFlt‑1/PLGF ratio was in general dominated (that is, it had higher costs and produced fewer QALYs). But the committee noted that differences in costs and QALYs were small, and that there was uncertainty about their relative cost effectiveness. The committee also noted that the cost of doing the DELFIA Xpress sFlt‑1/PLGF ratio was higher than the DELFIA Xpress PLGF 1‑2‑3 alone, and questioned whether commissioners would want to use the more expensive test without evidence of benefit. Clinical experts said that there may be some additional benefit to including a measurement of sFlt‑1 because it may improve test performance. The committee concluded that the DELFIA Xpress sFlt‑1/PLGF 1‑2‑3 ratio was cost effective, compared with standard assessment, when used to rule out and rule in preterm pre‑eclampsia. It said that commissioners could make a decision to add the DELFIA Xpress sFlt‑1 assay to the DELFIA Xpress PLGF 1‑2‑3 assay, based on locally available costs.\n\n## There is not enough data to recommend the BRAHMS Kryptor ratio test and it's not clear how the test is intended to be used\n\nFor the BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio test, the DSU's initial modelling used accuracy estimates from the Simon et al. (2020) study. The committee noted that this study used a threshold of 38 for rule out that was not specified by the manufacturer (see section\xa03.6). This was also a case-control study that was not done in the UK and included participants from a high-risk population that were already known to have pre-eclampsia or fetal growth restriction, rather than a population with suspected preterm pre-eclampsia. The committee noted that for this reason, the EAG had excluded this study from its original report. The committee said that it had concerns about the size and case‑control design of the Simon et al. study. At consultation, a consultee noted that Andersen et al. (2021) gave further diagnostic accuracy evidence for the BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio test (see section\xa03.6). This retrospective study included 501\xa0pregnant women with suspected pre-eclampsia. It calculated diagnostic accuracy for previously suggested threshold values of 33 and 85 and determined a further ratio of 66, which the authors described as optimal. They concluded that this single threshold could be used as a simpler alternative to dual thresholds. The committee noted that this was not a prespecified threshold. The DSU did a quality assessment of Anderson et al. using QUADAS‑2, and concluded that this could have biased the study results. The committee highlighted the importance of using separate populations to establish test thresholds and assess accuracy at a given threshold to obtain reliable estimates of performance. It noted that data was available for the DELFIA Xpress tests from studies with prespecified thresholds (see section\xa03.11 and section\xa03.12). The committee acknowledged the extra detail from the updated instructions for use for the BRAHMS ratio test but, as previously noted, this did not clear up the uncertainty about how the test should be interpreted (see section\xa03.6). The committee acknowledged the new evidence from Andersen et al. but concluded that there was still too much uncertainty about the diagnostic performance of the BRAHMS ratio test to recommend routine adoption. A study using a prespecified threshold, or thresholds, done in a population not used to derive these thresholds (external validation) was needed to demonstrate performance (see section\xa04.1).\n\n## PLGF-based tests should not be used to make decisions about timing of birth in women with preterm pre-eclampsia\n\nThe committee recalled that data from trials had reassured it that using the tests to help rule in preterm pre-eclampsia had not led to unnecessary early births. Clinical experts emphasised that if the tests were used more widely, it was important that they were not used to make decisions about timing of birth. The committee concluded that it was important to highlight this in the recommendations.\n\n# Research considerations\n\n## Research is needed on test cut-offs for women pregnant with more than 1\xa0baby\n\nThe INSPIRE and PARROT studies only included women pregnant with 1\xa0baby. Clinical experts said that PLGF or sFlt‑1 levels may differ in pregnancies with more than 1\xa0baby because of increased placental mass. Therefore, specialists using the tests in this group would interpret the results with caution and potentially not use the specified cut-offs. They said that research is needed to find out if different cut-offs are needed.\n\n## There is no international standard reference material for PLGF testing\n\nThe committee noted that there is currently no international standard or reference method procedure for PLGF or sFlt‑1 testing. This is important for the external quality assurance of laboratories offering this testing, and the committee encouraged the development of such standards.", 'Recommendations for further research': "A high-quality test accuracy study is needed for the BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio test, using thresholds defined by the company, done in a population independent from that used to establish the test's thresholds, and with the test used as intended in the NHS.\n\nFurther research is recommended on repeat PLGF (placental growth factor)‑based testing, with standard clinical assessment, in women presenting with suspected preterm pre-eclampsia, who have had a previous PLGF‑based test result (see section\xa03.7). This should include:\n\nexploring the different scenarios in which repeat testing may be indicated\n\nthe appropriate intervals between PLGF‑based tests\n\nthe diagnostic accuracy of repeat PLGF‑based testing in women with suspected preterm pre-eclampsia.\n\nFurther research is recommended into how well the tests work when women are pregnant with more than 1\xa0baby to find out if different cut-offs are needed (see section\xa03.15)."}	https://www.nice.org.uk/guidance/dg49	Evidence-based recommendations on placental growth factor (PLGF)-based testing to help diagnose suspected preterm pre-eclampsia. The tests are: DELFIA Xpress PLGF 1‑2‑3, DELFIA Xpress sFlt‑1/PLGF 1‑2‑3 ratio, Elecsys immunoassay sFlt‑1/PLGF ratio, Triage PLGF Test.
4cf6bc9ebfd17097a5d4a9314b1e41a03c121eb5	nice	Transcatheter tricuspid valve annuloplasty for tricuspid regurgitation	Transcatheter tricuspid valve annuloplasty for tricuspid regurgitation Evidence-based recommendations on transcatheter tricuspid valve annuloplasty for tricuspid regurgitation in adults. This involves putting a device on the heart valve to help it close. # Recommendations For people with severe and symptomatic tricuspid regurgitation, evidence on the efficacy of transcatheter tricuspid valve annuloplasty is limited in quantity and quality. Evidence on its safety shows there are serious but well-recognised complications. Therefore, for these people, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. For people with mild or moderate tricuspid regurgitation, evidence on the safety and efficacy of transcatheter tricuspid valve annuloplasty is inadequate in quantity and quality. Therefore, for these people, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. Clinicians wanting to do transcatheter tricuspid valve annuloplasty for people with severe and symptomatic tricuspid regurgitation should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Ensure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. The procedure should only be done in specialised centres with experience of the interventional management of tricuspid regurgitation. There should be immediate, onsite access to cardiac and vascular surgery. Further research should include details of patient selection, including the type and severity of tricuspid regurgitation.# The condition, current treatments and procedure # The condition Tricuspid regurgitation is when blood flows backwards through the tricuspid valve because it does not close properly during systole. It can be caused by a problem with the valve itself (primary). But it is more commonly secondary to an underlying cardiac problem that has caused the heart to become dilated. People with mild tricuspid regurgitation do not usually have any symptoms. If the regurgitation is severe people may have fatigue and weakness, active pulsing in the neck veins, liver enlargement, ascites, peripheral oedema and renal impairment. Pulmonary hypertension may develop. # Current treatments Treatment may not be needed if there are no or mild symptoms. There are no specific medicines for treating tricuspid regurgitation itself, but symptoms of heart failure are managed with diuretics and other medicines. Medication to reduce pulmonary artery pressure or pulmonary vascular resistance, or both, is used for severe functional tricuspid regurgitation and severe pulmonary hypertension. People with severe symptoms may have surgery to repair or replace the tricuspid valve. Isolated tricuspid valve surgery is rarely done because it is associated with high morbidity and mortality. More commonly, it is done at the same time as surgery to the valves on the left side of the heart (mitral and aortic). # The procedure Transcatheter tricuspid valve annuloplasty is designed to improve the function of the tricuspid valve with less morbidity and mortality than conventional surgical annuloplasty. It has been proposed as an option for people in whom conventional open surgery poses a high risk. The procedure aims to reduce regurgitation, increase quality of life, reduce hospital admissions related to heart failure and improve survival. The procedure is done under general anaesthesia using transoesophageal echocardiography and fluoroscopy guidance. Access to the heart is through the femoral or jugular vein. Different systems have been used and details of the technique vary. In one example, an annuloplasty ring or band is delivered through a catheter and implanted around the circumference, or annulus, of the tricuspid valve. A size adjustment tool is used to contract the device, which reduces the tricuspid annular diameter and brings the valve leaflets together. When the appropriate amount of reduction has been achieved, the implant is detached from the delivery system, which is then removed. In other systems, sutures are used to either exclude the posterior leaflet and create a functional bicuspid valve or to reduce the area of the tricuspid annulus. Adequate reduction of tricuspid regurgitation is assessed using echocardiography.	{'Recommendations': "For people with severe and symptomatic tricuspid regurgitation, evidence on the efficacy of transcatheter tricuspid valve annuloplasty is limited in quantity and quality. Evidence on its safety shows there are serious but well-recognised complications. Therefore, for these people, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nFor people with mild or moderate tricuspid regurgitation, evidence on the safety and efficacy of transcatheter tricuspid valve annuloplasty is inadequate in quantity and quality. Therefore, for these people, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nClinicians wanting to do transcatheter tricuspid valve annuloplasty for people with severe and symptomatic tricuspid regurgitation should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nThe procedure should only be done in specialised centres with experience of the interventional management of tricuspid regurgitation. There should be immediate, onsite access to cardiac and vascular surgery.\n\nFurther research should include details of patient selection, including the type and severity of tricuspid regurgitation.", 'The condition, current treatments and procedure': '# The condition\n\nTricuspid regurgitation is when blood flows backwards through the tricuspid valve because it does not close properly during systole. It can be caused by a problem with the valve itself (primary). But it is more commonly secondary to an underlying cardiac problem that has caused the heart to become dilated.\n\nPeople with mild tricuspid regurgitation do not usually have any symptoms. If the regurgitation is severe people may have fatigue and weakness, active pulsing in the neck veins, liver enlargement, ascites, peripheral oedema and renal impairment. Pulmonary hypertension may develop.\n\n# Current treatments\n\nTreatment may not be needed if there are no or mild symptoms. There are no specific medicines for treating tricuspid regurgitation itself, but symptoms of heart failure are managed with diuretics and other medicines. Medication to reduce pulmonary artery pressure or pulmonary vascular resistance, or both, is used for severe functional tricuspid regurgitation and severe pulmonary hypertension.\n\nPeople with severe symptoms may have surgery to repair or replace the tricuspid valve. Isolated tricuspid valve surgery is rarely done because it is associated with high morbidity and mortality. More commonly, it is done at the same time as surgery to the valves on the left side of the heart (mitral and aortic).\n\n# The procedure\n\nTranscatheter tricuspid valve annuloplasty is designed to improve the function of the tricuspid valve with less morbidity and mortality than conventional surgical annuloplasty. It has been proposed as an option for people in whom conventional open surgery poses a high risk. The procedure aims to reduce regurgitation, increase quality of life, reduce hospital admissions related to heart failure and improve survival.\n\nThe procedure is done under general anaesthesia using transoesophageal echocardiography and fluoroscopy guidance. Access to the heart is through the femoral or jugular vein.\n\nDifferent systems have been used and details of the technique vary. In one example, an annuloplasty ring or band is delivered through a catheter and implanted around the circumference, or annulus, of the tricuspid valve. A size adjustment tool is used to contract the device, which reduces the tricuspid annular diameter and brings the valve leaflets together. When the appropriate amount of reduction has been achieved, the implant is detached from the delivery system, which is then removed. In other systems, sutures are used to either exclude the posterior leaflet and create a functional bicuspid valve or to reduce the area of the tricuspid annulus. Adequate reduction of tricuspid regurgitation is assessed using echocardiography.'}	https://www.nice.org.uk/guidance/ipg730	Evidence-based recommendations on transcatheter tricuspid valve annuloplasty for tricuspid regurgitation in adults. This involves putting a device on the heart valve to help it close.
96cac9ede4d5aca1dceedde4b0ae818cedeb3062	nice	Transcatheter tricuspid valve leaflet repair for tricuspid regurgitation	Transcatheter tricuspid valve leaflet repair for tricuspid regurgitation Evidence-based recommendations on transcatheter tricuspid valve leaflet repair for tricuspid regurgitation in adults. This involves putting a device on the heart valve to help it close. # Recommendations For people with severe and symptomatic tricuspid regurgitation, evidence on the efficacy of transcatheter tricuspid valve leaflet repair is limited in quantity and quality. Evidence on its safety shows there are serious but well-recognised complications. Therefore, for these people, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. For people with mild or moderate tricuspid regurgitation, evidence on the safety and efficacy of transcatheter tricuspid valve leaflet repair is inadequate in quantity and quality. Therefore, for these people, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. Clinicians wanting to do transcatheter tricuspid valve leaflet repair for people with severe and symptomatic tricuspid regurgitation should: Inform the clinical governance leads in their healthcare organisation. Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure. Regularly review data on outcomes and safety for this procedure. The procedure should only be done in specialised centres with experience of the interventional management of tricuspid regurgitation. There should be immediate, onsite access to cardiac and vascular surgery. Further research should include details of patient selection, including the type and severity of tricuspid regurgitation.# The condition, current treatments and procedure # The condition Tricuspid regurgitation is when blood flows backwards through the tricuspid valve because it does not close properly during systole. It can be caused by a problem with the valve itself (primary). But it is more commonly secondary to an underlying cardiac problem that has caused the heart to become dilated. People with mild tricuspid regurgitation do not usually have any symptoms. If the regurgitation is severe people may have fatigue and weakness, active pulsing in the neck veins, liver enlargement, ascites, peripheral oedema and renal impairment. Pulmonary hypertension may develop. # Current treatments Treatment may not be needed if there are no or mild symptoms. There are no specific medicines for treating tricuspid regurgitation itself, but symptoms of heart failure are managed with diuretics and other medicines. Medication to reduce pulmonary artery pressure or pulmonary vascular resistance, or both, are used when there is severe functional tricuspid regurgitation and severe pulmonary hypertension. People with severe symptoms may have surgery to repair or replace the tricuspid valve. Isolated tricuspid valve surgery is rarely done because it is associated with high morbidity and mortality. More commonly, it is done at the same time as surgery to the valves on the left side of the heart (mitral and aortic). # The procedure Transcatheter tricuspid valve leaflet repair for tricuspid regurgitation is designed to improve the function of the tricuspid valve with less morbidity and mortality than conventional surgical valve repair. It has been proposed as an option for people in whom conventional open surgery poses a high risk. The procedure aims to reduce regurgitation, increase quality of life, reduce hospital admissions related to heart failure and improve survival. The procedure is done under general anaesthesia using transoesophageal echocardiography and fluoroscopy guidance. Access to the heart is through the femoral or jugular vein. Different systems have been used and details of the technique vary. A delivery system is used to introduce a device into the heart that can grip the leaflets of the tricuspid valve and bring them closer together. The device is then released from the delivery system. Adequate reduction of tricuspid regurgitation is assessed using echocardiography.	{'Recommendations': "For people with severe and symptomatic tricuspid regurgitation, evidence on the efficacy of transcatheter tricuspid valve leaflet repair is limited in quantity and quality. Evidence on its safety shows there are serious but well-recognised complications. Therefore, for these people, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nFor people with mild or moderate tricuspid regurgitation, evidence on the safety and efficacy of transcatheter tricuspid valve leaflet repair is inadequate in quantity and quality. Therefore, for these people, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nClinicians wanting to do transcatheter tricuspid valve leaflet repair for people with severe and symptomatic tricuspid regurgitation should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nThe procedure should only be done in specialised centres with experience of the interventional management of tricuspid regurgitation. There should be immediate, onsite access to cardiac and vascular surgery.\n\nFurther research should include details of patient selection, including the type and severity of tricuspid regurgitation.", 'The condition, current treatments and procedure': '# The condition\n\nTricuspid regurgitation is when blood flows backwards through the tricuspid valve because it does not close properly during systole. It can be caused by a problem with the valve itself (primary). But it is more commonly secondary to an underlying cardiac problem that has caused the heart to become dilated.\n\nPeople with mild tricuspid regurgitation do not usually have any symptoms. If the regurgitation is severe people may have fatigue and weakness, active pulsing in the neck veins, liver enlargement, ascites, peripheral oedema and renal impairment. Pulmonary hypertension may develop.\n\n# Current treatments\n\nTreatment may not be needed if there are no or mild symptoms. There are no specific medicines for treating tricuspid regurgitation itself, but symptoms of heart failure are managed with diuretics and other medicines. Medication to reduce pulmonary artery pressure or pulmonary vascular resistance, or both, are used when there is severe functional tricuspid regurgitation and severe pulmonary hypertension.\n\nPeople with severe symptoms may have surgery to repair or replace the tricuspid valve. Isolated tricuspid valve surgery is rarely done because it is associated with high morbidity and mortality. More commonly, it is done at the same time as surgery to the valves on the left side of the heart (mitral and aortic).\n\n# The procedure\n\nTranscatheter tricuspid valve leaflet repair for tricuspid regurgitation is designed to improve the function of the tricuspid valve with less morbidity and mortality than conventional surgical valve repair. It has been proposed as an option for people in whom conventional open surgery poses a high risk. The procedure aims to reduce regurgitation, increase quality of life, reduce hospital admissions related to heart failure and improve survival.\n\nThe procedure is done under general anaesthesia using transoesophageal echocardiography and fluoroscopy guidance. Access to the heart is through the femoral or jugular vein.\n\nDifferent systems have been used and details of the technique vary. A delivery system is used to introduce a device into the heart that can grip the leaflets of the tricuspid valve and bring them closer together. The device is then released from the delivery system. Adequate reduction of tricuspid regurgitation is assessed using echocardiography.'}	https://www.nice.org.uk/guidance/ipg731	Evidence-based recommendations on transcatheter tricuspid valve leaflet repair for tricuspid regurgitation in adults. This involves putting a device on the heart valve to help it close.
ca6db3aefc98be1106ee9ff774f8da31ca681a3c	nice	Melanoma: assessment and management	Melanoma: assessment and management This guideline covers the assessment and management of melanoma (a type of skin cancer) in children, young people and adults. It aims to reduce variation in practice and improve survival. # Stages of melanoma The stages of melanoma referred to in this guideline are based on the 8th editions of the Union for International Cancer Control (UICC) tumour node metastasis (TNM) classification of malignant tumours and the American Joint Committee on Cancer (AJCC) melanoma staging system.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Communication and support Give people with melanoma accurate and easy to understand information (both written and spoken) in a sensitive and timely manner throughout their care, tailored to their needs and circumstances. Topics to discuss include: melanoma and different types of skin cancer treatment options, including the risks and benefits where the person's appointments will take place which healthcare professionals will undertake the person's care and how to get in touch with them expected waiting times for consultations, investigations and treatments follow-up after treatment (see the section on follow-up after treatment for melanoma) preventing recurrence, and how to protect their skin from damage caused by exposure to the sun, while avoiding vitamin D depletion recognising signs and symptoms of suspicious skin lesions what to do if they have any concerns and how to re-access services local services and how to get in touch with them.For more guidance on giving information to people and discussing their preferences, follow the recommendations on communication and patient centred care in NICE's guidelines on patient experience in adult NHS services and shared decision making. Discuss the psychological and emotional impact of melanoma with the person, ask whether they have any psychological or support care needs, and offer to carry out a holistic needs assessment. Topics to discuss include: their understanding of melanoma and its prognosis their specific concerns and preferences important values or personal goals for care and treatment risk of recurrence, metastatic spread or new primary cancers whether family members are at risk. Explain to people with melanoma that they are welcome to bring a companion with them to appointments. Ensure that each local skin cancer multidisciplinary team and specialist skin cancer multidisciplinary team has: at least 1 skin cancer clinical nurse specialist to provide people with information and support access to psychological support services for people with melanoma. Ensure that healthcare professionals can support people with melanoma by attending training and being competent in: communicating complex and sensitive information clearly tailoring information and support to the person's individual needs and circumstances. # Managing vitamin D levels and concurrent drug treatment Measure vitamin D levels at diagnosis in secondary care in all people with melanoma. Give people whose vitamin D levels are thought to be suboptimal advice on vitamin D supplementation and monitoring in line with local policies and NICE's guideline on vitamin D. Do not withhold or change drug treatment for other conditions, except immunosuppressants and immunomodulators, on the basis of a diagnosis of melanoma. For people on immunosuppressive or immunomodulatory treatments, seek advice from the person's specialist team, aiming to optimise quality of life while minimising the person's risk. # Assessing melanoma ## Dermoscopy and other visualisation techniques Assess all pigmented skin lesions that are either referred for assessment or identified during follow-up in secondary or tertiary care, using dermoscopy carried out by healthcare professionals trained in this technique. Do not routinely use confocal microscopy or computer assisted diagnostic tools to assess pigmented skin lesions. ## Photography For a clinically atypical melanocytic lesion that does not need excision at first presentation in secondary or tertiary care: use baseline photography (preferably dermoscopic) and review the clinical appearance of the lesion, and compare it with the baseline photographic images, 3 months after first presentation to identify early signs of melanoma. ## Assessing and managing atypical Spitzoid lesions Discuss all suspected atypical Spitzoid lesions at the specialist skin cancer multidisciplinary team meeting. Make the diagnosis of a Spitzoid lesion of uncertain malignant potential on the basis of the histology, clinical features and behaviour. Manage a Spitzoid lesion of uncertain malignant potential as melanoma. ## Taking tumour samples for genetic testing If targeted systemic therapy is a treatment option, offer genetic testing using: a secondary melanoma tissue sample if there is adequate cellularity or a primary melanoma tissue sample if a secondary sample is not available or is of inadequate cellularity. ## BRAF analysis of primary melanoma tissue samples Do not offer BRAF analysis of melanoma tissue samples from people with stage IA or IB primary melanoma at presentation except as part of a clinical trial. Consider BRAF analysis of melanoma tissue samples from people with stage IIA or IIB primary melanoma. Carry out BRAF analysis of melanoma tissue samples from people with stage IIC to IV primary melanoma. Local skin multidisciplinary teams should arrange BRAF analysis of melanoma tissue samples and state the preferred tissue block for analysis. When doing BRAF analysis, consider immunohistochemistry as the first test for BRAF V600E, if available. If BRAF V600E immunohistochemistry is negative or inconclusive, use a different BRAF genetic test. Offer BRAF analysis of melanoma tissue samples to people with melanoma if they are potential candidates for any ongoing clinical trials that require knowledge of genetic status. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on BRAF analysis of melanoma tissue samples . Full details of the evidence and the committee's discussion are in evidence review A: genetic testing for melanoma. Loading. Please wait. # Staging with sentinel lymph node biopsy Do not offer imaging or sentinel lymph node biopsy (SLNB) to people who have stage IA melanoma. Do not offer imaging before SLNB unless lymph node or distant metastases are suspected. Consider SLNB for people who have melanoma with a Breslow thickness of 0.8 mm to 1.0 mm and at least one of the following features: ulceration lymphovascular invasion a mitotic index of 2 or more. Consider SLNB for people who have melanoma with a Breslow thickness greater than 1.0 mm. For women who are pregnant, discuss the option of delaying SLNB until after the pregnancy is completed. Consider staging with whole-body and brain contrast-enhanced (CE)-CT for people with stage IIB melanoma. Offer staging with whole-body and brain CE-CT to people with stage IIC to IV melanoma. Consider staging with brain MRI, instead of brain CE-CT, if locally available and after discussion and agreement with the specialist skin cancer multidisciplinary team. Offer staging with whole body and brain MRI, instead of CE-CT, to: children and young adults (from birth to 24 years) with stage IIB to IV melanoma women with stage IIB to IV melanoma who are pregnant. Consider staging with brain MRI, instead of brain CE-CT, for people with stage IIIC to IV melanoma and one of the following risk factors: a mitotic index of 5 or more primary melanoma located on the scalp. Consider a repeat staging scan before starting adjuvant treatment, unless imaging done within the past 8 weeks is available. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on staging with sentinel lymph node biopsy and imaging . Full details of the evidence and the committee's discussion are in evidence review B: use of sentinel lymph node biopsy in people with melanoma. Loading. Please wait. # Managing stages 0 to II melanoma ## Excision for stages 0 to II melanoma Consider a clinical margin of at least 0.5 cm when excising stage 0 melanoma. If excision for stage 0 melanoma does not achieve an adequate histological margin, discuss further management with the specialist skin cancer multidisciplinary team. Use a clinical margin of: cm when excising stage I melanoma or when a 2 cm excision margin would cause unacceptable disfigurement or morbidity cm when excising stage II melanoma.The clinical margin should be around the histological biopsy scar and take into account the primary melanoma margin. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on excision for stages 0 to II melanoma . Full details of the evidence and the committee's discussion are in evidence review C: surgical and histopathological excision margins for people with stage 0 to II melanoma. Loading. Please wait. ## Imiquimod for stage 0 melanoma Consider topical imiquimod to treat stage 0 melanoma in adults if surgery to remove the entire lesion with a 0.5 cm clinical margin would lead to unacceptable disfigurement or morbidity. Consider a repeat skin biopsy for histopathological assessment after treatment with topical imiquimod for stage 0 melanoma, to check whether it has been effective. In July 2022, this was an off-label use of topical imiquimod in adults and imiquimod was not licensed for use in the UK in children and young people under 18. See NICE's information on prescribing medicines. # Managing stage III melanoma ## Completion lymph node dissection for stage III melanoma Do not routinely offer completion lymph node dissection to people with stage III melanoma and micrometastatic nodal disease detected by SLNB unless: there are factors that might make recurrent nodal disease difficult to manage, and after discussion with the person and the specialist skin cancer multidisciplinary team.Examples of factors that might make recurrent nodal disease difficult to manage include melanoma of the head and neck, people for whom stage III adjuvant therapies are contraindicated, or when regular follow‑up is not possible. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on managing stage III melanoma . Full details of the evidence and the committee's discussion are in: evidence review D: completion lymphadenectomy for micrometastatic nodal disease in stage III melanoma evidence review E: use of sentinel lymph node biopsy for people with stage III melanoma with microsatellite lesions. Loading. Please wait. ## Therapeutic lymph node dissection for stage III melanoma Offer therapeutic lymph node dissection to people with palpable stage IIIB to IIID melanoma, or cytologically or histologically confirmed nodal disease detected by imaging. ## Adjuvant treatments for resected stage III melanoma For guidance on specific treatments, see NICE's technology appraisal guidance on dabrafenib with trametinib for adjuvant treatment of resected BRAF V600 mutation-positive melanoma, pembrolizumab for adjuvant treatment of completely resected stage 3 melanoma and nivolumab for adjuvant treatment of completely resected melanoma with lymph node involvement or metastatic disease. Do not offer adjuvant radiotherapy to people with stage IIIA melanoma. Do not offer adjuvant radiotherapy to people with resected stage IIIB to IIID melanoma unless a reduction in the risk of local recurrence is estimated to outweigh the risk of significant adverse effects. ## Non-curative treatment for superficial skin metastases in stage III melanoma Consider topical imiquimod to palliate superficial melanoma skin metastases. In July 2022, this was an off-label use of topical imiquimod in adults and imiquimod was not licensed for use in the UK in children and young people under 18. See NICE's information on prescribing medicines. ## Genomic biomarker-based treatment for stage III melanoma The point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See NICE's topic page on genomic biomarker-based cancer treatments for guidance on specific treatments. # Treating in-transit metastases in stages III and IV melanoma Discuss management of in-transit metastases, including surgery or treatment in a regional specialist centre, with the specialist skin cancer multidisciplinary team. Offer surgery as the first option and if surgery is not feasible, or if the person has recurrent in-transit metastases, consider one of the following options based on their suitability for the person: systemic anticancer therapy (see recommendations 1.8.6 to 1.8.15 on systemic anticancer treatments for untreated stage IV and unresectable stage III melanoma) talimogene laherparepvec, in line with NICE's technology appraisal guidance on talimogene laherparepvec isolated limb infusion or perfusion radiotherapy electrochemotherapy, in line with NICE's interventional procedures guidance on electrochemotherapy for metastases in the skin from tumours of non-skin origin and melanoma a topical agent such as imiquimod. In July 2022, most of the therapies recommended in this guideline were not licensed for use in the UK in children and young people under 18. See NICE's information on prescribing medicines. Refer to the summary of product characteristics for the individual treatments because there are differences in their licensed populations. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treating in-transit metastases in stages III and IV melanoma . Full details of the evidence and the committee's discussion are in evidence review F: systematic and localised anticancer treatment for people with stage IV and unresectable stage III melanoma. Loading. Please wait. # Managing stage IV and unresectable stage III melanoma ## Management of oligometastatic stage IV melanoma Refer the care of people who appear to have oligometastatic melanoma to the specialist skin cancer multidisciplinary team for recommendations about staging and management. Consider surgery or other ablative treatments to prevent or control symptoms of oligometastatic stage IV melanoma in consultation with other site specific multidisciplinary teams. ## Brain metastases For guidance on diagnosing, monitoring and managing brain metastases in people aged 16 or over see NICE's guideline on brain tumours (primary) and brain metastases in over 16s. Discuss the care of people with melanoma and brain metastases with the specialist skin cancer multidisciplinary team. Refer people with melanoma and brain metastases that might be suitable for surgery or stereotactic radiotherapy to the neuro-oncology multidisciplinary team for a recommendation about treatment. ## Systemic anticancer treatments for untreated stage IV and unresectable stage III melanoma In July 2022, most of the therapies in recommendations 1.8.7 to 1.8.12 and 1.8.14 and 1.8.15 were unlicensed for use in the UK in children and young people under 18. See NICE's information on prescribing medicines. Refer to the summary of product characteristics for the individual treatments because there are differences in their licensed populations. When choosing systemic anticancer treatment for untreated stage IV or unresectable stage III melanoma, base treatment decisions on the following factors: comorbidities and performance status risk of treatment toxicity whether potential treatment toxicity will be tolerated presence of symptomatic brain metastases tumour biology (for example, high disease burden, rapid progression, lactate dehydrogenase level).Treatment decisions should be made after a full assessment of the risks and benefits by the treating oncologist and discussion with the person, in line with NICE's guideline on shared decision making. Offer treatment with immunotherapy to people with untreated stage IV or unresectable stage III melanoma, as set out in recommendations 1.8.8 to 1.8.9. If immunotherapy is contraindicated or unsuitable, based on the factors in recommendation 1.8.6, follow recommendations 1.8.10 to 1.8.12 for alternative treatments based on BRAF type. For other guidance on treatments for advanced melanoma, see NICE's technology appraisal guidance on the NICE topic page for skin cancer. Offer nivolumab plus ipilimumab to people with untreated stage IV or unresectable stage III melanoma if suitable for them based on the factors in recommendation 1.8.6. See NICE's technology appraisal guidance on nivolumab in combination with ipilimumab for treating advanced melanoma. If nivolumab plus ipilimumab is unsuitable or unacceptable (for example, because of potential toxicity), offer pembrolizumab or nivolumab monotherapy. See NICE's technology appraisal guidance on pembrolizumab for advanced melanoma not previously treated with ipilimumab and nivolumab for treating advanced (unresectable or metastatic) melanoma. Offer encorafenib plus binimetinib, or dabrafenib plus trametinib, to people with untreated BRAF-mutant stage IV or unresectable stage III melanoma if: nivolumab plus ipilimumab, pembrolizumab, and nivolumab are contraindicated or it is predicted there is not enough time for an adequate immune response (for example, because of high disease burden or rapid progression). See NICE's technology appraisal guidance on encorafenib with binimetinib for unresectable or metastatic BRAF V600 mutation-positive melanoma and trametinib in combination with dabrafenib for treating unresectable or metastatic melanoma. If encorafenib plus binimetinib, and dabrafenib plus trametinib, are both unsuitable or unacceptable to the person: -ffer dabrafenib or vemurafenib to people for whom binimetinib and trametinib are contraindicated or if targeted treatment is contraindicated, consider treatment with chemotherapy (dacarbazine) or best supportive care. See NICE's technology appraisal guidance on dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma and vemurafenib for treating locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma.For other guidance on targeted therapies see NICE's technology appraisal guidance on the NICE topic page for skin cancer. For people with untreated BRAF-wild type stage IV or unresectable stage III melanoma for whom nivolumab plus ipilimumab, pembrolizumab, and nivolumab are contraindicated, consider: treatment with chemotherapy (dacarbazine) or best supportive care. For guidance on immunotherapies, see NICE's technology appraisal guidance on ipilimumab, nivolumab, nivolumab with ipilimumab and pembrolizumab. For guidance on targeted therapies for BRAF V600 mutation-positive melanoma, see NICE's technology appraisal guidance on encorafenib with binimetinib and trametinib with dabrafenib. When making treatment decisions for previously treated melanoma, take into account the factors listed in recommendation 1.8.6. For people with previously treated melanoma in whom immunotherapies and targeted therapies are contraindicated, unsuitable or unacceptable, consider: treatment with chemotherapy (dacarbazine) or best supportive care. Do not routinely offer further cytotoxic chemotherapy to people with stage IV or unresectable stage III melanoma who have had previous treatment with dacarbazine except in the context of a clinical trial. ## Referral to specialist palliative care services Refer people with incurable melanoma to specialist palliative care services for symptom management. See NICE's guideline on end of life care for adults: service delivery. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing stage IV and unresectable stage III melanoma . Full details of the evidence and the committee's discussion are in evidence review F: systemic and localised anticancer treatment for people with stage IV and unresectable stage III melanoma. Loading. Please wait. ## Genomic biomarker-based treatment The point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See NICE's topic page on genomic biomarker-based cancer treatments for guidance on specific treatments. # Follow-up after treatment for melanoma ## Information and support for people who have had melanoma Ensure that people who have completed treatment for melanoma have been given direct contact details for specialist skin cancer services that can provide advice about problems or concerns related to their melanoma. Offer psychosocial support to the person and their family or carers at all follow-up appointments. Ensure that local follow-up policies: are in line with recommendations 1.1.1 to 1.1.3 in the section on communication and support include: reinforcing advice about self examination health promotion for people with melanoma and their families, including sun awareness and avoiding vitamin D depletion (see NICE's guideline on sunlight exposure: risks and benefits) advice on stopping smoking for people who smoke (see NICE's guideline on tobacco: preventing uptake, promoting quitting and treating dependence). ## Exceptions to routine follow-up For people who have had stage 0 melanoma, provide advice at a clinic visit during the first year after treatment has been completed, in line with recommendation 1.9.3. Offer personalised follow-up to people with unresectable stage III or IV melanoma. Consider personalised follow-up for people who are at increased risk of further primary melanomas (for example, people with atypical mole syndrome, previous melanoma, multiple in-situ melanomas, or a history of melanoma in first degree relatives or other relevant familial cancer syndromes). Offer whole-body and brain MRI, instead of CE-CT, to children and young adults (from birth to 24 years) having imaging as part of follow-up. Offer whole-body and brain MRI, instead of CE-CT, to women who are pregnant and having imaging as part of follow-up. Offer brain MRI for follow-up imaging, instead of brain CE-CT, to people with known or resected brain metastases. Consider brain MRI for follow-up imaging, instead of brain CE-CT, if preferred locally and after discussion and agreement with the specialist skin cancer multidisciplinary team. ## Planning routine follow-up Full examination of the skin and regional lymph nodes at clinic appointments should be done by a healthcare professional who has skills and expertise in skin cancer and lymph node examination. They should have access to dermoscopy and medical photography as part of examinations. For people having both CE-CT and ultrasound scans, alternate between the 2 types of scan. Do not routinely use PET-CT during follow-up of people with melanoma. Continue to follow the recommendations on managing concurrent drug treatment. Offer follow-up for 1 year to people who have had stage IA melanoma, and for 5 years to people who have had stages IB to IV melanoma, using the table on follow-up after stages I to IV melanoma. Stage of melanoma Follow-up IA Year 1: Consider 2 clinic appointments, with discharge at the end of year 1. Do not routinely offer screening investigations (including imaging and blood tests) as part of follow-up IB Year 1: Offer 2 clinic appointments, and consider adding 2 ultrasound scans of the draining nodal basin if sentinel lymph node biopsy (SLNB) was considered but not done Years 2 and 3: Offer 1 clinic appointment each year, and consider adding 1 ultrasound scan of the draining nodal basin each year if SLNB was considered but not done Years 4 and 5: Offer 1 clinic appointment each year. Discharge at the end of year 5 IIA Years 1 and 2: Offer 2 clinic appointments each year, and consider adding 2 ultrasound scans of the draining nodal basin each year if SLNB was considered but not done Year 3: Offer 1 clinic appointment, and consider adding 1 ultrasound scan of the draining nodal basin if SLNB was considered but not done Years 4 and 5: Offer 1 clinic appointment each year. Discharge at the end of year 5 IIB Years 1 and 2: Offer 4 clinic appointments each year, and consider 2 whole-body and brain contrast-enhanced CT (CE-CT) scans each year. Consider adding 2 ultrasound scans of the draining nodal basin each year if SLNB was considered but not done Year 3: Offer 2 clinic appointments and consider 2 whole-body and brain CE-CT scans. Consider adding 2 ultrasound scans of the draining nodal basin if SLNB was considered but not done Years 4 and 5: Offer 1 clinic appointment each year and consider 1 whole-body and brain CE-CT scan each year. Discharge at the end of year 5 IIC Years 1 and 2: Offer 4 clinic appointments and 2 whole-body and brain CE CT scans each year. Consider adding 2 ultrasound scans of the draining nodal basin each year if SLNB was considered but not done Year 3: Offer 2 clinic appointments and 2 whole-body and brain CE-CT scans. Consider adding 2 ultrasound scans of the draining nodal basin if SLNB was considered but not done Years 4 and 5: Offer 1 clinic appointment and 1 whole-body and brain CE-CT scan each year. Discharge at the end of year 5 IIIA to IIIC not currently having adjuvant therapy Years 1 to 3: Offer 4 clinic appointments and 2 whole-body and brain CE-CT scans each year. Consider adding 2 ultrasound scans of the draining nodal basin each year if the person has a positive sentinel lymph node Years 4 and 5: Offer 2 clinic appointments and 1 whole-body and brain CE-CT scan each year. Discharge at the end of year 5 IIID and resected IV not currently having adjuvant therapy Years 1 to 3: Offer 4 clinic appointments and 4 whole-body and brain CE-CT scans each year Years 4 and 5: Offer 2 clinic appointments and 2 whole-body and brain CE-CT scans each year. Discharge at the end of year 5 IIIA to IIIC, IIID and resected IV having adjuvant therapy During adjuvant therapy, base follow-up on therapeutic requirements Whole body CE-CT scans will routinely include the thorax, abdomen and pelvis. However, other sites such as the neck may need including based on the person's individual needs and circumstances (for example, when there is an increased risk of the melanoma spreading or for people who are exempt from routine follow-up). This table sets out routine follow-up. Offer personalised follow-up to people with unresectable stage III or IV melanoma, people at increased risk of further primary melanomas, children and young adults, and women who are pregnant, in line with recommendations 1.9.5 to 1.9.10. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up after treatment for melanoma . Full details of the evidence and the committee's discussion are in evidence review G: follow-up of people with melanoma. Loading. Please wait.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Monitoring and response biomarkers Can biomarkers accurately classify recurrence, progression and response to treatment? For a short explanation of why the committee made the recommendation for research, see the rationale section on BRAF analysis of melanoma tissue samples . Full details of the evidence and the committee's discussion are in evidence review A: genetic testing for melanoma. Loading. Please wait. ## Safety, prognostic and predictive biomarkers Can biomarkers be used for risk stratification and treatment planning for people with melanoma? For a short explanation of why the committee made the recommendation for research, see the rationale section on BRAF analysis of melanoma tissue samples . Full details of the evidence and the committee's discussion are in evidence review A: genetic testing for melanoma. Loading. Please wait. ## Effectiveness of localised treatments What is the effectiveness of localised treatment for people with stages III and IV melanoma? For a short explanation of why the committee made this recommendation for research, see the rationale section on treating in-transit metastases in stages III and IV melanoma . Full details of the evidence and the committee's discussion are in evidence review F: systematic and localised anticancer treatment for people with stage IV and unresectable stage III melanoma. Loading. Please wait. ## Histological margins What is the optimal histological excision margin in stage 0 melanoma? For a short explanation of why the committee made this recommendation for research, see the rationale section on excision for stages 0 to II melanoma . Full details of the evidence and the committee's discussion are in evidence review C: surgical and histopathological excision margins for people with stage 0 to II melanoma. Loading. Please wait. ## Surveillance strategies How frequently should surveillance imaging be conducted, and which imaging modality should be used for people with stage IIB to IIIC melanoma? For a short explanation of why the committee made this recommendation for research, see the rationale and section on follow-up after treatment for melanoma . Full details of the evidence and the committee's discussion are in evidence review G: follow-up of people with melanoma. Loading. Please wait. # Other recommendations for research ## Survivorship What are the experiences of people who are living with, through and beyond a melanoma diagnosis in terms of survivorship and their disease journey? For a short explanation of why the committee made this recommendation for research, see the rationale and section on follow-up after treatment for melanoma . Full details of the evidence and the committee's discussion are in evidence review G: follow-up of people with melanoma. Loading. Please wait. ## Techniques for confirming a diagnosis in people with suspected atypical Spitzoid melanocytic lesions In people with reported atypical Spitzoid lesions, how effective are fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH) and tests to detect driver mutations compared with histopathological examination alone in predicting disease specific survival? This should be investigated in a prospective diagnostic study. Secondary outcomes should include sensitivity, specificity, accuracy, positive predictive value, disease specific survival and progression free survival. Atypical Spitzoid lesions continue to be diagnostically challenging. There are no reliably reproducible histological, immunohistochemistry or molecular features that allow exact typing and prognostic assessment of these lesions. The current 'gold standard' is histological examination with expert review, but it is not always possible to distinguish Spitzoid melanoma from benign Spitzoid melanocytic lesions. Current molecular technologies such as FISH and CGH provide some help, but the results are difficult to interpret and may not be conclusive. Understanding and mapping changes in molecular pathways could predict outcome and inform individual treatment planning. ## Surgical excision for people with lentigo maligna For people with lentigo maligna (stage 0 in sun damaged skin, usually on the face) how effective is Mohs micrographic surgery, compared with excision with a 0.5 cm clinical margin, in preventing biopsy proven local recurrence at 5 years? This should be investigated in a randomised controlled trial. Secondary outcomes should include cosmetic and functional outcomes. Mohs micrographic surgery is a microscopically controlled surgical technique designed to allow complete excision of the tumour with minimal tissue loss. The technique can be useful for people with lentigo maligna because their lesions can be very large and located in a cosmetically sensitive site where surgery may cause significant scarring. However, the histological detection of small numbers of melanocytes at the edge of a sample is difficult, and can lead to false negative results. In addition, lentigo maligna may occur in an area of field change with a risk of skip lesions at the edge. Therefore, although Mohs micrographic surgery may ensure complete excision of lentigo maligna, it can be accompanied by the recurrence of a similar lesion in adjacent skin. ## Vitamin D supplementation In people with stage I to III melanoma does vitamin D supplementation improve overall survival? This should be investigated in a placebo controlled randomised trial. Secondary outcomes should include disease specific survival and toxicity, including the development of renal stones and hypercalcaemia. It has been reported that suboptimal levels of vitamin D at diagnosis are common in people with melanoma from the north of England and that higher levels are associated with lower melanoma related mortality. However, vitamin D levels are higher in leaner, fitter people and the nature of the relationship between vitamin D levels and melanoma survival is unclear. There are 2 adjuvant trials of vitamin D supplementation listed as active currently, 1 in Italy and 1 in Australia. However, there are many uncertainties about the design of vitamin D trials, which might become clearer in the next few years. These include the dose of vitamin D, use of concurrent aspirin therapy and the baseline level at which vitamin D supplementation would be started. ## The effect of drug therapy for concurrent conditions on melanoma survival In people diagnosed with melanoma what is the effect of drug therapy to treat concurrent conditions on disease specific survival? This should be investigated in a national prospective cohort study. Secondary outcomes should include overall survival and quality of life. Drugs such as immunosuppressants and those used to treat conditions such as diabetes have effects that may affect survival in people with melanoma. For example, metformin, the most frequently prescribed drug for type 2 diabetes, is thought to reduce overall cancer rates in people with diabetes but to increase mortality from melanoma in approximately 40% of these people who have a somatic BRAF mutation. There is a need to balance the risk of melanoma deaths with the benefits from the most effective treatment of the concurrent conditions. But there is currently no evidence to inform this decision.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # BRAF analysis of melanoma tissue samples Recommendations 1.3.8 to 1.3.14 ## Why the committee made the recommendations The 2015 guideline recommended genetic testing for stage IIC and above melanoma. The 2022 committee extended this by recommending that BRAF analysis be considered for stage IIA or IIB melanoma, and carried out for stage IIC to IV melanoma. The committee agreed, based on their experience and in view of advances in targeted treatments since 2015, that early determination of BRAF status has practical utility. They noted that disease relapse occurs in a significant proportion of people with stage IIA to IIC melanoma (up to 50% at 5 years in people with stage IIC melanoma). Knowing BRAF status can speed up decisions about treatment for relapsed melanoma and optimise the use of these newer treatments. The committee also noted that BRAF analysis of melanoma tissue samples should be arranged by the local skin cancer multidisciplinary team to provide a more coordinated process. The pathology report on the primary lesion should also include the relevant tissue block suitable for molecular genetic testing, as specified by the dermatopathologist within the local skin cancer multidisciplinary team. The 2015 guideline did not specify the type of genetic test. The 2022 committee looked at specific types of test. They concluded that immunohistochemistry using BRAF V600E analysis is the most rapid method and enables treatment to be started sooner than is the case with other types of genetic testing. They also noted evidence that showed BRAF V600E immunohistochemistry rarely produces false positive results. However, some false negative results do occur so the committee agreed that a different BRAF genetic test should be used to double-check a negative or inconclusive result. The committee agreed to retain the 2015 recommendation that genetic testing should not be offered to people with stages IA to IB melanoma. Genetic testing for people with melanoma who are potential candidates for clinical trials will streamline enrolment into clinical trials and identify more candidates for trials. Biomarkers are of increasing relevance in the diagnosis and monitoring of various cancers, but their utility in the context of melanoma is still unclear. The committee made recommendations for research on monitoring and response biomarkers, and safety, prognostic and predictive biomarkers. ## How the recommendations might affect practice The recommendations might increase the use of genetic testing. They are expected to increase immunohistochemistry with BRAF V600E analysis as a means of genetic testing and reduce variations in genetic testing practice. Return to recommendations # Staging with sentinel lymph node biopsy and imaging Recommendations 1.4.1 to 1.4.11 ## Why the committee made the recommendations Evidence showed that sentinel lymph node biopsy (SLNB) should be done (or ruled out) before imaging for most people because imaging does not accurately detect lymph node metastases during staging. The committee agreed that imaging should only be offered before SLNB if lymph node or distant metastases are suspected. Specific risk factors were shown by the evidence to be strongly associated with a positive sentinel lymph node and the committee recommended that SLNB be considered for people with any of these risk factors. They agreed that SLNB is not cost effective if the risk of sentinel node metastases is low. The committee noted that the existing economic evidence was highly contradictory. They also noted that the model previously developed for the 2015 guideline and 1 study showed that SLNB was not cost effective. The committee noted that women who are pregnant may have concerns about having SLNB because it needs to be done under a general anaesthetic and uses a radioactive tracer and an unlicensed drug. The committee agreed that, in their experience, there is no harm associated with delaying SLNB until after pregnancy. They noted that the decision should be made within the specialist skin cancer multidisciplinary team on a case-by-case basis after discussion with the person. Most of the evidence concerned imaging during follow-up. There was less evidence on imaging during staging, but the committee agreed that the imaging used for staging should be consistent with the imaging that will be used during follow-up, and made recommendations to reflect this (see the recommendations on imaging in the section on follow-up after treatment for melanoma). The committee agreed that MRI has utility during staging, due to the increased sensitivity for detecting brain metastases compared with CE-CT. They recommended considering brain MRI instead of CE-CT when staging people with stage IIIC to IV melanoma because of their higher risk of developing brain metastases. The committee noted that many clinical factors are also associated with an increased risk of developing brain metastases and included the main risk factors in the recommendations. The evidence showed a high rate of recurrence in the interim period between surgery and starting adjuvant therapy. The committee agreed that for people starting adjuvant therapy, imaging should be repeated to exclude recurrence if recent imaging is not available. They agreed to define this as imaging done within the past 8 weeks, based on their experience and noting that 1 study had used a definition of 7.4 weeks. ## How the recommendations might affect practice In current practice SLNB is commonly offered to people with melanoma and a Breslow thickness of 0.8 mm to 1.0 mm. The recommendations are expected to reduce SLNB in this group by targeting it specifically to those with risk factors for a positive SLNB. Ulceration is the most common risk factor and is therefore likely to be the main reason for offering SLNBs. Variation in the use of imaging during staging is expected to be reduced, with an increase in the use of CE-CT. Return to recommendations # Excision for stages 0 to II melanoma Recommendations 1.5.1 to 1.5.3 ## Why the committee made the recommendations The committee agreed to retain the 2015 recommendations on clinical margins for excision. The 2015 committee found no evidence on the optimal clinical margin for stage 0 melanoma. They made the recommendation on the basis of clinical experience suggesting that local recurrence may be seen when margins smaller than 0.5 cm are used. The 2022 committee found no further evidence so retained the recommendation. Evidence supported the 2015 recommendations to use minimum clinical margins of 1 cm in stage I melanoma and 2 cm in stage II melanoma. The margin should be around the histological biopsy scar and take into account the primary melanoma margins. The committee acknowledged that smaller margins may be needed for cosmetic reasons on sites such as the face, head and digits. However, the use of smaller margins should be discussed within the specialist skin cancer multidisciplinary team. The reasoning for a smaller margin should be justified and the person should have clinical surveillance. The evidence confirmed that larger margins of 4 cm to 5 cm are associated with more adverse events and no improvement in outcomes. The committee acknowledged continuing uncertainty about optimal excision margins, particularly in stage 0 disease, and made a recommendation for research on histological margins. ## How the recommendations might affect practice The recommendations are unchanged and are not expected to change current practice. Return to recommendations # Managing stage III melanoma Recommendation 1.6.1 ## Why the committee made the recommendation Evidence suggested that completion lymph node dissection for people with stage III melanoma does not improve survival or melanoma-specific survival when compared with routine surveillance, and that it is associated with an increased risk of lymphoedema. The committee concluded that the overall risks of completion lymph node dissection outweigh the benefits for most people, and agreed to amend the 2015 recommendation to reflect this. However, there is evidence of less nodal basin disease control in people who had SLNB and surveillance compared with people who had completion lymph node dissection. The committee acknowledged that certain factors can make it difficult to manage recurrent nodal disease. They therefore agreed that completion lymph node dissection may be considered for people with these factors. There was no evidence on the benefit of SLNB for people with stage III melanoma and microsatellite lesions. The committee discussed the potential benefits and harms in the absence of evidence. They agreed that the presence of microsatellite lesions indicates that the melanoma has progressed beyond the lymph nodes and so would automatically become stage IIIB or IIIC disease without the need for SLNB. The committee agreed that SLNB may sometimes be thought useful as a way of finding out whether the melanoma has spread to the lymph nodes. However, its prognostic utility in this context is unclear. The committee also agreed that most centres in the UK do not currently offer SLNB to people with stage III disease. Therefore they agreed not to make recommendations in this area. ## How the recommendation might affect practice Completion lymph node dissection is no longer standard practice and the recommendations will not change this. Return to recommendation # Treating in-transit metastases in stages III and IV melanoma Recommendations 1.7.1 and 1.7.2 ## Why the committee made the recommendations Good quality evidence on localised treatments is lacking. The committee agreed that several treatment options can be considered but that in the absence of good evidence, this decision should be based on treatment suitability for the person with melanoma. They also agreed to remove the option of CO2 laser listed in the 2015 guideline because it is no longer used in standard practice. The committee concurred that there is uncertainty about the best option for people with different clinical characteristics and made a recommendation for research on effectiveness of localised treatments. ## How the recommendations might affect practice Treatments for in-transit metastases are rarely used. The recommendations may help to target these treatments but will not lead to substantial changes in practice. Return to recommendations # Managing stage IV and unresectable stage III melanoma Recommendations 1.8.3 and 1.8.6 to 1.8.16 ## Why the committee made the recommendations The committee looked at evidence on immunotherapies (ipilimumab, nivolumab, pembrolizumab, and nivolumab plus ipilimumab) and targeted therapies (encorafenib plus binimetinib, trametinib plus dabrafenib, dabrafenib monotherapy and vemurafenib monotherapy). These therapies were also compared in a health economic model. The committee noted the complexities and nuances in the treatment pathway. They identified a number of factors that should be taken into account when considering treatment choices to allow appropriate and individualised treatment decisions. The evidence showed that, overall, the immunotherapies are more clinically effective than the targeted therapies. Within the immunotherapies, nivolumab plus ipilimumab was the most clinically effective. The health economic model demonstrated that it is also the most cost effective. However, the committee noted evidence showing that the risk of toxicity with immunotherapies is higher than with targeted therapies, and that this risk increases when immunotherapies are used in combination. They therefore agreed that monotherapy should be an option if combination immunotherapy is deemed unsuitable for people, for example those with poor performance status or comorbidities who are less likely to tolerate toxicity. The evidence showed that nivolumab and pembrolizumab have similar clinical effectiveness and cost effectiveness when used as monotherapies so the committee agreed that either of these options should be offered. The committee noted NICE technology appraisal guidance recommending ipilimumab monotherapy for untreated advanced (unresectable or metastatic) melanoma, but did not include this option in their recommendation because it is not commonly used as first-line treatment and monotherapy with either nivolumab or pembrolizumab is more cost effective in this population. The committee also acknowledged that ipilimumab is licensed for use as monotherapy in adults and young people aged 12 and over. However, based on their clinical experience, its use as a monotherapy is considered to be the same as in adults. If immunotherapy, either in combination or as monotherapy, is unsuitable, the committee agreed that targeted therapies based on BRAF status are an option. The committee noted that someone with symptomatic brain metastases will usually need steroids, which excludes treatment with immunotherapy. In addition, for people with a high disease burden or rapid progression there may not be enough time to generate the necessary immune response that is associated with immunotherapy. Within the targeted therapies, evidence showed that encorafenib plus binimetinib, or trametinib plus dabrafenib, had similar clinical effectiveness. The health economic model did not demonstrate clear differences in cost effectiveness between these 2 options. Therefore, the committee agreed that either of these options for combination treatment could be recommended. If both of these options are unsuitable, the committee agreed that monotherapy with dabrafenib or vemurafenib should be offered. If targeted treatment for BRAF-mutated melanoma is unsuitable, or if the melanoma is BRAF-wild type, the committee agreed that the options are limited to chemotherapy with dacarbazine or best supportive care. The committee made recommendations on treatments for previously treated stage IV or unresectable stage III melanoma. The evidence for the clinical and cost effectiveness of treatment in this area was limited. Therefore, the committee preferred to list the available treatment options, and to highlight the factors that should be taken into account when considering treatment choices for previously treated melanoma. No evidence was found for the effectiveness of systemic cancer therapies specific to children and young people. However, the committee agreed that treatment should not differ between children and adults, and that recommendations also apply to children and young people. When treating children and young people, healthcare professionals should refer to the individual summary of product characteristics for the treatment being considered. This is because most of the treatments recommended in this guideline are not licensed for use in the UK in children and young people under 18, but there are differences in their licensed populations. The committee noted that people with incurable melanoma have a high symptom burden which should be managed at an early stage, and recommended referral to specialist palliative care services. ## How the recommendations might affect practice The recommendations are expected to increase the proportion of people who are offered nivolumab plus ipilimumab as systemic treatment for stage IV and unresectable stage III melanoma. The recommendations for previously treated melanoma are not expected to have an impact on practice, as all available treatments are listed alongside the factors that should be considered when making treatment recommendations. Return to recommendations # Follow-up after treatment for melanoma Recommendations 1.9.1 to 1.9.15 ## Why the committee made the recommendations The committee agreed, based on their experience, that the information given to people after treatment for melanoma varies, and that it is particularly important to give people details of a specialist skin cancer service that they can contact if they have questions or concerns after treatment. The committee agreed to retain the 2015 recommendation to provide psychosocial support and to include provision of advice in local follow-up policies. The committee noted the lack of evidence on the views of people who have had melanoma and made a recommendation for research on survivorship. Based on their experience, the committee agreed that people who have completed treatment for stage 0 melanoma can be discharged after a clinic visit for advice. They also identified groups who should be offered personalised follow-up, including people with unresectable melanoma and those at increased risk of further primary melanomas. The committee also identified groups for whom MRI should be considered, as a substitute for CE-CT. See the rationale section on imaging during follow-up . Loading. Please wait. The committee sought to find a frequency of clinical follow-up that would balance the need for prompt identification of recurrence or progression with the need to reduce the burden of follow-up appointments for people with melanoma and avoid the costs of unnecessary follow-up. Evidence showed that for stage IB to IIC disease, a lower frequency of follow-up visits did not increase mortality or cancer recurrence, or worsen quality of life. The committee therefore agreed to reduce the frequency of follow-up visits. They agreed to retain 4 visits per year for the first 2 years after stages IIB to IIC melanoma to coincide with their recommended imaging frequency, but to reduce this to 2 visits in year 3. Recommendations for clinic visits after resected stage III to IV disease were made to allow for a clinic visit after each imaging scan. The committee agreed that CT scanning during follow-up after all stages of melanoma should include the head because of the frequency of brain metastases developing during follow-up. The committee considered that the radiation risk from exposure to ionising radiation during CE-CT scans was not serious. However, the committee agreed that brain MRI could be considered instead of CE-CT, if it is more suitable (for example, when there are high-risk factors associated with brain metastases or when MRI has been used in staging). This will reduce radiation exposure and potentially increase accuracy of assessing brain metastases. They noted that this should be after a discussion with the specialist skin cancer multidisciplinary team. The committee acknowledged the logistical difficulties and increased burden on MRI capacity of arranging separate CE-CT and MRI scans. Evidence on stage III melanoma suggested that while PET-CT is more sensitive for detecting metastases compared with CE-CT it was not cost effective. The committee agreed that frequent imaging with CE-CT, particularly in the first 2 to 3 years when rates of recurrence are highest, will ensure timely identification of recurrences. The committee therefore agreed to recommend twice yearly imaging with CE-CT in the first 3 years, then once yearly in years 4 and 5. There was no evidence on CE-CT after stages IIB and IIC melanoma, but there was evidence suggesting a high risk of recurrence, particularly in stage IIC melanoma, that was worse than the risk of recurrence after stage IIIA disease. Based on this, the committee agreed that CE-CT imaging should be considered after stage IIB, and offered after stage IIC, at the same frequency as stage III. The committee agreed that MRI should be offered for children and young adults having follow-up because of the cumulative risk of radiation associated with CE-CT scanning, and during pregnancy when CE-CT is undesirable. Ultrasound scanning was shown by the evidence to be more sensitive than clinical examination and alternative imaging modalities (particularly CE-CT) for detecting local lymph node metastases. The committee agreed, based on their experience, that CE-CT alone can miss or delay detection of lymph node recurrences. However, there was no good quality evidence to show that ultrasound reduces mortality or time to recurrence in people with positive sentinel lymph nodes. Moreover, in current practice people with positive sentinel lymph nodes are offered frequent cross-sectional imaging and it is unclear whether ultrasound offers practical benefit above and beyond this imaging. This guideline does not recommend routine completion lymph node dissection, based on evidence comparing it with ultrasound scanning. However, there is no randomised controlled trial evidence comparing completion lymph node dissection with surveillance alone (with no ultrasound scanning). In addition, evidence suggested that most nodal recurrences develop within the first few years of diagnosis. The committee noted that nodal status is unknown in people who have not had an SNLB, and thus their staging is incomplete. Based on this, the committee agreed to recommend ultrasound surveillance for 3 years for people with a positive sentinel lymph node and those who were considered for but did not have an SLNB. The committee acknowledged the practical implications of ultrasound imaging during follow-up, such as the capacity to provide increased numbers of scans and the variable experience of healthcare professionals involved in follow-up. They noted the need for more evidence to inform future guidance on follow-up after melanoma and made a recommendation for research on surveillance strategies. ## How the recommendations might affect practice Current practice varies and it is expected that these recommendations will help to standardise practice across centres. Clinic visits for people with stages I to IIC melanoma may be reduced, especially for people with stage IA melanoma. It is therefore important that people are given contact details for the specialist skin cancer multidisciplinary team. The use of ultrasound, CE-CT or MRI scanning is expected to increase, but the use of PET-CT is expected to decrease. Return to recommendations# Context Melanoma is the fifth most common skin cancer in the UK, accounting for 4% of all new cancer cases and more cancer deaths than all other skin cancers combined. During 2016 to 2018 there were 16,744 new cases of melanoma and 2,333 deaths from melanoma. Of those who develop melanoma, 87% survive for 10 years or longer. Incidence rates for melanoma skin cancer in the UK are highest in people aged 85 to 89. Each year more than a quarter (29%) of all new melanoma skin cancer cases in the UK are diagnosed in people aged 75 and over. Since the early 1990s, melanoma skin cancer incidence rates have more than doubled (140%) in the UK. Rates in females have around doubled (106%), and rates in males have almost tripled (186%), from 2016 to 2018. Incidence rates for melanoma skin cancer are projected to rise by 7% in the UK between 2014 and 2035, to 32 cases per 100,000 people by 2035. A person's risk of developing cancer depends on many factors, including age, genetics, and exposure to risk factors (including some potentially avoidable lifestyle factors). Most cases of melanoma (86%) in the UK are preventable. Melanoma is most common in people with pale skin however it is often diagnosed at a more advanced stage in people with darker skin. This highlights a need for equal opportunity of diagnoses for people with darker skin. The risk factors are skin that tends to burn in the sun, having many moles, intermittent sun exposure and sunburn.	{'Stages of melanoma': 'The stages of melanoma referred to in this guideline are based on the 8th editions of the Union for International Cancer Control (UICC) tumour node metastasis (TNM) classification of malignant tumours and the American Joint Committee on Cancer (AJCC) melanoma staging system.', 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Communication and support\n\nGive people with melanoma accurate and easy to understand information (both written and spoken) in a sensitive and timely manner throughout their care, tailored to their needs and circumstances. Topics to discuss include:\n\nmelanoma and different types of skin cancer\n\ntreatment options, including the risks and benefits\n\nwhere the person's appointments will take place\n\nwhich healthcare professionals will undertake the person's care and how to get in touch with them\n\nexpected waiting times for consultations, investigations and treatments\n\nfollow-up after treatment (see the section on follow-up after treatment for melanoma)\n\npreventing recurrence, and how to protect their skin from damage caused by exposure to the sun, while avoiding vitamin D depletion\n\nrecognising signs and symptoms of suspicious skin lesions\n\nwhat to do if they have any concerns and how to re-access services local services and how to get in touch with them.For more guidance on giving information to people and discussing their preferences, follow the recommendations on communication and patient centred care in NICE's guidelines on patient experience in adult NHS services and shared decision making. \n\nDiscuss the psychological and emotional impact of melanoma with the person, ask whether they have any psychological or support care needs, and offer to carry out a holistic needs assessment. Topics to discuss include:\n\ntheir understanding of melanoma and its prognosis\n\ntheir specific concerns and preferences\n\nimportant values or personal goals for care and treatment\n\nrisk of recurrence, metastatic spread or new primary cancers\n\nwhether family members are at risk. \n\nExplain to people with melanoma that they are welcome to bring a companion with them to appointments. \n\nEnsure that each local skin cancer multidisciplinary team and specialist skin cancer multidisciplinary team has:\n\nat least 1 skin cancer clinical nurse specialist to provide people with information and support\n\naccess to psychological support services for people with melanoma. \n\nEnsure that healthcare professionals can support people with melanoma by attending training and being competent in:\n\ncommunicating complex and sensitive information clearly\n\ntailoring information and support to the person's individual needs and circumstances. \n\n# Managing vitamin D levels and concurrent drug treatment\n\nMeasure vitamin D levels at diagnosis in secondary care in all people with melanoma. \n\nGive people whose vitamin D levels are thought to be suboptimal advice on vitamin D supplementation and monitoring in line with local policies and NICE's guideline on vitamin D. \n\nDo not withhold or change drug treatment for other conditions, except immunosuppressants and immunomodulators, on the basis of a diagnosis of melanoma. For people on immunosuppressive or immunomodulatory treatments, seek advice from the person's specialist team, aiming to optimise quality of life while minimising the person's risk. [2015, amended 2022]\n\n# Assessing melanoma\n\n## Dermoscopy and other visualisation techniques\n\nAssess all pigmented skin lesions that are either referred for assessment or identified during follow-up in secondary or tertiary care, using dermoscopy carried out by healthcare professionals trained in this technique. \n\nDo not routinely use confocal microscopy or computer assisted diagnostic tools to assess pigmented skin lesions. \n\n## Photography\n\nFor a clinically atypical melanocytic lesion that does not need excision at first presentation in secondary or tertiary care:\n\nuse baseline photography (preferably dermoscopic) and\n\nreview the clinical appearance of the lesion, and compare it with the baseline photographic images, 3\xa0months after first presentation to identify early signs of melanoma. \n\n## Assessing and managing atypical Spitzoid lesions\n\nDiscuss all suspected atypical Spitzoid lesions at the specialist skin cancer multidisciplinary team meeting. \n\nMake the diagnosis of a Spitzoid lesion of uncertain malignant potential on the basis of the histology, clinical features and behaviour. \n\nManage a Spitzoid lesion of uncertain malignant potential as melanoma. \n\n## Taking tumour samples for genetic testing\n\nIf targeted systemic therapy is a treatment option, offer genetic testing using:\n\na secondary melanoma tissue sample if there is adequate cellularity or\n\na primary melanoma tissue sample if a secondary sample is not available or is of inadequate cellularity. \n\n## BRAF analysis of primary melanoma tissue samples\n\nDo not offer BRAF analysis of melanoma tissue samples from people with stage\xa0IA or IB primary melanoma at presentation except as part of a clinical trial. \n\nConsider BRAF analysis of melanoma tissue samples from people with stage\xa0IIA or IIB primary melanoma. \n\nCarry out BRAF analysis of melanoma tissue samples from people with stage\xa0IIC to IV primary melanoma. \n\nLocal skin multidisciplinary teams should arrange BRAF analysis of melanoma tissue samples and state the preferred tissue block for analysis. \n\nWhen doing BRAF analysis, consider immunohistochemistry as the first test for BRAF\xa0V600E, if available. \n\nIf BRAF\xa0V600E immunohistochemistry is negative or inconclusive, use a different BRAF genetic test. \n\nOffer BRAF analysis of melanoma tissue samples to people with melanoma if they are potential candidates for any ongoing clinical trials that require knowledge of genetic status. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on BRAF analysis of melanoma tissue samples\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: genetic testing for melanoma.\n\nLoading. Please wait.\n\n# Staging with sentinel lymph node biopsy\n\nDo not offer imaging or sentinel lymph node biopsy (SLNB) to people who have stage\xa0IA melanoma. \n\nDo not offer imaging before SLNB unless lymph node or distant metastases are suspected. \n\nConsider SLNB for people who have melanoma with a Breslow thickness of 0.8\xa0mm to 1.0\xa0mm and at least one of the following features:\n\nulceration\n\nlymphovascular invasion\n\na mitotic index of 2 or more. \n\nConsider SLNB for people who have melanoma with a Breslow thickness greater than 1.0\xa0mm. \n\nFor women who are pregnant, discuss the option of delaying SLNB until after the pregnancy is completed. \n\nConsider staging with whole-body and brain contrast-enhanced (CE)-CT for people with stage\xa0IIB melanoma. \n\nOffer staging with whole-body and brain CE-CT to people with stage\xa0IIC to IV melanoma. \n\nConsider staging with brain MRI, instead of brain CE-CT, if locally available and after discussion and agreement with the specialist skin cancer multidisciplinary team. \n\nOffer staging with whole body and brain MRI, instead of CE-CT, to:\n\nchildren and young adults (from birth to 24 years) with stage\xa0IIB to IV melanoma\n\nwomen with stage\xa0IIB to IV melanoma who are pregnant. \n\nConsider staging with brain MRI, instead of brain CE-CT, for people with stage\xa0IIIC to IV melanoma and one of the following risk factors:\n\na mitotic index of 5 or more\n\nprimary melanoma located on the scalp. \n\nConsider a repeat staging scan before starting adjuvant treatment, unless imaging done within the past 8\xa0weeks is available. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on staging with sentinel lymph node biopsy and imaging\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: use of sentinel lymph node biopsy in people with melanoma.\n\nLoading. Please wait.\n\n# Managing stages\xa00 to II melanoma\n\n## Excision for stages\xa00 to II melanoma\n\nConsider a clinical margin of at least 0.5\xa0cm when excising stage 0 melanoma. \n\nIf excision for stage\xa00 melanoma does not achieve an adequate histological margin, discuss further management with the specialist skin cancer multidisciplinary team. \n\nUse a clinical margin of:\n\ncm when excising stage I melanoma or when a 2\xa0cm excision margin would cause unacceptable disfigurement or morbidity\n\ncm when excising stage\xa0II melanoma.The clinical margin should be around the histological biopsy scar and take into account the primary melanoma margin. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on excision for stages\xa00 to II melanoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: surgical and histopathological excision margins for people with stage 0 to II melanoma.\n\nLoading. Please wait.\n\n## Imiquimod for stage\xa00 melanoma\n\nConsider topical imiquimod to treat stage\xa00 melanoma in adults if surgery to remove the entire lesion with a 0.5\xa0cm clinical margin would lead to unacceptable disfigurement or morbidity. \n\nConsider a repeat skin biopsy for histopathological assessment after treatment with topical imiquimod for stage\xa00 melanoma, to check whether it has been effective. In July 2022, this was an off-label use of topical imiquimod in adults and imiquimod was not licensed for use in the UK in children and young people under 18. See NICE's information on prescribing medicines.\n\n# Managing stage\xa0III melanoma\n\n## Completion lymph node dissection for stage\xa0III melanoma\n\nDo not routinely offer completion lymph node dissection to people with stage III melanoma and micrometastatic nodal disease detected by SLNB unless:\n\nthere are factors that might make recurrent nodal disease difficult to manage, and\n\nafter discussion with the person and the specialist skin cancer multidisciplinary team.Examples of factors that might make recurrent nodal disease difficult to manage include melanoma of the head and neck, people for whom stage\xa0III adjuvant therapies are contraindicated, or when regular follow‑up is not possible. \n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on managing stage\xa0III melanoma\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0D: completion lymphadenectomy for micrometastatic nodal disease in stage III melanoma\n\nevidence review\xa0E: use of sentinel lymph node biopsy for people with stage\xa0III melanoma with microsatellite lesions.\n\nLoading. Please wait.\n\n## Therapeutic lymph node dissection for stage\xa0III melanoma\n\nOffer therapeutic lymph node dissection to people with palpable stage\xa0IIIB to IIID melanoma, or cytologically or histologically confirmed nodal disease detected by imaging. \n\n## Adjuvant treatments for resected stage\xa0III melanoma\n\nFor guidance on specific treatments, see NICE's technology appraisal guidance on dabrafenib with trametinib for adjuvant treatment of resected BRAF V600 mutation-positive melanoma, pembrolizumab for adjuvant treatment of completely resected stage 3 melanoma and nivolumab for adjuvant treatment of completely resected melanoma with lymph node involvement or metastatic disease.\n\nDo not offer adjuvant radiotherapy to people with stage\xa0IIIA melanoma. \n\nDo not offer adjuvant radiotherapy to people with resected stage\xa0IIIB to IIID melanoma unless a reduction in the risk of local recurrence is estimated to outweigh the risk of significant adverse effects. \n\n## Non-curative treatment for superficial skin metastases in stage III melanoma\n\nConsider topical imiquimod to palliate superficial melanoma skin metastases. In July 2022, this was an off-label use of topical imiquimod in adults and imiquimod was not licensed for use in the UK in children and young people under 18. See NICE's information on prescribing medicines.\n\n## Genomic biomarker-based treatment for stage\xa0III melanoma\n\nThe point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See NICE's topic page on genomic biomarker-based cancer treatments for guidance on specific treatments.\n\n# Treating in-transit metastases in stages\xa0III and IV melanoma\n\nDiscuss management of in-transit metastases, including surgery or treatment in a regional specialist centre, with the specialist skin cancer multidisciplinary team. \n\nOffer surgery as the first option and if surgery is not feasible, or if the person has recurrent in-transit metastases, consider one of the following options based on their suitability for the person:\n\nsystemic anticancer therapy (see recommendations 1.8.6 to 1.8.15 on systemic anticancer treatments for untreated stage IV and unresectable stage III melanoma)\n\ntalimogene laherparepvec, in line with NICE's technology appraisal guidance on talimogene laherparepvec\n\nisolated limb infusion or perfusion\n\nradiotherapy\n\nelectrochemotherapy, in line with NICE's interventional procedures guidance on electrochemotherapy for metastases in the skin from tumours of non-skin origin and melanoma\n\na topical agent such as imiquimod. In July 2022, most of the therapies recommended in this guideline were not licensed for use in the UK in children and young people under 18. See NICE's information on prescribing medicines. Refer to the summary of product characteristics for the individual treatments because there are differences in their licensed populations.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treating in-transit metastases in stages\xa0III and IV melanoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: systematic and localised anticancer treatment for people with stage\xa0IV and unresectable stage\xa0III melanoma.\n\nLoading. Please wait.\n\n# Managing stage\xa0IV and unresectable stage\xa0III melanoma\n\n## Management of oligometastatic stage\xa0IV melanoma\n\nRefer the care of people who appear to have oligometastatic melanoma to the specialist skin cancer multidisciplinary team for recommendations about staging and management. \n\nConsider surgery or other ablative treatments to prevent or control symptoms of oligometastatic stage\xa0IV melanoma in consultation with other site specific multidisciplinary teams. [2015, amended 2022]\n\n## Brain metastases\n\nFor guidance on diagnosing, monitoring and managing brain metastases in people aged 16 or over see NICE's guideline on brain tumours (primary) and brain metastases in over 16s. \n\nDiscuss the care of people with melanoma and brain metastases with the specialist skin cancer multidisciplinary team. \n\nRefer people with melanoma and brain metastases that might be suitable for surgery or stereotactic radiotherapy to the neuro-oncology multidisciplinary team for a recommendation about treatment. [2015, amended 2022]\n\n## Systemic anticancer treatments for untreated stage\xa0IV and unresectable stage\xa0III melanoma\n\nIn July 2022, most of the therapies in recommendations 1.8.7 to 1.8.12 and 1.8.14 and 1.8.15 were unlicensed for use in the UK in children and young people under 18. See NICE's information on prescribing medicines. Refer to the summary of product characteristics for the individual treatments because there are differences in their licensed populations.\n\nWhen choosing systemic anticancer treatment for untreated stage IV or unresectable stage III melanoma, base treatment decisions on the following factors:\n\ncomorbidities and performance status\n\nrisk of treatment toxicity\n\nwhether potential treatment toxicity will be tolerated\n\npresence of symptomatic brain metastases\n\ntumour biology (for example, high disease burden, rapid progression, lactate dehydrogenase level).Treatment decisions should be made after a full assessment of the risks and benefits by the treating oncologist and discussion with the person, in line with NICE's guideline on shared decision making. \n\nOffer treatment with immunotherapy to people with untreated stage IV or unresectable stage III melanoma, as set out in recommendations 1.8.8 to 1.8.9. If immunotherapy is contraindicated or unsuitable, based on the factors in recommendation 1.8.6, follow recommendations 1.8.10 to 1.8.12 for alternative treatments based on BRAF type. For other guidance on treatments for advanced melanoma, see NICE's technology appraisal guidance on the NICE topic page for skin cancer.\n\nOffer nivolumab plus ipilimumab to people with untreated stage\xa0IV or unresectable stage\xa0III melanoma if suitable for them based on the factors in recommendation\xa01.8.6. See NICE's technology appraisal guidance on nivolumab in combination with ipilimumab for treating advanced melanoma.\n\nIf nivolumab plus ipilimumab is unsuitable or unacceptable (for example, because of potential toxicity), offer pembrolizumab or nivolumab monotherapy. See NICE's technology appraisal guidance on pembrolizumab for advanced melanoma not previously treated with ipilimumab and nivolumab for treating advanced (unresectable or metastatic) melanoma.\n\nOffer encorafenib plus binimetinib, or dabrafenib plus trametinib, to people with untreated BRAF-mutant stage\xa0IV or unresectable stage\xa0III melanoma if:\n\nnivolumab plus ipilimumab, pembrolizumab, and nivolumab are contraindicated or\n\nit is predicted there is not enough time for an adequate immune response (for example, because of high disease burden or rapid progression). See NICE's technology appraisal guidance on encorafenib with binimetinib for unresectable or metastatic BRAF V600 mutation-positive melanoma and trametinib in combination with dabrafenib for treating unresectable or metastatic melanoma.\n\nIf encorafenib plus binimetinib, and dabrafenib plus trametinib, are both unsuitable or unacceptable to the person:\n\noffer dabrafenib or vemurafenib to people for whom binimetinib and trametinib are contraindicated or\n\nif targeted treatment is contraindicated, consider treatment with chemotherapy (dacarbazine) or best supportive care. See NICE's technology appraisal guidance on dabrafenib for treating unresectable or metastatic BRAF\xa0V600 mutation-positive melanoma and vemurafenib for treating locally advanced or metastatic BRAF\xa0V600 mutation-positive malignant melanoma.For other guidance on targeted therapies see NICE's technology appraisal guidance on the NICE topic page for skin cancer.\n\nFor people with untreated BRAF-wild type stage\xa0IV or unresectable stage\xa0III melanoma for whom nivolumab plus ipilimumab, pembrolizumab, and nivolumab are contraindicated, consider:\n\ntreatment with chemotherapy (dacarbazine) or\n\nbest supportive care. \n\nFor guidance on immunotherapies, see NICE's technology appraisal guidance on ipilimumab, nivolumab, nivolumab with ipilimumab and pembrolizumab. For guidance on targeted therapies for BRAF\xa0V600 mutation-positive melanoma, see NICE's technology appraisal guidance on encorafenib with binimetinib and trametinib with dabrafenib.\n\nWhen making treatment decisions for previously treated melanoma, take into account the factors listed in recommendation\xa01.8.6. \n\nFor people with previously treated melanoma in whom immunotherapies and targeted therapies are contraindicated, unsuitable or unacceptable, consider:\n\ntreatment with chemotherapy (dacarbazine) or\n\nbest supportive care. \n\nDo not routinely offer further cytotoxic chemotherapy to people with stage\xa0IV or unresectable stage\xa0III melanoma who have had previous treatment with dacarbazine except in the context of a clinical trial. \n\n## Referral to specialist palliative care services\n\nRefer people with incurable melanoma to specialist palliative care services for symptom management. See NICE's guideline on end of life care for adults: service delivery. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing stage\xa0IV and unresectable stage\xa0III melanoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: systemic and localised anticancer treatment for people with stage\xa0IV and unresectable stage\xa0III melanoma.\n\nLoading. Please wait.\n\n## Genomic biomarker-based treatment\n\nThe point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See NICE's topic page on genomic biomarker-based cancer treatments for guidance on specific treatments.\n\n# Follow-up after treatment for melanoma\n\n## Information and support for people who have had melanoma\n\nEnsure that people who have completed treatment for melanoma have been given direct contact details for specialist skin cancer services that can provide advice about problems or concerns related to their melanoma. \n\nOffer psychosocial support to the person and their family or carers at all follow-up appointments. \n\nEnsure that local follow-up policies:\n\nare in line with recommendations\xa01.1.1 to 1.1.3 in the section on communication and support\n\ninclude:\n\n\n\nreinforcing advice about self examination\n\nhealth promotion for people with melanoma and their families, including sun awareness and avoiding vitamin D depletion (see NICE's guideline on sunlight exposure: risks and benefits)\n\nadvice on stopping smoking for people who smoke (see NICE's guideline on tobacco: preventing uptake, promoting quitting and treating dependence). \n\n\n\n## Exceptions to routine follow-up\n\nFor people who have had stage\xa00 melanoma, provide advice at a clinic visit during the first year after treatment has been completed, in line with recommendation 1.9.3. \n\nOffer personalised follow-up to people with unresectable stage\xa0III or IV melanoma. \n\nConsider personalised follow-up for people who are at increased risk of further primary melanomas (for example, people with atypical mole syndrome, previous melanoma, multiple in-situ melanomas, or a history of melanoma in first degree relatives or other relevant familial cancer syndromes). \n\nOffer whole-body and brain MRI, instead of CE-CT, to children and young adults (from birth to 24\xa0years) having imaging as part of follow-up. \n\nOffer whole-body and brain MRI, instead of CE-CT, to women who are pregnant and having imaging as part of follow-up. \n\nOffer brain MRI for follow-up imaging, instead of brain CE-CT, to people with known or resected brain metastases. \n\nConsider brain MRI for follow-up imaging, instead of brain CE-CT, if preferred locally and after discussion and agreement with the specialist skin cancer multidisciplinary team. \n\n## Planning routine follow-up\n\nFull examination of the skin and regional lymph nodes at clinic appointments should be done by a healthcare professional who has skills and expertise in skin cancer and lymph node examination. They should have access to dermoscopy and medical photography as part of examinations. \n\nFor people having both CE-CT and ultrasound scans, alternate between the 2 types of scan. \n\nDo not routinely use PET-CT during follow-up of people with melanoma. \n\nContinue to follow the recommendations on managing concurrent drug treatment. \n\nOffer follow-up for 1\xa0year to people who have had stage\xa0IA melanoma, and for 5\xa0years to people who have had stages\xa0IB to IV melanoma, using the table on follow-up after stages\xa0I to IV melanoma. \n\nStage of melanoma\n\nFollow-up\n\nIA\n\nYear 1: Consider 2 clinic appointments, with discharge at the end of year 1. Do not routinely offer screening investigations (including imaging and blood tests) as part of follow-up\n\nIB\n\nYear 1: Offer 2 clinic appointments, and consider adding 2 ultrasound scans of the draining nodal basin if sentinel lymph node biopsy (SLNB) was considered but not done\n\nYears 2 and 3: Offer 1 clinic appointment each year, and consider adding 1 ultrasound scan of the draining nodal basin each year if SLNB was considered but not done\n\nYears 4 and 5: Offer 1 clinic appointment each year. Discharge at the end of year 5\n\nIIA\n\nYears 1 and 2: Offer 2 clinic appointments each year, and consider adding 2 ultrasound scans of the draining nodal basin each year if SLNB was considered but not done\n\nYear 3: Offer 1 clinic appointment, and consider adding 1 ultrasound scan of the draining nodal basin if SLNB was considered but not done\n\nYears 4 and 5: Offer 1 clinic appointment each year. Discharge at the end of year 5\n\nIIB\n\nYears 1 and 2: Offer 4 clinic appointments each year, and consider 2 whole-body and brain contrast-enhanced CT (CE-CT) scans each year. Consider adding 2 ultrasound scans of the draining nodal basin each year if SLNB was considered but not done\n\nYear 3: Offer 2 clinic appointments and consider 2 whole-body and brain CE-CT scans. Consider adding 2 ultrasound scans of the draining nodal basin if SLNB was considered but not done\n\nYears 4 and 5: Offer 1 clinic appointment each year and consider 1 whole-body and brain CE-CT scan each year. Discharge at the end of year 5\n\nIIC\n\nYears 1 and 2: Offer 4 clinic appointments and 2 whole-body and brain CE CT scans each year. Consider adding 2 ultrasound scans of the draining nodal basin each year if SLNB was considered but not done\n\nYear 3: Offer 2 clinic appointments and 2 whole-body and brain CE-CT scans. Consider adding 2 ultrasound scans of the draining nodal basin if SLNB was considered but not done\n\nYears 4 and 5: Offer 1 clinic appointment and 1 whole-body and brain CE-CT scan each year. Discharge at the end of year 5\n\nIIIA to IIIC not currently having adjuvant therapy\n\nYears 1 to 3: Offer 4 clinic appointments and 2 whole-body and brain CE-CT scans each year. Consider adding 2 ultrasound scans of the draining nodal basin each year if the person has a positive sentinel lymph node\n\nYears 4 and 5: Offer 2 clinic appointments and 1 whole-body and brain CE-CT scan each year. Discharge at the end of year 5\n\nIIID and resected IV not currently having adjuvant therapy\n\nYears 1 to 3: Offer 4 clinic appointments and 4 whole-body and brain CE-CT scans each year\n\nYears 4 and 5: Offer 2 clinic appointments and 2 whole-body and brain CE-CT scans each year. Discharge at the end of year 5\n\nIIIA to IIIC, IIID and resected IV having adjuvant therapy\n\nDuring adjuvant therapy, base follow-up on therapeutic requirements\n\nWhole body CE-CT scans will routinely include the thorax, abdomen and pelvis. However, other sites such as the neck may need including based on the person's individual needs and circumstances (for example, when there is an increased risk of the melanoma spreading or for people who are exempt from routine follow-up).\n\nThis table sets out routine follow-up. Offer personalised follow-up to people with unresectable stage III or IV melanoma, people at increased risk of further primary melanomas, children and young adults, and women who are pregnant, in line with recommendations 1.9.5 to 1.9.10.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up after treatment for melanoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: follow-up of people with melanoma.\n\nLoading. Please wait.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Monitoring and response biomarkers\n\nCan biomarkers accurately classify recurrence, progression and response to treatment? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on BRAF analysis of melanoma tissue samples\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: genetic testing for melanoma.\n\nLoading. Please wait.\n\n## Safety, prognostic and predictive biomarkers\n\nCan biomarkers be used for risk stratification and treatment planning for people with melanoma? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on BRAF analysis of melanoma tissue samples\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: genetic testing for melanoma.\n\nLoading. Please wait.\n\n## Effectiveness of localised treatments\n\nWhat is the effectiveness of localised treatment for people with stages\xa0III and IV melanoma? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on treating in-transit metastases in stages\xa0III and IV melanoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: systematic and localised anticancer treatment for people with stage\xa0IV and unresectable stage\xa0III melanoma.\n\nLoading. Please wait.\n\n## Histological margins\n\nWhat is the optimal histological excision margin in stage\xa00 melanoma? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on excision for stages\xa00 to II melanoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: surgical and histopathological excision margins for people with stage\xa00 to II melanoma.\n\nLoading. Please wait.\n\n## Surveillance strategies\n\nHow frequently should surveillance imaging be conducted, and which imaging modality should be used for people with stage\xa0IIB to IIIC melanoma? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale and section on follow-up after treatment for melanoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: follow-up of people with melanoma.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Survivorship\n\nWhat are the experiences of people who are living with, through and beyond a melanoma diagnosis in terms of survivorship and their disease journey? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale and section on follow-up after treatment for melanoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: follow-up of people with melanoma.\n\nLoading. Please wait.\n\n## Techniques for confirming a diagnosis in people with suspected atypical Spitzoid melanocytic lesions\n\nIn people with reported atypical Spitzoid lesions, how effective are fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH) and tests to detect driver mutations compared with histopathological examination alone in predicting disease specific survival?\n\nThis should be investigated in a prospective diagnostic study. Secondary outcomes should include sensitivity, specificity, accuracy, positive predictive value, disease specific survival and progression free survival. \n\nAtypical Spitzoid lesions continue to be diagnostically challenging. There are no reliably reproducible histological, immunohistochemistry or molecular features that allow exact typing and prognostic assessment of these lesions. The current 'gold standard' is histological examination with expert review, but it is not always possible to distinguish Spitzoid melanoma from benign Spitzoid melanocytic lesions.\n\nCurrent molecular technologies such as FISH and CGH provide some help, but the results are difficult to interpret and may not be conclusive. Understanding and mapping changes in molecular pathways could predict outcome and inform individual treatment planning.\n\n## Surgical excision for people with lentigo maligna\n\nFor people with lentigo maligna (stage\xa00 in sun damaged skin, usually on the face) how effective is Mohs micrographic surgery, compared with excision with a 0.5\xa0cm clinical margin, in preventing biopsy proven local recurrence at 5\xa0years?\n\nThis should be investigated in a randomised controlled trial. Secondary outcomes should include cosmetic and functional outcomes. \n\nMohs micrographic surgery is a microscopically controlled surgical technique designed to allow complete excision of the tumour with minimal tissue loss. The technique can be useful for people with lentigo maligna because their lesions can be very large and located in a cosmetically sensitive site where surgery may cause significant scarring. However, the histological detection of small numbers of melanocytes at the edge of a sample is difficult, and can lead to false negative results. In addition, lentigo maligna may occur in an area of field change with a risk of skip lesions at the edge. Therefore, although Mohs micrographic surgery may ensure complete excision of lentigo maligna, it can be accompanied by the recurrence of a similar lesion in adjacent skin.\n\n## Vitamin D supplementation\n\nIn people with stage\xa0I to III melanoma does vitamin D supplementation improve overall survival?\n\nThis should be investigated in a placebo controlled randomised trial. Secondary outcomes should include disease specific survival and toxicity, including the development of renal stones and hypercalcaemia. \n\nIt has been reported that suboptimal levels of vitamin D at diagnosis are common in people with melanoma from the north of England and that higher levels are associated with lower melanoma related mortality. However, vitamin D levels are higher in leaner, fitter people and the nature of the relationship between vitamin D levels and melanoma survival is unclear.\n\nThere are 2 adjuvant trials of vitamin D supplementation listed as active currently, 1 in Italy and 1 in Australia. However, there are many uncertainties about the design of vitamin D trials, which might become clearer in the next few years. These include the dose of vitamin D, use of concurrent aspirin therapy and the baseline level at which vitamin D supplementation would be started.\n\n## The effect of drug therapy for concurrent conditions on melanoma survival\n\nIn people diagnosed with melanoma what is the effect of drug therapy to treat concurrent conditions on disease specific survival?\n\nThis should be investigated in a national prospective cohort study. Secondary outcomes should include overall survival and quality of life. \n\nDrugs such as immunosuppressants and those used to treat conditions such as diabetes have effects that may affect survival in people with melanoma. For example, metformin, the most frequently prescribed drug for type 2 diabetes, is thought to reduce overall cancer rates in people with diabetes but to increase mortality from melanoma in approximately 40% of these people who have a somatic BRAF mutation.\n\nThere is a need to balance the risk of melanoma deaths with the benefits from the most effective treatment of the concurrent conditions. But there is currently no evidence to inform this decision.", 'Rationale and impact': 'These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# BRAF analysis of melanoma tissue samples\n\nRecommendations 1.3.8 to 1.3.14\n\n## Why the committee made the recommendations\n\nThe 2015 guideline recommended genetic testing for stage\xa0IIC and above melanoma. The 2022 committee extended this by recommending that BRAF analysis be considered for stage\xa0IIA or IIB melanoma, and carried out for stage\xa0IIC to IV melanoma. The committee agreed, based on their experience and in view of advances in targeted treatments since 2015, that early determination of BRAF status has practical utility. They noted that disease relapse occurs in a significant proportion of people with stage\xa0IIA to IIC melanoma (up to 50% at 5\xa0years in people with stage\xa0IIC melanoma). Knowing BRAF status can speed up decisions about treatment for relapsed melanoma and optimise the use of these newer treatments.\n\nThe committee also noted that BRAF analysis of melanoma tissue samples should be arranged by the local skin cancer multidisciplinary team to provide a more coordinated process. The pathology report on the primary lesion should also include the relevant tissue block suitable for molecular genetic testing, as specified by the dermatopathologist within the local skin cancer multidisciplinary team.\n\nThe 2015 guideline did not specify the type of genetic test. The 2022 committee looked at specific types of test. They concluded that immunohistochemistry using BRAF\xa0V600E analysis is the most rapid method and enables treatment to be started sooner than is the case with other types of genetic testing. They also noted evidence that showed BRAF\xa0V600E immunohistochemistry rarely produces false positive results. However, some false negative results do occur so the committee agreed that a different BRAF genetic test should be used to double-check a negative or inconclusive result.\n\nThe committee agreed to retain the 2015 recommendation that genetic testing should not be offered to people with stages\xa0IA to IB melanoma.\n\nGenetic testing for people with melanoma who are potential candidates for clinical trials will streamline enrolment into clinical trials and identify more candidates for trials.\n\nBiomarkers are of increasing relevance in the diagnosis and monitoring of various cancers, but their utility in the context of melanoma is still unclear. The committee made recommendations for research on monitoring and response biomarkers, and safety, prognostic and predictive biomarkers.\n\n## How the recommendations might affect practice\n\nThe recommendations might increase the use of genetic testing. They are expected to increase immunohistochemistry with BRAF\xa0V600E analysis as a means of genetic testing and reduce variations in genetic testing practice.\n\nReturn to recommendations\n\n# Staging with sentinel lymph node biopsy and imaging\n\nRecommendations 1.4.1 to 1.4.11\n\n## Why the committee made the recommendations\n\nEvidence showed that sentinel lymph node biopsy (SLNB) should be done (or ruled out) before imaging for most people because imaging does not accurately detect lymph node metastases during staging. The committee agreed that imaging should only be offered before SLNB if lymph node or distant metastases are suspected.\n\nSpecific risk factors were shown by the evidence to be strongly associated with a positive sentinel lymph node and the committee recommended that SLNB be considered for people with any of these risk factors. They agreed that SLNB is not cost effective if the risk of sentinel node metastases is low. The committee noted that the existing economic evidence was highly contradictory. They also noted that the model previously developed for the 2015 guideline and 1 study showed that SLNB was not cost effective.\n\nThe committee noted that women who are pregnant may have concerns about having SLNB because it needs to be done under a general anaesthetic and uses a radioactive tracer and an unlicensed drug. The committee agreed that, in their experience, there is no harm associated with delaying SLNB until after pregnancy. They noted that the decision should be made within the specialist skin cancer multidisciplinary team on a case-by-case basis after discussion with the person.\n\nMost of the evidence concerned imaging during follow-up. There was less evidence on imaging during staging, but the committee agreed that the imaging used for staging should be consistent with the imaging that will be used during follow-up, and made recommendations to reflect this (see the recommendations on imaging in the section on follow-up after treatment for melanoma).\n\nThe committee agreed that MRI has utility during staging, due to the increased sensitivity for detecting brain metastases compared with CE-CT. They recommended considering brain MRI instead of CE-CT when staging people with stage\xa0IIIC to IV melanoma because of their higher risk of developing brain metastases. The committee noted that many clinical factors are also associated with an increased risk of developing brain metastases and included the main risk factors in the recommendations.\n\nThe evidence showed a high rate of recurrence in the interim period between surgery and starting adjuvant therapy. The committee agreed that for people starting adjuvant therapy, imaging should be repeated to exclude recurrence if recent imaging is not available. They agreed to define this as imaging done within the past 8\xa0weeks, based on their experience and noting that 1\xa0study had used a definition of 7.4\xa0weeks.\n\n## How the recommendations might affect practice\n\nIn current practice SLNB is commonly offered to people with melanoma and a Breslow thickness of 0.8\xa0mm to 1.0\xa0mm. The recommendations are expected to reduce SLNB in this group by targeting it specifically to those with risk factors for a positive SLNB. Ulceration is the most common risk factor and is therefore likely to be the main reason for offering SLNBs.\n\nVariation in the use of imaging during staging is expected to be reduced, with an increase in the use of CE-CT.\n\nReturn to recommendations\n\n# Excision for stages\xa00 to II melanoma\n\nRecommendations 1.5.1 to 1.5.3\n\n## Why the committee made the recommendations\n\nThe committee agreed to retain the 2015 recommendations on clinical margins for excision.\n\nThe 2015 committee found no evidence on the optimal clinical margin for stage\xa00 melanoma. They made the recommendation on the basis of clinical experience suggesting that local recurrence may be seen when margins smaller than 0.5\xa0cm are used. The 2022 committee found no further evidence so retained the recommendation.\n\nEvidence supported the 2015 recommendations to use minimum clinical margins of 1\xa0cm in stage\xa0I melanoma and 2\xa0cm in stage\xa0II melanoma. The margin should be around the histological biopsy scar and take into account the primary melanoma margins. The committee acknowledged that smaller margins may be needed for cosmetic reasons on sites such as the face, head and digits. However, the use of smaller margins should be discussed within the specialist skin cancer multidisciplinary team. The reasoning for a smaller margin should be justified and the person should have clinical surveillance. The evidence confirmed that larger margins of 4\xa0cm to 5\xa0cm are associated with more adverse events and no improvement in outcomes.\n\nThe committee acknowledged continuing uncertainty about optimal excision margins, particularly in stage\xa00 disease, and made a recommendation for research on histological margins.\n\n## How the recommendations might affect practice\n\nThe recommendations are unchanged and are not expected to change current practice.\n\nReturn to recommendations\n\n# Managing stage\xa0III melanoma\n\nRecommendation 1.6.1\n\n## Why the committee made the recommendation\n\nEvidence suggested that completion lymph node dissection for people with stage\xa0III melanoma does not improve survival or melanoma-specific survival when compared with routine surveillance, and that it is associated with an increased risk of lymphoedema. The committee concluded that the overall risks of completion lymph node dissection outweigh the benefits for most people, and agreed to amend the 2015 recommendation to reflect this. However, there is evidence of less nodal basin disease control in people who had SLNB and surveillance compared with people who had completion lymph node dissection. The committee acknowledged that certain factors can make it difficult to manage recurrent nodal disease. They therefore agreed that completion lymph node dissection may be considered for people with these factors.\n\nThere was no evidence on the benefit of SLNB for people with stage\xa0III melanoma and microsatellite lesions. The committee discussed the potential benefits and harms in the absence of evidence. They agreed that the presence of microsatellite lesions indicates that the melanoma has progressed beyond the lymph nodes and so would automatically become stage\xa0IIIB or IIIC disease without the need for SLNB.\n\nThe committee agreed that SLNB may sometimes be thought useful as a way of finding out whether the melanoma has spread to the lymph nodes. However, its prognostic utility in this context is unclear. The committee also agreed that most centres in the UK do not currently offer SLNB to people with stage III disease. Therefore they agreed not to make recommendations in this area.\n\n## How the recommendation might affect practice\n\nCompletion lymph node dissection is no longer standard practice and the recommendations will not change this.\n\nReturn to recommendation\n\n# Treating in-transit metastases in stages\xa0III and IV melanoma\n\nRecommendations 1.7.1 and 1.7.2\n\n## Why the committee made the recommendations\n\nGood quality evidence on localised treatments is lacking. The committee agreed that several treatment options can be considered but that in the absence of good evidence, this decision should be based on treatment suitability for the person with melanoma. They also agreed to remove the option of CO2 laser listed in the 2015 guideline because it is no longer used in standard practice.\n\nThe committee concurred that there is uncertainty about the best option for people with different clinical characteristics and made a recommendation for research on effectiveness of localised treatments.\n\n## How the recommendations might affect practice\n\nTreatments for in-transit metastases are rarely used. The recommendations may help to target these treatments but will not lead to substantial changes in practice.\n\nReturn to recommendations\n\n# Managing stage\xa0IV and unresectable stage\xa0III melanoma\n\nRecommendations 1.8.3 and 1.8.6 to 1.8.16\n\n## Why the committee made the recommendations\n\nThe committee looked at evidence on immunotherapies (ipilimumab, nivolumab, pembrolizumab, and nivolumab plus ipilimumab) and targeted therapies (encorafenib plus binimetinib, trametinib plus dabrafenib, dabrafenib monotherapy and vemurafenib monotherapy). These therapies were also compared in a health economic model.\n\nThe committee noted the complexities and nuances in the treatment pathway. They identified a number of factors that should be taken into account when considering treatment choices to allow appropriate and individualised treatment decisions.\n\nThe evidence showed that, overall, the immunotherapies are more clinically effective than the targeted therapies. Within the immunotherapies, nivolumab plus ipilimumab was the most clinically effective. The health economic model demonstrated that it is also the most cost effective.\n\nHowever, the committee noted evidence showing that the risk of toxicity with immunotherapies is higher than with targeted therapies, and that this risk increases when immunotherapies are used in combination. They therefore agreed that monotherapy should be an option if combination immunotherapy is deemed unsuitable for people, for example those with poor performance status or comorbidities who are less likely to tolerate toxicity. The evidence showed that nivolumab and pembrolizumab have similar clinical effectiveness and cost effectiveness when used as monotherapies so the committee agreed that either of these options should be offered.\n\nThe committee noted NICE technology appraisal guidance recommending ipilimumab monotherapy for untreated advanced (unresectable or metastatic) melanoma, but did not include this option in their recommendation because it is not commonly used as first-line treatment and monotherapy with either nivolumab or pembrolizumab is more cost effective in this population. The committee also acknowledged that ipilimumab is licensed for use as monotherapy in adults and young people aged 12 and over. However, based on their clinical experience, its use as a monotherapy is considered to be the same as in adults.\n\nIf immunotherapy, either in combination or as monotherapy, is unsuitable, the committee agreed that targeted therapies based on BRAF status are an option. The committee noted that someone with symptomatic brain metastases will usually need steroids, which excludes treatment with immunotherapy. In addition, for people with a high disease burden or rapid progression there may not be enough time to generate the necessary immune response that is associated with immunotherapy. Within the targeted therapies, evidence showed that encorafenib plus binimetinib, or trametinib plus dabrafenib, had similar clinical effectiveness. The health economic model did not demonstrate clear differences in cost effectiveness between these 2 options. Therefore, the committee agreed that either of these options for combination treatment could be recommended. If both of these options are unsuitable, the committee agreed that monotherapy with dabrafenib or vemurafenib should be offered.\n\nIf targeted treatment for BRAF-mutated melanoma is unsuitable, or if the melanoma is BRAF-wild type, the committee agreed that the options are limited to chemotherapy with dacarbazine or best supportive care.\n\nThe committee made recommendations on treatments for previously treated stage\xa0IV or unresectable stage\xa0III melanoma. The evidence for the clinical and cost effectiveness of treatment in this area was limited. Therefore, the committee preferred to list the available treatment options, and to highlight the factors that should be taken into account when considering treatment choices for previously treated melanoma.\n\nNo evidence was found for the effectiveness of systemic cancer therapies specific to children and young people. However, the committee agreed that treatment should not differ between children and adults, and that recommendations also apply to children and young people. When treating children and young people, healthcare professionals should refer to the individual summary of product characteristics for the treatment being considered. This is because most of the treatments recommended in this guideline are not licensed for use in the UK in children and young people under 18, but there are differences in their licensed populations.\n\nThe committee noted that people with incurable melanoma have a high symptom burden which should be managed at an early stage, and recommended referral to specialist palliative care services.\n\n## How the recommendations might affect practice\n\nThe recommendations are expected to increase the proportion of people who are offered nivolumab plus ipilimumab as systemic treatment for stage\xa0IV and unresectable stage III melanoma.\n\nThe recommendations for previously treated melanoma are not expected to have an impact on practice, as all available treatments are listed alongside the factors that should be considered when making treatment recommendations.\n\nReturn to recommendations\n\n# Follow-up after treatment for melanoma\n\nRecommendations 1.9.1 to 1.9.15\n\n## Why the committee made the recommendations\n\nThe committee agreed, based on their experience, that the information given to people after treatment for melanoma varies, and that it is particularly important to give people details of a specialist skin cancer service that they can contact if they have questions or concerns after treatment. The committee agreed to retain the 2015 recommendation to provide psychosocial support and to include provision of advice in local follow-up policies. The committee noted the lack of evidence on the views of people who have had melanoma and made a recommendation for research on survivorship.\n\nBased on their experience, the committee agreed that people who have completed treatment for stage\xa00 melanoma can be discharged after a clinic visit for advice. They also identified groups who should be offered personalised follow-up, including people with unresectable melanoma and those at increased risk of further primary melanomas.\n\nThe committee also identified groups for whom MRI should be considered, as a substitute for CE-CT. See the rationale section on imaging during follow-up\xa0.\n\nLoading. Please wait.\n\nThe committee sought to find a frequency of clinical follow-up that would balance the need for prompt identification of recurrence or progression with the need to reduce the burden of follow-up appointments for people with melanoma and avoid the costs of unnecessary follow-up.\n\nEvidence showed that for stage\xa0IB to IIC disease, a lower frequency of follow-up visits did not increase mortality or cancer recurrence, or worsen quality of life. The committee therefore agreed to reduce the frequency of follow-up visits. They agreed to retain 4\xa0visits per year for the first 2\xa0years after stages\xa0IIB to IIC melanoma to coincide with their recommended imaging frequency, but to reduce this to 2\xa0visits in year\xa03. Recommendations for clinic visits after resected stage\xa0III to IV disease were made to allow for a clinic visit after each imaging scan.\n\nThe committee agreed that CT scanning during follow-up after all stages of melanoma should include the head because of the frequency of brain metastases developing during follow-up. The committee considered that the radiation risk from exposure to ionising radiation during CE-CT scans was not serious. However, the committee agreed that brain MRI could be considered instead of CE-CT, if it is more suitable (for example, when there are high-risk factors associated with brain metastases or when MRI has been used in staging). This will reduce radiation exposure and potentially increase accuracy of assessing brain metastases. They noted that this should be after a discussion with the specialist skin cancer multidisciplinary team. The committee acknowledged the logistical difficulties and increased burden on MRI capacity of arranging separate CE-CT and MRI scans.\n\nEvidence on stage\xa0III melanoma suggested that while PET-CT is more sensitive for detecting metastases compared with CE-CT it was not cost effective. The committee agreed that frequent imaging with CE-CT, particularly in the first 2 to 3\xa0years when rates of recurrence are highest, will ensure timely identification of recurrences. The committee therefore agreed to recommend twice yearly imaging with CE-CT in the first 3\xa0years, then once yearly in years\xa04 and 5. There was no evidence on CE-CT after stages\xa0IIB and IIC melanoma, but there was evidence suggesting a high risk of recurrence, particularly in stage IIC melanoma, that was worse than the risk of recurrence after stage\xa0IIIA disease. Based on this, the committee agreed that CE-CT imaging should be considered after stage\xa0IIB, and offered after stage\xa0IIC, at the same frequency as stage\xa0III.\n\nThe committee agreed that MRI should be offered for children and young adults having follow-up because of the cumulative risk of radiation associated with CE-CT scanning, and during pregnancy when CE-CT is undesirable.\n\nUltrasound scanning was shown by the evidence to be more sensitive than clinical examination and alternative imaging modalities (particularly CE-CT) for detecting local lymph node metastases. The committee agreed, based on their experience, that CE-CT alone can miss or delay detection of lymph node recurrences. However, there was no good quality evidence to show that ultrasound reduces mortality or time to recurrence in people with positive sentinel lymph nodes. Moreover, in current practice people with positive sentinel lymph nodes are offered frequent cross-sectional imaging and it is unclear whether ultrasound offers practical benefit above and beyond this imaging. This guideline does not recommend routine completion lymph node dissection, based on evidence comparing it with ultrasound scanning. However, there is no randomised controlled trial evidence comparing completion lymph node dissection with surveillance alone (with no ultrasound scanning). In addition, evidence suggested that most nodal recurrences develop within the first few years of diagnosis. The committee noted that nodal status is unknown in people who have not had an SNLB, and thus their staging is incomplete. Based on this, the committee agreed to recommend ultrasound surveillance for 3\xa0years for people with a positive sentinel lymph node and those who were considered for but did not have an SLNB.\n\nThe committee acknowledged the practical implications of ultrasound imaging during follow-up, such as the capacity to provide increased numbers of scans and the variable experience of healthcare professionals involved in follow-up. They noted the need for more evidence to inform future guidance on follow-up after melanoma and made a recommendation for research on surveillance strategies.\n\n## How the recommendations might affect practice\n\nCurrent practice varies and it is expected that these recommendations will help to standardise practice across centres. Clinic visits for people with stages\xa0I to IIC melanoma may be reduced, especially for people with stage\xa0IA melanoma. It is therefore important that people are given contact details for the specialist skin cancer multidisciplinary team. The use of ultrasound, CE-CT or MRI scanning is expected to increase, but the use of PET-CT is expected to decrease.\n\nReturn to recommendations', 'Context': "Melanoma is the fifth most common skin cancer in the UK, accounting for 4% of all new cancer cases and more cancer deaths than all other skin cancers combined. During 2016 to 2018 there were 16,744 new cases of melanoma and 2,333 deaths from melanoma. Of those who develop melanoma, 87% survive for 10\xa0years or longer.\n\nIncidence rates for melanoma skin cancer in the UK are highest in people aged 85 to 89. Each year more than a quarter (29%) of all new melanoma skin cancer cases in the UK are diagnosed in people aged 75 and over. Since the early 1990s, melanoma skin cancer incidence rates have more than doubled (140%) in the UK. Rates in females have around doubled (106%), and rates in males have almost tripled (186%), from 2016 to 2018. Incidence rates for melanoma skin cancer are projected to rise by 7% in the UK between 2014 and 2035, to 32 cases per 100,000 people by 2035.\n\nA person's risk of developing cancer depends on many factors, including age, genetics, and exposure to risk factors (including some potentially avoidable lifestyle factors). Most cases of melanoma (86%) in the UK are preventable. Melanoma is most common in people with pale skin however it is often diagnosed at a more advanced stage in people with darker skin. This highlights a need for equal opportunity of diagnoses for people with darker skin. The risk factors are skin that tends to burn in the sun, having many moles, intermittent sun exposure and sunburn."}	https://www.nice.org.uk/guidance/ng14	This guideline covers the assessment and management of melanoma (a type of skin cancer) in children, young people and adults. It aims to reduce variation in practice and improve survival.
0a0b7aa6a74acdd516e9eef6ca13b64485702338	nice	Urinary tract infection in under 16s: diagnosis and management	Urinary tract infection in under 16s: diagnosis and management This guideline covers diagnosing and managing first or recurrent upper or lower urinary tract infection (UTI) in babies, children and young people under 16. It aims to achieve more consistent clinical practice, based on accurate diagnosis and effective management. It does not cover babies, children and young people with urinary catheters in situ, neurogenic bladders, significant pre-existing urinary tract disorders (uropathies), underlying renal disease or immunosuppression, or recurrent UTI in sexually active girls and young women under 16. It also does not cover babies, children and young people in intensive care units. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Diagnosis ## Symptoms and signs Test the urine of babies, children and young people who have symptoms and signs that increase the likelihood that a urinary tract infection (UTI) is present (see table 1 and the explanation of how to use the table beneath it). Consider testing the urine of babies, children and young people if they are unwell and there is a suspicion of a UTI but none of the signs or symptoms listed in table 1 are present. Refer babies under 3 months with a suspected UTI (see table 1 and recommendation 1.1.2) to paediatric specialist care, and: send a urine sample for urgent microscopy and culture manage in line with the sections on management by the non-paediatric practitioner and management by the paediatric specialist in the NICE guideline on fever in under 5s: assessment and initial management. Do not routinely test the urine of babies, children and young people 3 months and over who have symptoms and signs that suggest an infection other than a UTI. If they remain unwell and there is diagnostic uncertainty, consider urine testing. Symptoms and signs that increase the likelihood that a urinary tract infection (UTI) is present Symptoms and signs that decrease the likelihood that a UTI is present Painful urination (dysuria) More frequent urination New bedwetting Foul smelling (malodorous) urine Darker urine Cloudy urine Frank haematuria (visible blood in urine) Reduced fluid intake Fever Shivering Abdominal pain Loin tenderness or suprapubic tenderness Capillary refill longer than 3 seconds Previous history of confirmed urinary tract infection Absence of painful urination (dysuria) Nappy rash Breathing difficulties Abnormal chest sounds Abnormal ear examination Fever with known alternative cause When using the table, be aware that: The symptoms and signs in this table should be used to inform a decision about whether urine collection and testing is necessary. It is not an exhaustive list of symptoms or signs and should be used as a guide alongside clinical judgement. The presence or absence of a single symptom or sign in isolation in either column should not necessarily be used to decide whether or not to test for UTI. Multiple symptoms and signs will probably increase the likelihood that there is a UTI. It may be useful to consider alternative diagnoses where the symptoms and signs decrease the likelihood that a UTI is present. For babies or children under 5 with fever with no obvious cause where a UTI is no longer suspected, see the NICE guideline on fever in under 5s: assessment and initial management. Paediatric specialists should consult the section on management by the paediatric specialist in the NICE guideline on fever in under 5s: assessment and initial management, which covers when to test urine for a UTI in babies and children under 5 with fever who are in their care. Avoid delay when collecting and testing the urine sample. If the sample cannot be collected at the consultation, advise the parents or carers (as appropriate) to collect and return the urine sample as soon as possible, ideally within 24 hours. See the sections on urine collection, preservation and testing. If a baby, child or young person has suspected sepsis, assess and manage their condition in line with the NICE guideline on sepsis: recognition, diagnosis and early management. If a baby of up to and including 28 days corrected gestational age has suspected or confirmed bacterial infection, assess and manage their condition in line with the NICE guideline on neonatal infection: antibiotics for prevention and treatment. For early-onset neonatal infection, see the section on assessing and managing the risk of early-onset neonatal infection after birth, and for late-onset neonatal infection, see the section on risk factors for and clinical indicators of possible late-onset neonatal infection in the NICE guideline on neonatal infection: antibiotics for prevention and treatment. For guidance on when to consider sexual abuse, see recommendation 1.1.21 in the NICE guideline on child maltreatment. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on symptoms and signs of urinary tract infection . Full details of the evidence and the committee's discussion for the 2017 recommendation are in evidence review A: urinary tract infection diagnosis in infants and children under 3 months and 3 months to 3 years. Full details of the evidence and the committee's discussion for the 2022 recommendations are in evidence review B: symptoms and signs. Loading. Please wait. ## Assessment of risk of serious illness Assess the level of illness in babies and children in accordance with the section on clinical assessment of children with fever in the NICE guideline on fever in under 5s: assessment and initial management. ## Urine collection Take urine samples from children and young people before they are given antibiotics. This is in line with the NICE antimicrobial prescribing guidelines on pyelonephritis (acute) and urinary tract infection (lower). Babies and children with a high risk of serious illness should have a urine sample taken, but treatment should not be delayed if a urine sample cannot be obtained. Use a clean catch method for urine collection wherever possible. If a clean catch urine sample is not possible, use other non-invasive methods such as urine collection pads. It is important to follow the manufacturer's instructions when using urine collection pads. Do not use cotton wool balls, gauze or sanitary towels to collect urine from babies and children. Use catheter samples or suprapubic aspiration (SPA) when it is not possible or practical to collect urine by non-invasive methods. Use ultrasound guidance to confirm that there is urine in the bladder before SPA. ## Urine preservation Immediately refrigerate or use boric acid to preserve urine samples that are to be cultured but cannot be cultured within 4 hours of collection. Follow the manufacturer's instructions when using boric acid to ensure the correct specimen volume and avoid potential toxicity against bacteria in the specimen. ## Urine testing Use dipstick testing for babies and children between 3 months and 3 years with suspected UTI, and: if both leukocyte esterase and nitrite are negative: do not give antibiotics do not send a urine sample for microscopy and culture unless at least 1 of the criteria in recommendation 1.1.21 apply. if leukocyte esterase or nitrite, or both are positive: send the urine sample for culture give antibiotics. Use the urine-testing strategy for children aged 3 years or older shown in table 2. Assess the risk of serious illness in line with the section on clinical assessment of children with fever in the NICE guideline on fever in under 5s to ensure appropriate urine tests and interpretation, both of which depend on the child's age and risk of serious illness. Urine dipstick test result Strategy Leukocyte esterase and nitrite are both positive Assume the child has a urinary tract infection (UTI) and give them antibiotics. If the child has a high or intermediate risk of serious illness or a history of previous UTI, send a urine sample for culture. Leukocyte esterase is negative and nitrite is positive Give the child antibiotics if the urine test was carried out on a fresh urine sample. Send a urine sample for culture. Subsequent management will depend on the result of urine culture. Leukocyte esterase is positive and nitrite is negative Send a urine sample for microscopy and culture. Do not give the child antibiotics unless there is good clinical evidence of a UTI (for example, obvious urinary symptoms). A positive leukocyte esterase result may indicate an infection outside the urinary tract that may need to be managed differently. Leukocyte esterase and nitrite are both negative Assume the child does not have a UTI. Do not give the child antibiotics for a UTI or send a urine sample for culture. Explore other possible causes of the child's illness. Dipstick testing for leukocyte esterase and nitrite is diagnostically as useful as microscopy and culture, and can safely be used. Send urine samples for culture if a baby or child: is thought to have acute upper UTI (pyelonephritis; see the section on clinical differentiation between acute upper UTI and lower UTI) has a high to intermediate risk of serious illness (see the section on assessment of risk of serious illness) is under 3 months old has a positive result for leukocyte esterase or nitrite has recurrent UTI has an infection that does not respond to treatment within 24 to 48 hours, if no sample has already been sent has clinical symptoms and signs but dipstick tests do not correlate. For a short explanation of why the committee made the 2017 recommendations and how they might affect practice, see the rationale and impact section on urine testing . Full details of the evidence and the committee's discussion are in the evidence review A: urinary tract infection diagnosis in infants and children under 3 months and 3 months to 3 years. Loading. Please wait. Interpret microscopy results as shown in table 3. Use clinical criteria for decision making if a urine test does not support findings, because in a small number of cases, this may be the result of a false negative. Microscopy results Interpretation Pyuria and bacteriuria are both positive Assume the baby or child has a urinary tract infection (UTI) Pyuria is positive and bacteriuria is negative Start antibiotic treatment if the baby or child has symptoms or signs of a UTI Pyuria is negative and bacteriuria is positive Assume the baby or child has a UTI Pyuria and bacteriuria are both negative Assume the baby or child does not have a UTI ## History and examination of confirmed UTI Record the following risk factors for UTI and serious underlying pathology: poor urine flow history suggesting previous UTI or confirmed previous UTI recurrent fever of uncertain origin antenatally diagnosed renal abnormality family history of vesicoureteral reflux (VUR) or renal disease constipation dysfunctional voiding enlarged bladder abdominal mass evidence of spinal lesion poor growth high blood pressure. ## Clinical differentiation between acute upper UTI and lower UTI Assume a diagnosis of acute upper UTI in babies or children who have either: bacteriuria and fever of 38°C or higher or bacteriuria, fever lower than 38°C and loin pain or tenderness. Assume that babies and children who have bacteriuria but no systemic symptoms or signs have lower UTI (cystitis). ## Laboratory tests for localising UTI Do not use C-reactive protein alone to differentiate acute upper UTI from lower UTI in babies and children. # Acute management Note that the antibiotic requirements for babies and children with conditions that are outside the scope of this guideline (for example, babies and children already known to have significant pre-existing uropathies) have not been addressed and may be different from those given here. Immediately refer babies and children with a high risk of serious illness (see the section on assessment of risk of serious illness) to a paediatric specialist. Immediately refer babies under 3 months with a suspected UTI to a paediatric specialist. Paediatric specialists should give babies under 3 months with a suspected UTI parenteral antibiotics in line with the section on management by the paediatric specialist in the NICE guideline on fever in under 5s. Consider referring babies and children over 3 months with upper UTI to a paediatric specialist. Give babies and children over 3 months with an acute upper UTI antibiotics in line with the NICE guideline on pyelonephritis (acute): antimicrobial prescribing. Give babies and children over 3 months with lower UTI antibiotics in line with the NICE guideline on urinary tract infection (lower): antimicrobial prescribing. For information about treating babies and children who were already on prophylactic antibiotics who then developed a UTI see the NICE guidelines on pyelonephritis (acute): antimicrobial prescribing, urinary tract infection (lower): antimicrobial prescribing and urinary tract infection (recurrent): antimicrobial prescribing. Do not use antibiotics to treat asymptomatic bacteriuria in babies and children. Laboratories should monitor patterns of urinary pathogen resistance and make this information routinely available to prescribers. ## Preventing recurrence Manage dysfunctional elimination syndromes and constipation in babies and children who have had a UTI. Encourage children who have had a UTI to drink enough water to avoid dehydration. Ensure that children who have had a UTI have access to clean toilets when needed and do not have to delay voiding unnecessarily. ## Prophylactic antibiotics Do not routinely give prophylactic antibiotics to babies and children following first-time UTI. See the NICE guideline on urinary tract infection (recurrent): antimicrobial prescribing for prophylactic antibiotic treatment for recurrent UTI in babies and children. Do not give prophylactic antibiotics to babies and children with asymptomatic bacteriuria. ## Imaging tests for localising UTI Do not routinely use imaging to localise UTI. In rare instances when it is clinically important to confirm or exclude acute upper UTI, use either: power doppler ultrasound or a dimercaptosuccinic acid (DMSA) scintigraphy scan if power doppler ultrasound is not available or the diagnosis has not been confirmed. # Imaging tests Send babies and children with atypical UTI (see box 1) for a urinary tract ultrasound during the acute infection, to identify structural abnormalities such as obstruction and to ensure prompt management, as outlined in tables 4, 5 and 6. Send babies younger than 6 months with first-time UTI that responds to treatment for ultrasound within 6 weeks of the UTI, as outlined in table 4. Box 1 Definitions of atypical and recurrent urinary tract infection (UTI) Atypical UTI includes: Seriously ill (for more information, refer to the NICE guideline on fever in under 5s: assessment and initial management) Poor urine flow Abdominal or bladder mass Raised creatinine Septicaemia Failure to respond to treatment with suitable antibiotics within 48 hours Infection with non-E. coli organisms Recurrent UTI: Two or more episodes of UTI with acute upper UTI (acute pyelonephritis), or One episode of UTI with acute upper UTI plus 1 or more episodes of UTI with lower UTI (cystitis), or Three or more episodes of UTI with lower UTI Do not routinely send babies and children over 6 months with first-time UTI who respond to treatment for an ultrasound, unless they have atypical UTI as outlined in tables 5 and 6. Babies and children who have had a lower UTI should be sent for ultrasound (within 6 weeks) only if they: are younger than 6 months or have had recurrent infections. Use a DMSA scan 4 to 6 months after the acute infection to detect renal parenchymal defects in babies and children, as outlined in tables 4, 5 and 6. If the baby or child has a subsequent UTI while waiting for a DMSA scan, review the timing of the scan and consider doing it sooner. Do not routinely use imaging to identify VUR in babies and children who have had a UTI, except in specific circumstances as outlined in tables 4, 5 and 6. When a micturating cystourethrogram (MCUG) is done, give prophylactic antibiotics orally for 3 days with the MCUG on the second day. Send babies and children who have had a UTI for imaging, as outlined in tables 4, 5 and 6. Test Responds well to treatment within 48 hours Atypical urinary tract infection Recurrent urinary tract infection Ultrasound during the acute infection No Yes Yes Ultrasound within 6 weeks Yes If abnormal consider micturating cystourethrogram (MCUG) No No Dimercaptosuccinic acid scintigraphy scan 4 to 6 months after the acute infection No Yes Yes Micturating cystourethrogram No Yes Yes See box 1 for definitions of atypical and recurrent urinary tract infection. In a baby with a non-E. coli urinary tract infection that is responding well to antibiotics and has no other features of atypical infection, a non-urgent ultrasound can be requested, to happen within 6 weeks. Test Responds well to treatment within 48 hours Atypical urinary tract infection Recurrent urinary tract infection Ultrasound during the acute infection No Yes No Ultrasound within 6 weeks No No Yes Dimercaptosuccinic acid scintigraphy scan 4 to 6 months after the acute infection No Yes Yes Micturating cystourethrogram No No No See box 1 for definitions of atypical and recurrent urinary tract infection. While MCUG should not be performed routinely it should be considered if the following features are present: dilatation on ultrasound poor urine flow non-E. coli-infection family history of VUR. In babies and children with a non-E. coli urinary tract infection that is responding well to antibiotics and has no other features of atypical infection, a non-urgent ultrasound can be requested, to happen within 6 weeks. Test Responds well to treatment within 48 hours Atypical urinary tract infection Recurrent urinary tract infection Ultrasound during the acute infection No Yes No Ultrasound within 6 weeks No No Yes Dimercaptosuccinic acid scintigraphy scan 4 to 6 months after the acute infection No No Yes Micturating cystourethrogram No No No See box 1 for definitions of atypical and recurrent urinary tract infection. Ultrasound in toilet-trained children should be performed with a full bladder with an estimate of bladder volume before and after urination. In a child with a non-E. coli urinary tract infection that is responding well to antibiotics and has no other features of atypical infection, a non-urgent ultrasound can be requested, to happen within 6 weeks. # Surgical intervention Do not routinely use surgery for management of VUR. # Follow up Do not routinely follow up babies and children who have not had imaging investigations. Discuss and agree with parents, carers or the young person (as appropriate) how the results of imaging will be communicated. Do not routinely offer follow-up outpatient appointments when the results of investigations are normal. Give parents or carers the results of all investigations in writing. Refer babies and children who have recurrent UTI or abnormal imaging results for assessment by a paediatric specialist. When assessing babies and children with renal parenchymal defects, include height, weight, blood pressure and routine testing for proteinuria. Do not offer long-term follow up to babies and children with minor, unilateral renal parenchymal defects, unless they have recurrent UTI, family history or lifestyle risk factors for hypertension. Babies and children who have bilateral renal abnormalities, impaired kidney function, raised blood pressure or proteinuria should have monitoring and appropriate management by a paediatric nephrologist to slow the progression of chronic kidney disease. Do not routinely retest babies' and children's urine for infection if they are asymptomatic after an episode of UTI. Do not follow up babies and children based only on the presence of asymptomatic bacteriuria. # Information and advice Healthcare professionals should ensure that when a child or young person has a suspected UTI, they and their parents or carers (as appropriate) are told about the need for treatment, the importance of completing any course of treatment and given advice about prevention and long-term management. Ensure that children and young people, and their parents or carers (as appropriate), know that UTIs can recur and that it is important to remain vigilant and to seek prompt treatment for any suspected reinfection. Offer children and young people, and their parents or carers (as appropriate) advice and information on: prompt recognition of symptoms urine collection, storage and testing treatment options prevention the nature of and reason for any urinary tract investigation prognosis reasons and arrangements for long-term management if required. # Terms used in this guideline ## Bacteriuria Bacteria in the urine with or without UTI. ## Fever Elevation of body temperature above the normal daily variation unless otherwise specified in a particular recommendation. ## Pyuria White cells in the urine.# Recommendations for research The guideline committee has made the following recommendations for research. The committee's full set of recommendations for research is detailed in the full guideline. # Key recommendations for research ## Symptoms and signs of urinary tract infection in children and young people aged 5 years and above but under 16 years What are the symptoms and signs of urinary tract infection (UTI) in children and young people aged 5 years and above but under 16 years? For a short explanation of why the committee made this recommendation for research, see the rationale section on symptoms and signs . Full details of the evidence and the committee's discussion are in evidence review B: symptoms and signs. Loading. Please wait. ## Long-term risk of renal scarring and impaired renal function A well designed cohort study investigating long-term outcomes including renal scarring and renal function of children who have had UTI should be conducted in the UK. Urinary tract infection and vesicoureteral reflux (VUR) in young children have been shown to be associated with both congenital and acquired renal damage. Progressive scarring is well documented in children with high grade VUR and recurrent UTI. Scarring has been associated with severe hypertension, proteinuria, complications in pregnancy and progression to established renal failure. These risks are likely to be greater in children with bilateral renal parenchymal defects. However, the frequency and magnitude of these risks for children with unilateral and bilateral renal damage are unclear. Knowledge of the risk of serious or progressive complications would be useful to determine the management of children with first‑time and recurrent UTIs. ## Symptoms and signs of recurrent UTI Do the symptoms and signs of UTI in babies, children and young people aged under 16 years differ in those with a history of recurrent UTIs compared with those without a history of recurrent UTI? For a short explanation of why the committee made this recommendation for research, see the rationale section on symptoms and signs . Full details of the evidence and the committee's discussion are in evidence review B: symptoms and signs. Loading. Please wait. ## Symptoms and signs of long-term (chronic) UTI What symptoms and signs do children and young people with long-term (chronic) UTI report and what do they perceive is the impact on their health and quality of life? For a short explanation of why the committee made this recommendation for research, see the rationale section on symptoms and signs . Full details of the evidence and the committee's discussion are in evidence review B: symptoms and signs. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Symptoms and signs Recommendations 1.1.1 to 1.1.9 ## Why the committee made the recommendations The committee discussed evidence from studies that looked at symptoms and signs of urinary tract infections (UTIs). They agreed that it is important to diagnose UTI quickly and accurately to prevent unnecessary suffering and serious complications like renal scarring. Table 1 shows several symptoms and signs that increase, or decrease, the likelihood of a UTI being present. The committee agreed that the table gives more certainty about which symptoms and signs increase or decrease the likelihood of a UTI being present. The committee also highlighted that many symptoms and signs from the 2007 version of the guideline (dysuria , urinary frequency, loin tenderness and bedwetting) are still useful. However, the evidence around many of these symptoms and signs as indicators of UTI was low- or very-low quality. This was because many of the studies were not designed to assess diagnostic accuracy and had poor definitions of the symptoms and signs they reported. Therefore, the committee agreed that due to the remaining uncertainty, the table should be used as a guide alongside clinical judgement. Because the list in table 1 is not exhaustive, the committee were concerned that some unwell babies, children and young people with a possible UTI might not have further tests if they lack symptoms or signs from the table. There are other symptoms and signs that could suggest a UTI for which no evidence was found or for which data was not reported in the studies. The committee therefore agreed that it may still be necessary to test for UTI, if healthcare professionals suspect UTI despite the absence of any symptoms or signs listed in the table. The committee also looked at evidence for several algorithms that used combinations of symptoms and signs to help with diagnosis of UTI. None of the algorithms were particularly accurate, so the committee did not recommend their use. However, in the committee's opinion the presence of multiple symptoms or signs will probably increase the likelihood that there is a UTI. Table 1 does not specify relevant ages for particular symptoms and signs. This is because most of the evidence was for children under 5 years and the trials mostly did not report results by age. The committee agreed that the symptoms and signs could be generalised across age groups, but that clinical judgement was needed when deciding which are relevant for an individual baby, child or young person. This is because age or ability to communicate (or if their symptoms cannot be accurately assessed) will affect the usefulness of a particular symptom or sign. For example, in all ages, the presence of dysuria increased the likelihood that a UTI was present and, when absent, decreased the likelihood. But it may be more difficult to assess in babies, children or young people who are not toilet trained or cannot communicate their symptoms. The committee also chose to include a confirmed history of UTI as a symptom or sign. Although it is not strictly a symptom or sign, it is associated with an increased likelihood of UTI. The committee looked at evidence for other symptoms and signs that are not included in table 1. These included sleepiness or lethargy, irritability, poor feeding, vomiting, failure to thrive and jaundice. However, these were not found to be clinically useful in suggesting whether a UTI is present based on the evidence included in this review. The committee noted that some symptoms (for example haematuria , cloudy urine or dark urine) that were associated with an increased likelihood of UTI, could not be assessed by healthcare professionals without a urine sample. However, the symptoms and signs recommendations in this section are intended to provide guidance about when urine collection and testing is necessary. The committee therefore agreed to include these symptoms or signs in the table, based on the child self-reporting, or parental or caregiver reporting, rather than clinician assessment. The committee were aware that there may be limitations with these symptoms. For example, darker urine is not specific to urinary tract infection and can be common in those who are unwell and dehydrated (a poor fluid intake not being uncommon in unwell children). Additionally, a report of visible blood, in the committee's opinion, was not common in UTI and would always require further investigation. However, the committee agreed that symptoms and signs that are less specific to the urinary tract might still be useful indicators of a UTI, particularly if they are present in combination with other symptoms and signs. The committee noted that the symptoms and signs that decrease the likelihood of a UTI may suggest a different site of infection (such as the respiratory tract) but do not necessarily rule out a UTI. The list is not exhaustive (due to limitations in the evidence base) and other symptoms and signs may be present that suggest other sources of infection. The committee agreed that the urine of babies, children and young people aged 3 months and over should not be routinely tested if they have symptoms and signs that suggest another type of infection. This is because it would be clinically unnecessary, waste resources and could increase the stress experienced by the baby or child and their family or carers. However, if they remain unwell and there is diagnostic uncertainty, a urine test may be needed to exclude UTI. For babies and children under 5 with fever with no obvious cause where a UTI is no longer suspected, the NICE guideline on fever in under 5s: assessment and initial management could provide guidance in identifying the cause of their fever. The guideline also contains a section on diagnostic tests carried out by paediatric specialists on babies and children with fever in their care, including when to test urine for a UTI. The committee acknowledged that in practice there may be delays in obtaining a urine sample for testing if one cannot be obtained during consultation. They agreed that both urine collection and testing should happen without delay to ensure rapid and accurate diagnosis. However, the committee were aware that urine cultures will not necessarily detect every UTI. Therefore, there is a risk of these babies, children and young people remaining undiagnosed. But they noted that recommendation 1.1.23 addresses this situation. When making the 2017 recommendation, the committee agreed that there are concerns about sepsis in babies under 3 months with suspected UTI, and usual practice is referral rather than the GP managing symptoms. So, the committee recommended that all babies under 3 months should be referred to specialist paediatric care and have a urine sample sent for urgent microscopy and culture. The committee identified several gaps in the evidence. Most studies looked at symptoms and signs of UTI in babies and children aged under 5. Those that did include older children still had average ages closer to 5 than 16 and did not present data separately for older children. The committee therefore made a recommendation for research on the symptoms and signs of UTI in children and young people aged 5 years and above but under 16 years. They also made a recommendation for research on whether the symptoms and signs of recurrent UTI in babies, children and young people under 16 differed to acute UTI, because there was no evidence in this area. Finally, they made a recommendation for research to investigate the symptoms and signs experienced by children and young people with long-term (chronic) UTI as this was also not covered by the evidence. ## How the recommendations might affect practice The 2022 recommendations are unlikely to substantially change practice because the diagnostic pathway remains the same, although some of the symptoms and signs suggesting a UTI have changed. The absence of a recommendation for any diagnostic algorithm combining symptoms and signs, means that there will be little impact on clinical resources or training. The committee believed the 2017 recommendation would provide concise and clear guidance for healthcare professionals and more efficient diagnosis for babies under 3 months. Return to recommendations # Urine testing Recommendations 1.1.19 and 1.1.21 ## Why the committee made the recommendations Evidence showed that a positive urine dipstick test for leukocyte esterase or nitrite in children 3 months or older but younger than 3 years, greatly increases the likelihood of a positive urine culture. Sending only positive samples for culture offered a better balance of benefits and costs for these children than prescribing antibiotics and urine culture for all children. In children aged 3 months or older but younger than 3 years, symptoms are easier to identify, and antibiotics should only be started if a dipstick test is positive for either or both leukocyte esterase or nitrite. Children in this age group with a positive dipstick test should also have a urine sample sent for culture. ## How the recommendations might affect practice Recommending dipstick testing in babies and children aged 3 months or older but younger than 3 years clarifies the role of dipstick testing in this age group and encourages immediate diagnosis and treatment in primary care. The committee believe the new recommendations will provide concise and clear guidance for healthcare professionals and more efficient diagnosis. The recommendations will also be cost saving and reduce burden on laboratories by reducing the number of urine samples sent for culture. Return to recommendations# Context In the past 30 to 50 years, the natural history of urinary tract infection (UTI) in children has changed as a result of the introduction of antibiotics and improvements in healthcare. This change has contributed to uncertainty about the most appropriate and effective way to manage UTI in children, and whether investigations and follow up are justified. UTI is a common bacterial infection that causes illness in babies and children. It may be difficult to recognise UTI in children because the presenting symptoms and signs are non-specific, particularly in babies and children younger than 3 years. Collecting urine and interpreting results is not easy in this age group, so it may not always be possible to unequivocally confirm the diagnosis. Current management, which includes imaging, prophylaxis and prolonged follow up, has placed a heavy burden on NHS resources. It is based on limited evidence, is costly and unpleasant for children and is distressing for their parents or carers. This guideline has been developed with the aim of providing guidance on several aspects of UTI in babies and children from birth up to the age of 16 years.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Diagnosis\n\n## Symptoms and signs\n\nTest the urine of babies, children and young people who have symptoms and signs that increase the likelihood that a urinary tract infection (UTI) is present (see table 1 and the explanation of how to use the table beneath it). \n\nConsider testing the urine of babies, children and young people if they are unwell and there is a suspicion of a UTI but none of the signs or symptoms listed in table 1 are present. \n\nRefer babies under 3\xa0months with a suspected UTI (see table\xa01 and recommendation 1.1.2) to paediatric specialist care, and:\n\nsend a urine sample for urgent microscopy and culture\n\nmanage in line with the sections on management by the non-paediatric practitioner and management by the paediatric specialist in the NICE guideline on fever in under\xa05s: assessment and initial management. [2017, amended 2022]\n\nDo not routinely test the urine of babies, children and young people 3\xa0months and over who have symptoms and signs that suggest an infection other than a UTI. If they remain unwell and there is diagnostic uncertainty, consider urine testing. \n\nSymptoms and signs that increase the likelihood that a urinary tract infection (UTI) is present\n\nSymptoms and signs that decrease the likelihood that a UTI is present\n\nPainful urination (dysuria)\n\nMore frequent urination\n\nNew bedwetting\n\nFoul smelling (malodorous) urine\n\nDarker urine\n\nCloudy urine\n\nFrank haematuria (visible blood in urine)\n\nReduced fluid intake\n\nFever\n\nShivering\n\nAbdominal pain\n\nLoin tenderness or suprapubic tenderness\n\nCapillary refill longer than 3\xa0seconds\n\nPrevious history of confirmed urinary tract infection\n\nAbsence of painful urination (dysuria)\n\nNappy rash\n\nBreathing difficulties\n\nAbnormal chest sounds\n\nAbnormal ear examination\n\nFever with known alternative cause\n\nWhen using the table, be aware that:\n\nThe symptoms and signs in this table should be used to inform a decision about whether urine collection and testing is necessary.\n\nIt is not an exhaustive list of symptoms or signs and should be used as a guide alongside clinical judgement.\n\nThe presence or absence of a single symptom or sign in isolation in either column should not necessarily be used to decide whether or not to test for UTI.\n\nMultiple symptoms and signs will probably increase the likelihood that there is a UTI.\n\nIt may be useful to consider alternative diagnoses where the symptoms and signs decrease the likelihood that a UTI is present.\n\nFor babies or children under\xa05 with fever with no obvious cause where a UTI is no longer suspected, see the NICE guideline on fever in under 5s: assessment and initial management. \n\nPaediatric specialists should consult the section on management by the paediatric specialist in the NICE guideline on fever in under 5s: assessment and initial management, which covers when to test urine for a UTI in babies and children under\xa05 with fever who are in their care. \n\nAvoid delay when collecting and testing the urine sample. If the sample cannot be collected at the consultation, advise the parents or carers (as appropriate) to collect and return the urine sample as soon as possible, ideally within 24\xa0hours. See the sections on urine collection, preservation and testing.\n\nIf a baby, child or young person has suspected sepsis, assess and manage their condition in line with the NICE guideline on sepsis: recognition, diagnosis and early management. \n\nIf a baby of up to and including 28\xa0days corrected gestational age has suspected or confirmed bacterial infection, assess and manage their condition in line with the NICE guideline on neonatal infection: antibiotics for prevention and treatment. For early-onset neonatal infection, see the section on assessing and managing the risk of early-onset neonatal infection after birth, and for late-onset neonatal infection, see the section on risk factors for and clinical indicators of possible late-onset neonatal infection in the NICE guideline on neonatal infection: antibiotics for prevention and treatment. For guidance on when to consider sexual abuse, see recommendation 1.1.21 in the NICE guideline on child maltreatment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on symptoms and signs of urinary tract infection\xa0.\n\nFull details of the evidence and the committee's discussion for the 2017 recommendation are in evidence review\xa0A: urinary tract infection diagnosis in infants and children under 3 months and 3 months to 3 years.\n\nFull details of the evidence and the committee's discussion for the 2022 recommendations are in evidence review\xa0B: symptoms and signs.\n\nLoading. Please wait.\n\n## Assessment of risk of serious illness\n\nAssess the level of illness in babies and children in accordance with the section on clinical assessment of children with fever in the NICE guideline on fever in under\xa05s: assessment and initial management. \n\n## Urine collection\n\nTake urine samples from children and young people before they are given antibiotics. This is in line with the NICE antimicrobial prescribing guidelines on pyelonephritis (acute) and urinary tract infection (lower). \n\nBabies and children with a high risk of serious illness should have a urine sample taken, but treatment should not be delayed if a urine sample cannot be obtained. \n\nUse a clean catch method for urine collection wherever possible. \n\nIf a clean catch urine sample is not possible, use other non-invasive methods such as urine collection pads. It is important to follow the manufacturer's instructions when using urine collection pads. \n\nDo not use cotton wool balls, gauze or sanitary towels to collect urine from babies and children. \n\nUse catheter samples or suprapubic aspiration (SPA) when it is not possible or practical to collect urine by non-invasive methods. Use ultrasound guidance to confirm that there is urine in the bladder before SPA. \n\n## Urine preservation\n\nImmediately refrigerate or use boric acid to preserve urine samples that are to be cultured but cannot be cultured within 4\xa0hours of collection. \n\nFollow the manufacturer's instructions when using boric acid to ensure the correct specimen volume and avoid potential toxicity against bacteria in the specimen. \n\n## Urine testing\n\nUse dipstick testing for babies and children between 3\xa0months and 3\xa0years with suspected UTI, and:\n\nif both leukocyte esterase and nitrite are negative:\n\n\n\ndo not give antibiotics\n\ndo not send a urine sample for microscopy and culture unless at least 1 of the criteria in recommendation 1.1.21 apply.\n\n\n\nif leukocyte esterase or nitrite, or both are positive:\n\n\n\nsend the urine sample for culture\n\ngive antibiotics. \n\n\n\nUse the urine-testing strategy for children aged 3\xa0years or older shown in table\xa02. Assess the risk of serious illness in line with the section on clinical assessment of children with fever in the NICE guideline on fever in under 5s to ensure appropriate urine tests and interpretation, both of which depend on the child's age and risk of serious illness. \n\nUrine dipstick test result\n\nStrategy\n\nLeukocyte esterase and nitrite are both positive\n\nAssume the child has a urinary tract infection (UTI) and give them antibiotics. If the child has a high or intermediate risk of serious illness or a history of previous UTI, send a urine sample for culture.\n\nLeukocyte esterase is negative and nitrite is positive\n\nGive the child antibiotics if the urine test was carried out on a fresh urine sample. Send a urine sample for culture. Subsequent management will depend on the result of urine culture.\n\nLeukocyte esterase is positive and nitrite is negative\n\nSend a urine sample for microscopy and culture. Do not give the child antibiotics unless there is good clinical evidence of a UTI (for example, obvious urinary symptoms). A positive leukocyte esterase result may indicate an infection outside the urinary tract that may need to be managed differently.\n\nLeukocyte esterase and nitrite are both negative\n\nAssume the child does not have a UTI. Do not give the child antibiotics for a UTI or send a urine sample for culture. Explore other possible causes of the child's illness.\n\nDipstick testing for leukocyte esterase and nitrite is diagnostically as useful as microscopy and culture, and can safely be used.\n\nSend urine samples for culture if a baby or child:\n\nis thought to have acute upper UTI (pyelonephritis; see the section on clinical differentiation between acute upper UTI and lower UTI)\n\nhas a high to intermediate risk of serious illness (see the section on assessment of risk of serious illness)\n\nis under 3\xa0months old\n\nhas a positive result for leukocyte esterase or nitrite\n\nhas recurrent UTI\n\nhas an infection that does not respond to treatment within 24\xa0to\xa048\xa0hours, if no sample has already been sent\n\nhas clinical symptoms and signs but dipstick tests do not correlate. \n\nFor a short explanation of why the committee made the 2017 recommendations and how they might affect practice, see the rationale and impact section on urine testing\xa0.\n\nFull details of the evidence and the committee's discussion are in the evidence review\xa0A: urinary tract infection diagnosis in infants and children under 3 months and 3 months to 3 years.\n\nLoading. Please wait.\n\nInterpret microscopy results as shown in table\xa03. \n\nUse clinical criteria for decision making if a urine test does not support findings, because in a small number of cases, this may be the result of a false negative. \n\nMicroscopy results\n\nInterpretation\n\nPyuria and bacteriuria are both positive\n\nAssume the baby or child has a urinary tract infection (UTI)\n\nPyuria is positive and bacteriuria is negative\n\nStart antibiotic treatment if the baby or child has symptoms or signs of a UTI\n\nPyuria is negative and bacteriuria is positive\n\nAssume the baby or child has a UTI\n\nPyuria and bacteriuria are both negative\n\nAssume the baby or child does not have a UTI\n\n## History and examination of confirmed UTI\n\nRecord the following risk factors for UTI and serious underlying pathology:\n\npoor urine flow\n\nhistory suggesting previous UTI or confirmed previous UTI\n\nrecurrent fever of uncertain origin\n\nantenatally diagnosed renal abnormality\n\nfamily history of vesicoureteral reflux (VUR) or renal disease\n\nconstipation\n\ndysfunctional voiding\n\nenlarged bladder\n\nabdominal mass\n\nevidence of spinal lesion\n\npoor growth\n\nhigh blood pressure. \n\n## Clinical differentiation between acute upper UTI and lower UTI\n\nAssume a diagnosis of acute upper UTI in babies or children who have either:\n\nbacteriuria and fever of 38°C or higher or\n\nbacteriuria, fever lower than 38°C and loin pain or tenderness. \n\nAssume that babies and children who have bacteriuria but no systemic symptoms or signs have lower UTI (cystitis). \n\n## Laboratory tests for localising UTI\n\nDo not use C-reactive protein alone to differentiate acute upper UTI from lower UTI in babies and children. \n\n# Acute management\n\nNote that the antibiotic requirements for babies and children with conditions that are outside the scope of this guideline (for example, babies and children already known to have significant pre-existing uropathies) have not been addressed and may be different from those given here.\n\nImmediately refer babies and children with a high risk of serious illness (see the section on assessment of risk of serious illness) to a paediatric specialist. \n\nImmediately refer babies under 3\xa0months with a suspected UTI to a paediatric specialist. \n\nPaediatric specialists should give babies under 3\xa0months with a suspected UTI parenteral antibiotics in line with the section on management by the paediatric specialist in the NICE guideline on fever in under\xa05s. [2007, amended 2022]\n\nConsider referring babies and children over 3\xa0months with upper UTI to a paediatric specialist. \n\nGive babies and children over 3\xa0months with an acute upper UTI antibiotics in line with the NICE guideline on pyelonephritis (acute): antimicrobial prescribing. [2007, amended 2018]\n\nGive babies and children over 3\xa0months with lower UTI antibiotics in line with the NICE guideline on urinary tract infection (lower): antimicrobial prescribing. [2007, amended 2018]\n\nFor information about treating babies and children who were already on prophylactic antibiotics who then developed a UTI see the NICE guidelines on pyelonephritis (acute): antimicrobial prescribing, urinary tract infection (lower): antimicrobial prescribing and urinary tract infection (recurrent): antimicrobial prescribing. \n\nDo not use antibiotics to treat asymptomatic bacteriuria in babies and children. \n\nLaboratories should monitor patterns of urinary pathogen resistance and make this information routinely available to prescribers. \n\n## Preventing recurrence\n\nManage dysfunctional elimination syndromes and constipation in babies and children who have had a UTI. \n\nEncourage children who have had a UTI to drink enough water to avoid dehydration. \n\nEnsure that children who have had a UTI have access to clean toilets when needed and do not have to delay voiding unnecessarily. \n\n## Prophylactic antibiotics\n\nDo not routinely give prophylactic antibiotics to babies and children following first-time UTI. \n\nSee the NICE guideline on urinary tract infection (recurrent): antimicrobial prescribing for prophylactic antibiotic treatment for recurrent UTI in babies and children. \n\nDo not give prophylactic antibiotics to babies and children with asymptomatic bacteriuria. \n\n## Imaging tests for localising UTI\n\nDo not routinely use imaging to localise UTI. \n\nIn rare instances when it is clinically important to confirm or exclude acute upper UTI, use either:\n\npower doppler ultrasound or\n\na dimercaptosuccinic acid (DMSA) scintigraphy scan if power doppler ultrasound is not available or the diagnosis has not been confirmed. \n\n# Imaging tests\n\nSend babies and children with atypical UTI (see box\xa01) for a urinary tract ultrasound during the acute infection, to identify structural abnormalities such as obstruction and to ensure prompt management, as outlined in tables\xa04,\xa05 and\xa06. \n\nSend babies younger than 6\xa0months with first-time UTI that responds to treatment for ultrasound within 6\xa0weeks of the UTI, as outlined in table\xa04. \n\nBox 1 Definitions of atypical and recurrent urinary tract infection (UTI)\n\nAtypical UTI includes:\n\nSeriously ill (for more information, refer to the NICE guideline on fever in under\xa05s: assessment and initial management)\n\nPoor urine flow\n\nAbdominal or bladder mass\n\nRaised creatinine\n\nSepticaemia\n\nFailure to respond to treatment with suitable antibiotics within 48\xa0hours\n\nInfection with non-E. coli organisms\n\nRecurrent UTI:\n\nTwo or more episodes of UTI with acute upper UTI (acute pyelonephritis), or\n\nOne episode of UTI with acute upper UTI plus 1 or more episodes of UTI with lower UTI (cystitis), or\n\nThree or more episodes of UTI with lower UTI\n\nDo not routinely send babies and children over 6\xa0months with first-time UTI who respond to treatment for an ultrasound, unless they have atypical UTI as outlined in tables\xa05 and 6. \n\nBabies and children who have had a lower UTI should be sent for ultrasound (within 6\xa0weeks) only if they:\n\nare younger than 6\xa0months or\n\nhave had recurrent infections. \n\nUse a DMSA scan 4 to 6\xa0months after the acute infection to detect renal parenchymal defects in babies and children, as outlined in tables\xa04,\xa05\xa0and\xa06. \n\nIf the baby or child has a subsequent UTI while waiting for a DMSA scan, review the timing of the scan and consider doing it sooner. \n\nDo not routinely use imaging to identify VUR in babies and children who have had a UTI, except in specific circumstances as outlined in tables\xa04,\xa05\xa0and\xa06. \n\nWhen a micturating cystourethrogram (MCUG) is done, give prophylactic antibiotics orally for 3\xa0days with the MCUG on the second day. \n\nSend babies and children who have had a UTI for imaging, as outlined in tables 4, 5 and 6. \n\nTest\n\nResponds well to treatment within 48\xa0hours\n\nAtypical urinary tract infection\n\nRecurrent urinary tract infection\n\nUltrasound during the acute infection\n\nNo\n\nYes\n\nYes\n\nUltrasound within 6\xa0weeks\n\nYes\n\nIf abnormal consider micturating cystourethrogram (MCUG)\n\nNo\n\nNo\n\nDimercaptosuccinic acid scintigraphy scan 4 to 6\xa0months after the acute infection\n\nNo\n\nYes\n\nYes\n\nMicturating cystourethrogram\n\nNo\n\nYes\n\nYes\n\nSee box\xa01 for definitions of atypical and recurrent urinary tract infection.\n\nIn a baby with a non-E. coli urinary tract infection that is responding well to antibiotics and has no other features of atypical infection, a non-urgent ultrasound can be requested, to happen within 6\xa0weeks.\n\nTest\n\nResponds well to treatment within 48\xa0hours\n\nAtypical urinary tract infection\n\nRecurrent urinary tract infection\n\nUltrasound during the acute infection\n\nNo\n\nYes\n\nNo\n\nUltrasound within 6\xa0weeks\n\nNo\n\nNo\n\nYes\n\nDimercaptosuccinic acid scintigraphy scan 4 to 6\xa0months after the acute infection\n\nNo\n\nYes\n\nYes\n\nMicturating cystourethrogram\n\nNo\n\nNo\n\nNo\n\nSee box\xa01 for definitions of atypical and recurrent urinary tract infection.\n\nWhile MCUG should not be performed routinely it should be considered if the following features are present:\n\ndilatation on ultrasound\n\npoor urine flow\n\nnon-E. coli-infection\n\nfamily history of VUR.\n\nIn babies and children with a non-E. coli urinary tract infection that is responding well to antibiotics and has no other features of atypical infection, a non-urgent ultrasound can be requested, to happen within 6\xa0weeks.\n\nTest\n\nResponds well to treatment within 48\xa0hours\n\nAtypical urinary tract infection\n\nRecurrent urinary tract infection\n\nUltrasound during the acute infection\n\nNo\n\nYes\n\nNo\n\nUltrasound within 6\xa0weeks\n\nNo\n\nNo\n\nYes\n\nDimercaptosuccinic acid scintigraphy scan 4 to 6\xa0months after the acute infection\n\nNo\n\nNo\n\nYes\n\nMicturating cystourethrogram\n\nNo\n\nNo\n\nNo\n\nSee box\xa01 for definitions of atypical and recurrent urinary tract infection.\n\nUltrasound in toilet-trained children should be performed with a full bladder with an estimate of bladder volume before and after urination.\n\nIn a child with a non-E. coli urinary tract infection that is responding well to antibiotics and has no other features of atypical infection, a non-urgent ultrasound can be requested, to happen within 6\xa0weeks.\n\n# Surgical intervention\n\nDo not routinely use surgery for management of VUR. \n\n# Follow up\n\nDo not routinely follow up babies and children who have not had imaging investigations. \n\nDiscuss and agree with parents, carers or the young person (as appropriate) how the results of imaging will be communicated. \n\nDo not routinely offer follow-up outpatient appointments when the results of investigations are normal. \n\nGive parents or carers the results of all investigations in writing. \n\nRefer babies and children who have recurrent UTI or abnormal imaging results for assessment by a paediatric specialist. \n\nWhen assessing babies and children with renal parenchymal defects, include height, weight, blood pressure and routine testing for proteinuria. \n\nDo not offer long-term follow up to babies and children with minor, unilateral renal parenchymal defects, unless they have recurrent UTI, family history or lifestyle risk factors for hypertension. \n\nBabies and children who have bilateral renal abnormalities, impaired kidney function, raised blood pressure or proteinuria should have monitoring and appropriate management by a paediatric nephrologist to slow the progression of chronic kidney disease. \n\nDo not routinely retest babies' and children's urine for infection if they are asymptomatic after an episode of UTI. \n\nDo not follow up babies and children based only on the presence of asymptomatic bacteriuria. \n\n# Information and advice\n\nHealthcare professionals should ensure that when a child or young person has a suspected UTI, they and their parents or carers (as appropriate) are told about the need for treatment, the importance of completing any course of treatment and given advice about prevention and long-term management. \n\nEnsure that children and young people, and their parents or carers (as appropriate), know that UTIs can recur and that it is important to remain vigilant and to seek prompt treatment for any suspected reinfection. \n\nOffer children and young people, and their parents or carers (as appropriate) advice and information on:\n\nprompt recognition of symptoms\n\nurine collection, storage and testing\n\ntreatment options\n\nprevention\n\nthe nature of and reason for any urinary tract investigation\n\nprognosis\n\nreasons and arrangements for long-term management if required. \n\n# Terms used in this guideline\n\n## Bacteriuria\n\nBacteria in the urine with or without UTI.\n\n## Fever\n\nElevation of body temperature above the normal daily variation unless otherwise specified in a particular recommendation.\n\n## Pyuria\n\nWhite cells in the urine.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of recommendations for research is detailed in the full guideline.\n\n# Key recommendations for research\n\n## Symptoms and signs of urinary tract infection in children and young people aged 5 years and above but under 16 years\n\nWhat are the symptoms and signs of urinary tract infection (UTI) in children and young people aged 5\xa0years and above but under 16\xa0years? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on symptoms and signs\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: symptoms and signs.\n\nLoading. Please wait.\n\n## Long-term risk of renal scarring and impaired renal function\n\nA well designed cohort study investigating long-term outcomes including renal scarring and renal function of children who have had UTI should be conducted in the UK. \n\nUrinary tract infection and vesicoureteral reflux (VUR) in young children have been shown to be associated with both congenital and acquired renal damage. Progressive scarring is well documented in children with high grade VUR and recurrent UTI. Scarring has been associated with severe hypertension, proteinuria, complications in pregnancy and progression to established renal failure. These risks are likely to be greater in children with bilateral renal parenchymal defects. However, the frequency and magnitude of these risks for children with unilateral and bilateral renal damage are unclear. Knowledge of the risk of serious or progressive complications would be useful to determine the management of children with first‑time and recurrent UTIs.\n\n## Symptoms and signs of recurrent UTI\n\nDo the symptoms and signs of UTI in babies, children and young people aged under 16\xa0years differ in those with a history of recurrent UTIs compared with those without a history of recurrent UTI? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on symptoms and signs\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: symptoms and signs.\n\nLoading. Please wait.\n\n## Symptoms and signs of long-term (chronic) UTI\n\nWhat symptoms and signs do children and young people with long-term (chronic) UTI report and what do they perceive is the impact on their health and quality of life? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on symptoms and signs\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: symptoms and signs.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Symptoms and signs\n\nRecommendations 1.1.1 to 1.1.9\n\n## Why the committee made the recommendations\n\nThe committee discussed evidence from studies that looked at symptoms and signs of urinary tract infections (UTIs). They agreed that it is important to diagnose UTI quickly and accurately to prevent unnecessary suffering and serious complications like renal scarring.\n\nTable 1 shows several symptoms and signs that increase, or decrease, the likelihood of a UTI being present. The committee agreed that the table gives more certainty about which symptoms and signs increase or decrease the likelihood of a UTI being present. The committee also highlighted that many symptoms and signs from the 2007 version of the guideline (dysuria [painful urination], urinary frequency, loin tenderness and bedwetting) are still useful. However, the evidence around many of these symptoms and signs as indicators of UTI was low- or very-low quality. This was because many of the studies were not designed to assess diagnostic accuracy and had poor definitions of the symptoms and signs they reported. Therefore, the committee agreed that due to the remaining uncertainty, the table should be used as a guide alongside clinical judgement.\n\nBecause the list in table\xa01 is not exhaustive, the committee were concerned that some unwell babies, children and young people with a possible UTI might not have further tests if they lack symptoms or signs from the table. There are other symptoms and signs that could suggest a UTI for which no evidence was found or for which data was not reported in the studies. The committee therefore agreed that it may still be necessary to test for UTI, if healthcare professionals suspect UTI despite the absence of any symptoms or signs listed in the table.\n\nThe committee also looked at evidence for several algorithms that used combinations of symptoms and signs to help with diagnosis of UTI. None of the algorithms were particularly accurate, so the committee did not recommend their use. However, in the committee's opinion the presence of multiple symptoms or signs will probably increase the likelihood that there is a UTI.\n\nTable 1 does not specify relevant ages for particular symptoms and signs. This is because most of the evidence was for children under 5\xa0years and the trials mostly did not report results by age. The committee agreed that the symptoms and signs could be generalised across age groups, but that clinical judgement was needed when deciding which are relevant for an individual baby, child or young person. This is because age or ability to communicate (or if their symptoms cannot be accurately assessed) will affect the usefulness of a particular symptom or sign. For example, in all ages, the presence of dysuria increased the likelihood that a UTI was present and, when absent, decreased the likelihood. But it may be more difficult to assess in babies, children or young people who are not toilet trained or cannot communicate their symptoms. The committee also chose to include a confirmed history of UTI as a symptom or sign. Although it is not strictly a symptom or sign, it is associated with an increased likelihood of UTI.\n\nThe committee looked at evidence for other symptoms and signs that are not included in table\xa01. These included sleepiness or lethargy, irritability, poor feeding, vomiting, failure to thrive and jaundice. However, these were not found to be clinically useful in suggesting whether a UTI is present based on the evidence included in this review.\n\nThe committee noted that some symptoms (for example haematuria [blood in the urine], cloudy urine or dark urine) that were associated with an increased likelihood of UTI, could not be assessed by healthcare professionals without a urine sample. However, the symptoms and signs recommendations in this section are intended to provide guidance about when urine collection and testing is necessary. The committee therefore agreed to include these symptoms or signs in the table, based on the child self-reporting, or parental or caregiver reporting, rather than clinician assessment.\n\nThe committee were aware that there may be limitations with these symptoms. For example, darker urine is not specific to urinary tract infection and can be common in those who are unwell and dehydrated (a poor fluid intake not being uncommon in unwell children). Additionally, a report of visible blood, in the committee's opinion, was not common in UTI and would always require further investigation. However, the committee agreed that symptoms and signs that are less specific to the urinary tract might still be useful indicators of a UTI, particularly if they are present in combination with other symptoms and signs.\n\nThe committee noted that the symptoms and signs that decrease the likelihood of a UTI may suggest a different site of infection (such as the respiratory tract) but do not necessarily rule out a UTI. The list is not exhaustive (due to limitations in the evidence base) and other symptoms and signs may be present that suggest other sources of infection. The committee agreed that the urine of babies, children and young people aged 3\xa0months and over should not be routinely tested if they have symptoms and signs that suggest another type of infection. This is because it would be clinically unnecessary, waste resources and could increase the stress experienced by the baby or child and their family or carers. However, if they remain unwell and there is diagnostic uncertainty, a urine test may be needed to exclude UTI.\n\nFor babies and children under\xa05 with fever with no obvious cause where a UTI is no longer suspected, the NICE guideline on fever in under 5s: assessment and initial management could provide guidance in identifying the cause of their fever. The guideline also contains a section on diagnostic tests carried out by paediatric specialists on babies and children with fever in their care, including when to test urine for a UTI.\n\nThe committee acknowledged that in practice there may be delays in obtaining a urine sample for testing if one cannot be obtained during consultation. They agreed that both urine collection and testing should happen without delay to ensure rapid and accurate diagnosis. However, the committee were aware that urine cultures will not necessarily detect every UTI. Therefore, there is a risk of these babies, children and young people remaining undiagnosed. But they noted that recommendation\xa01.1.23 addresses this situation.\n\nWhen making the 2017 recommendation, the committee agreed that there are concerns about sepsis in babies under 3\xa0months with suspected UTI, and usual practice is referral rather than the GP managing symptoms. So, the committee recommended that all babies under 3\xa0months should be referred to specialist paediatric care and have a urine sample sent for urgent microscopy and culture.\n\nThe committee identified several gaps in the evidence. Most studies looked at symptoms and signs of UTI in babies and children aged under\xa05. Those that did include older children still had average ages closer to 5 than 16 and did not present data separately for older children. The committee therefore made a recommendation for research on the symptoms and signs of UTI in children and young people aged 5 years and above but under 16 years. They also made a recommendation for research on whether the symptoms and signs of recurrent UTI in babies, children and young people under\xa016 differed to acute UTI, because there was no evidence in this area. Finally, they made a recommendation for research to investigate the symptoms and signs experienced by children and young people with long-term (chronic) UTI as this was also not covered by the evidence.\n\n## How the recommendations might affect practice\n\nThe 2022 recommendations are unlikely to substantially change practice because the diagnostic pathway remains the same, although some of the symptoms and signs suggesting a UTI have changed. The absence of a recommendation for any diagnostic algorithm combining symptoms and signs, means that there will be little impact on clinical resources or training.\n\nThe committee believed the 2017 recommendation would provide concise and clear guidance for healthcare professionals and more efficient diagnosis for babies under 3\xa0months.\n\nReturn to recommendations\n\n# Urine testing\n\nRecommendations 1.1.19 and 1.1.21\n\n## Why the committee made the recommendations\n\nEvidence showed that a positive urine dipstick test for leukocyte esterase or nitrite in children 3\xa0months or older but younger than 3\xa0years, greatly increases the likelihood of a positive urine culture. Sending only positive samples for culture offered a better balance of benefits and costs for these children than prescribing antibiotics and urine culture for all children. In children aged 3\xa0months or older but younger than 3\xa0years, symptoms are easier to identify, and antibiotics should only be started if a dipstick test is positive for either or both leukocyte esterase or nitrite. Children in this age group with a positive dipstick test should also have a urine sample sent for culture.\n\n## How the recommendations might affect practice\n\nRecommending dipstick testing in babies and children aged 3\xa0months or older but younger than 3\xa0years clarifies the role of dipstick testing in this age group and encourages immediate diagnosis and treatment in primary care. The committee believe the new recommendations will provide concise and clear guidance for healthcare professionals and more efficient diagnosis. The recommendations will also be cost saving and reduce burden on laboratories by reducing the number of urine samples sent for culture.\n\nReturn to recommendations", 'Context': 'In the past 30 to 50\xa0years, the natural history of urinary tract infection (UTI) in children has changed as a result of the introduction of antibiotics and improvements in healthcare. This change has contributed to uncertainty about the most appropriate and effective way to manage UTI in children, and whether investigations and follow up are justified.\n\nUTI is a common bacterial infection that causes illness in babies and children. It may be difficult to recognise UTI in children because the presenting symptoms and signs are non-specific, particularly in babies and children younger than 3\xa0years. Collecting urine and interpreting results is not easy in this age group, so it may not always be possible to unequivocally confirm the diagnosis.\n\nCurrent management, which includes imaging, prophylaxis and prolonged follow up, has placed a heavy burden on NHS resources. It is based on limited evidence, is costly and unpleasant for children and is distressing for their parents or carers. This guideline has been developed with the aim of providing guidance on several aspects of UTI in babies and children from birth up to the age of 16\xa0years.'}	https://www.nice.org.uk/guidance/ng224	This guideline covers diagnosing and managing first or recurrent upper or lower urinary tract infection (UTI) in babies, children and young people under 16. It aims to achieve more consistent clinical practice, based on accurate diagnosis and effective management. It does not cover babies, children and young people with urinary catheters in situ, neurogenic bladders, significant pre-existing urinary tract disorders (uropathies), underlying renal disease or immunosuppression, or recurrent UTI in sexually active girls and young women under 16. It also does not cover babies, children and young people in intensive care units.
a67ec099566df5d4b59bc2e8226189679d9cdf83	nice	Imlifidase for desensitisation treatment before kidney transplant in people with chronic kidney disease	Imlifidase for desensitisation treatment before kidney transplant in people with chronic kidney disease Evidence-based recommendations on imlifidase (Idefirix) for desensitisation treatment before kidney transplant in people with chronic kidney disease. # Recommendations Imlifidase is recommended as a desensitisation treatment option for adults who: are waiting for a kidney transplant from a deceased donor are highly sensitised to human leukocyte antigens (HLA) have a positive crossmatch with the donor and are unlikely to have a transplant under the available kidney allocation system (including prioritisation programmes for highly sensitised people).It is recommended only if: a maximum of 1 dose is given it is given in a specialist centre with experience of treating high sensitisation to HLA the company provides imlifidase according to the commercial arrangement. This recommendation is not intended to affect treatment with imlifidase that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Many people with kidney disease may be on dialysis while they wait for a kidney transplant. This can have a substantial negative effect on health and quality of life. People can be highly sensitised usually because they have previously had a transfusion with a blood product, had a transplant or been pregnant, and they may have to wait several years for a suitable kidney. Some people on the waiting list may never have an offer of a donor kidney or may become too unwell to have a transplant. Imlifidase temporarily removes a substantial proportion of a person's antibodies, including those against HLA, so that a transplant can be done. It allows a donor kidney to be used that might otherwise not be a suitable match. The best available clinical evidence is limited and short term. Studies suggest that imlifidase gives a short period of time to do a transplant for people who are highly sensitised to HLA. Using imlifidase might increase the time from a kidney being donated to the transplant taking place. Kidneys are a scarce resource, and the UK Kidney Offering Scheme is responsible for ensuring that transplants are allocated in an equitable way. The changes to the UK Kidney Offering Scheme in 2019 have improved access for people who are highly sensitised to HLA. But there is still an unmet need for these people. People with certain protected characteristics (those from Black, Asian or minority ethnic family backgrounds and women who have been pregnant) have an increased chance of becoming highly sensitised and so would be the main groups to benefit from imlifidase. The cost-effectiveness estimates are within the range that NICE usually considers an acceptable use of NHS resources. There is substantial uncertainty about the estimates, but this uncertainty needs to be balanced against the benefits of more equitable access to transplants. Also, integrating imlifidase into the existing transplant process will be challenging. So, it is recommended, but it is essential that only 1 dose per person is used, in centres with experience of treating high sensitisation to HLA. This will help to minimise the time from a kidney being donated to the transplant taking place.# Information about imlifidase # Conditional marketing authorisation indication Imlifidase (Idefirix, Hansa Biopharma) is indicated for the 'desensitisation treatment of highly sensitised adult kidney transplant patients with positive crossmatch against an available deceased donor. The use of imlifidase should be reserved for patients unlikely to be transplanted under the available kidney allocation system including prioritisation programmes for highly sensitised patients.' The marketing authorisation for imlifidase is conditional based on trial results being provided in 2023 and 2025. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for imlifidase. # Price The proposed list price for imlifidase is £135,000 per 11 mg vial. An average course of treatment is expected to cost £282,150 at list price. The company has a commercial arrangement. This makes imlifidase available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Hansa Biopharma, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence. # Target population and NHS treatment pathway ## Renal replacement therapies while waiting for a kidney transplant can have a substantial effect on quality of life Many people who are waiting for a deceased donor kidney are on dialysis. This filters waste products out of the blood. Both haemodialysis and peritoneal dialysis have a substantial effect on day-to-day life for someone with advanced chronic kidney disease. The patient expert explained that before both types of dialysis, the person needs to have surgery. People on dialysis have restricted fluid intake and diets, and may have very reduced energy levels. Also, people having haemodialysis need 2 or 3 sessions a week, each lasting 5 hours, so there is a substantial impact on time. They explained that it is often difficult for people on dialysis to make plans to see friends and family, or go on holidays, and that the time needed for haemodialysis can affect their ability to work full time. Long-term dialysis can also have a range of effects on physical and mental health, such as bone disease, heart disease, and a loss of hope. In some cases, people die while on the transplant waiting list. One of the patient groups highlighted that being on dialysis can feel like "sitting and waiting and feeling like everything's on hold". The patient expert explained that although people recognise that a kidney transplant is not without risk, and lifelong immunosuppression afterwards can have side effects (such as skin cancer risks with older regimens), a kidney transplant gives hope for a more normal life. The committee recognised that people who are on dialysis, especially for a long time while waiting for a kidney transplant, have reduced quality of life. ## People who are highly sensitised wait longer for a suitable donor kidney, and imlifidase can improve access to kidney transplantation Some people who need a transplant have an immunological barrier to transplantation. They have antibodies to human leukocyte antigens (HLA), which is known as being sensitised. Exposure to tissue with different HLAs is the most common cause of sensitisation, and it can happen from transfusion of blood products, pregnancy or a previous transplant. People with a high level of sensitisation and no appropriate living donor can spend a long time on the waiting list for a deceased donor kidney. This is because they have antibodies against almost all donors' HLA (known as a positive crossmatch). In these circumstances, the donor kidney would be at very high risk of antibody-mediated rejection. One of the clinical experts explained that people who need a kidney transplant are encouraged to find a living donor if possible. This is because this creates the opportunity of either directed-donation transplant or transplant through the UK Living Kidney Sharing Scheme. If that is not possible, then people have dialysis until a suitable deceased donor is found through the national deceased donor allocation algorithm (UK Kidney Offering Scheme). NHS Blood and Transplant data reported in 2020 that the median wait for a deceased donor kidney was about 5 years for people who are highly sensitised, although a small number of people could wait more than 7 years. This is compared with a median waiting time of 1.5 to 2 years for people who are not sensitised at all. The UK Kidney Offering Scheme algorithm changed in 2019, with the aim of increasing access to transplants in the most sensitised population. Since 2019, the number of people in this group getting transplants has increased (see section 3.5). But the committee recognised that people who are highly sensitised still wait longer for a suitable donor kidney than those who are not. It recognised there is still an unmet need, and imlifidase offers the possibility of improving access to kidney transplantation. ## People who have waited a long time for a transplant may not be well enough to have one by the time a suitable donor is found While it is possible for a well-matched deceased donor kidney to become available for someone who is highly sensitised to HLA, it is unlikely. The likelihood of a favourable crossmatch may be measured by the calculated reaction frequency (CRF). That is, if someone waiting for a kidney had a CRF of 99%, this means 99% of the last 10,000 deceased donors would have HLA that would react with the blood serum of the person waiting for a kidney. In recent years, some centres have had success with antibody-incompatible transplants. Clinicians may 'delist' particular types of antigens from the individual's waiting list profile, because they believe those particular antibodies can be well managed to avoid antibody-mediated rejection. But the degree of risk-taking for incompatible transplants that centres are willing to take can vary. Delisting to increase the chances of finding a deceased donor match may not be possible for everyone who is highly sensitised. If these people do not have a suitable living donor available for a directed transplant or transplant through a kidney sharing scheme, then they have no other options but to continue waiting for a well-matched deceased donor kidney. If they wait too long, they may no longer be well enough to have a transplant. ## An intensive immunosuppression regimen is needed for some people Imlifidase is an enzyme that breaks down a major class of human antibodies (immunoglobulin G). This includes the antibodies that a person already has against potential donor kidneys. If imlifidase is given immediately before a transplant, it can change a positive crossmatch to a negative one. This allows a brief window for a transplant to be done without rapid rejection. It is considered innovative by some clinical experts. Because the treatment has a transient effect, antibody levels in the body rise after transplant. Some people who had imlifidase in the trials also had a more intensive regimen of immunosuppression drugs after transplant than is currently used in the NHS for transplants without imlifidase. The committee was aware that some people who might have imlifidase might need more intensive immunosuppression regimens. But it was also aware of the impact staying on dialysis can have on health and quality of life. The committee concluded that some people who are highly sensitised may need more intense immunosuppression after having a transplant with imlifidase. ## The proposed population is appropriate but needs to be considered in the context of current NHS clinical practice The deceased donor UK Kidney Offering Scheme was updated in 2019 (see section 3.2). This allowed kidneys to be donated from people who had died by circulatory death, in addition to those who had died by brainstem death, to be included in the UK Kidney Offering Scheme. It also increased the priority level of people who were previously harder to find a match for, or who have waited over 7 years for a transplant. People who joined the waiting list before the change, and who are highly sensitised and would have been unlikely to have a transplant, may no longer be in this population, because transplant rates have increased with the increased prioritisation. The company used data provided by NHS Blood and Transplant and clinical expert input to define its proposed eligible population for imlifidase. According to the company definition, people must have the following criteria to be eligible for imlifidase: a CRF of at least 99% a matchability score of 10 (a measure from 1 to 10 of how difficult it is to match a person with an organ donor in the UK) have been on the waiting list for a transplant for at least 2 years.The company had also included a requirement for people to have been on dialysis for at least 2 years to be eligible for imlifidase. This was to allow time to find a suitable organ using the Kidney Offering Scheme. But the ERG noted that this might exclude a small number of people who might otherwise have met the eligibility criteria. So, based on clinical feedback, the company agreed that being on dialysis should not necessarily be a requirement (see section 3.11). The clinical experts agreed that people with a CRF of 99% to 100% who were considered unlikely to have a transplant did represent the NHS population that this technology would be most suitable for. They noted that the proportion of deceased donor kidney transplants going to people with a CRF of 100% had doubled from 2% to 4% in the first year of applying the new UK algorithm, and suggested that the change in criteria had improved the prospects for people for whom it is difficult to find a match. But there are still people who would only be able to have a transplant if imlifidase were to become available. The company stated that this group of people represented around 10% of people on the Kidney Offering Scheme waiting list. It explained that despite the recent changes to the UK allocation algorithm, there are still people who do not benefit from the scheme and so are still unlikely to have a transplant. This is because the proposed population has substantially increased wait times for transplant, and many may never have a suitable donor organ offer. Consultation feedback noted that people who are highly sensitised are still disadvantaged in the new algorithm (see section 3.8). It suggested that access to transplantation for people who are highly sensitised could be increased by allowing antibody-incompatible transplants. This could be made more possible with imlifidase. The company stated that the major advantage of imlifidase would be greater equity of access to kidneys for transplant. The committee recognised that the availability of imlifidase would not increase the number of deceased donor kidneys available for transplant. But it acknowledged that it could change which people on the waiting list would benefit from this limited resource. The ERG noted that only a small number of people included in the company's trials met the company's proposed eligibility criteria. So, there was uncertainty about the generalisability of the clinical evidence to other people in the NHS (see section 3.8). Clinical feedback at consultation suggested the proposed population reflected the people who would be most likely to have imlifidase. The committee concluded that the company's proposed population is appropriate but needs to be considered in the context of NHS clinical practice (see section 3.6). ## Protocols should be developed to mitigate the impact of increased cold ischaemic time on donor kidneys when using imlifidase When a deceased donor kidney becomes available, it is allocated to an eligible person through the UK Kidney Offering Scheme. Various factors are considered to account for the suitability, urgency and need of a person who could have the donor kidney. The committee considered the impact this might have on the organ's cold ischaemic time (that is, the length of time between a kidney being removed from a donor and being transplanted). The clinical experts explained that the average cold ischaemic time varies across the transplant centres in the UK but is around 12 to 16 hours. It also varies for donations after brain stem death and for donations after circulatory death. The committee understood that going beyond a 12‑hour cold ischaemic time with kidneys after circulatory death may present a greater risk of delayed graft failure, and therefore they need to be transplanted within a shorter time window. Other factors can increase cold ischaemic time, including transporting the kidney and the number of crossmatch tests needed. The clinical experts agreed that an increased cold ischaemic time is likely to have some negative effects on transplant outcomes. But the company noted that recent data from NHS Blood and Transplant suggested that many transplants with a cold ischaemic time of more than 24 hours are still being carried out successfully. The clinical experts explained that procedures can be put in place to mitigate the impact of extended cold ischaemic time and prevent delays to transplantation. These could include pre-donation blood samples and virtual crossmatch testing. Already in NHS practice, a second person from the waiting list is lined up ready to have a transplant as a back-up, in case the first person matched cannot have the transplant. So, for imlifidase, if a negative crossmatch was not reached in time, the donor kidney could be used for someone else. The committee noted that the centres in the clinical trial were not based in the UK and might have been well placed for short cold ischaemic times, by providing high numbers of transplants and donors close by. The NHS England commissioning lead explained that a clinically led national multidisciplinary team would be needed to develop the pathways and protocols for using imlifidase if it was recommended. The committee agreed that these protocols could allow people needing imlifidase to be treated in a specialist centre with experience of transplantation in people who are highly sensitised. It concluded that protocols should be developed in a small number of specialist centres to mitigate the impact of increased cold ischaemic time on donor kidneys when using imlifidase. ## A limit of 1 imlifidase infusion should be used for people who are highly sensitised Adding a second imlifidase infusion could potentially increase the cold ischaemic time because an additional crossmatch test would be needed. Clinical feedback at consultation suggested that adding a second dose could add an extra 8 to 10 hours to the transplant process. Only a small number of people in the clinical trials who had imlifidase needed a second imlifidase infusion (the exact proportions are confidential). The clinical experts advised that 1 infusion would be sufficient in most situations. The committee agreed that giving only 1 infusion of imlifidase would allow for safe transplantation within acceptable cold ischaemic time thresholds. The committee accepted that this would be a pragmatic option given the challenges of the increased cold ischaemic time, and would allow for most people who are highly sensitised to have imlifidase. It concluded that there should be a limit of only 1 imlifidase infusion for people who are highly sensitised. # Perspective and scope of decision making ## Kidneys are a scarce resource, but decisions should consider equity of access for people who are highly sensitised Principle 7 of the principles that guide the development of NICE guidance and standards states that recommendations should be based on population benefits and value for money. As stated in NICE's guide to the methods of technology appraisal, 'the reference-case perspective on outcomes aims to maximise health gain from available healthcare resources.' The committee understood that any donor kidney used with imlifidase could have been used for someone else who is likely to incur lower costs, and have better outcomes and equal related savings from avoiding dialysis. The clinical experts had a wide range of views on which costs and benefits should be included. The company felt a utilitarian analysis at the population level would not capture the benefit of increased equity of access to transplants. It considered that allocation of deceased donor kidneys already relies on a trade-off between equitable access and providing best quality matching. The committee recognised the equity issues of people who are highly sensitised and agreed that these should be taken into account. The company had not provided much evidence of the differences in outcomes for people who are highly sensitised who had imlifidase, compared with those who are not highly sensitised and who would no longer get a transplant. The committee recognised these populations were different. But it was aware that both groups would be competing for the same resource. The company had not explored the potential consequences of this. The committee noted that principle 9 of the principles that guide the development of NICE guidance and standards aims to reduce health inequalities, which emphasises that NICE guidance should support strategies that improve population health as a whole. It considered that people who would be eligible for imlifidase are likely to have been on the waiting list for a long time and they would likely still be disadvantaged using the new Kidney Offering Scheme algorithm. The committee concluded that kidneys are a scarce resource, but decisions should consider opportunity costs as well as equity of access for people who are highly sensitised. # Clinical evidence ## The outcome data is short term but is the best data available Evidence for the clinical effectiveness of imlifidase originally came from 4 non-UK based, uncontrolled, open-label studies. The primary outcomes reported on safety and ability to achieve a crossmatch conversion after treatment with imlifidase. For this reason, they had short follow-up times that ranged between 64 days and 180 days. This meant that longer-term outcomes to assess the success of transplant were not estimated. The clinical experts agreed that the trial outcomes were too short for this clinical context (with potential graft loss at 5, 10 and 15 years). The company had acknowledged that longer-term data was needed and provided further clinical evidence for imlifidase from the trials originally included. The ERG had requested the company provide clinical evidence for 3 populations. These included: the company's newly defined patient population (see section 3.5) the most relevant patient population (defined by the company as people who are 'unlikely' to have a transplant, as informed by US-based criteria , receipt of a kidney from a deceased donor, and a calculated panel-reactive antibodies score of at least 99.9%) in the absence of evidence for the new population the sample of people in the company's included clinical trials who had imlifidase.The ERG considered that the quality of data beyond the original trials was limited. Very few people in the new eligible patient population for imlifidase were enrolled in the follow-up study. The company considers the actual number to be commercial in confidence so it cannot be reported here. There were high levels of withdrawals in the sample. Data was only available for 46% of people who had a calculated panel-reactive antibody score (the estimated proportion of deceased donors who are not compatible with a crossmatch) of 99.9% and had a deceased donor transplant at the final 3‑year follow up. The ERG stated that this meant data had been provided up to 3 years rather than a follow-up period based upon a minimum or median time period, which is usual in reporting clinical trial data. The company clarified that the data represented the longest-term available clinical data to date. Although the sample size was small, it reflected the relatively small group of people who would be eligible for imlifidase. The company's longer-term outcome data included rates of transplant rejection, median graft survival and overall survival. The exact details are confidential and cannot be reported here. The committee considered that although this represented the best available evidence for imlifidase, it was still limited. The ERG stated that the company's new evidence related to an initial 6 months after transplant. Clinical opinion sought by the ERG suggested that longer-term data beyond 3 years would be needed to better determine clinical outcomes, especially on graft survival and health-related quality of life, for people who have a transplant with imlifidase. The company confirmed it has submitted a protocol for a phase 3, controlled, non-randomised, open-label study. Nevertheless, the 3‑year outcomes are at least as good as those in antibody-incompatible live donor transplants in the UK. The company stated that its 3‑year follow-up data provided the longest-term clinical data for highly sensitised people needing kidney transplants. The committee concluded that although there was a lack of medium or long-term outcome data, this provided the best currently available data. ## Some antibody-mediated rejection is to be expected in people who are highly sensitised In the company's model, antibody-mediated rejection had been captured using data from its clinical trials. There was a high rate of antibody-mediated rejection (40%) in the company's original clinical data. There was no comparator arm in the trials nor a matched population. So, it was also not clear whether the 40% antibody-mediated rejection was a consequence of a very unwell population in the imlifidase trials, or a consequence of people having had imlifidase in the trials. Clinical experts explained that in clinical practice they would normally expect only 10% of people to have antibody-mediated rejection after an average transplant, based on UK experience. The committee noted that the antibody-mediated rejection rates were still high in the company's newly defined population. The exact rates cannot be reported because they are commercial in confidence. The clinical experts explained that it is difficult to establish exact rates because reasons will vary depending on individual characteristics. But a 30% to 50% antibody-mediated rejection rate for people who are highly sensitised in the first month after transplant would be plausible. At consultation, the company stated the antibody-mediated reaction rates in its trials were in line with what is expected in clinical practice for HLA-incompatible kidney transplants. In the company's trial data, no antibody-mediated rejection events were reported after the first year after transplant. So, the company had only included the events and related costs of antibody-mediated rejection events in the first 2 cycles of its model. The committee was concerned that antibody-mediated rejection had not been fully accounted for in the company's model. The model also did not differentiate between a graft needing intensive immunosuppression therapy and one that was more successful. Antibody-mediated rejection can be chronic and difficult to treat, with changes in immunosuppression regimens, biopsies and limited graft survival. Feedback at consultation clarified that an antibody-mediated rejection rate of 40% was consistent with HLA antibody-incompatible transplantation. The committee concluded that some antibody-mediated rejection is to be expected in people who are highly sensitised, but their quality of life will be improved while the transplant is working. # The economic model ## A small number of people would not have dialysis before having a transplant with imlifidase In its revised model, the company used NHS Blood and Transplant data to estimate the proportion of people who were not having imlifidase who had dialysis. It originally adjusted the proportions so that everyone would have had dialysis for at least 2 years. The ERG agreed that NHS Blood and Transplant data was an appropriate source to inform this distribution, but it did not agree that everyone would be having dialysis. Based on clinical opinion, it considered that there may be a small number of people who could otherwise meet the eligibility criteria but might not be able to have imlifidase if it assumed everyone had to have had dialysis for at least 2 years. The ERG therefore assumed that 5% of people in its base case would not have dialysis before imlifidase. The company later agreed that people who had not previously had dialysis would also be eligible for imlifidase (see section 3.5). It accepted that being on dialysis should not be a requirement but considered that a 5% proportion was too high. Based on clinical feedback it suggested it was unlikely that people who did not have dialysis would stay on the kidney waiting list for longer than 6 months. The committee recognised that there was some uncertainty around applying the estimate. But it concluded that some people would not be having dialysis before having a transplant with imlifidase. ## Not everyone who has imlifidase treatment goes on to have a kidney transplant, but the exact proportion is uncertain The company's original submission assumed that 100% of people who had imlifidase would go on to have a kidney transplant. However, this was not the case in its clinical trials. For its base case, the ERG used the trial data from everyone who had imlifidase. Two out of 54 people did not get the full dose of imlifidase before transplant, so 96.3% had a transplant in the imlifidase arm of the model. The ERG also considered a scenario taking into account the 1 person (out of 52) who did not have a negative flow cytometry crossmatch (the outcome of the trial) but who had a negative virtual crossmatch after imlifidase and had a transplant anyway. In the ERG's scenario, the proportion of people having a transplant in the imlifidase arm was informed by those who had a full dose, multiplied by those who had a negative crossmatch. So, 94.4% had a transplant in the imlifidase arm in this scenario. The committee considered both the ERG base case and scenario plausible and took these into account for decision making. The company updated its base case in line with the ERG preference that 96.3% of people having imlifidase will have a transplant after treatment. The committee accepted this change but recognised that there was still some uncertainty around the appropriate value, based on the small number of people there is data for. It concluded that not everyone who has imlifidase goes on to have a kidney transplant, but the exact proportion is uncertain. ## Graft survival projections from iBox are highly uncertain so a hazard ratio should be applied to account for this To extrapolate 6 months of post-transplant data from its trials, the company used the iBox predictive model for kidney graft survival. This was developed using data from a general transplant population in France, rather than a population consisting only of people who are highly sensitised. The iBox model was run with the company's trial data based on its original target population and using a Weibull distribution to extrapolate this to project long-term graft survival with imlifidase. Although the ERG considered iBox to be a high-quality predictive model, it was aware that iBox is a proprietary model that is not owned by the company. It had been unable to check how various factors were weighted, and the statistical power is unknown. The committee had originally considered the iBox projection and extrapolation to be too optimistic. It was concerned that the projection of trial data done through the iBox model was not a good long-term fit. This was because the 10‑year graft survival rates looked similar but seemed to improve for the company's highly sensitised population in relative terms at 20 years. This would suggest that people who are highly sensitised do relatively better over time, or the iBox general population (including people who are not highly sensitised) does relatively worse over time. This is implausible without evidence to support it. The committee considered that: Over longer time horizons, graft survival could be quite different between a general transplant population and the highly sensitised target population. So, it may not be appropriate to use the predictions from iBox (which was developed based on a general transplant population) and to apply them to a different population. There is a high antibody-mediated rejection rate in the company's target population in the trials (see section 3.10), with some people having chronic antibody-mediated rejection after imlifidase. Therefore, it could be reasonable to assume that graft survival is worse in people who are highly sensitised, and that these people may eventually need dialysis after transplant or need another transplant. If graft survival after imlifidase in clinical practice for people who are highly sensitised was worse than the modelled extrapolation of graft survival from the trial, then more people than modelled would start dialysis more quickly after transplant. This would mean there would be no further dialysis cost savings for them, and the incremental cost-effectiveness ratio (ICER) would increase. Graft survival could be related to how well immunosuppressant regimens are adhered to, which is not captured by iBox. The company later revised its graft survival extrapolations using its 3‑year follow-up data (see section 3.9) to inform graft loss, extrapolated with an exponential distribution. It suggested that this data showed graft survival rates were higher than the iBox prediction at 3 years. The ERG noted that the company's updated analysis used data from the company-defined most relevant population rather than the newly defined population (see section 3.9). But it did not think this assumption was reasonable. It considered that the trial data was still too immature to provide good estimates of graft survival. This was because data from only 6 people in the company's updated clinical analysis was informing the extrapolation over a lifetime horizon. So, it applied a hazard ratio of 0.90. This is because clinical feedback had suggested graft survival in people having imlifidase may not be as successful as in people who are not sensitised. The clinical experts explained that antibody-mediated rejection was not easy to predict because it is influenced by lots of factors, but applying a hazard ratio was appropriate. The committee agreed with this. At consultation, the company clarified that it still considered its 3‑year follow-up data was the most appropriate source to inform graft survival. But it provided a scenario using iBox and long-term graft survival estimates from 2 additional data sources as validation. This data showed that graft survival estimates were higher than those from iBox. So, the company considered it would not be appropriate to apply a hazard ratio to the iBox extrapolation. The ERG did not consider that the data sources used as validation by the company appropriately reflected the groups of people that would be eligible for imlifidase. It maintained its position that applying a hazard ratio of 0.90 was appropriate. The committee concluded that graft survival predictions were highly uncertain, so a hazard ratio should be applied to account for this. ## Extrapolations for overall survival with a functioning graft should be taken from the 'unlikely to be transplanted' population To estimate overall survival in people who had a functioning graft, the company base case extrapolated overall survival from all people who had imlifidase and a transplant (the 'all imlifidase' population) in the company trials. The company also provided a scenario analysis using data from the 'unlikely to have a transplant' population in its trials. Although the ERG considered using the 'all imlifidase' group reasonable, it considered it to make the cost-effectiveness results highly uncertain. The ERG noted the overall survival data was too uncertain to produce reasonable long-term estimates to be used for modelling a lifetime horizon in the population considered for this evaluation. The ERG considered that, in the absence of better data, either extrapolation using the 'all imlifidase' or the 'unlikely to be transplanted' data could be reasonably used to inform overall survival with a functioning graft. The ERG explored using the 'unlikely to be transplanted' overall survival data in a scenario analysis. The committee noted this substantially increased the ICER. It considered the 'unlikely to be transplanted' population to be more appropriate to extrapolate overall survival with a functioning graft. This would be the population that would be most likely to have imlifidase in clinical practice (see section 3.8). It concluded the extrapolations for overall survival with a functioning graft should be taken from the 'unlikely to be transplanted' population. # Cost-effectiveness estimates ## The most plausible cost-effectiveness estimates are lower than £30,000 per QALY gained NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The exact ICERs are confidential, but the committee preferred the ERG's assumptions; in the ERG's base case: % of people would not have dialysis before having imlifidase treatment predictions for graft survival were based on iBox with a 0.90 hazard ratio the number of crossmatch tests was set to 2.4.When individual assumptions were varied, some scenarios increased the ICER. The committee considered several assumptions to be plausible that would affect the ICER: Potentially no lower dialysis costs overall because of displacement of donor kidneys away from people who then have to stay on or start dialysis (see section 3.13). Correcting this would increase the ICER. Using data from the population who are unlikely to have a transplant would increase the ICER.The committee considered it was more plausible for the data informing overall survival with a functioning graft to be drawn from the 'unlikely to be transplanted' population in the company's clinical trials, because this would better reflect the relevant population in clinical practice (see section 3.14). It also recognised that there was substantial uncertainty surrounding the ICERs, and that if kidneys were used by less-sensitised populations this might lead to greater QALYs overall. But the committee considered that it needed to consider these points in the context of addressing equity of access issues (see section 3.8). Taking each of these issues into consideration, the committee concluded that the most plausible cost-effectiveness estimate would have to be less than £30,000 per QALY gained. # Other considerations ## People with protected characteristics have an increased chance of becoming highly sensitised Consultation feedback noted that changes to the Kidney Offering Scheme would improve access but never completely resolve inequity of access for people who are highly sensitised (see section 3.8). In particular, feedback stated that in people who have had previous blood transfusions, blood type and pregnancy are some of the risk factors that can increase the chances of developing an HLA sensitisation. For these reasons, some people from Black, Asian or minority ethnic family backgrounds, and people who have been pregnant, would be more likely to be highly sensitised. People with these protected characteristics may wait longer to have a transplant and might have difficulty accessing a matched kidney without imlifidase, compared with people who are not highly sensitised. This could have negative outcomes for people from these groups. The company stated that imlifidase could allow transplantation for people who are highly sensitised, regardless of the cause of their sensitisation. The committee was mindful of its responsibilities for people with protected characteristics under the Equality Act 2010 (see principle 9 of the principles that guide the development of NICE guidance and standards). The committee recognised that everyone who is highly sensitised and is offered a kidney under the Kidney Offering Scheme and meets the company's defined population would be considered eligible for imlifidase. It concluded that people with these protected characteristics have an increased chance of becoming very highly sensitised, and this should be taken into account in its decision making. ## Imlifidase could provide a step-change in treatment, but implementation should be done using robust NHS systems The committee considered whether imlifidase was innovative. It considered that imlifidase has the potential to provide a step-change to current treatment. But it was mindful of ensuring all costs and benefits were captured. The company had said that introducing imlifidase could allow people who would previously have been unlikely to get a transplant to go on to have a successful transplant, thereby improving equity of access for certain groups (see section 3.16). For this reason, the company suggested that imlifidase was innovative because it provided substantial benefits that may not be captured by measuring health gains directly. The committee agreed that imlifidase is a novel treatment because of its mechanism of action and that it could provide a brief window for a transplant to happen without rapid rejection. But it noted the challenges of introducing the technology, relating to increased cold ischaemic times and the issues around factoring in a second imlifidase infusion if it was needed (see section 3.6). The committee acknowledged that these factors must be taken into account in understanding whether a technology provides a step-change in treatment. It considered that implementation should be carefully considered. It was guided by the clinical experts that it was important to limit the number of centres providing imlifidase to minimise the impact on cold ischaemic time (see section 3.6). It considered that protocols were needed to support this when using imlifidase. The committee concluded that imlifidase could provide a step-change in treatment but that to allow this, implementation should be done using robust NHS systems. ## A managed access agreement is not appropriate The committee considered whether a managed access agreement would be appropriate. It considered that managed access is not appropriate to explore uncertainty around patient eligibility or the treatment pathway. It noted that a principle of managed access is that the entire eligible population should have access to treatment. It also noted that there are ethical issues with making a managed access recommendation when there are a finite number of donor kidneys. The committee considered it would be unlikely that a managed access recommendation for imlifidase aligned with the principles of resolving uncertainty through data collection, and considered whether the whole patient population could get access. It considered that the ongoing studies are unlikely to provide meaningful additional data for decision making. Collecting additional data in clinical practice would have ethical implications, which could add extra time to access to treatment. It concluded that a managed access agreement is not appropriate. # Conclusion ## Imlifidase is recommended, provided a maximum of 1 dose is given in a specialist centre with experience of treating high sensitisation to HLA The conditional marketing authorisation specifies that imlifidase should be reserved for people unlikely to have a transplant under the available kidney allocation system, including prioritisation programmes for people who are highly sensitised. The committee understood that it can be very difficult for some people who are highly sensitised to have an appropriately matched kidney transplant. It recognised that the changes to the UK Kidney Offering Scheme in 2019 had improved access to transplants for people who are highly sensitised, but that there is still an unmet need for this population. The committee preferred the ICERs based on the ERG analyses over the company's analysis. But these were also associated with a high level of uncertainty related to integration into the existing treatment pathway and long-term clinical effectiveness. It considered that kidneys are a scarce resource that need to be allocated fairly. The committee recalled that cold ischaemic time could be mitigated by allowing only 1 dose of imlifidase (see section 3.7). Protocols would need to be developed to allow imlifidase to be used in a small number of specialist centres with experience of transplantation in people who are highly sensitised (see section 3.6). The committee recognised that the company had attempted to address the uncertainties in its cost-effectiveness analyses. It recognised that imlifidase could help improve equity of access to kidneys for people who are highly sensitised (see section 3.16). It noted the protocols that would need to be developed by the NHS when using imlifidase would be clinically led, and should take into account the following criteria: a CRF of at least 99% (see section 3.5) a matchability score of 10 (see section 3.5) having been on the waiting list for a transplant for at least 2 years (see section 3.5) measures to minimise cold ischaemic time that would only be given in a specialist centre with experience of treating high sensitisation to HLA.The committee therefore recommended imlifidase provided that a maximum of 1 dose is given, and only in a specialist centre with experience of treating high sensitisation to HLA.	{'Recommendations': "Imlifidase is recommended as a desensitisation treatment option for adults who:\n\nare waiting for a kidney transplant from a deceased donor\n\nare highly sensitised to human leukocyte antigens (HLA)\n\nhave a positive crossmatch with the donor and are unlikely to have a transplant under the available kidney allocation system (including prioritisation programmes for highly sensitised people).It is recommended only if:\n\na maximum of 1 dose is given\n\nit is given in a specialist centre with experience of treating high sensitisation to HLA\n\nthe company provides imlifidase according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with imlifidase that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nMany people with kidney disease may be on dialysis while they wait for a kidney transplant. This can have a substantial negative effect on health and quality of life. People can be highly sensitised usually because they have previously had a transfusion with a blood product, had a transplant or been pregnant, and they may have to wait several years for a suitable kidney. Some people on the waiting list may never have an offer of a donor kidney or may become too unwell to have a transplant. Imlifidase temporarily removes a substantial proportion of a person's antibodies, including those against HLA, so that a transplant can be done. It allows a donor kidney to be used that might otherwise not be a suitable match.\n\nThe best available clinical evidence is limited and short term. Studies suggest that imlifidase gives a short period of time to do a transplant for people who are highly sensitised to HLA. Using imlifidase might increase the time from a kidney being donated to the transplant taking place.\n\nKidneys are a scarce resource, and the UK Kidney Offering Scheme is responsible for ensuring that transplants are allocated in an equitable way. The changes to the UK Kidney Offering Scheme in 2019 have improved access for people who are highly sensitised to HLA. But there is still an unmet need for these people. People with certain protected characteristics (those from Black, Asian or minority ethnic family backgrounds and women who have been pregnant) have an increased chance of becoming highly sensitised and so would be the main groups to benefit from imlifidase.\n\nThe cost-effectiveness estimates are within the range that NICE usually considers an acceptable use of NHS resources. There is substantial uncertainty about the estimates, but this uncertainty needs to be balanced against the benefits of more equitable access to transplants. Also, integrating imlifidase into the existing transplant process will be challenging. So, it is recommended, but it is essential that only 1\xa0dose per person is used, in centres with experience of treating high sensitisation to HLA. This will help to minimise the time from a kidney being donated to the transplant taking place.", 'Information about imlifidase': "# Conditional marketing authorisation indication\n\nImlifidase (Idefirix, Hansa Biopharma) is indicated for the 'desensitisation treatment of highly sensitised adult kidney transplant patients with positive crossmatch against an available deceased donor. The use of imlifidase should be reserved for patients unlikely to be transplanted under the available kidney allocation system including prioritisation programmes for highly sensitised patients.' The marketing authorisation for imlifidase is conditional based on trial results being provided in 2023 and 2025.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for imlifidase.\n\n# Price\n\nThe proposed list price for imlifidase is £135,000 per 11\xa0mg vial. An average course of treatment is expected to cost £282,150 at list price.\n\nThe company has a commercial arrangement. This makes imlifidase available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': 'The appraisal committee considered evidence submitted by Hansa Biopharma, a review of this submission by the evidence review group (ERG), NICE\'s technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Target population and NHS treatment pathway\n\n## Renal replacement therapies while waiting for a kidney transplant can have a substantial effect on quality of life\n\nMany people who are waiting for a deceased donor kidney are on dialysis. This filters waste products out of the blood. Both haemodialysis and peritoneal dialysis have a substantial effect on day-to-day life for someone with advanced chronic kidney disease. The patient expert explained that before both types of dialysis, the person needs to have surgery. People on dialysis have restricted fluid intake and diets, and may have very reduced energy levels. Also, people having haemodialysis need 2 or 3\xa0sessions a week, each lasting 5\xa0hours, so there is a substantial impact on time. They explained that it is often difficult for people on dialysis to make plans to see friends and family, or go on holidays, and that the time needed for haemodialysis can affect their ability to work full time. Long-term dialysis can also have a range of effects on physical and mental health, such as bone disease, heart disease, and a loss of hope. In some cases, people die while on the transplant waiting list. One of the patient groups highlighted that being on dialysis can feel like "sitting and waiting and feeling like everything\'s on hold". The patient expert explained that although people recognise that a kidney transplant is not without risk, and lifelong immunosuppression afterwards can have side effects (such as skin cancer risks with older regimens), a kidney transplant gives hope for a more normal life. The committee recognised that people who are on dialysis, especially for a long time while waiting for a kidney transplant, have reduced quality of life.\n\n## People who are highly sensitised wait longer for a suitable donor kidney, and imlifidase can improve access to kidney transplantation\n\nSome people who need a transplant have an immunological barrier to transplantation. They have antibodies to human leukocyte antigens (HLA), which is known as being sensitised. Exposure to tissue with different HLAs is the most common cause of sensitisation, and it can happen from transfusion of blood products, pregnancy or a previous transplant. People with a high level of sensitisation and no appropriate living donor can spend a long time on the waiting list for a deceased donor kidney. This is because they have antibodies against almost all donors\' HLA (known as a positive crossmatch). In these circumstances, the donor kidney would be at very high risk of antibody-mediated rejection. One of the clinical experts explained that people who need a kidney transplant are encouraged to find a living donor if possible. This is because this creates the opportunity of either directed-donation transplant or transplant through the UK Living Kidney Sharing Scheme. If that is not possible, then people have dialysis until a suitable deceased donor is found through the national deceased donor allocation algorithm (UK Kidney Offering Scheme). NHS Blood and Transplant data reported in 2020 that the median wait for a deceased donor kidney was about 5\xa0years for people who are highly sensitised, although a small number of people could wait more than 7\xa0years. This is compared with a median waiting time of 1.5\xa0to 2\xa0years for people who are not sensitised at all. The UK Kidney Offering Scheme algorithm changed in 2019, with the aim of increasing access to transplants in the most sensitised population. Since 2019, the number of people in this group getting transplants has increased (see section\xa03.5). But the committee recognised that people who are highly sensitised still wait longer for a suitable donor kidney than those who are not. It recognised there is still an unmet need, and imlifidase offers the possibility of improving access to kidney transplantation.\n\n## People who have waited a long time for a transplant may not be well enough to have one by the time a suitable donor is found\n\nWhile it is possible for a well-matched deceased donor kidney to become available for someone who is highly sensitised to HLA, it is unlikely. The likelihood of a favourable crossmatch may be measured by the calculated reaction frequency (CRF). That is, if someone waiting for a kidney had a CRF of 99%, this means 99% of the last 10,000 deceased donors would have HLA that would react with the blood serum of the person waiting for a kidney. In recent years, some centres have had success with antibody-incompatible transplants. Clinicians may \'delist\' particular types of antigens from the individual\'s waiting list profile, because they believe those particular antibodies can be well managed to avoid antibody-mediated rejection. But the degree of risk-taking for incompatible transplants that centres are willing to take can vary. Delisting to increase the chances of finding a deceased donor match may not be possible for everyone who is highly sensitised. If these people do not have a suitable living donor available for a directed transplant or transplant through a kidney sharing scheme, then they have no other options but to continue waiting for a well-matched deceased donor kidney. If they wait too long, they may no longer be well enough to have a transplant.\n\n## An intensive immunosuppression regimen is needed for some people\n\nImlifidase is an enzyme that breaks down a major class of human antibodies (immunoglobulin\xa0G). This includes the antibodies that a person already has against potential donor kidneys. If imlifidase is given immediately before a transplant, it can change a positive crossmatch to a negative one. This allows a brief window for a transplant to be done without rapid rejection. It is considered innovative by some clinical experts. Because the treatment has a transient effect, antibody levels in the body rise after transplant. Some people who had imlifidase in the trials also had a more intensive regimen of immunosuppression drugs after transplant than is currently used in the NHS for transplants without imlifidase. The committee was aware that some people who might have imlifidase might need more intensive immunosuppression regimens. But it was also aware of the impact staying on dialysis can have on health and quality of life. The committee concluded that some people who are highly sensitised may need more intense immunosuppression after having a transplant with imlifidase.\n\n## The proposed population is appropriate but needs to be considered in the context of current NHS clinical practice\n\nThe deceased donor UK Kidney Offering Scheme was updated in 2019 (see section\xa03.2). This allowed kidneys to be donated from people who had died by circulatory death, in addition to those who had died by brainstem death, to be included in the UK Kidney Offering Scheme. It also increased the priority level of people who were previously harder to find a match for, or who have waited over 7\xa0years for a transplant. People who joined the waiting list before the change, and who are highly sensitised and would have been unlikely to have a transplant, may no longer be in this population, because transplant rates have increased with the increased prioritisation. The company used data provided by NHS Blood and Transplant and clinical expert input to define its proposed eligible population for imlifidase. According to the company definition, people must have the following criteria to be eligible for imlifidase:\n\na CRF of at least 99%\n\na matchability score of 10 (a measure from 1 to 10 of how difficult it is to match a person with an organ donor in the UK)\n\nhave been on the waiting list for a transplant for at least 2\xa0years.The company had also included a requirement for people to have been on dialysis for at least 2\xa0years to be eligible for imlifidase. This was to allow time to find a suitable organ using the Kidney Offering Scheme. But the ERG noted that this might exclude a small number of people who might otherwise have met the eligibility criteria. So, based on clinical feedback, the company agreed that being on dialysis should not necessarily be a requirement (see section\xa03.11). The clinical experts agreed that people with a CRF of 99%\xa0to 100% who were considered unlikely to have a transplant did represent the NHS population that this technology would be most suitable for. They noted that the proportion of deceased donor kidney transplants going to people with a CRF of 100% had doubled from 2% to 4% in the first year of applying the new UK algorithm, and suggested that the change in criteria had improved the prospects for people for whom it is difficult to find a match. But there are still people who would only be able to have a transplant if imlifidase were to become available. The company stated that this group of people represented around 10% of people on the Kidney Offering Scheme waiting list. It explained that despite the recent changes to the UK allocation algorithm, there are still people who do not benefit from the scheme and so are still unlikely to have a transplant. This is because the proposed population has substantially increased wait times for transplant, and many may never have a suitable donor organ offer. Consultation feedback noted that people who are highly sensitised are still disadvantaged in the new algorithm (see section 3.8). It suggested that access to transplantation for people who are highly sensitised could be increased by allowing antibody-incompatible transplants. This could be made more possible with imlifidase. The company stated that the major advantage of imlifidase would be greater equity of access to kidneys for transplant. The committee recognised that the availability of imlifidase would not increase the number of deceased donor kidneys available for transplant. But it acknowledged that it could change which people on the waiting list would benefit from this limited resource. The ERG noted that only a small number of people included in the company\'s trials met the company\'s proposed eligibility criteria. So, there was uncertainty about the generalisability of the clinical evidence to other people in the NHS (see section\xa03.8). Clinical feedback at consultation suggested the proposed population reflected the people who would be most likely to have imlifidase. The committee concluded that the company\'s proposed population is appropriate but needs to be considered in the context of NHS clinical practice (see section\xa03.6).\n\n## Protocols should be developed to mitigate the impact of increased cold ischaemic time on donor kidneys when using imlifidase\n\nWhen a deceased donor kidney becomes available, it is allocated to an eligible person through the UK Kidney Offering Scheme. Various factors are considered to account for the suitability, urgency and need of a person who could have the donor kidney. The committee considered the impact this might have on the organ\'s cold ischaemic time (that is, the length of time between a kidney being removed from a donor and being transplanted). The clinical experts explained that the average cold ischaemic time varies across the transplant centres in the UK but is around 12\xa0to 16\xa0hours. It also varies for donations after brain stem death and for donations after circulatory death. The committee understood that going beyond a 12‑hour cold ischaemic time with kidneys after circulatory death may present a greater risk of delayed graft failure, and therefore they need to be transplanted within a shorter time window. Other factors can increase cold ischaemic time, including transporting the kidney and the number of crossmatch tests needed. The clinical experts agreed that an increased cold ischaemic time is likely to have some negative effects on transplant outcomes. But the company noted that recent data from NHS Blood and Transplant suggested that many transplants with a cold ischaemic time of more than 24\xa0hours are still being carried out successfully. The clinical experts explained that procedures can be put in place to mitigate the impact of extended cold ischaemic time and prevent delays to transplantation. These could include pre-donation blood samples and virtual crossmatch testing. Already in NHS practice, a second person from the waiting list is lined up ready to have a transplant as a back-up, in case the first person matched cannot have the transplant. So, for imlifidase, if a negative crossmatch was not reached in time, the donor kidney could be used for someone else. The committee noted that the centres in the clinical trial were not based in the UK and might have been well placed for short cold ischaemic times, by providing high numbers of transplants and donors close by. The NHS England commissioning lead explained that a clinically led national multidisciplinary team would be needed to develop the pathways and protocols for using imlifidase if it was recommended. The committee agreed that these protocols could allow people needing imlifidase to be treated in a specialist centre with experience of transplantation in people who are highly sensitised. It concluded that protocols should be developed in a small number of specialist centres to mitigate the impact of increased cold ischaemic time on donor kidneys when using imlifidase.\n\n## A limit of 1\xa0imlifidase infusion should be used for people who are highly sensitised\n\nAdding a second imlifidase infusion could potentially increase the cold ischaemic time because an additional crossmatch test would be needed. Clinical feedback at consultation suggested that adding a second dose could add an extra 8\xa0to 10\xa0hours to the transplant process. Only a small number of people in the clinical trials who had imlifidase needed a second imlifidase infusion (the exact proportions are confidential). The clinical experts advised that 1\xa0infusion would be sufficient in most situations. The committee agreed that giving only 1\xa0infusion of imlifidase would allow for safe transplantation within acceptable cold ischaemic time thresholds. The committee accepted that this would be a pragmatic option given the challenges of the increased cold ischaemic time, and would allow for most people who are highly sensitised to have imlifidase. It concluded that there should be a limit of only 1\xa0imlifidase infusion for people who are highly sensitised.\n\n# Perspective and scope of decision making\n\n## Kidneys are a scarce resource, but decisions should consider equity of access for people who are highly sensitised\n\nPrinciple\xa07 of the principles that guide the development of NICE guidance and standards states that recommendations should be based on population benefits and value for money. As stated in NICE\'s guide to the methods of technology appraisal, \'the reference-case perspective on outcomes aims to maximise health gain from available healthcare resources.\' The committee understood that any donor kidney used with imlifidase could have been used for someone else who is likely to incur lower costs, and have better outcomes and equal related savings from avoiding dialysis. The clinical experts had a wide range of views on which costs and benefits should be included. The company felt a utilitarian analysis at the population level would not capture the benefit of increased equity of access to transplants. It considered that allocation of deceased donor kidneys already relies on a trade-off between equitable access and providing best quality matching. The committee recognised the equity issues of people who are highly sensitised and agreed that these should be taken into account. The company had not provided much evidence of the differences in outcomes for people who are highly sensitised who had imlifidase, compared with those who are not highly sensitised and who would no longer get a transplant. The committee recognised these populations were different. But it was aware that both groups would be competing for the same resource. The company had not explored the potential consequences of this. The committee noted that principle\xa09 of the principles that guide the development of NICE guidance and standards aims to reduce health inequalities, which emphasises that NICE guidance should support strategies that improve population health as a whole. It considered that people who would be eligible for imlifidase are likely to have been on the waiting list for a long time and they would likely still be disadvantaged using the new Kidney Offering Scheme algorithm. The committee concluded that kidneys are a scarce resource, but decisions should consider opportunity costs as well as equity of access for people who are highly sensitised.\n\n# Clinical evidence\n\n## The outcome data is short term but is the best data available\n\nEvidence for the clinical effectiveness of imlifidase originally came from 4\xa0non-UK based, uncontrolled, open-label studies. The primary outcomes reported on safety and ability to achieve a crossmatch conversion after treatment with imlifidase. For this reason, they had short follow-up times that ranged between 64\xa0days and 180\xa0days. This meant that longer-term outcomes to assess the success of transplant were not estimated. The clinical experts agreed that the trial outcomes were too short for this clinical context (with potential graft loss at 5, 10 and 15\xa0years). The company had acknowledged that longer-term data was needed and provided further clinical evidence for imlifidase from the trials originally included. The ERG had requested the company provide clinical evidence for 3\xa0populations. These included:\n\nthe company\'s newly defined patient population (see section\xa03.5)\n\nthe most relevant patient population (defined by the company as people who are \'unlikely\' to have a transplant, as informed by US-based criteria [crossmatch positive], receipt of a kidney from a deceased donor, and a calculated panel-reactive antibodies score of at least 99.9%) in the absence of evidence for the new population\n\nthe sample of people in the company\'s included clinical trials who had imlifidase.The ERG considered that the quality of data beyond the original trials was limited. Very few people in the new eligible patient population for imlifidase were enrolled in the follow-up study. The company considers the actual number to be commercial in confidence so it cannot be reported here. There were high levels of withdrawals in the sample. Data was only available for 46% of people who had a calculated panel-reactive antibody score (the estimated proportion of deceased donors who are not compatible with a crossmatch) of 99.9% and had a deceased donor transplant at the final 3‑year follow up. The ERG stated that this meant data had been provided up to 3\xa0years rather than a follow-up period based upon a minimum or median time period, which is usual in reporting clinical trial data. The company clarified that the data represented the longest-term available clinical data to date. Although the sample size was small, it reflected the relatively small group of people who would be eligible for imlifidase. The company\'s longer-term outcome data included rates of transplant rejection, median graft survival and overall survival. The exact details are confidential and cannot be reported here. The committee considered that although this represented the best available evidence for imlifidase, it was still limited. The ERG stated that the company\'s new evidence related to an initial 6\xa0months after transplant. Clinical opinion sought by the ERG suggested that longer-term data beyond 3\xa0years would be needed to better determine clinical outcomes, especially on graft survival and health-related quality of life, for people who have a transplant with imlifidase. The company confirmed it has submitted a protocol for a phase\xa03, controlled, non-randomised, open-label study. Nevertheless, the 3‑year outcomes are at least as good as those in antibody-incompatible live donor transplants in the UK. The company stated that its 3‑year follow-up data provided the longest-term clinical data for highly sensitised people needing kidney transplants. The committee concluded that although there was a lack of medium or long-term outcome data, this provided the best currently available data.\n\n## Some antibody-mediated rejection is to be expected in people who are highly sensitised\n\nIn the company\'s model, antibody-mediated rejection had been captured using data from its clinical trials. There was a high rate of antibody-mediated rejection (40%) in the company\'s original clinical data. There was no comparator arm in the trials nor a matched population. So, it was also not clear whether the 40% antibody-mediated rejection was a consequence of a very unwell population in the imlifidase trials, or a consequence of people having had imlifidase in the trials. Clinical experts explained that in clinical practice they would normally expect only 10% of people to have antibody-mediated rejection after an average transplant, based on UK experience. The committee noted that the antibody-mediated rejection rates were still high in the company\'s newly defined population. The exact rates cannot be reported because they are commercial in confidence. The clinical experts explained that it is difficult to establish exact rates because reasons will vary depending on individual characteristics. But a 30%\xa0to 50% antibody-mediated rejection rate for people who are highly sensitised in the first month after transplant would be plausible. At consultation, the company stated the antibody-mediated reaction rates in its trials were in line with what is expected in clinical practice for HLA-incompatible kidney transplants. In the company\'s trial data, no antibody-mediated rejection events were reported after the first year after transplant. So, the company had only included the events and related costs of antibody-mediated rejection events in the first 2\xa0cycles of its model. The committee was concerned that antibody-mediated rejection had not been fully accounted for in the company\'s model. The model also did not differentiate between a graft needing intensive immunosuppression therapy and one that was more successful. Antibody-mediated rejection can be chronic and difficult to treat, with changes in immunosuppression regimens, biopsies and limited graft survival. Feedback at consultation clarified that an antibody-mediated rejection rate of 40% was consistent with HLA antibody-incompatible transplantation. The committee concluded that some antibody-mediated rejection is to be expected in people who are highly sensitised, but their quality of life will be improved while the transplant is working.\n\n# The economic model\n\n## A small number of people would not have dialysis before having a transplant with imlifidase\n\nIn its revised model, the company used NHS Blood and Transplant data to estimate the proportion of people who were not having imlifidase who had dialysis. It originally adjusted the proportions so that everyone would have had dialysis for at least 2\xa0years. The ERG agreed that NHS Blood and Transplant data was an appropriate source to inform this distribution, but it did not agree that everyone would be having dialysis. Based on clinical opinion, it considered that there may be a small number of people who could otherwise meet the eligibility criteria but might not be able to have imlifidase if it assumed everyone had to have had dialysis for at least 2\xa0years. The ERG therefore assumed that 5% of people in its base case would not have dialysis before imlifidase. The company later agreed that people who had not previously had dialysis would also be eligible for imlifidase (see section\xa03.5). It accepted that being on dialysis should not be a requirement but considered that a 5% proportion was too high. Based on clinical feedback it suggested it was unlikely that people who did not have dialysis would stay on the kidney waiting list for longer than 6\xa0months. The committee recognised that there was some uncertainty around applying the estimate. But it concluded that some people would not be having dialysis before having a transplant with imlifidase.\n\n## Not everyone who has imlifidase treatment goes on to have a kidney transplant, but the exact proportion is uncertain\n\nThe company\'s original submission assumed that 100% of people who had imlifidase would go on to have a kidney transplant. However, this was not the case in its clinical trials. For its base case, the ERG used the trial data from everyone who had imlifidase. Two out of 54\xa0people did not get the full dose of imlifidase before transplant, so 96.3% had a transplant in the imlifidase arm of the model. The ERG also considered a scenario taking into account the 1\xa0person (out of 52) who did not have a negative flow cytometry crossmatch (the outcome of the trial) but who had a negative virtual crossmatch after imlifidase and had a transplant anyway. In the ERG\'s scenario, the proportion of people having a transplant in the imlifidase arm was informed by those who had a full dose, multiplied by those who had a negative crossmatch. So, 94.4% had a transplant in the imlifidase arm in this scenario. The committee considered both the ERG base case and scenario plausible and took these into account for decision making. The company updated its base case in line with the ERG preference that 96.3% of people having imlifidase will have a transplant after treatment. The committee accepted this change but recognised that there was still some uncertainty around the appropriate value, based on the small number of people there is data for. It concluded that not everyone who has imlifidase goes on to have a kidney transplant, but the exact proportion is uncertain.\n\n## Graft survival projections from iBox are highly uncertain so a hazard ratio should be applied to account for this\n\nTo extrapolate 6\xa0months of post-transplant data from its trials, the company used the iBox predictive model for kidney graft survival. This was developed using data from a general transplant population in France, rather than a population consisting only of people who are highly sensitised. The iBox model was run with the company\'s trial data based on its original target population and using a Weibull distribution to extrapolate this to project long-term graft survival with imlifidase. Although the ERG considered iBox to be a high-quality predictive model, it was aware that iBox is a proprietary model that is not owned by the company. It had been unable to check how various factors were weighted, and the statistical power is unknown. The committee had originally considered the iBox projection and extrapolation to be too optimistic. It was concerned that the projection of trial data done through the iBox model was not a good long-term fit. This was because the 10‑year graft survival rates looked similar but seemed to improve for the company\'s highly sensitised population in relative terms at 20\xa0years. This would suggest that people who are highly sensitised do relatively better over time, or the iBox general population (including people who are not highly sensitised) does relatively worse over time. This is implausible without evidence to support it. The committee considered that:\n\nOver longer time horizons, graft survival could be quite different between a general transplant population and the highly sensitised target population. So, it may not be appropriate to use the predictions from iBox (which was developed based on a general transplant population) and to apply them to a different population.\n\nThere is a high antibody-mediated rejection rate in the company\'s target population in the trials (see section\xa03.10), with some people having chronic antibody-mediated rejection after imlifidase. Therefore, it could be reasonable to assume that graft survival is worse in people who are highly sensitised, and that these people may eventually need dialysis after transplant or need another transplant.\n\nIf graft survival after imlifidase in clinical practice for people who are highly sensitised was worse than the modelled extrapolation of graft survival from the trial, then more people than modelled would start dialysis more quickly after transplant. This would mean there would be no further dialysis cost savings for them, and the incremental cost-effectiveness ratio (ICER) would increase. Graft survival could be related to how well immunosuppressant regimens are adhered to, which is not captured by iBox. The company later revised its graft survival extrapolations using its 3‑year follow-up data (see section\xa03.9) to inform graft loss, extrapolated with an exponential distribution. It suggested that this data showed graft survival rates were higher than the iBox prediction at 3\xa0years. The ERG noted that the company\'s updated analysis used data from the company-defined most relevant population rather than the newly defined population (see section\xa03.9). But it did not think this assumption was reasonable. It considered that the trial data was still too immature to provide good estimates of graft survival. This was because data from only 6\xa0people in the company\'s updated clinical analysis was informing the extrapolation over a lifetime horizon. So, it applied a hazard ratio of 0.90. This is because clinical feedback had suggested graft survival in people having imlifidase may not be as successful as in people who are not sensitised. The clinical experts explained that antibody-mediated rejection was not easy to predict because it is influenced by lots of factors, but applying a hazard ratio was appropriate. The committee agreed with this. At consultation, the company clarified that it still considered its 3‑year follow-up data was the most appropriate source to inform graft survival. But it provided a scenario using iBox and long-term graft survival estimates from 2\xa0additional data sources as validation. This data showed that graft survival estimates were higher than those from iBox. So, the company considered it would not be appropriate to apply a hazard ratio to the iBox extrapolation. The ERG did not consider that the data sources used as validation by the company appropriately reflected the groups of people that would be eligible for imlifidase. It maintained its position that applying a hazard ratio of 0.90 was appropriate. The committee concluded that graft survival predictions were highly uncertain, so a hazard ratio should be applied to account for this.\n\n## Extrapolations for overall survival with a functioning graft should be taken from the \'unlikely to be transplanted\' population\n\nTo estimate overall survival in people who had a functioning graft, the company base case extrapolated overall survival from all people who had imlifidase and a transplant (the \'all imlifidase\' population) in the company trials. The company also provided a scenario analysis using data from the \'unlikely to have a transplant\' population in its trials. Although the ERG considered using the \'all imlifidase\' group reasonable, it considered it to make the cost-effectiveness results highly uncertain. The ERG noted the overall survival data was too uncertain to produce reasonable long-term estimates to be used for modelling a lifetime horizon in the population considered for this evaluation. The ERG considered that, in the absence of better data, either extrapolation using the \'all imlifidase\' or the \'unlikely to be transplanted\' data could be reasonably used to inform overall survival with a functioning graft. The ERG explored using the \'unlikely to be transplanted\' overall survival data in a scenario analysis. The committee noted this substantially increased the ICER. It considered the \'unlikely to be transplanted\' population to be more appropriate to extrapolate overall survival with a functioning graft. This would be the population that would be most likely to have imlifidase in clinical practice (see section 3.8). It concluded the extrapolations for overall survival with a functioning graft should be taken from the \'unlikely to be transplanted\' population.\n\n# Cost-effectiveness estimates\n\n## The most plausible cost-effectiveness estimates are lower than £30,000 per QALY gained\n\nNICE\'s guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The exact ICERs are confidential, but the committee preferred the ERG\'s assumptions; in the ERG\'s base case:\n\n% of people would not have dialysis before having imlifidase treatment\n\npredictions for graft survival were based on iBox with a 0.90 hazard ratio\n\nthe number of crossmatch tests was set to 2.4.When individual assumptions were varied, some scenarios increased the ICER. The committee considered several assumptions to be plausible that would affect the ICER:\n\nPotentially no lower dialysis costs overall because of displacement of donor kidneys away from people who then have to stay on or start dialysis (see section\xa03.13). Correcting this would increase the ICER.\n\nUsing data from the population who are unlikely to have a transplant would increase the ICER.The committee considered it was more plausible for the data informing overall survival with a functioning graft to be drawn from the \'unlikely to be transplanted\' population in the company\'s clinical trials, because this would better reflect the relevant population in clinical practice (see section\xa03.14). It also recognised that there was substantial uncertainty surrounding the ICERs, and that if kidneys were used by less-sensitised populations this might lead to greater QALYs overall. But the committee considered that it needed to consider these points in the context of addressing equity of access issues (see section\xa03.8). Taking each of these issues into consideration, the committee concluded that the most plausible cost-effectiveness estimate would have to be less than £30,000 per QALY gained.\n\n# Other considerations\n\n## People with protected characteristics have an increased chance of becoming highly sensitised\n\nConsultation feedback noted that changes to the Kidney Offering Scheme would improve access but never completely resolve inequity of access for people who are highly sensitised (see section\xa03.8). In particular, feedback stated that in people who have had previous blood transfusions, blood type and pregnancy are some of the risk factors that can increase the chances of developing an HLA sensitisation. For these reasons, some people from Black, Asian or minority ethnic family backgrounds, and people who have been pregnant, would be more likely to be highly sensitised. People with these protected characteristics may wait longer to have a transplant and might have difficulty accessing a matched kidney without imlifidase, compared with people who are not highly sensitised. This could have negative outcomes for people from these groups. The company stated that imlifidase could allow transplantation for people who are highly sensitised, regardless of the cause of their sensitisation. The committee was mindful of its responsibilities for people with protected characteristics under the Equality Act\xa02010 (see principle\xa09 of the principles that guide the development of NICE guidance and standards). The committee recognised that everyone who is highly sensitised and is offered a kidney under the Kidney Offering Scheme and meets the company\'s defined population would be considered eligible for imlifidase. It concluded that people with these protected characteristics have an increased chance of becoming very highly sensitised, and this should be taken into account in its decision making.\n\n## Imlifidase could provide a step-change in treatment, but implementation should be done using robust NHS systems\n\nThe committee considered whether imlifidase was innovative. It considered that imlifidase has the potential to provide a step-change to current treatment. But it was mindful of ensuring all costs and benefits were captured. The company had said that introducing imlifidase could allow people who would previously have been unlikely to get a transplant to go on to have a successful transplant, thereby improving equity of access for certain groups (see section\xa03.16). For this reason, the company suggested that imlifidase was innovative because it provided substantial benefits that may not be captured by measuring health gains directly. The committee agreed that imlifidase is a novel treatment because of its mechanism of action and that it could provide a brief window for a transplant to happen without rapid rejection. But it noted the challenges of introducing the technology, relating to increased cold ischaemic times and the issues around factoring in a second imlifidase infusion if it was needed (see section\xa03.6). The committee acknowledged that these factors must be taken into account in understanding whether a technology provides a step-change in treatment. It considered that implementation should be carefully considered. It was guided by the clinical experts that it was important to limit the number of centres providing imlifidase to minimise the impact on cold ischaemic time (see section 3.6). It considered that protocols were needed to support this when using imlifidase. The committee concluded that imlifidase could provide a step-change in treatment but that to allow this, implementation should be done using robust NHS systems.\n\n## A managed access agreement is not appropriate\n\nThe committee considered whether a managed access agreement would be appropriate. It considered that managed access is not appropriate to explore uncertainty around patient eligibility or the treatment pathway. It noted that a principle of managed access is that the entire eligible population should have access to treatment. It also noted that there are ethical issues with making a managed access recommendation when there are a finite number of donor kidneys. The committee considered it would be unlikely that a managed access recommendation for imlifidase aligned with the principles of resolving uncertainty through data collection, and considered whether the whole patient population could get access. It considered that the ongoing studies are unlikely to provide meaningful additional data for decision making. Collecting additional data in clinical practice would have ethical implications, which could add extra time to access to treatment. It concluded that a managed access agreement is not appropriate.\n\n# Conclusion\n\n## Imlifidase is recommended, provided a maximum of 1\xa0dose is given in a specialist centre with experience of treating high sensitisation to HLA\n\nThe conditional marketing authorisation specifies that imlifidase should be reserved for people unlikely to have a transplant under the available kidney allocation system, including prioritisation programmes for people who are highly sensitised. The committee understood that it can be very difficult for some people who are highly sensitised to have an appropriately matched kidney transplant. It recognised that the changes to the UK Kidney Offering Scheme in 2019 had improved access to transplants for people who are highly sensitised, but that there is still an unmet need for this population. The committee preferred the ICERs based on the ERG analyses over the company\'s analysis. But these were also associated with a high level of uncertainty related to integration into the existing treatment pathway and long-term clinical effectiveness. It considered that kidneys are a scarce resource that need to be allocated fairly. The committee recalled that cold ischaemic time could be mitigated by allowing only 1\xa0dose of imlifidase (see section\xa03.7). Protocols would need to be developed to allow imlifidase to be used in a small number of specialist centres with experience of transplantation in people who are highly sensitised (see section\xa03.6). The committee recognised that the company had attempted to address the uncertainties in its cost-effectiveness analyses. It recognised that imlifidase could help improve equity of access to kidneys for people who are highly sensitised (see section\xa03.16). It noted the protocols that would need to be developed by the NHS when using imlifidase would be clinically led, and should take into account the following criteria:\n\na CRF of at least 99% (see section\xa03.5)\n\na matchability score of 10 (see section\xa03.5)\n\nhaving been on the waiting list for a transplant for at least 2\xa0years (see section\xa03.5)\n\nmeasures to minimise cold ischaemic time that would only be given in a specialist centre with experience of treating high sensitisation to HLA.The committee therefore recommended imlifidase provided that a maximum of 1\xa0dose is given, and only in a specialist centre with experience of treating high sensitisation to HLA.'}	https://www.nice.org.uk/guidance/ta809	Evidence-based recommendations on imlifidase (Idefirix) for desensitisation treatment before kidney transplant in people with chronic kidney disease.
f16136ed2c1386271031ded136fa1e22e12a6cb3	nice	Abemaciclib with endocrine therapy for adjuvant treatment of hormone receptor-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence	Abemaciclib with endocrine therapy for adjuvant treatment of hormone receptor-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence Evidence-based recommendations on abemaciclib (Verzenios) with endocrine therapy for adjuvant treatment of hormone receptor-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence in adults. # Recommendations Abemaciclib with endocrine therapy is recommended, within its marketing authorisation, as an option for adjuvant treatment of hormone receptor-positive, HER2-negative, node‑positive early breast cancer in adults whose disease is at high risk of recurrence, defined by the following clinical and pathological features: at least 4 positive axillary lymph nodes, or to 3 positive axillary lymph nodes, and at least one of the following criteria: grade 3 disease (defined as at least 8 points on the modified Bloom–Richardson grading system or equivalent), or primary tumour size of at least 5 cm.It is recommended only if the company provides it according to the commercial arrangement. Why the committee made these recommendations Adjuvant treatment aims to reduce the risk of cancer returning after surgery. Chemotherapy followed by endocrine therapy is standard care for adjuvant treatment of hormone receptor-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence. Abemaciclib plus endocrine therapy is another adjuvant treatment option. Clinical trial evidence shows that adjuvant treatment with abemaciclib plus endocrine therapy increases how long people are free of disease compared with endocrine therapy alone. This is for people whose condition is at high risk of recurrence because the cancer has spread into: at least 4 axillary (armpit) lymph nodes, or to 3 axillary lymph nodes, and there is either grade 3 disease or the primary tumour is at least 5 cm. It is uncertain how long the benefit of abemaciclib with endocrine therapy lasts because data is still being collected. The cost-effectiveness estimates are also uncertain, but the most likely estimates are within the range NICE considers an acceptable use of NHS resources. Therefore, abemaciclib is recommended.# Information about abemaciclib # Marketing authorisation indication Abemaciclib (Verzenios, Eli Lilly) 'in combination with endocrine therapy is indicated for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive early breast cancer at high risk of recurrence. In pre- or perimenopausal women, aromatase inhibitor endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for abemaciclib. # Price The list price for abemaciclib is £2,950 per 28‑day cycle of 150‑mg tablets (£1,475 per 28‑tablet pack or £2,950 per 56‑tablet pack; excluding VAT; BNF online, accessed May 2022). The company has a commercial arrangement. This makes abemaciclib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Eli Lilly, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # New treatment option and treatment pathway ## People with early breast cancer and their families would welcome a new effective treatment option that reduces the risk of recurrence Breast cancer is the most common cancer in the UK. Hormone receptor‑positive, HER2-negative breast cancer is the most common subtype, accounting for about 70% of all breast cancers. The patient experts explained that hormone receptor-positive, HER2-negative, node-positive early-stage breast cancer at high risk of recurrence has a considerable impact on quality of life. Initial diagnosis is distressing and the fear of the cancer returning is a common cause of stress and anxiety for patients and their families. This is because of the need to have further treatment or the possibility of progression to non-curable metastatic disease. For people with HER2-negative disease, treatment options are limited and are associated with unpleasant side effects that make completing the recommended course of therapy difficult. The clinical expert noted that early breast cancer relapses after initial treatment in 30% of people. They noted that the risk of recurrence is higher with certain clinical and pathological risk factors such as a high number of positive lymph nodes, large tumour size, or high cellular proliferation measured by tumour grade or biomarkers. People whose disease is at high risk of recurrence after surgery have significant unmet need. Patients and clinicians would greatly value targeted therapies to reduce the risk of recurrence. The committee concluded that people with hormone receptor-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, and their families, would welcome a new effective treatment option that reduces the risk of recurrence. ## Abemaciclib plus endocrine therapy is an important step-change for managing the condition Adjuvant treatment with cytotoxic chemotherapy or endocrine therapy, or both, has remained the standard of care for many years. After surgery, adjuvant treatment is prescribed based on prognostic and predictive factors. The clinical experts explained that most people whose cancer is at high risk of recurrence are first offered adjuvant chemotherapy. Extended adjuvant endocrine therapy is then offered for 5 years to 10 years. They noted that the risk of recurrence does not decrease with time for people with hormone receptor-positive, HER2-negative, node-positive early breast cancer. But, people whose disease is identified as being at high risk of recurrence have the highest risk during the first 3 years after surgery. Abemaciclib plus endocrine therapy offers a targeted adjuvant treatment option earlier in the treatment pathway, thereby increasing the chance of curing the disease and reducing the likelihood of developing incurable advanced disease. The clinical expert also noted that although abemaciclib can cause diarrhoea and other side effects, these can usually be managed. The committee concluded that abemaciclib plus endocrine therapy is an important step-change in the treatment of hormone receptor-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence. # Clinical evidence ## Cohort 1 from monarchE is the relevant population for consideration and is generalisable to NHS clinical practice The evidence for abemaciclib with endocrine therapy came from monarchE. This is an ongoing multicentre, open-label, randomised trial in 5,637 people with hormone receptor-positive, HER2‑negative, node-positive early breast cancer at high risk of recurrence. The committee noted that abemaciclib should be taken continuously for 2 years, or until disease recurrence or unacceptable toxicity occurs. In MonarchE, abemaciclib (taken for up to 2 years) plus endocrine therapy (taken for 5 years to 10 years) was compared with endocrine therapy alone (taken for 5 years to 10 years). Over 60% of people in the trial had prior adjuvant chemotherapy but no more than 12 weeks of endocrine therapy before randomisation. The trial included 199 people from the UK and included 2 cohorts that used different inclusion criteria to define high risk of recurrence. The ERG raised concerns about whether the overall trial population reflected people with high-risk disease that could easily be identified in clinical practice. It considered that results from cohort 1 of monarchE would be more relevant to the NHS. Cohort 1 enrolled people at high risk of recurrence based on the following clinical and pathological features: pathological tumour involvement in at least 4 positive axillary lymph nodes, or pathological tumour involvement in 1 to 3 positive axillary lymph nodes, and at least one of the following criteria: grade 3 disease (defined as at least 8 points on the modified Bloom–Richardson grading system or equivalent), or primary tumour size of at least 5 cm.Cohort 2 was a smaller group that enrolled people at high risk of recurrence based on a Ki‑67 index value of at least 20%. The company noted that this biomarker is not routinely tested in the NHS and it was not proposing introducing Ki‑67 testing. The clinical experts explained that people whose disease is at high risk of recurrence, based on clinical and pathological risk factors, represented a small population in clinical practice (see section 3.1). They considered that cohort 1 was an adequate representation of this population and results from analyses using cohort 1 data were suitable for decision making. The committee noted that the marketing authorisation was granted only for cohort 1 from monarchE and concluded it is generalisable to NHS clinical practice. ## Abemaciclib with endocrine therapy improves invasive disease-free survival compared with endocrine therapy The primary outcome for monarchE was invasive disease-free survival. In cohort 1, people having abemaciclib with endocrine therapy had improved invasive disease-free survival compared with people having endocrine therapy alone (hazard ratio 0.680; 95% confidence interval 0.572 to 0.808). Median overall survival has not been reached in either treatment arm of monarchE (results are confidential and cannot be reported here). The clinical experts noted that although disease-free survival is a widely accepted surrogate for overall survival, studies have successfully used invasive disease-free survival as a compound surrogate outcome for overall survival. The Cancer Drugs Fund clinical lead considered that improved invasive disease-free survival with abemaciclib may take up to 10 years to show a clinically worthwhile overall survival benefit. The clinical experts considered overall survival benefit may be seen earlier, from 5 years onwards for people whose disease is at high risk of recurrence. The committee acknowledged the difficulty of obtaining mature overall survival data for adjuvant treatments which are used at early stages when there is no known residual disease after surgery. It concluded that, in the absence of mature overall survival data, invasive disease-free survival is a suitable surrogate for decision making. However, it recognised that the extent to which invasive disease-free survival translates into long-term overall survival benefit is not known. ## Differences in treatment effect based on menopausal status and type of endocrine therapy used are minimal The type of endocrine therapy used in clinical practice depends on menopausal status. The ERG noted that bias may be introduced because of differences in comparators for pre- and postmenopausal people. It further noted that outcomes for invasive disease-free survival and distant relapse-free survival are better for premenopausal people; therefore, results for pre- and postmenopausal subgroups should be considered separately. The clinical expert explained that many people in clinical practice cannot tolerate one endocrine treatment, and switch to another. A key challenge for clinicians is finding a treatment combination that balances treatment benefit and side effects and helps treatment adherence. Often clinicians will try different endocrine therapies to find the optimal treatment combination for the person's individual needs. The company also highlighted that in monarchE cohort 1, there were no statistically significant differences for menopausal status at diagnosis for invasive disease-free survival and distant relapse-free survival. It also highlighted that previous NICE technology appraisals for hormone receptor-positive, HER2-positive breast cancer had not considered subgroups by menopausal status. The clinical experts explained that abemaciclib had a treatment benefit irrespective of the endocrine therapy option taken alongside abemaciclib. Despite an initial difference in treatment effect between pre- and postmenopausal subgroups at 12 months and 24 months, the treatment effect at 36 months was similar between the 2 groups. The committee concluded that differences in treatment effect based on menopausal status and type of endocrine therapy used are minimal and that the whole monarchE cohort 1 population is suitable for decision making. # Adverse effects ## The safety profile of abemaciclib with endocrine therapy is acceptable The committee noted that treatment discontinuations because of adverse events were more common with abemaciclib plus endocrine therapy than endocrine therapy alone. The patient experts explained that adverse events reported in monarchE were consistent with the known safety profile for abemaciclib, which is used in the NHS to treat advanced breast cancer. The most common side effect of abemaciclib is diarrhoea, which can disrupt day-to-day activities in the worst cases, but can generally be managed through medication or treatment breaks. For many patients, the potential benefit of abemaciclib with endocrine therapy outweighs the risk of side effects. The clinical experts agreed that abemaciclib's adverse effects are generally well tolerated. But, they noted that treatment delays because of toxicities and subsequent burden of increased appointments with GPs and oncologists are a potential disadvantage of the treatment. The committee concluded that the safety profile of abemaciclib with endocrine therapy is acceptable to patients. # The company's economic model ## Extrapolation of invasive disease-free survival using the log-logistic curve is a source of uncertainty but is suitable for decision making The company presented a cohort state transition model with 5 health states: invasive disease-free survival, non-metastatic recurrence, remission, metastatic recurrence and death. The non-metastatic recurrence state was split into 2 substates, second primary neoplasm and locoregional or contralateral. The company model included subsequent treatments after metastatic recurrence of the disease, occurring either during endocrine therapy (endocrine resistant) or 12 months after endocrine therapy (endocrine sensitive). Because there is limited trial data available, the company used parametric curves to extrapolate invasive disease-free survival data over a lifetime time horizon. This results in considerable uncertainty in the long-term effectiveness of abemaciclib with endocrine therapy compared with endocrine therapy alone. The company and ERG both used the log‑logistic curve to extrapolate invasive disease-free survival data in their base-case analyses because it provided the best statistical fit. However, the ERG noted that the choice of curve is a source of substantial uncertainty because of the very limited trial data available. A scenario analysis using an alternative curve (lognormal) to extrapolate invasive disease-free survival data increased the cost-effectiveness estimate. The company noted that the lognormal curve provided the worst statistical fit to the first 3 years of Kaplan–Meier data from monarchE and was not clinically plausible. The clinical experts considered invasive disease-free survival predicted by extrapolation of data using the log-logistic curve for the endocrine therapy arm was clinically plausible for a population whose disease was at high risk of recurrence. The committee concluded that extrapolation of long-term invasive disease-free survival using the log-logistic curve is a source of uncertainty, but in the absence of an alternative option, is suitable for decision making. ## The assumed duration of treatment effect and treatment waning assumptions for abemaciclib are very uncertain The company's base-case analysis assumed a full treatment effect for abemaciclib with endocrine therapy that is maintained for 8 years, and then a treatment waning effect lasting 19 years until year 27. This was based on NICE's technology appraisal guidance on neratinib. The committee recalled that abemaciclib should be taken continuously for 2 years, or until disease recurrence or unacceptable toxicity occurs. The ERG considered that there was no evidence to support the treatment effect for abemaciclib lasting 8 years and for the treatment waning assumptions used by the company. In the ERG's base case, the abemaciclib treatment effect is maintained for 3 years based on monarchE follow-up data, then gradually decreases to no treatment effect at 8 years. The company considered the ERG's approach to be more conservative than previously accepted in NICE technology appraisals for early breast cancer, in which the full treatment effect was assumed to last for a minimum of 4 years. It noted that monarchE demonstrates a treatment effect of abemaciclib with endocrine therapy beyond discontinuation. Furthermore, the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial reporting up to 10 years of data for anastrazole and tamoxifen showed a lasting treatment benefit up to 8 years for 1 endocrine therapy over the other. This was used as a proxy to inform plausible duration of treatment effect for abemaciclib. The ERG acknowledged that its base-case analysis could potentially be conservative. It explored different waning assumptions in scenario analyses, noting that this was one of the key drivers for the cost‑effectiveness analyses. The committee noted that the ERG scenario analyses with varied assumptions about the duration of treatment effect using the patient access scheme price for abemaciclib without other confidential discounts, still resulted in cost-effectiveness estimates within the acceptable range. This was except the very conservative scenario when treatment was assumed to stop completely at 3 years, which was not supported by the Kaplan–Meier trial data. The committee concluded that the duration of treatment effect and treatment effect waning for abemaciclib with endocrine therapy that would be seen in clinical practice is highly uncertain. It took into consideration a range of potentially plausible estimates. ## Adherence to adjuvant endocrine therapy has not been included in the economic model but is not critical for decision making Non-adherence to adjuvant endocrine therapy in clinical practice was considered a concern by the ERG, who noted that its impact was not modelled in the company model. The company explained that the pattern of non-adherence seen in monarchE is representative of clinical practice in the NHS. Also, any reduction in endocrine therapy cost is likely to have a small impact on the cost-effectiveness estimates because the overall costs for endocrine therapy are relatively low. The clinical expert considered that people whose condition is at high risk of recurrence are highly motivated to continue treatment to prevent their cancer returning and tend to adhere to treatment. Furthermore, medication adherence rate is likely to be the same for those taking it with and after abemaciclib, and those taking it as monotherapy. There is no evidence to suggest a larger impact on the abemaciclib with endocrine therapy arm. The committee concluded that adherence to adjuvant endocrine therapy is not critical for decision making. # Cost-effectiveness estimates ## The most plausible ICER is uncertain but likely to be cost effective The company's base-case incremental cost-effectiveness ratio (ICER) for abemaciclib with endocrine therapy compared with endocrine therapy alone was £9,164 per quality-adjusted life year (QALY) gained. This includes the confidential patient access scheme discount for abemaciclib but list prices for endocrine therapy in both arms and subsequent treatments in response to a metastatic recurrence of the disease. The company's base case: used the log-logistic curve to extrapolate invasive disease-free survival data beyond the trial period (see section 3.7) assumed a constant treatment effect for 8 years assumed a treatment waning effect for 19 years until year 27 (see section 3.8)The ERG also used the log-logistic curve to extrapolate invasive disease‑free survival data beyond the trial period but made the following changes to the duration of treatment effect and treatment waning assumptions: assumed a constant treatment effect for 3 years assumed treatment waning for 5 years with no treatment effect beyond year 8 (see section 3.8).The ERG's preferred base-case ICER for abemaciclib with endocrine therapy compared with endocrine therapy alone, including the patient access scheme discount for abemaciclib but list prices for all other treatments, was £17,810 per QALY gained. The committee recalled that there is substantial uncertainty in the predicted benefit of adjuvant abemaciclib over a long time horizon and the actual duration of treatment effect and treatment effect waning for abemaciclib with endocrine therapy. However, with a range of scenarios considered, the cost-effectiveness estimates remained within the range considered a cost-effective use of NHS resources. The committee concluded that the most plausible ICER for abemaciclib with endocrine therapy compared with endocrine therapy alone is uncertain but likely to be cost effective. ## Some people who develop metastatic disease after having abemaciclib may have another CDK4/6 inhibitor, but the proportion is unknown Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. The company assumed that people who had abemaciclib as adjuvant therapy would not have another CDK4/6 inhibitor later in the treatment pathway if they developed metastatic disease. The ERG carried out a scenario analysis which assumed that someone who developed metastatic disease after abemaciclib would be just as likely to have another CDK4/6 inhibitor as someone who had not had abemaciclib. The clinical experts and Cancer Drugs Fund clinical lead explained that people whose disease had an early recurrence after abemaciclib would not likely be treated with another CDK4/6 inhibitor. However, if they had a later recurrence, clinicians would consider treating with another CDK4/6 inhibitor. The committee considered that the ERG scenario analysis assuming all people would receive a CDK4/6 inhibitor again after metastatic disease was very conservative and unlikely in clinical practice. The committee concluded that subsequent treatments after metastatic disease may include a proportion of people who have another CDK4/6 treatment, but the proportion is unknown. ## The cost-effectiveness estimates are uncertain but within the range that NICE considers an acceptable use of NHS resources The confidential discounts for abemaciclib, the treatment distribution assumed for endocrine therapy and subsequent treatments in response to a metastatic recurrence of the disease were considered. Both the company's and the ERG's preferred ICERs are within the range NICE normally considers an acceptable use of NHS resources. The exact ICERs are commercial in confidence and cannot be reported here. The committee was aware of the uncertainty associated with the extrapolation of invasive disease-free survival data over a lifetime time horizon (see section 3.7), treatment effect duration (see section 3.8), and treatment waning assumptions (see section 3.8). It considered that the most plausible ICER is uncertain. However, it agreed that the most plausible ICER is unlikely to be above what NICE normally considers an acceptable use of NHS resources. It therefore recommended abemaciclib with endocrine therapy as an option for the adjuvant treatment of hormone receptor-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence.	{'Recommendations': 'Abemaciclib with endocrine therapy is recommended, within its marketing authorisation, as an option for adjuvant treatment of hormone receptor-positive, HER2-negative, node‑positive early breast cancer in adults whose disease is at high risk of recurrence, defined by the following clinical and pathological features:\n\nat least 4 positive axillary lymph nodes, or\n\nto 3 positive axillary lymph nodes, and at least one of the following criteria:\n\n\n\ngrade\xa03 disease (defined as at least 8\xa0points on the modified Bloom–Richardson grading system or equivalent), or\n\nprimary tumour size of at least 5\xa0cm.It is recommended only if the company provides it according to the commercial arrangement.\n\n\n\nWhy the committee made these recommendations\n\nAdjuvant treatment aims to reduce the risk of cancer returning after surgery. Chemotherapy followed by endocrine therapy is standard care for adjuvant treatment of hormone receptor-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence. Abemaciclib plus endocrine therapy is another adjuvant treatment option.\n\nClinical trial evidence shows that adjuvant treatment with abemaciclib plus endocrine therapy increases how long people are free of disease compared with endocrine therapy alone. This is for people whose condition is at high risk of recurrence because the cancer has spread into:\n\nat least 4 axillary (armpit) lymph nodes, or\n\nto 3 axillary lymph nodes, and there is either grade\xa03 disease or the primary tumour is at least 5\xa0cm.\n\nIt is uncertain how long the benefit of abemaciclib with endocrine therapy lasts because data is still being collected.\n\nThe cost-effectiveness estimates are also uncertain, but the most likely estimates are within the range NICE considers an acceptable use of NHS resources. Therefore, abemaciclib is recommended.', 'Information about abemaciclib': "# Marketing authorisation indication\n\nAbemaciclib (Verzenios, Eli Lilly) 'in combination with endocrine therapy is indicated for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive early breast cancer at high risk of recurrence. In pre- or perimenopausal women, aromatase inhibitor endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for abemaciclib.\n\n# Price\n\nThe list price for abemaciclib is £2,950 per 28‑day cycle of 150‑mg tablets (£1,475 per 28‑tablet pack or £2,950 per 56‑tablet pack; excluding VAT; BNF online, accessed May\xa02022).\n\nThe company has a commercial arrangement. This makes abemaciclib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Eli Lilly, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# New treatment option and treatment pathway\n\n## People with early breast cancer and their families would welcome a new effective treatment option that reduces the risk of recurrence\n\nBreast cancer is the most common cancer in the UK. Hormone receptor‑positive, HER2-negative breast cancer is the most common subtype, accounting for about 70% of all breast cancers. The patient experts explained that hormone receptor-positive, HER2-negative, node-positive early-stage breast cancer at high risk of recurrence has a considerable impact on quality of life. Initial diagnosis is distressing and the fear of the cancer returning is a common cause of stress and anxiety for patients and their families. This is because of the need to have further treatment or the possibility of progression to non-curable metastatic disease. For people with HER2-negative disease, treatment options are limited and are associated with unpleasant side effects that make completing the recommended course of therapy difficult. The clinical expert noted that early breast cancer relapses after initial treatment in 30% of people. They noted that the risk of recurrence is higher with certain clinical and pathological risk factors such as a high number of positive lymph nodes, large tumour size, or high cellular proliferation measured by tumour grade or biomarkers. People whose disease is at high risk of recurrence after surgery have significant unmet need. Patients and clinicians would greatly value targeted therapies to reduce the risk of recurrence. The committee concluded that people with hormone receptor-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, and their families, would welcome a new effective treatment option that reduces the risk of recurrence.\n\n## Abemaciclib plus endocrine therapy is an important step-change for managing the condition\n\nAdjuvant treatment with cytotoxic chemotherapy or endocrine therapy, or both, has remained the standard of care for many years. After surgery, adjuvant treatment is prescribed based on prognostic and predictive factors. The clinical experts explained that most people whose cancer is at high risk of recurrence are first offered adjuvant chemotherapy. Extended adjuvant endocrine therapy is then offered for 5\xa0years to 10\xa0years. They noted that the risk of recurrence does not decrease with time for people with hormone receptor-positive, HER2-negative, node-positive early breast cancer. But, people whose disease is identified as being at high risk of recurrence have the highest risk during the first 3\xa0years after surgery. Abemaciclib plus endocrine therapy offers a targeted adjuvant treatment option earlier in the treatment pathway, thereby increasing the chance of curing the disease and reducing the likelihood of developing incurable advanced disease. The clinical expert also noted that although abemaciclib can cause diarrhoea and other side effects, these can usually be managed. The committee concluded that abemaciclib plus endocrine therapy is an important step-change in the treatment of hormone receptor-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence.\n\n# Clinical evidence\n\n## Cohort\xa01 from monarchE is the relevant population for consideration and is generalisable to NHS clinical practice\n\nThe evidence for abemaciclib with endocrine therapy came from monarchE. This is an ongoing multicentre, open-label, randomised trial in 5,637\xa0people with hormone receptor-positive, HER2‑negative, node-positive early breast cancer at high risk of recurrence. The committee noted that abemaciclib should be taken continuously for 2\xa0years, or until disease recurrence or unacceptable toxicity occurs. In MonarchE, abemaciclib (taken for up to 2\xa0years) plus endocrine therapy (taken for 5\xa0years to 10\xa0years) was compared with endocrine therapy alone (taken for 5\xa0years to 10\xa0years). Over 60% of people in the trial had prior adjuvant chemotherapy but no more than 12\xa0weeks of endocrine therapy before randomisation. The trial included 199\xa0people from the UK and included 2\xa0cohorts that used different inclusion criteria to define high risk of recurrence. The ERG raised concerns about whether the overall trial population reflected people with high-risk disease that could easily be identified in clinical practice. It considered that results from cohort\xa01 of monarchE would be more relevant to the NHS. Cohort\xa01 enrolled people at high risk of recurrence based on the following clinical and pathological features:\n\npathological tumour involvement in at least 4 positive axillary lymph nodes, or\n\npathological tumour involvement in 1\xa0to 3 positive axillary lymph nodes, and at least one of the following criteria:\n\n\n\ngrade 3 disease (defined as at least 8\xa0points on the modified Bloom–Richardson grading system or equivalent), or\n\nprimary tumour size of at least 5\xa0cm.Cohort\xa02 was a smaller group that enrolled people at high risk of recurrence based on a Ki‑67 index value of at least 20%. The company noted that this biomarker is not routinely tested in the NHS and it was not proposing introducing Ki‑67 testing. The clinical experts explained that people whose disease is at high risk of recurrence, based on clinical and pathological risk factors, represented a small population in clinical practice (see section\xa03.1). They considered that cohort\xa01 was an adequate representation of this population and results from analyses using cohort\xa01 data were suitable for decision making. The committee noted that the marketing authorisation was granted only for cohort\xa01 from monarchE and concluded it is generalisable to NHS clinical practice.\n\n\n\n## Abemaciclib with endocrine therapy improves invasive disease-free survival compared with endocrine therapy\n\nThe primary outcome for monarchE was invasive disease-free survival. In cohort\xa01, people having abemaciclib with endocrine therapy had improved invasive disease-free survival compared with people having endocrine therapy alone (hazard ratio 0.680; 95% confidence interval 0.572\xa0to 0.808). Median overall survival has not been reached in either treatment arm of monarchE (results are confidential and cannot be reported here). The clinical experts noted that although disease-free survival is a widely accepted surrogate for overall survival, studies have successfully used invasive disease-free survival as a compound surrogate outcome for overall survival. The Cancer Drugs Fund clinical lead considered that improved invasive disease-free survival with abemaciclib may take up to 10\xa0years to show a clinically worthwhile overall survival benefit. The clinical experts considered overall survival benefit may be seen earlier, from 5\xa0years onwards for people whose disease is at high risk of recurrence. The committee acknowledged the difficulty of obtaining mature overall survival data for adjuvant treatments which are used at early stages when there is no known residual disease after surgery. It concluded that, in the absence of mature overall survival data, invasive disease-free survival is a suitable surrogate for decision making. However, it recognised that the extent to which invasive disease-free survival translates into long-term overall survival benefit is not known.\n\n## Differences in treatment effect based on menopausal status and type of endocrine therapy used are minimal\n\nThe type of endocrine therapy used in clinical practice depends on menopausal status. The ERG noted that bias may be introduced because of differences in comparators for pre- and postmenopausal people. It further noted that outcomes for invasive disease-free survival and distant relapse-free survival are better for premenopausal people; therefore, results for pre- and postmenopausal subgroups should be considered separately. The clinical expert explained that many people in clinical practice cannot tolerate one endocrine treatment, and switch to another. A key challenge for clinicians is finding a treatment combination that balances treatment benefit and side effects and helps treatment adherence. Often clinicians will try different endocrine therapies to find the optimal treatment combination for the person's individual needs. The company also highlighted that in monarchE cohort\xa01, there were no statistically significant differences for menopausal status at diagnosis for invasive disease-free survival and distant relapse-free survival. It also highlighted that previous NICE technology appraisals for hormone receptor-positive, HER2-positive breast cancer had not considered subgroups by menopausal status. The clinical experts explained that abemaciclib had a treatment benefit irrespective of the endocrine therapy option taken alongside abemaciclib. Despite an initial difference in treatment effect between pre- and postmenopausal subgroups at 12\xa0months and 24\xa0months, the treatment effect at 36\xa0months was similar between the 2\xa0groups. The committee concluded that differences in treatment effect based on menopausal status and type of endocrine therapy used are minimal and that the whole monarchE cohort\xa01 population is suitable for decision making.\n\n# Adverse effects\n\n## The safety profile of abemaciclib with endocrine therapy is acceptable\n\nThe committee noted that treatment discontinuations because of adverse events were more common with abemaciclib plus endocrine therapy than endocrine therapy alone. The patient experts explained that adverse events reported in monarchE were consistent with the known safety profile for abemaciclib, which is used in the NHS to treat advanced breast cancer. The most common side effect of abemaciclib is diarrhoea, which can disrupt day-to-day activities in the worst cases, but can generally be managed through medication or treatment breaks. For many patients, the potential benefit of abemaciclib with endocrine therapy outweighs the risk of side effects. The clinical experts agreed that abemaciclib's adverse effects are generally well tolerated. But, they noted that treatment delays because of toxicities and subsequent burden of increased appointments with GPs and oncologists are a potential disadvantage of the treatment. The committee concluded that the safety profile of abemaciclib with endocrine therapy is acceptable to patients.\n\n# The company's economic model\n\n## Extrapolation of invasive disease-free survival using the log-logistic curve is a source of uncertainty but is suitable for decision making\n\nThe company presented a cohort state transition model with 5\xa0health states: invasive disease-free survival, non-metastatic recurrence, remission, metastatic recurrence and death. The non-metastatic recurrence state was split into 2 substates, second primary neoplasm and locoregional or contralateral. The company model included subsequent treatments after metastatic recurrence of the disease, occurring either during endocrine therapy (endocrine resistant) or 12\xa0months after endocrine therapy (endocrine sensitive). Because there is limited trial data available, the company used parametric curves to extrapolate invasive disease-free survival data over a lifetime time horizon. This results in considerable uncertainty in the long-term effectiveness of abemaciclib with endocrine therapy compared with endocrine therapy alone. The company and ERG both used the log‑logistic curve to extrapolate invasive disease-free survival data in their base-case analyses because it provided the best statistical fit. However, the ERG noted that the choice of curve is a source of substantial uncertainty because of the very limited trial data available. A scenario analysis using an alternative curve (lognormal) to extrapolate invasive disease-free survival data increased the cost-effectiveness estimate. The company noted that the lognormal curve provided the worst statistical fit to the first 3\xa0years of Kaplan–Meier data from monarchE and was not clinically plausible. The clinical experts considered invasive disease-free survival predicted by extrapolation of data using the log-logistic curve for the endocrine therapy arm was clinically plausible for a population whose disease was at high risk of recurrence. The committee concluded that extrapolation of long-term invasive disease-free survival using the log-logistic curve is a source of uncertainty, but in the absence of an alternative option, is suitable for decision making.\n\n## The assumed duration of treatment effect and treatment waning assumptions for abemaciclib are very uncertain\n\nThe company's base-case analysis assumed a full treatment effect for abemaciclib with endocrine therapy that is maintained for 8\xa0years, and then a treatment waning effect lasting 19\xa0years until year\xa027. This was based on NICE's technology appraisal guidance on neratinib. The committee recalled that abemaciclib should be taken continuously for 2\xa0years, or until disease recurrence or unacceptable toxicity occurs. The ERG considered that there was no evidence to support the treatment effect for abemaciclib lasting 8\xa0years and for the treatment waning assumptions used by the company. In the ERG's base case, the abemaciclib treatment effect is maintained for 3\xa0years based on monarchE follow-up data, then gradually decreases to no treatment effect at 8\xa0years. The company considered the ERG's approach to be more conservative than previously accepted in NICE technology appraisals for early breast cancer, in which the full treatment effect was assumed to last for a minimum of 4\xa0years. It noted that monarchE demonstrates a treatment effect of abemaciclib with endocrine therapy beyond discontinuation. Furthermore, the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial reporting up to 10\xa0years of data for anastrazole and tamoxifen showed a lasting treatment benefit up to 8\xa0years for 1\xa0endocrine therapy over the other. This was used as a proxy to inform plausible duration of treatment effect for abemaciclib. The ERG acknowledged that its base-case analysis could potentially be conservative. It explored different waning assumptions in scenario analyses, noting that this was one of the key drivers for the cost‑effectiveness analyses. The committee noted that the ERG scenario analyses with varied assumptions about the duration of treatment effect using the patient access scheme price for abemaciclib without other confidential discounts, still resulted in cost-effectiveness estimates within the acceptable range. This was except the very conservative scenario when treatment was assumed to stop completely at 3\xa0years, which was not supported by the Kaplan–Meier trial data. The committee concluded that the duration of treatment effect and treatment effect waning for abemaciclib with endocrine therapy that would be seen in clinical practice is highly uncertain. It took into consideration a range of potentially plausible estimates.\n\n## Adherence to adjuvant endocrine therapy has not been included in the economic model but is not critical for decision making\n\nNon-adherence to adjuvant endocrine therapy in clinical practice was considered a concern by the ERG, who noted that its impact was not modelled in the company model. The company explained that the pattern of non-adherence seen in monarchE is representative of clinical practice in the NHS. Also, any reduction in endocrine therapy cost is likely to have a small impact on the cost-effectiveness estimates because the overall costs for endocrine therapy are relatively low. The clinical expert considered that people whose condition is at high risk of recurrence are highly motivated to continue treatment to prevent their cancer returning and tend to adhere to treatment. Furthermore, medication adherence rate is likely to be the same for those taking it with and after abemaciclib, and those taking it as monotherapy. There is no evidence to suggest a larger impact on the abemaciclib with endocrine therapy arm. The committee concluded that adherence to adjuvant endocrine therapy is not critical for decision making.\n\n# Cost-effectiveness estimates\n\n## The most plausible ICER is uncertain but likely to be cost effective\n\nThe company's base-case incremental cost-effectiveness ratio (ICER) for abemaciclib with endocrine therapy compared with endocrine therapy alone was £9,164 per quality-adjusted life year (QALY) gained. This includes the confidential patient access scheme discount for abemaciclib but list prices for endocrine therapy in both arms and subsequent treatments in response to a metastatic recurrence of the disease. The company's base case:\n\nused the log-logistic curve to extrapolate invasive disease-free survival data beyond the trial period (see section\xa03.7)\n\nassumed a constant treatment effect for 8\xa0years\n\nassumed a treatment waning effect for 19\xa0years until year\xa027 (see section\xa03.8)The ERG also used the log-logistic curve to extrapolate invasive disease‑free survival data beyond the trial period but made the following changes to the duration of treatment effect and treatment waning assumptions:\n\nassumed a constant treatment effect for 3\xa0years\n\nassumed treatment waning for 5\xa0years with no treatment effect beyond year\xa08 (see section\xa03.8).The ERG's preferred base-case ICER for abemaciclib with endocrine therapy compared with endocrine therapy alone, including the patient access scheme discount for abemaciclib but list prices for all other treatments, was £17,810 per QALY gained. The committee recalled that there is substantial uncertainty in the predicted benefit of adjuvant abemaciclib over a long time horizon and the actual duration of treatment effect and treatment effect waning for abemaciclib with endocrine therapy. However, with a range of scenarios considered, the cost-effectiveness estimates remained within the range considered a cost-effective use of NHS resources. The committee concluded that the most plausible ICER for abemaciclib with endocrine therapy compared with endocrine therapy alone is uncertain but likely to be cost effective.\n\n## Some people who develop metastatic disease after having abemaciclib may have another CDK4/6 inhibitor, but the proportion is unknown\n\nAbemaciclib is a cyclin-dependent kinase\xa04 and 6 (CDK4/6) inhibitor. The company assumed that people who had abemaciclib as adjuvant therapy would not have another CDK4/6 inhibitor later in the treatment pathway if they developed metastatic disease. The ERG carried out a scenario analysis which assumed that someone who developed metastatic disease after abemaciclib would be just as likely to have another CDK4/6 inhibitor as someone who had not had abemaciclib. The clinical experts and Cancer Drugs Fund clinical lead explained that people whose disease had an early recurrence after abemaciclib would not likely be treated with another CDK4/6 inhibitor. However, if they had a later recurrence, clinicians would consider treating with another CDK4/6 inhibitor. The committee considered that the ERG scenario analysis assuming all people would receive a CDK4/6 inhibitor again after metastatic disease was very conservative and unlikely in clinical practice. The committee concluded that subsequent treatments after metastatic disease may include a proportion of people who have another CDK4/6 treatment, but the proportion is unknown.\n\n## The cost-effectiveness estimates are uncertain but within the range that NICE considers an acceptable use of NHS resources\n\nThe confidential discounts for abemaciclib, the treatment distribution assumed for endocrine therapy and subsequent treatments in response to a metastatic recurrence of the disease were considered. Both the company's and the ERG's preferred ICERs are within the range NICE normally considers an acceptable use of NHS resources. The exact ICERs are commercial in confidence and cannot be reported here. The committee was aware of the uncertainty associated with the extrapolation of invasive disease-free survival data over a lifetime time horizon (see section\xa03.7), treatment effect duration (see section\xa03.8), and treatment waning assumptions (see section\xa03.8). It considered that the most plausible ICER is uncertain. However, it agreed that the most plausible ICER is unlikely to be above what NICE normally considers an acceptable use of NHS resources. It therefore recommended abemaciclib with endocrine therapy as an option for the adjuvant treatment of hormone receptor-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence."}	https://www.nice.org.uk/guidance/ta810	Evidence-based recommendations on abemaciclib (Verzenios) with endocrine therapy for adjuvant treatment of hormone receptor-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence in adults.
4ed389b0d6d0a7b4a2fe3cd8393deb4321004d6f	nice	COVID-19 rapid guideline: haematopoietic stem cell transplantation	COVID-19 rapid guideline: haematopoietic stem cell transplantation The purpose of this guideline is to maximise the safety of patients who need haemopoietic stem cell transplantation and make the best use of NHS resources, while protecting staff from infection. # Minimising the risks of COVID-19 # Reducing the risk of exposure to COVID-19 Reduce the risk of patient and donor exposure to COVID‑19 and make best use of resources (workforce, facilities, intensive care, equipment), such as by minimising inpatient and day-case admissions. Follow hospital policy to reduce the risk of contracting or spreading SARS-CoV-2, for example: consider using telephone or video consultations, if appropriate ask patients to attend appointments with limited family or carers minimise time in the waiting area by: careful scheduling encouraging patients not to arrive early texting patients when you are ready to see them, so that they can wait outside or in their car. Before patients attend the transplant centre, tell them about the measures in place to keep them safe, as well as any steps they need to take. All healthcare workers involved in receiving, assessing and caring for patients who have known or suspected COVID 19 should follow NHS England's national infection prevention and control manual and the UK government COVID-19 guidance for health professionals. These contain information on using personal protective equipment (PPE). # Vaccination Encourage patients and donors to get vaccinated in line with the UK government COVID-19 vaccination programme and the British Society of Blood and Marrow Transplantation and Cellular Therapy Vaccination Sub-Committee (BSBMTCT-VSC) guidance on COVID-19 vaccination. # Pre-transplant care # Transplant recipients ## Reducing risk Advise patients that for at least 2 weeks before having haematopoietic stem cell transplantation (HSCT), they should follow the professional advice from their clinical team on how best to minimise their risk of respiratory infections (including COVID-19). Guidance for clinicians and patients to support risk assessments is available on the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT) website. Test patients for respiratory viruses, including for SARS-CoV-2, using a polymerase chain reaction (PCR) test: within 7 days before admission and -n admission before starting conditioning if local testing turnaround times allow. If not, ensure that a test result is available within 72 hours before conditioning starts. Consider deferring allogeneic HSCT if the patient has been in close contact with someone with COVID-19 in the past week. Assess the risks for the individual patient of having COVID-19 against the benefits of having HSCT without delay. ## Assessing whether to use fresh or cryopreserved cells Transplant centres should agree with the patient whether to use fresh or cryopreserved donations, taking into account: patient factors the donor's risk of COVID-19 current BSBMTCT COVID-19 guidelines or specific registry requirements. The decision should be shared with local processing laboratories to ensure that they have advance notice of each donation and whether to cryopreserve or not. If cryopreserved cells are requested, they should be received by the transplant centre before conditioning starts, unless exceptional circumstances mean this is not possible. # Transplant donors ## Reducing risk Explain to donors the importance of minimising their risk of exposure to COVID-19 before donation. Give advice on reducing risk in line with the UK government guidance on living safely with respiratory infections, including COVID-19. Explain to donors about the symptoms of COVID‑19 and advise on testing if they develop symptoms. Discuss transmission risks, donation restrictions and when to consider self-deferring from donating. If cells are going to be cryopreserved, test the donor for SARS-CoV-2: at the medical assessment and before starting granulocyte-colony stimulating factor (GCSF) for haematopoietic progenitor cell (HPC) apheresis or within 72 hours of HPC marrow collection. If fresh cell donations are being used, test the donor for SARS-CoV-2: at the medical assessment and before conditioning, ensuring that the test result is available within 72 hours before conditioning starts. Tell donors to contact the coordinating registry and the collection centre at which they donated if they develop any illness within 2 weeks after donating. ## Donors with COVID‑19 For HPC apheresis or mononuclear cell (MNC) donors who test positive for SARS-CoV-2: defer donations by 14 days from when their symptoms resolve or from a positive PCR test or if donation is urgent and less than 14 days have passed since testing positive, refer to a designated donor medical officer for risk assessment and earlier discretionary clearance. For HPC marrow donors who test positive for SARS-Cov-2, defer donations for a period of time agreed in discussion with an anaesthetist. If a donor tests positive for SARS-CoV2 at a late stage, after conditioning has started, discuss with the donor registry and the collection centre whether a SARS-CoV-2-positive donation can be accepted safely. # Post-transplant care Ensure that patients are cared for in strict protective isolation. Assess the need for any procedures outside of isolation against the risk of exposing the patient to nosocomial infections, such as COVID-19. Isolate patients who have tested positive for COVID‑19 in negative pressure cubicles, or neutral pressure cubicles if this is not possible. # Service provision and organisation Risk assess ambulatory transplant pathways to minimise exposure to COVID-19. This review should be reflected in the quality management plans and standard operating procedures in line with NICE's guideline on haematological cancers and Joint Accreditation Committee International Society for Cell and Gene Therapy (ISCT) -Europe and European Society for Blood and Marrow Transplantation (JACIE) standards. Work within clinical networks to support stem cell processing and harvesting, specialised diagnostics and cryopreservation. Make decisions about modifications to care at an organisational level according to current quality management systems within the HSCT programme and other JACIE accreditation requirements. If a centre cannot meet quality standards, temporary closure is an option. If a centre is temporarily closed, work within clinical networks to prioritise clinically urgent HSCT and transfer patients as needed. If patients are transferred: tell them who is in charge of their care ensure that they have a named key worker that they can contact with any questions take into account their practical needs, for example transport and accommodation. For patients having allogeneic HSCT, identify a back-up donor or cord blood unit in case there are problems with harvesting or transport. Be aware of the availability of any planned conditioning treatments and arrange alternatives based on availability and clinical indication. Think about undertaking viability testing on cryopreserved stem cells if there is any concern about the collection, transfer or cryopreservation of cells. This includes discretionary viability testing of cell therapy products cryopreserved in laboratories not associated with the transplant centre or at the request of the transplant director. # Services for children and young people For additional advice on services for children and young people under 16 years, see the Paediatric BSBMTCT Group guidance on management of paediatric patients during the COVID-19 outbreak. # Services for patients with COVID-19 Services, including satellite units, should have separate pathways and accommodation for patients who test positive for COVID-19, to minimise the risk of COVID-19 for other patients. These should be reflected in quality management plans and standard operating procedures and should meet JACIE standards. # Policies for staff returning to work after COVID-19 Ensure that healthcare professionals are aware of and follow the local policies of their transplant unit for returning to work after COVID-19.	{'Minimising the risks of COVID-19': "# Reducing the risk of exposure to COVID-19\n\nReduce the risk of patient and donor exposure to COVID‑19 and make best use of resources (workforce, facilities, intensive care, equipment), such as by minimising inpatient and day-case admissions. [Amended July 2022]\n\nFollow hospital policy to reduce the risk of contracting or spreading SARS-CoV-2, for example:\n\nconsider using telephone or video consultations, if appropriate\n\nask patients to attend appointments with limited family or carers\n\nminimise time in the waiting area by:\n\n\n\ncareful scheduling\n\nencouraging patients not to arrive early\n\ntexting patients when you are ready to see them, so that they can wait outside or in their car. [Amended July 2022]\n\n\n\nBefore patients attend the transplant centre, tell them about the measures in place to keep them safe, as well as any steps they need to take. [July 2020]\n\nAll healthcare workers involved in receiving, assessing and caring for patients who have known or suspected COVID 19 should follow NHS England's national infection prevention and control manual and the UK government COVID-19 guidance for health professionals. These contain information on using personal protective equipment (PPE). [Amended July 2022]\n\n# Vaccination\n\nEncourage patients and donors to get vaccinated in line with the UK government COVID-19 vaccination programme and the British Society of Blood and Marrow Transplantation and Cellular Therapy Vaccination Sub-Committee (BSBMTCT-VSC) guidance on COVID-19 vaccination. [Amended July 2022]", 'Pre-transplant care': "# Transplant recipients\n\n## Reducing risk\n\nAdvise patients that for at least 2\xa0weeks before having haematopoietic stem cell transplantation (HSCT), they should follow the professional advice from their clinical team on how best to minimise their risk of respiratory infections (including COVID-19). Guidance for clinicians and patients to support risk assessments is available on the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT) website. [July 2020]\n\nTest patients for respiratory viruses, including for SARS-CoV-2, using a polymerase chain reaction (PCR) test: [July 2021]\n\nwithin 7\xa0days before admission and\n\non admission before starting conditioning if local testing turnaround times allow. If not, ensure that a test result is available within 72\xa0hours before conditioning starts. [July 2020]\n\nConsider deferring allogeneic HSCT if the patient has been in close contact with someone with COVID-19 in the past week. Assess the risks for the individual patient of having COVID-19 against the benefits of having HSCT without delay. [Amended July 2022]\n\n## Assessing whether to use fresh or cryopreserved cells\n\nTransplant centres should agree with the patient whether to use fresh or cryopreserved donations, taking into account:\n\npatient factors\n\nthe donor's risk of COVID-19\n\ncurrent BSBMTCT COVID-19 guidelines or specific registry requirements. The decision should be shared with local processing laboratories to ensure that they have advance notice of each donation and whether to cryopreserve or not. [Amended July 2022]\n\nIf cryopreserved cells are requested, they should be received by the transplant centre before conditioning starts, unless exceptional circumstances mean this is not possible. [Amended July 2022]\n\n# Transplant donors\n\n## Reducing risk\n\nExplain to donors the importance of minimising their risk of exposure to COVID-19 before donation. Give advice on reducing risk in line with the UK government guidance on living safely with respiratory infections, including COVID-19. [Amended July 2022]\n\nExplain to donors about the symptoms of COVID‑19 and advise on testing if they develop symptoms. Discuss transmission risks, donation restrictions and when to consider self-deferring from donating. [Amended July 2022]\n\nIf cells are going to be cryopreserved, test the donor for SARS-CoV-2:\n\nat the medical assessment and\n\nbefore starting granulocyte-colony stimulating factor (GCSF) for haematopoietic progenitor cell (HPC) apheresis or within 72\xa0hours of HPC\xa0marrow collection. [Amended July 2022]\n\nIf fresh cell donations are being used, test the donor for SARS-CoV-2:\n\nat the medical assessment and\n\nbefore conditioning, ensuring that the test result is available within 72\xa0hours before conditioning starts. [Amended July 2022]\n\nTell donors to contact the coordinating registry and the collection centre at which they donated if they develop any illness within 2\xa0weeks after donating. [April 2020]\n\n## Donors with COVID‑19\n\nFor HPC apheresis or mononuclear cell (MNC) donors who test positive for SARS-CoV-2:\n\ndefer donations by 14\xa0days from when their symptoms resolve or from a positive PCR test or\n\nif donation is urgent and less than 14\xa0days have passed since testing positive, refer to a designated donor medical officer for risk assessment and earlier discretionary clearance. [Amended July 2022]\n\nFor HPC marrow donors who test positive for SARS-Cov-2, defer donations for a period of time agreed in discussion with an anaesthetist. [Amended July 2022]\n\nIf a donor tests positive for SARS-CoV2 at a late stage, after conditioning has started, discuss with the donor registry and the collection centre whether a SARS-CoV-2-positive donation can be accepted safely. [Amended July 2022]", 'Post-transplant care': 'Ensure that patients are cared for in strict protective isolation. Assess the need for any procedures outside of isolation against the risk of exposing the patient to nosocomial infections, such as COVID-19. [April 2020]\n\nIsolate patients who have tested positive for COVID‑19 in negative pressure cubicles, or neutral pressure cubicles if this is not possible. [April 2020]', 'Service provision and organisation': "Risk assess ambulatory transplant pathways to minimise exposure to COVID-19. This review should be reflected in the quality management plans and standard operating procedures in line with NICE's guideline on haematological cancers and Joint Accreditation Committee International Society for Cell and Gene Therapy (ISCT) -Europe and European Society for Blood and Marrow Transplantation (JACIE) standards. [July 2020]\n\nWork within clinical networks to support stem cell processing and harvesting, specialised diagnostics and cryopreservation. [April 2020]\n\nMake decisions about modifications to care at an organisational level according to current quality management systems within the HSCT programme and other JACIE accreditation requirements. If a centre cannot meet quality standards, temporary closure is an option. [April 2020]\n\nIf a centre is temporarily closed, work within clinical networks to prioritise clinically urgent HSCT and transfer patients as needed. If patients are transferred:\n\ntell them who is in charge of their care\n\nensure that they have a named key worker that they can contact with any questions\n\ntake into account their practical needs, for example transport and accommodation. [July 2020]\n\nFor patients having allogeneic HSCT, identify a back-up donor or cord blood unit in case there are problems with harvesting or transport. [April 2020]\n\nBe aware of the availability of any planned conditioning treatments and arrange alternatives based on availability and clinical indication. [April 2020]\n\nThink about undertaking viability testing on cryopreserved stem cells if there is any concern about the collection, transfer or cryopreservation of cells. This includes discretionary viability testing of cell therapy products cryopreserved in laboratories not associated with the transplant centre or at the request of the transplant director. [July 2020]\n\n# Services for children and young people\n\nFor additional advice on services for children and young people under 16\xa0years, see the Paediatric BSBMTCT Group guidance on management of paediatric patients during the COVID-19 outbreak. [Amended July 2022]\n\n# Services for patients with COVID-19\n\nServices, including satellite units, should have separate pathways and accommodation for patients who test positive for COVID-19, to minimise the risk of COVID-19 for other patients. These should be reflected in quality management plans and standard operating procedures and should meet JACIE standards. [July 2020]\n\n# Policies for staff returning to work after COVID-19\n\nEnsure that healthcare professionals are aware of and follow the local policies of their transplant unit for returning to work after COVID-19. [Amended July 2022]"}	https://www.nice.org.uk/guidance/ng164	The purpose of this guideline is to maximise the safety of patients who need haemopoietic stem cell transplantation and make the best use of NHS resources, while protecting staff from infection.
45fdb6ef197b2b91816e8c6b56de95f593d62737	nice	PeritX peritoneal catheter drainage system for vacuum-assisted drainage of treatment-resistant, recurrent malignant ascites	PeritX peritoneal catheter drainage system for vacuum-assisted drainage of treatment-resistant, recurrent malignant ascites Evidence-based recommendations on PeritX for vacuum-assisted drainage of treatment-resistant, recurrent malignant ascites. # Recommendations The PeritX system is recommended as an option for drainage of treatment-resistant, recurrent malignant peritoneal ascites. Why the committee made these recommendations Clinical evidence shows that the PeritX peritoneal catheter drainage system is effective for managing treatment-resistant, recurrent malignant peritoneal ascites. It may improve the quality of life of some people with cancer, by enabling early and frequent treatment of symptoms of ascites in the community, rather than waiting for inpatient treatment. The PeritX system can lead to an estimated cost saving of £1,095 per person compared with inpatient large-volume paracentesis.# The technology # Description of the technology The PeritX peritoneal catheter drainage system (BD) is intended for use in the management of treatment-resistant, recurrent malignant ascites (accumulation of fluid in the peritoneal cavity) in the community setting. The PeritX peritoneal catheter is made of silicone and is 71 cm in length and 5.12 mm (15.5 Fr) in diameter. The distal end of the catheter has several side holes and is placed in the peritoneal cavity. There is a polyester cuff midway along the catheter, which is sited 1 cm to 2 cm within a subcutaneous tunnel and helps to secure the catheter in place by encouraging tissue growth into the polyester. The external end of the PeritX peritoneal catheter has a safety valve that prevents air entering or fluid leaking out of the catheter. A cap protects the valve and prevents debris from building up. The drainage system comprises a 1‑litre vacuum bottle with a drainage line that connects to the PeritX peritoneal catheter for fluid removal. It also includes a procedure pack that contains the supplies needed to perform the drainage procedure and to replace the cap and the gauze pad dressing over the catheter. The PeritX peritoneal catheter is designed to remain in place indefinitely and patients and carers are trained to perform fluid drainage when needed by attaching the vacuum bottle to the catheter. A fresh valve cap and dressing are applied once the drainage is completed. For the majority of the time, the catheter is coiled up and covered with a gauze pad and a waterproof dressing. The list prices stated in the sponsor's submission for the PeritX peritoneal catheter and the PeritX drainage kit with a 1‑litre vacuum bottle are £245 and £64 per unit respectively. The updated costs are £257.25 and £66.94 respectively. The claimed benefits of the PeritX peritoneal catheter drainage system in the case for adoption presented by the sponsor are: Repeated drainage of ascitic fluid in community settings may allow greater patient independence, and the flexibility to fit the drainage procedure into their daily lives. Better symptom control by frequent drainage of smaller quantities of ascitic fluid. Symptoms associated with the accumulation of large amounts of ascites include breathlessness, nausea, bloating, acid reflux, abdominal pain, early satiety, reduced mobility and psychological distress related to negative body image. Reduced need for repeated large-volume paracentesis procedures and the associated risk of infection from repeated catheter insertion. Resource savings through a reduced need for hospital physician and nurse time, outpatient visits and hospital bed days. # Current management The conventional management of treatment-resistant, recurrent malignant ascites involves repeated large-volume paracentesis (needle drainage of fluid) procedures that are carried out in hospital. Most commonly this is done as an inpatient procedure, although some centres are able to offer paracentesis as a day case procedure. Inpatient paracentesis is carried out when patients have developed troublesome symptoms from recurrent ascites. This can entail some delay while waiting for admission, during which the patient continues to experience symptoms. Paracentesis involves inserting a catheter, often under local anaesthetic, into the peritoneal cavity to drain ascitic fluid. During large-volume paracentesis the catheter stays in place until most of the ascites has been drained, which often exceeds 5 litres of fluid. This may be done in one go, but some patients cannot tolerate rapid drainage and may need to stay in hospital for one or more nights for repeated drainage procedures.# Clinical evidence # Summary of clinical evidence PeritX is referred to by its previous name, PleurX, in this summary of clinical evidence (sections 3.1 to 3.10) because this was the name of the device at the time the evidence was compiled. The key clinical outcomes for the PleurX peritoneal catheter drainage system presented in the decision problem were: technical success of catheter insertion and drainage procedure resolution of symptoms (bloating, nausea, acid reflux, reduced appetite, negative perception of body image and resulting psychological distress) quality of life outcomes adverse events (catheter site infections, peritonitis, catheter occlusion, and haemorrhage or bowel perforation when the device is inserted) drainage frequency resource use outcomes, for example re-admission rates, re-interventions and duration of hospital stay. The clinical evidence for the PleurX peritoneal catheter drainage system was based on 9 observational studies (10 manuscripts), 2 of which were conducted in the UK. Six studies were case series with 10 or more patients, one study was a qualitative case series (4 patients), and there were 3 case reports (4 or fewer patients). The external assessment centre considered all the studies identified by the sponsor to be relevant and did not identify any further studies. Rosenberg et al. (2004) conducted a single-centre, retrospective, comparative case series. It evaluated treatment complication rates in patients whose malignant ascites was managed using the PleurX peritoneal catheter drainage system (n=40 patients and catheters) compared with inpatient large-volume paracentesis (n=67 patients, 392 procedures). Overall complication rates (using number of patients rather than number of procedures) were the same for both procedures: 7.5% (3 of 40; 95% confidence interval 1.6% to 20%) for the PleurX peritoneal catheter drainage system and 7.5% (5 of 67; 95% CI 2.2% to 15%) for large-volume paracentesis. In patients whose ascites was managed with PleurX, complications were infection (n=1), leakage (n=1) and loculations (n=1), and all catheters were subsequently removed. Large-volume paracentesis complications were peritonitis (n=3) and loculations (n=2). The PleurX peritoneal catheter patency rate (defined as the number of catheters known to be functioning at death, study end or resolution of ascites) was 67.5% (n=27); however 11 (27.5%) patients were lost to follow-up. Courtney et al. (2008) carried out a multi-centre, single-arm, prospective case series evaluating treatment outcomes in 34 patients with malignant ascites treated with the PleurX peritoneal catheter drainage system over a 12‑week follow-up period (or until death in some patients). It reported 100% technical success during the placement procedure (defined as intraperitoneal positioning of the device and the ability to withdraw ascitic fluid from the device at the completion of the procedure), with one minor procedural complication. Twenty patients experienced complications during the follow-up period including minor complications that resolved spontaneously. Two catheters needed to be removed, and other complications were infection (n=2), occlusion/loculations (n=4), leakage of ascitic fluid (n=7), dizziness (n=5), shortness of breath (n=1) and severe anaemia (n=1). Available records from 19 patients showed that the mean number of drainage sessions after placement of the PleurX peritoneal catheter was 23.3 per patient (range 5 to 56), and that of the total 433 sessions, 13% were performed by a nurse, and the remainder were carried out by the patient alone (28%) or a carer (58%). The catheter patency rate was 85% (n=29); the remaining 5 patients were lost to follow-up. Changes in symptom severity between baseline and at 2, 8 and 12 weeks were assessed using a validated tool. There was a reduction in the severity of abdominal discomfort, bloating, diarrhoea and nausea at 2 weeks and 8 weeks. An overall improvement in quality of life at 12 weeks was reported in 28% of respondents. In a single-arm retrospective case series study, Mullan et al. (2011b) evaluated the procedural safety, mean survival, long-term efficacy, long-term complication profile and cost benefit of the PleurX peritoneal catheter drainage system in the management of recurrent malignant ascites (n=50 patients, 52 catheters; 2 patients had their catheters re-inserted). On average, 5.3 inpatient large-volume paracentesis drainage procedures were performed before PleurX peritoneal catheter insertion. A 100% procedural success rate was reported. A mean patient survival of 59.4 days (range 4 days to 216 days) and 165 days (range 29 days to 1,036 days) was reported after the PleurX peritoneal catheter insertion and after the first inpatient large-volume paracentesis procedure respectively. The average hospital stay for patients having inpatient large-volume paracentesis was 2.8 days (range 1 day to 6 days; n=23) and the average ascitic fluid drainage per episode of paracentesis was 9.2 litres. Eight patients experienced complications after insertion of the PleurX peritoneal catheter, which were peritonitis (n=1), lymphangitis (n=1), occlusion/loculations (n=3), ascitic leakage (n=1), displacement (n=1) and pain (n=1); one catheter needed to be removed. Primary or secondary catheter patency at death was 100%, with management of complications augmented by multi-modality imaging and fibrinolysis of malfunctioning catheters. In a single-arm retrospective case series study (n=10 patients and catheters), Richard et al. (2001) evaluated the clinical outcomes after PleurX peritoneal catheter insertion in patients with treatment-resistant, recurrent malignant ascites. They reported 100% procedural success. Two patients experienced complications, which were occlusion/loculations (n=1) and displacement (n=1). The average time catheters remained in place was 70 days (range 1 day to 100 days). In a single-arm retrospective case, Tapping et al. (2011) evaluated the clinical outcomes after PleurX peritoneal catheter insertion in 28 patients (32 catheters) with treatment-resistant, recurrent malignant ascites. A technical success rate of 100% was reported. There were 12 complications, which comprised minor catheter site infections (n=5), ascitic leakage (n=1), displacement (n=4), hernia (n=1) and one further complication that was not described. No catheters needed to be removed other than those that were inadvertently dislodged. The catheters remained in place for an average of 113 days (range 5 days to 365 days) and catheter patency was 86% (24 of 28). Saiz-Mendiguren et al. (2010) conducted an observational descriptive case series study of patients (n=10) who had the PleurX peritoneal catheter inserted. They analysed the duration of the procedure, pain reported by the patient during the procedure (using a visual analogue scale score), short- and long-term complications, median patency of the catheter, and the volume of ascitic fluid drained at home (reported by telephone or during consultation). The technical success rate of the insertion procedure was 100%. Two patients reported discomfort during the procedure (visual analogue scale scores 2 and 3 out of 10). No complications were reported during or after the procedure. In one patient with generalised sepsis thought to be caused by a venous cannula, the PleurX peritoneal catheter was removed 58 days after placement as a precaution. Nine patients died; their catheters remained patent for a median of 52 days (range 13 days to 113 days). At the end of the study, one patient remained alive with a patent catheter 124 days after placement. The mean ascitic fluid drainage reported by patients or their carers was approximately 1 litre (one vacuum bottle) every 2 days to 10 days. Day et al. (2011) conducted a small qualitative case study, which is currently available in abstract form, and from which the committee considered detailed findings presented as academic-in-confidence data. Patients who had inpatient large-volume paracentesis were also included in the study, but no comparisons were drawn between the 2 treatment groups. Patient opinions and experiences were described in a narrative form and categorised into emergent themes following semi-structured interviews. The results revealed a positive trend of opinion towards PleurX, particularly relating to symptom improvement and increased convenience. All patients were reported to be glad that they had had the PleurX peritoneal catheter inserted. Some negative opinions were expressed including the fact that some patients did not like seeing the ascitic fluid, and others felt that the PleurX peritoneal catheter drainage system made them feel 'more of a patient'. Three case reports relevant to the decision problem were also identified. Brooks et al. (2006) described one patient who had had a PleurX peritoneal catheter in place for 18 months and had developed 3 complications: drain blockage (immediately relieved by flushing), hernia around the catheter site, and the presence of gram-negative bacilli in urine and ascites (treated successfully with ciprofloxacin). Iyengar et al. (2002) described 3 patients who had catheters in place for 6 weeks, 7 weeks and 12 weeks. One patient experienced dehydration, and one catheter was removed as a precaution in a patient with sepsis. Mullan et al. (2011a) reported experiences of 4 patients taken from a larger study (Mullan et al. 2011b) in whom streptokinase fibrinolytic therapy was successfully used to treat loculations. # Committee considerations The committee concluded from the available clinical evidence that the PeritX peritoneal catheter drainage system is effective in the palliative management of treatment-resistant, recurrent malignant ascites. It has a high procedural success rate, a low complication rate and the potential to improve patient quality of life. Patients with malignant ascites have a disability as defined by the Equality Act 2010. The committee recognised that treatment-resistant, recurrent malignant ascites often has an adverse impact on patients' activities of daily living, which may be improved with the PeritX peritoneal catheter drainage system. The committee was advised by the patient and clinical experts that improvement in quality of life is mainly a result of avoiding regular hospital visits and inpatient stays associated with large-volume paracentesis, and alleviation of symptoms associated with massive ascites through the frequent drainage of small volumes of ascitic fluid. The committee recognised the uncertainty about the point in the care pathway at which it would be clinically appropriate to treat patients with treatment-resistant, recurrent malignant ascites with the PeritX peritoneal catheter drainage system. Tapping et al. (2011) considered that patients who had had at least 3 previous large-volume paracentesis procedures would be suitable for treatment with the PeritX peritoneal catheter drainage system, whereas Courtney et al. (2008) inserted the PeritX peritoneal catheter in patients who had had at least 2 large-volume paracentesis procedures in the previous 30 days. The committee considered that the decision to start treatment with the PeritX peritoneal catheter drainage system should be shared between clinicians and patients. The committee was advised that the term 'treatment-resistant' is normally understood by clinicians to mean that there is a low likelihood of further medical or oncological interventions (particularly chemotherapy) being successful in preventing or reducing re-accumulation of ascites. The committee acknowledged that the current evidence is based on observational studies, with very limited data available comparing the PeritX peritoneal catheter drainage system with other treatments. The committee noted that there are 2 ongoing clinical trials using the PeritX peritoneal catheter drainage system. One is investigating the impact on quality of life and the other is comparing early stage PeritX peritoneal catheter insertion with standard large-volume paracentesis. Both trials are expected to be completed in 2012.# NHS considerations # System impact The evidence suggests that the PeritX peritoneal catheter drainage system is a safe and effective alternative to inpatient large-volume paracentesis, is cost saving and reduces hospital bed use. # Committee considerations The clinical experts advised the committee that the PeritX peritoneal catheter insertion procedure is unlikely to be more costly to the NHS than the large-volume paracentesis procedure. The main resource consideration with PeritX is the relative need for community nursing support for the ongoing drainage procedures. However, the committee was advised that the PeritX peritoneal catheter drainage system is unlikely to increase overall community nursing input as was assumed in the cost model (see section 5). This is because most patients in the terminal stages of cancer need community nursing support regardless of the PeritX peritoneal catheter drainage system, and large-volume-paracentesis is associated with a greater need for nursing for overall wound management. Indeed, the committee was advised that it is possible that using the PeritX peritoneal catheter drainage system could lead to an overall reduction in community nursing costs, which would further enhance the resource savings associated with its use. The committee recognised that training is needed for community nurses, patients or carers to perform drainage procedures in a community setting.# Cost considerations # Cost evidence The sponsor submitted a new cost analysis based on a decision tree model with an embedded Markov model. This model evaluated the costs per patient and system impact of the PeritX peritoneal catheter drainage system for the drainage of treatment-resistant, recurrent malignant ascites in the community setting when compared with inpatient and outpatient large-volume paracentesis. The time horizon of the model was 26 weeks (6 months) from the time of the initial PeritX peritoneal catheter insertion. The Markov model was run over 26‑weekly cycles to account for the short duration of survival in patients with malignant ascites. The cycles used transition probabilities based on 100% survival at week 0 to 4% survival at week 26. The cost of treatment was multiplied by the transition probability at each cycle; half-cycle corrections were used to incorporate changes in survival within a cycle. The key assumptions used in the model were: no change in the survival rate in both arms of the model the need for 2 nurse visits to train patients to self-manage the drainage at home using the PeritX peritoneal catheter drainage system similar levels of treatment monitoring needs in both arms of the model a nurse visit length of 15 minutes for the PeritX peritoneal catheter drainage system to help with drainage at home drainage volume of 9.2 litres per procedure in patients who have repeated large-volume paracentesis average drainage volume of 3.5 litres per week using the PeritX peritoneal catheter drainage system -ne nurse visit per litre of ascitic fluid drained using the PeritX peritoneal catheter drainage system the cost of re-intervention being equivalent to a first-time catheter insertion procedure. The model calculated the costs per patient of the PeritX peritoneal catheter drainage system and large-volume paracentesis as well as the incremental costs of the PeritX peritoneal catheter drainage system. The costs of the system included: inpatient stay (1 day), procedure consumables and other costs (including staff time), PeritX drainage kits, home nurse visits and treatment of complications (infection, catheter failure and re-intervention). The cost of large-volume paracentesis included: inpatient stay (2.8 days) or outpatient (1 day), procedure consumables and treatment of complications. In addition, the system impact was presented in terms of number of paracentesis sessions, number of litres of ascitic fluid drained, number of bed days, and number of nurse visits for both interventions. The cost per patient for the management of malignant ascites using the PeritX peritoneal catheter drainage system was estimated to be £2,466, whereas for inpatient and outpatient large-volume paracentesis it was estimated to be £3,146 and £1,457 respectively. The base-case analysis showed that managing treatment-resistant, recurrent malignant ascites with the PeritX peritoneal catheter drainage system may result in cost saving of £679 per patient when compared with inpatient large-volume paracentesis. In this scenario, 7.4 hospital bed days were saved per patient, but 23.5 more community nurse visits to the patients' home were needed. When the PeritX peritoneal catheter drainage system was compared with outpatient large-volume paracentesis, an additional cost of £1,010 per patient was incurred, including 23.5 extra nurse visits but 1.9 fewer hospital bed days used per patient. The key drivers of the new cost analysis were: cost of a hospital bed day, number of bed days per large-volume paracentesis session, number of large-volume paracentesis procedures per month, number of bed days for PeritX peritoneal catheter placement, cost per drainage kit box (10 units), and number of drainage kits used per week per patient. The analysis showed that cost savings associated with the PeritX peritoneal catheter drainage system, when compared with inpatient large-volume paracentesis, were heavily dependent on a reduction in hospital stay. The cost of a bed day was estimated at £312. The sponsor carried out one-way deterministic sensitivity analysis. All variables (except for population size) were tested, and were analysed using a variance of 20% regardless of the level of confidence in an input or the parameter-specific circumstances. Six key drivers were selected and subjected to further deterministic threshold analysis by the external assessment centre across a wide range of values, to identify the point at which the PeritX peritoneal catheter drainage system became more costly or cost saving compared with inpatient and outpatient large-volume paracentesis respectively. The findings of the threshold sensitivity analysis showed that using the PeritX peritoneal catheter drainage system may incur additional costs when compared with inpatient large-volume paracentesis in the following scenarios: the cost of an excess bed day is reduced to less than £220 per day; the frequency of an inpatient large-volume paracentesis procedure is reduced to fewer than one per month; the average length of inpatient stay after the large-volume paracentesis procedure is decreased to 2.1 days; the number of inpatient bed days following the PeritX peritoneal catheter insertion procedure is increased to more than 3.1 days; the cost of the PeritX drainage kit is increased to more than £915 (per 10 units); more than 5.1 drainage kit units are needed per week. The PeritX peritoneal catheter drainage system may become cost saving when compared with outpatient large-volume paracentesis in the following scenarios: the cost of an excess bed day is increased to more than £825 per day; the frequency of an outpatient large-volume paracentesis procedure is increased to more than 2.5 per month; the average length of hospital stay after the outpatient large-volume paracentesis procedure is increased to more than 2.1 days; the cost of the PeritX drainage kit is decreased to less than £225 (per 10 units); fewer than 1.14 drainage kit units are needed per week. The sensitivity analysis demonstrated that the PeritX peritoneal catheter drainage system is likely to remain cost saving when compared with inpatient large-volume paracentesis and is likely to incur extra costs when compared with outpatient large-volume paracentesis. # Committee considerations The new cost analysis showed that the PeritX peritoneal catheter drainage system was cost saving when compared with inpatient large-volume paracentesis, but incurred additional costs when compared with outpatient large-volume paracentesis. The additional costs, compared with outpatient treatment, were incurred mainly from an increased number of home nurse visits, with only a small offset saving in hospital bed days. However, the committee was advised that the additional cost burden imposed on community nursing staff as a result of the PeritX peritoneal catheter drainage system may have been overestimated, given that most patients will receive healthcare in the community regardless of whether or not they have a PeritX peritoneal catheter in place. The committee was advised that many patients may not prefer outpatient to inpatient large-volume paracentesis because it does not necessarily alleviate the intolerable symptoms associated with ascitic fluid build-up any better than inpatient large-volume paracentesis and yet still creates the need for repeated outpatient visits. The committee recognised that large-volume paracentesis is currently offered as an inpatient, outpatient or day case procedure and that practice varies across the UK. Moreover, the resource costs for outpatient and day case large-volume paracentesis differ, with the day case procedure being more costly (although this was not reflected in the cost model). The committee was advised that the PeritX peritoneal catheter drainage system is likely to be cost saving when compared with day case large-volume paracentesis. The clinical experts advised the committee that the mean hospital stay of 2.8 days following inpatient large-volume paracentesis that was used in the base-case analysis is a realistic estimate and reflects current practice in many NHS centres. The committee recognised that the NHS tariff used for the calculation of excess bed days underestimated the cost of an inpatient stay and that correcting this may further increase the cost savings attributable to the PeritX peritoneal catheter drainage system. # guidance review For the 2022 guidance review, the external assessment centre revised the model to reflect 2020 costs. The largest changes compared with the costs from the 2018 guidance review were increases in the cost of hospital bed days (£355 to £367.78) and decreases in the cost of home visit per hour (£68 to £49). The new costs for the technology were also included. Base-case results for the 2022 revised model (values after first guidance review are given in brackets) show a cost saving of £1,095 (£1,051) per patient. The differential cost between PeritX and paracentesis as an outpatient procedure has increased to an additional cost of £896 (£871) per patient. # Conclusions The committee concluded that the PeritX peritoneal catheter drainage system is a clinically safe and effective palliative therapy for the management of treatment-resistant, recurrent malignant ascites, which has the potential to improve quality of life and is cost saving when compared with inpatient large-volume paracentesis.	{'Recommendations': 'The PeritX system is recommended as an option for drainage of treatment-resistant, recurrent malignant peritoneal ascites.\n\nWhy the committee made these recommendations\n\nClinical evidence shows that the PeritX peritoneal catheter drainage system is effective for managing treatment-resistant, recurrent malignant peritoneal ascites. It may improve the quality of life of some people with cancer, by enabling early and frequent treatment of symptoms of ascites in the community, rather than waiting for inpatient treatment. The PeritX system can lead to an estimated cost saving of £1,095 per person compared with inpatient large-volume paracentesis.', 'The technology': "# Description of the technology\n\nThe PeritX peritoneal catheter drainage system (BD) is intended for use in the management of treatment-resistant, recurrent malignant ascites (accumulation of fluid in the peritoneal cavity) in the community setting. \n\nThe PeritX peritoneal catheter is made of silicone and is 71\xa0cm in length and 5.12\xa0mm (15.5\xa0Fr) in diameter. The distal end of the catheter has several side holes and is placed in the peritoneal cavity. There is a polyester cuff midway along the catheter, which is sited 1\xa0cm to 2\xa0cm within a subcutaneous tunnel and helps to secure the catheter in place by encouraging tissue growth into the polyester. The external end of the PeritX peritoneal catheter has a safety valve that prevents air entering or fluid leaking out of the catheter. A cap protects the valve and prevents debris from building up.\n\nThe drainage system comprises a 1‑litre vacuum bottle with a drainage line that connects to the PeritX peritoneal catheter for fluid removal. It also includes a procedure pack that contains the supplies needed to perform the drainage procedure and to replace the cap and the gauze pad dressing over the catheter.\n\nThe PeritX peritoneal catheter is designed to remain in place indefinitely and patients and carers are trained to perform fluid drainage when needed by attaching the vacuum bottle to the catheter. A fresh valve cap and dressing are applied once the drainage is completed. For the majority of the time, the catheter is coiled up and covered with a gauze pad and a waterproof dressing.\n\nThe list prices stated in the sponsor's submission for the PeritX peritoneal catheter and the PeritX drainage kit with a 1‑litre vacuum bottle are £245 and £64 per unit respectively. The updated costs are £257.25 and £66.94 respectively. \n\nThe claimed benefits of the PeritX peritoneal catheter drainage system in the case for adoption presented by the sponsor are:\n\nRepeated drainage of ascitic fluid in community settings may allow greater patient independence, and the flexibility to fit the drainage procedure into their daily lives.\n\nBetter symptom control by frequent drainage of smaller quantities of ascitic fluid. Symptoms associated with the accumulation of large amounts of ascites include breathlessness, nausea, bloating, acid reflux, abdominal pain, early satiety, reduced mobility and psychological distress related to negative body image.\n\nReduced need for repeated large-volume paracentesis procedures and the associated risk of infection from repeated catheter insertion.\n\nResource savings through a reduced need for hospital physician and nurse time, outpatient visits and hospital bed days.\n\n# Current management\n\nThe conventional management of treatment-resistant, recurrent malignant ascites involves repeated large-volume paracentesis (needle drainage of fluid) procedures that are carried out in hospital. Most commonly this is done as an inpatient procedure, although some centres are able to offer paracentesis as a day case procedure. Inpatient paracentesis is carried out when patients have developed troublesome symptoms from recurrent ascites. This can entail some delay while waiting for admission, during which the patient continues to experience symptoms.\n\nParacentesis involves inserting a catheter, often under local anaesthetic, into the peritoneal cavity to drain ascitic fluid. During large-volume paracentesis the catheter stays in place until most of the ascites has been drained, which often exceeds 5\xa0litres of fluid. This may be done in one go, but some patients cannot tolerate rapid drainage and may need to stay in hospital for one or more nights for repeated drainage procedures.", 'Clinical evidence': "# Summary of clinical evidence\n\nPeritX is referred to by its previous name, PleurX, in this summary of clinical evidence (sections\xa03.1 to 3.10) because this was the name of the device at the time the evidence was compiled.\n\nThe key clinical outcomes for the PleurX peritoneal catheter drainage system presented in the decision problem were:\n\ntechnical success of catheter insertion and drainage procedure\n\nresolution of symptoms (bloating, nausea, acid reflux, reduced appetite, negative perception of body image and resulting psychological distress)\n\nquality of life outcomes\n\nadverse events (catheter site infections, peritonitis, catheter occlusion, and haemorrhage or bowel perforation when the device is inserted)\n\ndrainage frequency\n\nresource use outcomes, for example re-admission rates, re-interventions and duration of hospital stay.\n\nThe clinical evidence for the PleurX peritoneal catheter drainage system was based on 9 observational studies (10 manuscripts), 2 of which were conducted in the UK. Six studies were case series with 10 or more patients, one study was a qualitative case series (4 patients), and there were 3 case reports (4 or fewer patients). The external assessment centre considered all the studies identified by the sponsor to be relevant and did not identify any further studies.\n\nRosenberg et al. (2004) conducted a single-centre, retrospective, comparative case series. It evaluated treatment complication rates in patients whose malignant ascites was managed using the PleurX peritoneal catheter drainage system (n=40 patients and catheters) compared with inpatient large-volume paracentesis (n=67 patients, 392 procedures). Overall complication rates (using number of patients rather than number of procedures) were the same for both procedures: 7.5% (3 of 40; 95% confidence interval [CI] 1.6% to 20%) for the PleurX peritoneal catheter drainage system and 7.5% (5 of 67; 95% CI 2.2% to 15%) for large-volume paracentesis. In patients whose ascites was managed with PleurX, complications were infection (n=1), leakage (n=1) and loculations (n=1), and all catheters were subsequently removed. Large-volume paracentesis complications were peritonitis (n=3) and loculations (n=2). The PleurX peritoneal catheter patency rate (defined as the number of catheters known to be functioning at death, study end or resolution of ascites) was 67.5% (n=27); however 11 (27.5%) patients were lost to follow-up.\n\nCourtney et al. (2008) carried out a multi-centre, single-arm, prospective case series evaluating treatment outcomes in 34 patients with malignant ascites treated with the PleurX peritoneal catheter drainage system over a 12‑week follow-up period (or until death in some patients). It reported 100% technical success during the placement procedure (defined as intraperitoneal positioning of the device and the ability to withdraw ascitic fluid from the device at the completion of the procedure), with one minor procedural complication. Twenty patients experienced complications during the follow-up period including minor complications that resolved spontaneously. Two catheters needed to be removed, and other complications were infection (n=2), occlusion/loculations (n=4), leakage of ascitic fluid (n=7), dizziness (n=5), shortness of breath (n=1) and severe anaemia (n=1). Available records from 19 patients showed that the mean number of drainage sessions after placement of the PleurX peritoneal catheter was 23.3 per patient (range 5\xa0to\xa056), and that of the total 433 sessions, 13% were performed by a nurse, and the remainder were carried out by the patient alone (28%) or a carer (58%). The catheter patency rate was 85% (n=29); the remaining 5 patients were lost to follow-up. Changes in symptom severity between baseline and at 2, 8 and 12\xa0weeks were assessed using a validated tool. There was a reduction in the severity of abdominal discomfort, bloating, diarrhoea and nausea at 2\xa0weeks and 8\xa0weeks. An overall improvement in quality of life at 12\xa0weeks was reported in 28% of respondents.\n\nIn a single-arm retrospective case series study, Mullan et al. (2011b) evaluated the procedural safety, mean survival, long-term efficacy, long-term complication profile and cost benefit of the PleurX peritoneal catheter drainage system in the management of recurrent malignant ascites (n=50 patients, 52\xa0catheters; 2 patients had their catheters re-inserted). On average, 5.3 inpatient large-volume paracentesis drainage procedures were performed before PleurX peritoneal catheter insertion. A 100% procedural success rate was reported. A mean patient survival of 59.4\xa0days (range 4\xa0days to 216 days) and 165\xa0days (range 29\xa0days to 1,036\xa0days) was reported after the PleurX peritoneal catheter insertion and after the first inpatient large-volume paracentesis procedure respectively. The average hospital stay for patients having inpatient large-volume paracentesis was 2.8\xa0days (range 1\xa0day to 6\xa0days; n=23) and the average ascitic fluid drainage per episode of paracentesis was 9.2\xa0litres. Eight patients experienced complications after insertion of the PleurX peritoneal catheter, which were peritonitis (n=1), lymphangitis (n=1), occlusion/loculations (n=3), ascitic leakage (n=1), displacement (n=1) and pain (n=1); one catheter needed to be removed. Primary or secondary catheter patency at death was 100%, with management of complications augmented by multi-modality imaging and fibrinolysis of malfunctioning catheters.\n\nIn a single-arm retrospective case series study (n=10 patients and catheters), Richard et al. (2001) evaluated the clinical outcomes after PleurX peritoneal catheter insertion in patients with treatment-resistant, recurrent malignant ascites. They reported 100% procedural success. Two patients experienced complications, which were occlusion/loculations (n=1) and displacement (n=1). The average time catheters remained in place was 70\xa0days (range 1\xa0day to 100\xa0days).\n\nIn a single-arm retrospective case, Tapping et al. (2011) evaluated the clinical outcomes after PleurX peritoneal catheter insertion in 28 patients (32 catheters) with treatment-resistant, recurrent malignant ascites. A technical success rate of 100% was reported. There were 12 complications, which comprised minor catheter site infections (n=5), ascitic leakage (n=1), displacement (n=4), hernia (n=1) and one further complication that was not described. No catheters needed to be removed other than those that were inadvertently dislodged. The catheters remained in place for an average of 113\xa0days (range 5\xa0days to 365\xa0days) and catheter patency was 86% (24 of 28).\n\nSaiz-Mendiguren et al. (2010) conducted an observational descriptive case series study of patients (n=10) who had the PleurX peritoneal catheter inserted. They analysed the duration of the procedure, pain reported by the patient during the procedure (using a visual analogue scale score), short- and long-term complications, median patency of the catheter, and the volume of ascitic fluid drained at home (reported by telephone or during consultation). The technical success rate of the insertion procedure was 100%. Two patients reported discomfort during the procedure (visual analogue scale scores 2 and 3 out of 10). No complications were reported during or after the procedure. In one patient with generalised sepsis thought to be caused by a venous cannula, the PleurX peritoneal catheter was removed 58 days after placement as a precaution. Nine patients died; their catheters remained patent for a median of 52\xa0days (range 13\xa0days to 113\xa0days). At the end of the study, one patient remained alive with a patent catheter 124\xa0days after placement. The mean ascitic fluid drainage reported by patients or their carers was approximately 1\xa0litre (one vacuum bottle) every 2\xa0days to 10\xa0days.\n\nDay et al. (2011) conducted a small qualitative case study, which is currently available in abstract form, and from which the committee considered detailed findings presented as academic-in-confidence data. Patients who had inpatient large-volume paracentesis were also included in the study, but no comparisons were drawn between the 2 treatment groups. Patient opinions and experiences were described in a narrative form and categorised into emergent themes following semi-structured interviews. The results revealed a positive trend of opinion towards PleurX, particularly relating to symptom improvement and increased convenience. All patients were reported to be glad that they had had the PleurX peritoneal catheter inserted. Some negative opinions were expressed including the fact that some patients did not like seeing the ascitic fluid, and others felt that the PleurX peritoneal catheter drainage system made them feel 'more of a patient'.\n\nThree case reports relevant to the decision problem were also identified. Brooks et al. (2006) described one patient who had had a PleurX peritoneal catheter in place for 18\xa0months and had developed 3 complications: drain blockage (immediately relieved by flushing), hernia around the catheter site, and the presence of gram-negative bacilli in urine and ascites (treated successfully with ciprofloxacin). Iyengar et al. (2002) described 3 patients who had catheters in place for 6\xa0weeks, 7\xa0weeks and 12\xa0weeks. One patient experienced dehydration, and one catheter was removed as a precaution in a patient with sepsis. Mullan et al. (2011a) reported experiences of 4 patients taken from a larger study (Mullan et al. 2011b) in whom streptokinase fibrinolytic therapy was successfully used to treat loculations.\n\n# Committee considerations\n\nThe committee concluded from the available clinical evidence that the PeritX peritoneal catheter drainage system is effective in the palliative management of treatment-resistant, recurrent malignant ascites. It has a high procedural success rate, a low complication rate and the potential to improve patient quality of life.\n\nPatients with malignant ascites have a disability as defined by the Equality Act 2010. The committee recognised that treatment-resistant, recurrent malignant ascites often has an adverse impact on patients' activities of daily living, which may be improved with the PeritX peritoneal catheter drainage system. The committee was advised by the patient and clinical experts that improvement in quality of life is mainly a result of avoiding regular hospital visits and inpatient stays associated with large-volume paracentesis, and alleviation of symptoms associated with massive ascites through the frequent drainage of small volumes of ascitic fluid.\n\nThe committee recognised the uncertainty about the point in the care pathway at which it would be clinically appropriate to treat patients with treatment-resistant, recurrent malignant ascites with the PeritX peritoneal catheter drainage system. Tapping et al. (2011) considered that patients who had had at least 3 previous large-volume paracentesis procedures would be suitable for treatment with the PeritX peritoneal catheter drainage system, whereas Courtney et al. (2008) inserted the PeritX peritoneal catheter in patients who had had at least 2 large-volume paracentesis procedures in the previous 30\xa0days. The committee considered that the decision to start treatment with the PeritX peritoneal catheter drainage system should be shared between clinicians and patients.\n\nThe committee was advised that the term 'treatment-resistant' is normally understood by clinicians to mean that there is a low likelihood of further medical or oncological interventions (particularly chemotherapy) being successful in preventing or reducing re-accumulation of ascites.\n\nThe committee acknowledged that the current evidence is based on observational studies, with very limited data available comparing the PeritX peritoneal catheter drainage system with other treatments.\n\nThe committee noted that there are 2 ongoing clinical trials using the PeritX peritoneal catheter drainage system. One is investigating the impact on quality of life and the other is comparing early stage PeritX peritoneal catheter insertion with standard large-volume paracentesis. Both trials are expected to be completed in 2012.", 'NHS considerations': '# System impact\n\nThe evidence suggests that the PeritX peritoneal catheter drainage system is a safe and effective alternative to inpatient large-volume paracentesis, is cost saving and reduces hospital bed use.\n\n# Committee considerations\n\nThe clinical experts advised the committee that the PeritX peritoneal catheter insertion procedure is unlikely to be more costly to the NHS than the large-volume paracentesis procedure.\n\nThe main resource consideration with PeritX is the relative need for community nursing support for the ongoing drainage procedures. However, the committee was advised that the PeritX peritoneal catheter drainage system is unlikely to increase overall community nursing input as was assumed in the cost model (see section 5). This is because most patients in the terminal stages of cancer need community nursing support regardless of the PeritX peritoneal catheter drainage system, and large-volume-paracentesis is associated with a greater need for nursing for overall wound management. Indeed, the committee was advised that it is possible that using the PeritX peritoneal catheter drainage system could lead to an overall reduction in community nursing costs, which would further enhance the resource savings associated with its use.\n\nThe committee recognised that training is needed for community nurses, patients or carers to perform drainage procedures in a community setting.', 'Cost considerations': "# Cost evidence\n\nThe sponsor submitted a new cost analysis based on a decision tree model with an embedded Markov model. This model evaluated the costs per patient and system impact of the PeritX peritoneal catheter drainage system for the drainage of treatment-resistant, recurrent malignant ascites in the community setting when compared with inpatient and outpatient large-volume paracentesis.\n\nThe time horizon of the model was 26\xa0weeks (6\xa0months) from the time of the initial PeritX peritoneal catheter insertion. The Markov model was run over 26‑weekly cycles to account for the short duration of survival in patients with malignant ascites. The cycles used transition probabilities based on 100% survival at week 0 to 4% survival at week\xa026. The cost of treatment was multiplied by the transition probability at each cycle; half-cycle corrections were used to incorporate changes in survival within a cycle.\n\nThe key assumptions used in the model were:\n\nno change in the survival rate in both arms of the model\n\nthe need for 2 nurse visits to train patients to self-manage the drainage at home using the PeritX peritoneal catheter drainage system\n\nsimilar levels of treatment monitoring needs in both arms of the model\n\na nurse visit length of 15\xa0minutes for the PeritX peritoneal catheter drainage system to help with drainage at home\n\ndrainage volume of 9.2\xa0litres per procedure in patients who have repeated large-volume paracentesis\n\naverage drainage volume of 3.5\xa0litres per week using the PeritX peritoneal catheter drainage system\n\none nurse visit per litre of ascitic fluid drained using the PeritX peritoneal catheter drainage system\n\nthe cost of re-intervention being equivalent to a first-time catheter insertion procedure.\n\nThe model calculated the costs per patient of the PeritX peritoneal catheter drainage system and large-volume paracentesis as well as the incremental costs of the PeritX peritoneal catheter drainage system. The costs of the system included: inpatient stay (1\xa0day), procedure consumables and other costs (including staff time), PeritX drainage kits, home nurse visits and treatment of complications (infection, catheter failure and re-intervention). The cost of large-volume paracentesis included: inpatient stay (2.8\xa0days) or outpatient (1\xa0day), procedure consumables and treatment of complications. In addition, the system impact was presented in terms of number of paracentesis sessions, number of\xa0litres of ascitic fluid drained, number of bed days, and number of nurse visits for both interventions.\n\nThe cost per patient for the management of malignant ascites using the PeritX peritoneal catheter drainage system was estimated to be £2,466, whereas for inpatient and outpatient large-volume paracentesis it was estimated to be £3,146 and £1,457 respectively.\n\nThe base-case analysis showed that managing treatment-resistant, recurrent malignant ascites with the PeritX peritoneal catheter drainage system may result in cost saving of £679 per patient when compared with inpatient large-volume paracentesis. In this scenario, 7.4 hospital bed days were saved per patient, but 23.5 more community nurse visits to the patients' home were needed. When the PeritX peritoneal catheter drainage system was compared with outpatient large-volume paracentesis, an additional cost of £1,010 per patient was incurred, including 23.5 extra nurse visits but 1.9 fewer hospital bed days used per patient.\n\nThe key drivers of the new cost analysis were: cost of a hospital bed day, number of bed days per large-volume paracentesis session, number of large-volume paracentesis procedures per month, number of bed days for PeritX peritoneal catheter placement, cost per drainage kit box (10\xa0units), and number of drainage kits used per week per patient. The analysis showed that cost savings associated with the PeritX peritoneal catheter drainage system, when compared with inpatient large-volume paracentesis, were heavily dependent on a reduction in hospital stay. The cost of a bed day was estimated at £312.\n\nThe sponsor carried out one-way deterministic sensitivity analysis. All variables (except for population size) were tested, and were analysed using a variance of 20% regardless of the level of confidence in an input or the parameter-specific circumstances. Six key drivers were selected and subjected to further deterministic threshold analysis by the external assessment centre across a wide range of values, to identify the point at which the PeritX peritoneal catheter drainage system became more costly or cost saving compared with inpatient and outpatient large-volume paracentesis respectively.\n\nThe findings of the threshold sensitivity analysis showed that using the PeritX peritoneal catheter drainage system may incur additional costs when compared with inpatient large-volume paracentesis in the following scenarios: the cost of an excess bed day is reduced to less than £220 per day; the frequency of an inpatient large-volume paracentesis procedure is reduced to fewer than one per month; the average length of inpatient stay after the large-volume paracentesis procedure is decreased to 2.1\xa0days; the number of inpatient bed days following the PeritX peritoneal catheter insertion procedure is increased to more than 3.1\xa0days; the cost of the PeritX drainage kit is increased to more than £915 (per 10\xa0units); more than 5.1 drainage kit units are needed per week. The PeritX peritoneal catheter drainage system may become cost saving when compared with outpatient large-volume paracentesis in the following scenarios: the cost of an excess bed day is increased to more than £825 per day; the frequency of an outpatient large-volume paracentesis procedure is increased to more than 2.5 per month; the average length of hospital stay after the outpatient large-volume paracentesis procedure is increased to more than 2.1 days; the cost of the PeritX drainage kit is decreased to less than £225 (per 10\xa0units); fewer than 1.14 drainage kit units are needed per week.\n\nThe sensitivity analysis demonstrated that the PeritX peritoneal catheter drainage system is likely to remain cost saving when compared with inpatient large-volume paracentesis and is likely to incur extra costs when compared with outpatient large-volume paracentesis.\n\n# Committee considerations\n\nThe new cost analysis showed that the PeritX peritoneal catheter drainage system was cost saving when compared with inpatient large-volume paracentesis, but incurred additional costs when compared with outpatient large-volume paracentesis. The additional costs, compared with outpatient treatment, were incurred mainly from an increased number of home nurse visits, with only a small offset saving in hospital bed days. However, the committee was advised that the additional cost burden imposed on community nursing staff as a result of the PeritX peritoneal catheter drainage system may have been overestimated, given that most patients will receive healthcare in the community regardless of whether or not they have a PeritX peritoneal catheter in place. The committee was advised that many patients may not prefer outpatient to inpatient large-volume paracentesis because it does not necessarily alleviate the intolerable symptoms associated with ascitic fluid build-up any better than inpatient large-volume paracentesis and yet still creates the need for repeated outpatient visits.\n\nThe committee recognised that large-volume paracentesis is currently offered as an inpatient, outpatient or day case procedure and that practice varies across the UK. Moreover, the resource costs for outpatient and day case large-volume paracentesis differ, with the day case procedure being more costly (although this was not reflected in the cost model). The committee was advised that the PeritX peritoneal catheter drainage system is likely to be cost saving when compared with day case large-volume paracentesis.\n\nThe clinical experts advised the committee that the mean hospital stay of 2.8\xa0days following inpatient large-volume paracentesis that was used in the base-case analysis is a realistic estimate and reflects current practice in many NHS centres.\n\nThe committee recognised that the NHS tariff used for the calculation of excess bed days underestimated the cost of an inpatient stay and that correcting this may further increase the cost savings attributable to the PeritX peritoneal catheter drainage system.\n\n# guidance review\n\nFor the 2022 guidance review, the external assessment centre revised the model to reflect 2020 costs. The largest changes compared with the costs from the 2018 guidance review were increases in the cost of hospital bed days (£355 to £367.78) and decreases in the cost of home visit per hour (£68 to £49). The new costs for the technology were also included. Base-case results for the 2022 revised model (values after first guidance review are given in brackets) show a cost saving of £1,095 (£1,051) per patient. The differential cost between PeritX and paracentesis as an outpatient procedure has increased to an additional cost of £896 (£871) per patient. ", 'Conclusions': 'The committee concluded that the PeritX peritoneal catheter drainage system is a clinically safe and effective palliative therapy for the management of treatment-resistant, recurrent malignant ascites, which has the potential to improve quality of life and is cost saving when compared with inpatient large-volume paracentesis.'}	https://www.nice.org.uk/guidance/mtg9	Evidence-based recommendations on PeritX for vacuum-assisted drainage of treatment-resistant, recurrent malignant ascites.
bea84176da88cea1345118c412a2c94493d930f4	nice	COVID-19 rapid guideline: vitamin D	COVID-19 rapid guideline: vitamin D This guideline covers vitamin D use in the context of COVID‑19. It is for adults, young people and children in hospitals and community settings. Vitamin D is important for bone and muscle health. It may also have a role in the body's immune response to respiratory viruses. # Recommendations Encourage people to follow UK government advice on taking a vitamin D supplement to maintain bone and muscle health. The advice is that: Adults (including women who are pregnant or breastfeeding), young people and children over 4 years should consider taking a daily supplement containing 10 micrograms (400 units; also called international units ) of vitamin D between October and early March because people do not make enough vitamin D from sunlight in these months. Adults, young people and children over 4 years should consider taking a daily supplement containing 10 micrograms (400 units) of vitamin D throughout the year: if they have little or no sunshine exposure including because they: are not often outdoors, for example, if they are frail, housebound or living in a care home usually wear clothes that cover up most of their skin when outdoors are spending most of their time indoors because of the COVID‑19 pandemic if they have dark skin, for example, if they are of African, African-Caribbean or south Asian family origin, because they may not make enough vitamin D from sunlight. Babies from birth to 1 year should have a daily supplement containing 8.5 micrograms (340 units) to 10 micrograms (400 units) of vitamin D throughout the year if they are: breastfed formula-fed and are having less than 500 ml of infant formula a day (because infant formula is already fortified with vitamin D). Children aged 1 year to 4 years should have a daily supplement containing 10 micrograms (400 units) of vitamin D throughout the year. Some people have a medical condition that means they cannot take vitamin D or should take a different amount from the general population. Do not offer a vitamin D supplement to people solely to prevent COVID‑19, except as part of a clinical trial. This recommendation has been replaced by recommendation 7.15 in NICE's COVID-19 rapid guideline on managing COVID-19. For a short explanation of why we made these recommendations see the rationale section on recommendations . Full details of the evidence are in the evidence review. Loading. Please wait.# Rationale # Why the panel made the recommendation The panel agreed that there was little evidence for using vitamin D supplements to prevent COVID‑19. However, they agreed that vitamin D use is well established for maintaining bone and muscle health. They expressed concerns that not everyone is aware of, or is following, UK government advice on taking a vitamin D supplement, so wanted to include a recommendation to emphasise the existing guidance. They stressed that everyone should consider taking a supplement containing 10 micrograms (400 units) of vitamin D daily between October and early March, when people in the UK do not make enough vitamin D from sunlight. They also stressed that this was particularly important during the COVID‑19 pandemic, when people may have been indoors more than usual over the spring and summer. The panel discussed that, for most people, 10 micrograms (400 units) of vitamin D a day will be enough to prevent serum 25(OH)D concentration from falling below 25 nmol/litre. They also noted that taking too high a dose of vitamin D over a long period of time could be harmful because it can cause too much calcium to build up in the body (hypercalcaemia). This can weaken the bones and damage the kidneys and the heart. They were aware that the tolerable upper intake level for adults and young people over 11 years is 100 micrograms (4,000 units) daily, and that this dose should not be exceeded. They discussed monitoring requirements if people have renal impairment or high doses are given, and were aware of cautions for use in people with certain medical conditions, such as sarcoidosis. They agreed that, if people are unsure whether they can take vitamin D, they should discuss this with their healthcare professional. The panel also discussed that vitamin D3 (colecalciferol) supplements can be derived from an animal source. They noted that people's concerns about using animal products because of a religious or ethical belief need to be considered when discussing vitamin D products. The panel also noted that it is important for some populations to take a supplement containing 10 micrograms (400 units) of vitamin D daily throughout the year. This includes people who are at a higher risk of not getting enough vitamin D because, for example, of lack of exposure to sunlight during the spring and summer months. The panel discussed access to vitamin D supplements, and were aware of the NICE guideline on vitamin D: supplement use in specific population groups and the NHS service supplying free daily vitamin D supplements for people at high risk (clinically extremely vulnerable) from COVID‑19. This service has been set up because it is particularly important for people who have been indoors more over the spring and summer when shielding to take vitamin D for bone and muscle health. ## Preventing COVID-19 The panel were presented with evidence from the NICE evidence review of vitamin D for COVID-19 on using vitamin D supplements to prevent SARS‑CoV‑2 infection (and subsequent COVID‑19), and evidence on vitamin D status and its association with COVID‑19. No evidence relevant to the protocol was found for the prevention question. The panel discussed the evidence for the association of vitamin D status with COVID‑19. They agreed that low vitamin D status was associated with more severe outcomes from COVID‑19. However, it is not possible to confirm causality because many of the risk factors for severe COVID‑19 outcomes are the same as the risk factors for low vitamin D status. Vitamin D is a negative acute phase reactant, meaning its serum concentration falls during a systemic inflammatory response, which may occur during severe COVID-19 illness. Therefore, it is difficult to know if low vitamin D status causes poorer outcomes or vice versa. The panel discussed the significant limitations in the retrospective association studies. These included historic and inaccurate vitamin D status measurements, lack of generalisability to UK practice, the likelihood of confounding and general low quality of the evidence. Because COVID‑19 mainly affects the respiratory tract, the panel also heard indirect evidence from the updated Scientific Advisory Committee on Nutrition (SACN) rapid review on using vitamin D supplements to prevent acute respiratory tract infections. They agreed that a systematic review and meta-analysis by Jolliffe et al. (2020) reported a modest protective effect of vitamin D supplementation compared with placebo. From subgroup analyses, this protection was associated with daily doses of 10 micrograms to 25 micrograms (400 units to 1,000 units) of vitamin D, but not higher doses. Also, from subgroup analysis, the protection was only seen in children and young people aged from 1 year to under 16 years (the panel noted that, for COVID‑19, poorer outcomes are more common in an older adult population). Beneficial effects on acute respiratory tract infection prevention were not seen with higher doses of vitamin D supplementation (over 25 micrograms daily or more), when supplementation was weekly or monthly, or in adults. The SACN rapid review highlighted limitations with the studies included in the meta-analysis by Joliffe et al. (2020) including: inconsistency between study results differences between studies in vitamin D supplementation doses and regimens, settings, populations, durations and definitions of outcomes (including type of respiratory infection). The panel were also aware of the updated SACN recommendations that a vitamin D intake of 10 micrograms (400 units) daily, as currently recommended, may provide some additional benefit in reducing the risk of acute respiratory tract infections. However, they noted that this topic is being kept under review and these recommendations may be updated if findings from robust, high-quality randomised controlled trials provide further clarification. Based on direct evidence from the NICE evidence review and indirect evidence from the SACN rapid review of vitamin D in acute respiratory tract infection (which did not include COVID‑19 as an outcome), the panel agreed that there was not enough evidence to recommend vitamin D supplements solely for preventing COVID‑19. The panel agreed that people should be encouraged to follow the existing UK government advice on vitamin D supplementation. They also agreed that the recommendations in this guideline on vitamin D supplements and COVID‑19 prevention should be considered for an update as additional evidence becomes available. The panel agreed that there is a need for research into vitamin D supplementation for preventing COVID‑19. However, they discussed issues around ethics, trial design and comparators, and agreed that it would be more appropriate for the research community to define an appropriate PICO (population, interventions, comparators, outcomes) framework. They were aware that the updated SACN rapid review on using vitamin D supplements to prevent acute respiratory tract infections has a recommendation that research is urgently needed on vitamin D and risk of acute respiratory tract infection in black, Asian and minority ethnic groups, and people living with overweight or obesity. The panel also noted that several randomised controlled trials of vitamin D supplements in preventing COVID‑19 are known to be in progress. As additional evidence becomes available, this guidance will be updated in line with NICE's interim process and methods for guidelines developed in response to health and social care emergencies. Full details of the evidence are in the NICE evidence review of vitamin D for COVID-19. Return to recommendations# Context Vitamin D is important for bone and muscle health. It may also have a role in the body's immune response to respiratory viruses. Sunlight exposure is the main source of vitamin D for most people in the UK during summer months. But, between October and early March, people in the UK do not make enough vitamin D from sunlight. Vitamin D is also found in a small number of foods and can be obtained from supplements. The 2 key forms of vitamin D, D3 (colecalciferol) and D2 (ergocalciferol), are licensed for preventing and treating vitamin D deficiency. They are not specifically licensed for preventing any infection, including SARS‑CoV‑2 that causes COVID‑19. Vitamin D status is determined by measuring serum concentrations of 25 hydroxyvitamin D (25D), the major circulating metabolite of vitamin D. Existing UK government recommendations on vitamin D are based on advice from the Scientific Advisory Committee on Nutrition (SACN). To protect bone and muscle health, the SACN vitamin D and health report recommends that serum 25(OH)D concentration should not fall below 25 nmol/litre at any time of the year. To achieve this, SACN recommends a reference nutrient intake of 10 micrograms (400 units; also called international units ) of vitamin D daily for the UK population aged 4 years and above. This is the average amount needed by 97.5% of the population to maintain a serum concentration of 25 nmol/litre when UVB sunshine exposure is minimal. UK government advice on taking a vitamin D supplement includes: micrograms (400 units) of vitamin D daily for everyone in the UK aged over 4 years between October and early March, and micrograms (400 units) of vitamin D daily throughout the year for people whose serum 25(OH)D concentrations may not reach 25 nmol/litre through sunlight alone. The dose of vitamin D in units can be calculated by multiplying the number of micrograms by 40; for example, 10 micrograms is equivalent to 400 units. This guideline uses 'units' instead of 'international units' or 'IU' for doses of vitamin D. This is consistent with the BNF guidance on prescription writing, and stems from the preferred convention of using 'units' because of safety concerns about using 'IU' in prescribing. There are services supplying free vitamin D supplements to some population groups. For example, there is an NHS service supplying free daily vitamin D supplements for people at high risk (clinically extremely vulnerable) from COVID‑19. This service has been set up because it is particularly important for people who have been indoors more over the spring and summer while shielding to take vitamin D for bone and muscle health. Women and children who qualify for the Healthy Start scheme can also get free supplements containing vitamin D.	{'Recommendations': "Encourage people to follow UK\xa0government advice on taking a vitamin\xa0D supplement to maintain bone and muscle health. The advice is that:\n\nAdults (including women who are pregnant or breastfeeding), young people and children over 4\xa0years should consider taking a daily supplement containing 10\xa0micrograms (400\xa0units; also called international units [IU]) of vitamin\xa0D between October and early March because people do not make enough vitamin\xa0D from sunlight in these months.\n\nAdults, young people and children over 4\xa0years should consider taking a daily supplement containing 10\xa0micrograms (400\xa0units) of vitamin\xa0D throughout the year:\n\n\n\nif they have little or no sunshine exposure including because they:\n\n\n\nare not often outdoors, for example, if they are frail, housebound or living in a care home\n\nusually wear clothes that cover up most of their skin when outdoors\n\nare spending most of their time indoors because of the COVID‑19 pandemic\n\n\n\nif they have dark skin, for example, if they are of African, African-Caribbean or south Asian family origin, because they may not make enough vitamin\xa0D from sunlight.\n\n\n\nBabies from birth to 1\xa0year should have a daily supplement containing 8.5\xa0micrograms (340\xa0units) to 10\xa0micrograms (400\xa0units) of vitamin\xa0D throughout the year if they are:\n\n\n\nbreastfed\n\nformula-fed and are having less than 500\xa0ml of infant formula a day (because infant formula is already fortified with vitamin\xa0D).\n\n\n\nChildren aged 1\xa0year to 4\xa0years should have a daily supplement containing 10\xa0micrograms (400\xa0units) of vitamin\xa0D throughout the year.\n\nSome people have a medical condition that means they cannot take vitamin\xa0D or should take a different amount from the general population.\n\nDo not offer a vitamin\xa0D supplement to people solely to prevent COVID‑19, except as part of a clinical trial.\n\nThis recommendation has been replaced by recommendation 7.15 in NICE's COVID-19 rapid guideline on managing COVID-19.\n\nFor a short explanation of why we made these recommendations see the rationale section on recommendations\xa0.\n\nFull details of the evidence are in the evidence review.\n\nLoading. Please wait.", 'Rationale': "# Why the panel made the recommendation\n\nThe panel agreed that there was little evidence for using vitamin\xa0D supplements to prevent COVID‑19. However, they agreed that vitamin\xa0D use is well established for maintaining bone and muscle health. They expressed concerns that not everyone is aware of, or is following, UK\xa0government advice on taking a vitamin\xa0D supplement, so wanted to include a recommendation to emphasise the existing guidance. They stressed that everyone should consider taking a supplement containing 10\xa0micrograms (400\xa0units) of vitamin\xa0D daily between October and early March, when people in the UK do not make enough vitamin\xa0D from sunlight. They also stressed that this was particularly important during the COVID‑19 pandemic, when people may have been indoors more than usual over the spring and summer.\n\nThe panel discussed that, for most people, 10\xa0micrograms (400\xa0units) of vitamin\xa0D a day will be enough to prevent serum 25(OH)D concentration from falling below 25\xa0nmol/litre. They also noted that taking too high a dose of vitamin\xa0D over a long period of time could be harmful because it can cause too much calcium to build up in the body (hypercalcaemia). This can weaken the bones and damage the kidneys and the heart. They were aware that the tolerable upper intake level for adults and young people over 11\xa0years is 100\xa0micrograms (4,000\xa0units) daily, and that this dose should not be exceeded. They discussed monitoring requirements if people have renal impairment or high doses are given, and were aware of cautions for use in people with certain medical conditions, such as sarcoidosis. They agreed that, if people are unsure whether they can take vitamin\xa0D, they should discuss this with their healthcare professional. The panel also discussed that vitamin\xa0D3 (colecalciferol) supplements can be derived from an animal source. They noted that people's concerns about using animal products because of a religious or ethical belief need to be considered when discussing vitamin\xa0D products.\n\nThe panel also noted that it is important for some populations to take a supplement containing 10\xa0micrograms (400\xa0units) of vitamin\xa0D daily throughout the year. This includes people who are at a higher risk of not getting enough vitamin\xa0D because, for example, of lack of exposure to sunlight during the spring and summer months.\n\nThe panel discussed access to vitamin\xa0D supplements, and were aware of the NICE guideline on vitamin\xa0D: supplement use in specific population groups and the NHS service supplying free daily vitamin\xa0D supplements for people at high risk (clinically extremely vulnerable) from COVID‑19. This service has been set up because it is particularly important for people who have been indoors more over the spring and summer when shielding to take vitamin\xa0D for bone and muscle health.\n\n## Preventing COVID-19\n\nThe panel were presented with evidence from the NICE evidence review of vitamin\xa0D for COVID-19 on using vitamin\xa0D supplements to prevent SARS‑CoV‑2 infection (and subsequent COVID‑19), and evidence on vitamin\xa0D status and its association with COVID‑19.\n\nNo evidence relevant to the protocol was found for the prevention question. The panel discussed the evidence for the association of vitamin\xa0D status with COVID‑19. They agreed that low vitamin\xa0D status was associated with more severe outcomes from COVID‑19. However, it is not possible to confirm causality because many of the risk factors for severe COVID‑19 outcomes are the same as the risk factors for low vitamin\xa0D status. Vitamin\xa0D is a negative acute phase reactant, meaning its serum concentration falls during a systemic inflammatory response, which may occur during severe COVID-19 illness. Therefore, it is difficult to know if low vitamin\xa0D status causes poorer outcomes or vice versa.\n\nThe panel discussed the significant limitations in the retrospective association studies. These included historic and inaccurate vitamin\xa0D status measurements, lack of generalisability to UK practice, the likelihood of confounding and general low quality of the evidence.\n\nBecause COVID‑19 mainly affects the respiratory tract, the panel also heard indirect evidence from the updated Scientific Advisory Committee on Nutrition (SACN) rapid review on using vitamin D supplements to prevent acute respiratory tract infections. They agreed that a systematic review and meta-analysis by Jolliffe et al. (2020) reported a modest protective effect of vitamin\xa0D supplementation compared with placebo. From subgroup analyses, this protection was associated with daily doses of 10\xa0micrograms to 25\xa0micrograms (400\xa0units to 1,000\xa0units) of vitamin\xa0D, but not higher doses. Also, from subgroup analysis, the protection was only seen in children and young people aged from 1\xa0year to under 16\xa0years (the panel noted that, for COVID‑19, poorer outcomes are more common in an older adult population). Beneficial effects on acute respiratory tract infection prevention were not seen with higher doses of vitamin\xa0D supplementation (over 25\xa0micrograms [1,000\xa0units] daily or more), when supplementation was weekly or monthly, or in adults. The SACN rapid review highlighted limitations with the studies included in the meta-analysis by Joliffe et al. (2020) including:\n\ninconsistency between study results\n\ndifferences between studies in vitamin\xa0D supplementation doses and regimens, settings, populations, durations and definitions of outcomes (including type of respiratory infection).\n\nThe panel were also aware of the updated SACN recommendations that a vitamin\xa0D intake of 10\xa0micrograms (400\xa0units) daily, as currently recommended, may provide some additional benefit in reducing the risk of acute respiratory tract infections. However, they noted that this topic is being kept under review and these recommendations may be updated if findings from robust, high-quality randomised controlled trials provide further clarification.\n\nBased on direct evidence from the NICE evidence review and indirect evidence from the SACN rapid review of vitamin\xa0D in acute respiratory tract infection (which did not include COVID‑19 as an outcome), the panel agreed that there was not enough evidence to recommend vitamin\xa0D supplements solely for preventing COVID‑19.\n\nThe panel agreed that people should be encouraged to follow the existing UK\xa0government advice on vitamin\xa0D supplementation. They also agreed that the recommendations in this guideline on vitamin\xa0D supplements and COVID‑19 prevention should be considered for an update as additional evidence becomes available.\n\nThe panel agreed that there is a need for research into vitamin\xa0D supplementation for preventing COVID‑19. However, they discussed issues around ethics, trial design and comparators, and agreed that it would be more appropriate for the research community to define an appropriate PICO (population, interventions, comparators, outcomes) framework. They were aware that the updated SACN rapid review on using vitamin\xa0D supplements to prevent acute respiratory tract infections has a recommendation that research is urgently needed on vitamin\xa0D and risk of acute respiratory tract infection in black, Asian and minority ethnic groups, and people living with overweight or obesity. The panel also noted that several randomised controlled trials of vitamin\xa0D supplements in preventing COVID‑19 are known to be in progress.\n\nAs additional evidence becomes available, this guidance will be updated in line with NICE's interim process and methods for guidelines developed in response to health and social care emergencies.\n\nFull details of the evidence are in the NICE evidence review of vitamin\xa0D for COVID-19.\n\nReturn to recommendations", 'Context': "Vitamin\xa0D is important for bone and muscle health. It may also have a role in the body's immune response to respiratory viruses. Sunlight exposure is the main source of vitamin\xa0D for most people in the UK during summer months. But, between October and early March, people in the UK do not make enough vitamin\xa0D from sunlight. Vitamin\xa0D is also found in a small number of foods and can be obtained from supplements. The 2\xa0key forms of vitamin\xa0D, D3\xa0(colecalciferol) and D2\xa0(ergocalciferol), are licensed for preventing and treating vitamin\xa0D deficiency. They are not specifically licensed for preventing any infection, including SARS‑CoV‑2 that causes COVID‑19.\n\nVitamin\xa0D status is determined by measuring serum concentrations of 25\xa0hydroxyvitamin\xa0D (25[OH]D), the major circulating metabolite of vitamin\xa0D. Existing UK\xa0government recommendations on vitamin\xa0D are based on advice from the Scientific Advisory Committee on Nutrition (SACN). To protect bone and muscle health, the SACN vitamin\xa0D and health report recommends that serum 25(OH)D concentration should not fall below 25\xa0nmol/litre at any time of the year. To achieve this, SACN recommends a reference nutrient intake of 10\xa0micrograms (400\xa0units; also called international units [IU]) of vitamin\xa0D daily for the UK population aged 4\xa0years and above. This is the average amount needed by 97.5% of the population to maintain a serum concentration of 25\xa0nmol/litre when UVB sunshine exposure is minimal. UK\xa0government advice on taking a vitamin\xa0D supplement includes:\n\nmicrograms (400\xa0units) of vitamin\xa0D daily for everyone in the UK aged over 4\xa0years between October and early March, and\n\nmicrograms (400\xa0units) of vitamin\xa0D daily throughout the year for people whose serum 25(OH)D concentrations may not reach 25\xa0nmol/litre through sunlight alone.\n\nThe dose of vitamin\xa0D in units can be calculated by multiplying the number of micrograms by\xa040; for example, 10\xa0micrograms is equivalent to 400\xa0units. This guideline uses 'units' instead of 'international units' or 'IU' for doses of vitamin\xa0D. This is consistent with the BNF guidance on prescription writing, and stems from the preferred convention of using 'units' because of safety concerns about using 'IU' in prescribing.\n\nThere are services supplying free vitamin\xa0D supplements to some population groups. For example, there is an NHS service supplying free daily vitamin\xa0D supplements for people at high risk (clinically extremely vulnerable) from COVID‑19. This service has been set up because it is particularly important for people who have been indoors more over the spring and summer while shielding to take vitamin\xa0D for bone and muscle health. Women and children who qualify for the Healthy Start scheme can also get free supplements containing vitamin\xa0D."}	https://www.nice.org.uk/guidance/ng187	This guideline covers vitamin D use in the context of COVID‑19. It is for adults, young people and children in hospitals and community settings. Vitamin D is important for bone and muscle health. It may also have a role in the body's immune response to respiratory viruses.
fd61fb362f88151d9960d528d9fbe5be2be00960	nice	Icosapent ethyl with statin therapy for reducing the risk of cardiovascular events in people with raised triglycerides	Icosapent ethyl with statin therapy for reducing the risk of cardiovascular events in people with raised triglycerides Evidence-based recommendations on icosapent ethyl (Vazkepa) with statin therapy for reducing the risk of cardiovascular events in adults with raised triglycerides. # Recommendations Icosapent ethyl is recommended as an option for reducing the risk of cardiovascular events in adults. It is recommended if they have a high risk of cardiovascular events and raised fasting triglycerides (1.7 mmol/litre or above) and are taking statins, but only if they have: established cardiovascular disease (secondary prevention), defined as a history of any of the following: acute coronary syndrome (such as myocardial infarction or unstable angina needing hospitalisation) coronary or other arterial revascularisation procedures coronary heart disease ischaemic stroke peripheral arterial disease, and low-density lipoprotein cholesterol (LDL‑C) levels above 1.04 mmol/litre and below or equal to 2.60 mmol/litre. This recommendation is not intended to affect treatment with icosapent ethyl that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations There are currently no treatment options to reduce the risk of cardiovascular events in people taking statins who have controlled levels of LDL-C but raised levels of triglycerides. Icosapent ethyl is licensed for people taking statins who have raised triglycerides and a high risk of cardiovascular events, and who have either: established cardiovascular disease (secondary prevention), or diabetes and at least one other cardiovascular risk factor (primary prevention). Clinical trial evidence suggests that icosapent ethyl reduces the risk of cardiovascular events, compared with placebo, in people with raised fasting triglycerides (1.7 mmol/litre or above) who are taking statins. The trial only included people with LDL-C levels above 1.04 mmol/litre and below or equal to 2.60 mmol/litre. The cost-effectiveness estimates for icosapent ethyl are uncertain. Icosapent ethyl is unlikely to be cost effective for primary prevention, so it is not recommended for this. But the most likely cost-effectiveness estimates for secondary prevention are within what NICE normally considers an acceptable use of NHS resources. So, icosapent ethyl is recommended for secondary prevention in people with LDL-C levels above 1.04 mmol/litre and below or equal to 2.60 mmol/litre. People must be taking a statin to have icosapent ethyl. People who cannot have statins are not covered by icosapent ethyl's marketing authorisation, so NICE cannot make any recommendations in this area.# Information about icosapent ethyl # Marketing authorisation indication Icosapent ethyl (Vazkepa, Amarin Corporation) is indicated 'to reduce the risk of cardiovascular events in adult statin-treated patients at high cardiovascular risk with elevated triglycerides (≥150 mg/dL ) and: established cardiovascular disease, or diabetes, and at least on other cardiovascular risk factor'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for icosapent ethyl. # Price Icosapent ethyl costs £144.21 per pack of 120 capsules (excluding VAT; company submission). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion The appraisal committee considered evidence submitted by Amarin, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Treatment pathway and comparator ## People with elevated triglycerides who are having statins with or without ezetimibe would welcome a treatment option NHS England estimated that between 25% and 35% of people having statin therapy have elevated triglycerides. The patient and clinical experts explained there is an unmet need for this population. This is because there are no pharmaceutical treatments for people at risk of cardiovascular events who have elevated triglycerides despite having statins with or without ezetimibe. They explained the aim of treatment would be to reduce the risk of cardiovascular events. The patient expert commented that lifestyle changes, including diet and exercise, can help to reduce the risk of cardiovascular events. The patient expert noted the importance of having treatment options because current ways of reducing cardiovascular risk may not work for everyone. The committee concluded that people with elevated triglycerides who are having statins with or without ezetimibe would welcome a treatment option. ## Statins with or without ezetimibe is an appropriate comparator The marketing authorisation for icosapent ethyl says it should be used in addition to statin therapy. The company submission, which was based on the REDUCE‑IT trial (see section 3.6), also noted people could have ezetimibe in addition to statins. The clinical experts said that fibrates are not used to reduce the risk of cardiovascular events in people with moderately elevated triglycerides. They explained that fibrates are used by people with very high triglycerides to prevent pancreatitis, which is a different indication. The clinical experts confirmed that there are no treatments to reduce cardiovascular risk for people with elevated triglycerides who have statins with or without ezetimibe. Therefore, the committee agreed statins with or without ezetimibe was the appropriate comparator. ## Icosapent ethyl is likely to be used mostly in a primary care setting The company noted it expected icosapent ethyl to be used in a primary care setting. The clinical experts commented that icosapent ethyl might be used in secondary care but it would likely be used more in primary care. The committee concluded icosapent ethyl would likely be used mostly in a primary care setting. # Population ## The population in the company's submission is narrower than the marketing authorisation in terms of LDL-C levels and is acceptable Icosapent ethyl's marketing authorisation does not specify age or low-density lipoprotein cholesterol (LDL‑C) thresholds (see section 2.1). However, the company only provided evidence for icosapent ethyl from the REDUCE‑IT trial. This included people aged 45 and older who had cardiovascular disease, and people aged 50 and older who had diabetes and at least 1 other cardiovascular risk factor (see section 3.5). The trial also only included people with LDL‑C levels above 1.04 mmol/litre and below or equal to 2.60 mmol/litre. A clinical expert noted that there are people younger than 45 who have cardiovascular disease and elevated fasting triglycerides in the NHS. They explained that many of these people have South Asian family backgrounds. The ERG commented that the treatment effect for icosapent ethyl varies by age, with a larger benefit observed in people under 65 (hazard ratio 0.65, 95% confidence interval 0.56 to 0.75) than in people aged 65 or older (HR 0.87, 95% CI 0.76 to 1.00). The company highlighted that these analyses did not include adjusting for potential confounders or multiple comparisons. The committee was aware that restricting by age may result in an equalities issue because age is a protected characteristic. The committee concluded that the company's submission for icosapent ethyl was narrower than the marketing authorisation and it was acceptable to use the LDL-C thresholds from REDUCE-IT. This would ensure its recommendation was based on the available evidence. ## It is appropriate to consider the effects of icosapent ethyl only for the secondary prevention subgroup In its original submission, the company provided evidence for 2 separate risk groups from the REDUCE‑IT trial: primary and secondary prevention. The primary prevention group included people aged 50 and older with type 1 or 2 diabetes and at least 1 additional cardiovascular risk factor. People in the secondary prevention group were aged 45 and older with established cardiovascular disease. The committee noted that NICE's technology appraisal guidance on alirocumab (TA393), evolocumab (TA394) and inclisiran (TA733) defined high risk of cardiovascular disease as a history of any of the following: a previous cardiovascular event, including acute coronary syndrome (such as myocardial infarction or unstable angina needing hospitalisation) previous coronary or other arterial revascularisation procedures coronary heart disease ischaemic stroke peripheral arterial disease.In response to the first consultation, the company provided analyses that focused only on the secondary prevention subgroup. The committee noted that icosapent ethyl was unlikely to be cost effective in the primary prevention subgroup, because the cost-effectiveness estimates presented at the first committee meeting were substantially higher than the range normally considered an acceptable use of NHS resources. It concluded that it was appropriate to focus on the effects of icosapent ethyl for the secondary prevention subgroup. This includes people with diabetes who have established cardiovascular disease. # Clinical evidence ## The REDUCE-IT trial may not be generalisable to the NHS in England The company provided clinical evidence from REDUCE‑IT, a randomised trial comparing icosapent ethyl with a mineral oil placebo. The trial included people who had statins with or without ezetimibe, fasting triglyceride levels of 1.53 mmol/litre or more and below 5.64 mmol/litre, and LDL-C levels of more than 1.04 mmol/litre to 2.60 mmol/litre. In the trial, 8,179 people were randomised and 29% were in the primary prevention group and 71% were in the secondary prevention group (see section 3.5). The primary endpoint was time from randomisation to the first occurrence of any component of the major adverse cardiovascular event (MACE) composite outcome. This comprised cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularisation and unstable angina. The ERG noted that REDUCE-IT did not include any people from the UK, which increases uncertainty around the generalisability of the results to the NHS in England. A clinical expert commented that the trial did not represent the ethnic diversity in England, because some family backgrounds were underrepresented. They noted that people with South Asian family backgrounds may benefit more from icosapent ethyl. The company compared the baseline characteristics of the secondary prevention subgroup with a similar population from Steen et al. 2016. This was a retrospective study of 183,565 people with or without atherosclerotic cardiovascular disease from The Health Improvement Network database in the UK. The company noted that BMI and systolic blood pressure were similar between REDUCE‑IT and Steen et al. However, the ERG noted that there were substantial differences between REDUCE-IT and Steen et al. that might modify the treatment effect. The mean age was higher in Steen et al. and the percentage of male patients was lower. There were also differences in comorbidities. In response to consultation, the company highlighted that the populations in England and REDUCE-IT had similar distributions by ethnic group. The company also stated that in REDUCE-IT, there was no interaction between the efficacy of icosapent ethyl in reducing the risk of cardiovascular events according to ethnicity ('white' HR 0.77, 95% CI 0.69 to 0.85, 'non-white' HR 0.60, 95% CI 0.43 to 0.83). It stated that an advisory board of 9 UK clinical experts considered the trial data would be generalisable to the UK population. The clinical adviser to NHS England noted that several treatments available in the NHS, such as SGLT2 inhibitors and GLP-1 agonists, were used by only a small proportion of people in REDUCE‑IT. The clinical adviser explained that the change in treatment landscape in the NHS in England since the trial began makes the generalisability of REDUCE‑IT to current practice uncertain. The company stated that the use of SGLT2 inhibitors and GLP-1 agonists in the trial was consistent with clinical practice at the time of the trial. It also noted that people who do not have diabetes would not necessarily be able to have these treatments. The committee concluded that REDUCE‑IT may not fully represent NHS clinical practice, which increases uncertainty around the generalisability of the results. ## There is uncertainty in the trial results because icosapent ethyl's mechanism of action is not fully understood The company stated that icosapent ethyl's mechanism of action is not fully understood. The company noted it appears to modulate the atherosclerosis pathway by lipid and non-lipid effects. It explained the primary lipid effect is to reduce triglyceride levels. It added that the non-lipid effects may include localised anti-inflammatory effects, regulation of lipid metabolism gene transcription, antithrombotic effects and plaque reduction. The clinical experts also commented that the mechanism of action is uncertain. They explained that the reduction in cardiovascular risk observed in REDUCE‑IT was larger than what would be expected from a reduction in triglycerides alone. It was also larger than that reported by an earlier trial (STRENGTH) of a drug with a similar mechanism of action to icosapent ethyl (see section 3.8). In response to consultation, the company stated that the mechanism of action is likely multifactorial and that icosapent ethyl can positively alter the development, progression and stabilisation of atherosclerotic plaque. It stated that triglyceride reduction only played a minor role in the reduction in the risk of cardiovascular events associated with icosapent ethyl. The company also noted that other related technologies that have been appraised by NICE, such as SGLT2 inhibitors, have uncertain mechanisms of action. The committee concluded that the mechanism of action for icosapent ethyl is not fully understood. This added uncertainty to the trial's results because the difference in benefit compared with STRENGTH had not been fully explained. ## The treatment effect of icosapent ethyl is uncertain because of the potential negative effect of mineral oil placebo in REDUCE-IT The placebo group in REDUCE‑IT had 4 g of light mineral oil per day. Icosapent ethyl significantly reduced the first occurrence of the MACE outcome in the secondary prevention subgroup compared with placebo (HR 0.73, 95% CI 0.65 to 0.81). A professional group and the NHS England clinical adviser expressed concerns about the REDUCE‑IT results, in part because of the use of mineral oil. They commented that mineral oil may not be a true neutral oil and may have increased the risk of cardiovascular events in the placebo group. This would exaggerate the observed difference in cardiovascular events between the icosapent ethyl and placebo groups. The professional group and NHS England clinical adviser also commented that results of a similar trial, STRENGTH, did not show the same magnitude of benefit as REDUCE-IT. STRENGTH compared a combination of eicosapentaenoic acid and docosahexaenoic acid (which is similar to, but not the same as, icosapent ethyl) with a corn oil placebo. The ERG explained that a 2021 paper by Doi et al. comparing REDUCE‑IT with STRENGTH suggested the differences in results might be partially explained by differences in placebo comparators. But the ERG cautioned that there were other possible explanations, including that corn oil could decrease the risk of MACE or that there were underlying differences in patient characteristics between the trials. The ERG highlighted a systematic review by Olshansky et al. 2020 that concluded that it is likely that mineral oil at the quantities used as placebos does not significantly affect the conclusion of REDUCE-IT. However, the ERG noted that this systematic review had some limitations and one of the co-authors was employed by the company. In response to consultation, the company acknowledged that some parameters associated with cardiovascular risk increased in the placebo group of REDUCE-IT. However, it stated that it was uncertain if these changes were because of the natural history of the disease, regression to the mean, or negative effects of mineral oil. The company provided a comparison of cardiovascular outcomes trials from 2003 to 2019. The comparison found that 79% of studies reported increases in LDL-C after statin stabilisation, similar to what was observed in the placebo group of REDUCE-IT. In response to consultation the company also highlighted that the drug in STRENGTH was different to icosapent ethyl because of different proportions of docosahexaenoic acid and eicosapentaenoic acid. So, comparing the results from the 2 trials was not appropriate. The experts explained that among cardiovascular disease researchers and clinicians, there is an ongoing debate about mineral oil placebos and the impact on trial outcomes. The committee concluded that the relative effect of icosapent ethyl was uncertain because of the potential negative effect of the mineral oil placebo. ## It is appropriate to consider scenarios for an estimated possible reduction in treatment effect from 1.5% to 3% At the first meeting, the NHS England clinical adviser explained they expected to see analyses with the magnitude of treatment effect reduced by 7% to account for the estimated negative effect of mineral oil. This estimate was based on the 2021 paper by Doi et al. comparing the results of REDUCE-IT and STRENGTH. The committee was aware that the company provided the analyses done by the Food and Drug Administration (FDA) in the US to the European Medicines Agency based on the 3-point MACE outcome assuming that the potential negative effect of mineral oil on MACE events was between 0.3% and 3%. The committee also noted that the Doi et al. 2021 paper commented that there was an unexplained additional 13% benefit in REDUCE‑IT. In response to the first consultation, the company provided scenarios with the clinical effectiveness of icosapent ethyl reduced by 0.3%, 1%, 2% or 3% based on the analyses provided to the European Medicines Agency. The company considered that the range of 7% to 13% was not plausible because it was based on a single simulated Danish observational study. A clinical expert commented that it was difficult to quantify the potential negative effects of mineral oil and there was significant uncertainty. As such, they could not state which percentage reduction in treatment effect was more plausible. The committee was aware that the European public assessment report on icosapent ethyl notes that a 10% putative negative effect of mineral oil would be a worst-case scenario but likely an overestimation. In response to the second consultation, the company presented an analysis replicating a Cox regression model made by the FDA to examine the effects of high-sensitivity C-reactive protein and LDL‑C on the relative benefit of icosapent ethyl. It presented a propensity score matched approach to the Cox regression analysis to account for overlapping effects of the biomarkers. It also presented an analysis exploring the relationship between on-treatment serum active drug concentration and cardiovascular outcomes to explore the effects on cardiovascular risk that are independent of serum eicosapentaenoic acid levels. The company considers the results of these analyses to be confidential so they cannot be reported here. On the basis of these analyses, the company updated its base-case model to include a 1.5% reduced treatment effect for icosapent ethyl. Considering the company's analyses and the conclusion of the European Medicines Agency, the committee concluded that it would be appropriate to consider scenarios estimating a possible reduction in treatment effect from 1.5% to 3%. ## Icosapent ethyl has manageable adverse events In REDUCE‑IT, similar proportions of people having icosapent ethyl (81.8%) and placebo (81.3%) reported adverse events. The clinical experts noted that icosapent ethyl appears to be generally well tolerated, but they had some concerns around specific adverse events. In REDUCE‑IT, there were significant differences in the incidence of atrial fibrillation (5.3% icosapent ethyl, 3.9% placebo), bleeding-related events (11.8% icosapent ethyl, 9.9% placebo), constipation (5.4% icosapent ethyl, 3.6% placebo) and peripheral oedema (6.5% icosapent ethyl, 5.0% placebo). The committee noted that some fish oil products can be associated with unpleasant burps that may affect adherence (icosapent ethyl is derived from fish oil). The company stated that unpleasant burps had very little impact on treatment adherence. The committee noted the concerns about some adverse events, but concluded icosapent ethyl was generally well tolerated with manageable adverse events. # The economic model ## The results from the company's model are uncertain The company's model included 8 health states: cardiovascular event-free, first event, post-first event, second event, post-second event, third or more event, post-third or more event, and death. The events in the model were based on the composite 5‑point MACE outcome from REDUCE‑IT (see section 3.6). The health states were populated by fitting parametric models to the Kaplan–Meier curves for first, second and third plus cardiovascular events from REDUCE‑IT using a partitioned survival approach. The model used a 1‑day cycle length and a lifetime horizon, equivalent to 36 years. The company used baseline utility values from the literature (Stevanovic et al. 2016 and O'Reilly et al. 2011) and health state multipliers from NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification. The ERG noted several concerns with the model structure and that the company's partitioned survival approach to estimate the probability of having a cardiovascular event deviated from the modelling approach in related NICE appraisals. In recent hypercholesterolaemia and mixed dyslipidaemia appraisals, the economic models have often followed a Markov approach and used specific cardiovascular event types as health states. The ERG was concerned that the model structure assumed independence of endpoints, meaning the probability of having a second or third cardiovascular event was independent of the time of the previous events. It commented that the company's model did not explicitly model nonfatal cardiovascular events and used a 1-day cycle length. The committee commented that it was unusual that the company's entire model was based on REDUCE‑IT, rather than applying the relative treatment effect observed in the trial to a baseline risk estimated using routine datasets. In response to consultation, the company explained that its model was designed to align with REDUCE-IT, in which people progressed through health states in a specific order. It also commented that time from randomisation to a first, second or third plus event was used so there were no issues with crossover of events during the trial period. Beyond the trial period, the company noted that any extrapolation curves that crossed were considered clinically implausible and disregarded. The ERG considered that these comments were insufficient justification for the model structure and uncertainty remains. The company provided a comparison of the model-estimated survival and mortality from REDUCE-IT. The committee noted that the model appeared to overestimate mortality in both the placebo and icosapent ethyl groups at 5 years. The committee concluded that the results of the company's model were uncertain because of the model structure and the discrepancy between model and trial outcomes. ## Using the composite 5-point MACE outcome in the model increases uncertainty The company's model used the same composite MACE outcome as REDUCE‑IT (see section 3.6). The ERG was concerned that the composite outcome could mask the treatment effect in relation to individual cardiovascular events. The ERG highlighted that in the intention to treat population, the hazard ratios for cardiovascular death (HR 0.80, 95% CI 0.66 to 0.98) and death from any cause (HR 0.87, 95% CI 0.74 to 1.02) were larger than that for the composite 5‑point MACE (HR 0.75, 95% CI 0.68 to 0.83). The company noted that although the composite outcome was used, the distribution of specific cardiovascular events was applied in the model. The company explained that the effect of icosapent ethyl on each specific event occurring as a first, second or third plus event was taken into account. However, the ERG commented that applying direct estimates of time to each event is not necessarily equivalent to combining time to composite event with the proportion of each event in the composite outcome. The clinical experts commented that using a composite MACE outcome is common for large clinical trials but one expert said that there was some debate about whether all components of the MACE should be used. The committee was concerned that the composite outcome might be double counting risk. It noted that revascularisations accounted for most second and third events (the exact values are considered confidential by the company and cannot be reported here). It also noted that coronary revascularisation could be an indicated procedure based on a preceding event, such as myocardial infarction. At its first meeting, the committee requested Kaplan–Meier curves and hazard ratios for each of the individual cardiovascular events. In response to consultation the company provided Kaplan–Meier curves and hazard ratios over time for each individual event type in the composite outcome. The ERG commented that in the Kaplan–Meier curves for cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, there appeared to be a lag in the separation of icosapent ethyl and placebo curves at around 1 to 2 years. This might mean the composite outcome biases the treatment effect in favour of icosapent ethyl in the first 1 to 2 years of treatment. The ERG also commented that when considering the hazard ratios over time, there are some differences between the individual events and the composite. The committee welcomed the additional information from the company but concluded that using the composite outcome in the model increased uncertainty. ## It is implausible that there is no loss of treatment effect at treatment discontinuation The company's base case assumed that the treatment effect for icosapent ethyl continued at the same level for the duration of the model with no loss of treatment effect at discontinuation. The company commented that similar technology appraisals did not include loss of treatment effect, including TA393, TA394 and TA733. The company provided an analysis of the treatment effect over time, which showed that it did not decrease during the follow-up period of REDUCE-IT. The clinical expert commented that given the absence of longer-term data it is difficult to determine the appropriateness of an assumption of treatment effect loss. However, the expert noted that related treatments for cardiovascular disease, such as statins, have long-term effects. The expert commented that the company's assumption of no loss of treatment effect was likely reasonable. However, the committee was concerned that treatment discontinuation was not linked to treatment effect in the icosapent ethyl model. At its first meeting, the committee noted that it would have preferred a method linking treatment effect and discontinuation by changing the hazard ratio to 1 at an appropriate time after people stopped icosapent ethyl. In response to consultation, the company commented that the clinical efficacy curves accounted for efficacy lost because of discontinuation because they are based on the intention to treat population, which includes all patients in the icosapent ethyl trial, regardless of treatment discontinuation. The committee acknowledged this, but considered that if the proportion of patients continuing treatment reduced over the model time horizon, it would expect the average treatment effect to be lower than that captured in the trial. The committee noted that in the recent related appraisal of bempedoic acid with ezetimibe (TA694), the company's model assumed results achieved at 12 weeks were maintained for the duration of the model's time horizon, or until treatment was stopped. It recognised that in TA393, the company had assumed 100% treatment continuation and compliance over the entire time horizon. The committee noted that this assumption likely would not be appropriate in this appraisal because many people had discontinued treatment by the end of follow-up in REDUCE‑IT (the value is considered confidential by the company and cannot be reported here). The company highlighted that follow-up was longer in REDUCE-IT and so it would be expected that more people would discontinue treatment. The committee noted that assumptions of complete continuation and no loss of treatment effect were also used in TA733. The committee commented that the icosapent ethyl appraisal had different considerations to those previous appraisals. It considered that there was large uncertainty around the assumption that the treatment effect observed over the REDUCE-IT trial period would continue for the entire modelled time horizon if more people discontinued treatment over time. The committee concluded that it was implausible that the treatment effect would not reduce at any point after discontinuation. ## It is plausible that the treatment effect may be lost after 10 years if treatment is discontinued The company's base case did not apply a loss of treatment effect. However, the company did provide 2 scenarios assuming that once a person discontinued treatment, after a period of either 10 or 20 years, they would have equivalent clinical outcomes to people in the placebo group. The company explained that because of the model structure, when assuming that people who discontinue treatment follow the efficacy of the placebo group, it was assuming that all events that were avoided occur at discontinuation, which was not clinically plausible. The committee agreed that the way in which the loss of treatment effect had been modelled was potentially biased against icosapent ethyl. This was mainly because it was implausible that all avoided events would occur at treatment discontinuation, but also because the efficacy curves for people staying on treatment included some people who had stopped treatment in the trial. The ERG's base-case included the company's scenario where people stopping icosapent ethyl would have the same clinical efficacy as the placebo group after 10 years. For people continuing treatment, the assumption was that the treatment effect would remain constant over the model time horizon. The committee acknowledged the limitations with the modelled scenarios but considered it reasonable to accept the scenario in which people stopping icosapent ethyl would lose treatment effect after 10 years and those continuing would maintain the treatment effect. However, it acknowledged that the true cost-effectiveness results would likely be lower than in the scenarios presented, had the loss of treatment effect been modelled more appropriately. ## The company's model has uncertainties so the comparison with the validation model is also uncertain Because of the ERG's concerns with the company's model, the company provided a microsimulation model for validation. The validation model was originally developed for the US setting but was adapted to the UK NHS setting by using the same costs, utilities and background mortality as the company's model. The validation model also used cardiovascular event data from REDUCE-IT. The company provided a comparison of its model with the validation model. The validation model explicitly modelled individual nonfatal cardiovascular events, had a cycle length of 6 months and assumed people experienced a disutility associated with an acute event for 18 months after an event, after which they experienced a post-event utility. The company also provided a 30‑year comparison of the expected number of first, second and third events, people discontinuing icosapent ethyl, and people alive in the company's and validation models. It noted the models had different structures but produced similar clinical estimates. The committee noted there were still uncertainties about the company's model structure (see section 3.11) and how treatment effect after discontinuation was modelled (see section 3.13). The ERG also noted that it was unclear to what extent the validation model should be used to inform decisions in the company's model. The committee concluded that the company's model remained uncertain and therefore the comparison with the validation model was uncertain. # Cost-effectiveness estimates ## Because of the uncertainty an acceptable ICER is towards the lower end of the range normally considered a cost-effective use of NHS resources NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of the high level of uncertainty in the clinical and economic evidence, the committee agreed that an acceptable ICER would be towards the lower end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). ## The most plausible ICER is between £21,750 and £24,821 per QALY gained After the second consultation, the company's base-case ICER for icosapent ethyl compared with a stable dose of statins with or without ezetimibe was £20,000 per QALY gained for the secondary prevention group. The company's base case assumed no loss of treatment effect for icosapent ethyl but did include a 1.5% treatment effect reduction to account for the possible effects of the mineral oil placebo. The ERG's base case included a loss of treatment effect for those discontinuing after 10 years but did not include a reduction in treatment effect for the mineral oil placebo. The ERG's base-case ICER was £21,062 per QALY gained. The ERG presented scenario analyses including a 0%, 1.5%, 3% or 7% treatment effect reduction to adjust for the possible effect of mineral oil. It also presented scenario analyses including a loss of treatment effect on discontinuation after 5 or 10 years, or not at all. The committee considered that the scenarios including a reduction of treatment effect of 1.5% and 3% (see section 3.9) and a loss of treatment effect on discontinuation at 10 years (see section 3.14) were the most plausible scenarios. However, it considered that the ICERs that included a loss of treatment effect on discontinuation were likely too high, because of the way this had been modelled. So, the committee also considered a scenario with a 3% reduction in treatment effect and no loss of treatment effect on discontinuation. Therefore, the committee considered that the most plausible ICER was between £21,750 and £24,821 per QALY gained. # Other factors ## The committee considered potential equality issues in its decision making A patient organisation and clinical expert raised several potential equalities issues. They noted that people with Black, Asian and minority ethnic family backgrounds are more likely to have elevated triglycerides. The patient organisation also commented that people living in England's most deprived areas are almost 4 times more likely to die prematurely from cardiovascular disease than those in the least deprived. It also explained that compared with the general population, people with severe mental illness are more likely to develop and die from preventable conditions, including cardiovascular disease. It also noted that people with learning disabilities are at increased risk of developing cardiovascular disease. The clinical expert noted that some religions have restrictions on fish products. The committee considered these to be important issues. The committee concluded that its recommendation for icosapent ethyl would apply to all patients and that the recommendation would not affect people protected by the equality legislation any differently. ## End of life criteria do not apply NICE's advice about life-extending treatments for people with a short life expectancy did not apply. ## The committee has not seen evidence of additional benefits that are not captured in the cost-effectiveness analysis The clinical experts noted that icosapent ethyl may be considered innovative because it appears to work on a disease pathway that is not fully understood. The committee concluded that it had not seen evidence of additional benefits associated with icosapent ethyl over those already included in the QALY calculations. # Conclusion ## Icosapent ethyl is recommended for reducing the risk of cardiovascular events in people with elevated triglycerides The committee noted uncertainty in the clinical effectiveness evidence for icosapent ethyl because of the mineral oil placebo in the REDUCE-IT trial (see section 3.8). It also noted concerns about the generalisability of the trial results to the NHS in England (see section 3.6). It was concerned about the company's modelling approach (see section 3.11), including how the treatment effect after discontinuation was modelled (see section 3.13) and the composite outcome (see section 3.12). Nevertheless, the most plausible ICER was towards the lower end of the range of what NICE normally considers a cost-effective use of NHS resources. Therefore, the committee recommended icosapent ethyl for reducing the risk of cardiovascular events in people with raised fasting triglycerides (1.7 mmol/litre or more) who are having statins and have established cardiovascular disease. Established cardiovascular disease is defined in line with the definition of high-risk cardiovascular disease in NICE's technology appraisal guidance on alirocumab, evolocumab and inclisiran (see section 3.5). Icosapent ethyl is recommended for people with LDL-C levels above 1.04 mmol/litre and below or equal to 2.60 mmol/litre, in line with the clinical evidence from REDUCE-IT (see section 3.4).	{'Recommendations': "Icosapent ethyl is recommended as an option for reducing the risk of cardiovascular events in adults. It is recommended if they have a high risk of cardiovascular events and raised fasting triglycerides (1.7\xa0mmol/litre or above) and are taking statins, but only if they have:\n\nestablished cardiovascular disease (secondary prevention), defined as a history of any of the following:\n\n\n\nacute coronary syndrome (such as myocardial infarction or unstable angina needing hospitalisation)\n\ncoronary or other arterial revascularisation procedures\n\ncoronary heart disease\n\nischaemic stroke\n\nperipheral arterial disease, and\n\n\n\nlow-density lipoprotein cholesterol (LDL‑C) levels above 1.04\xa0mmol/litre and below or equal to 2.60\xa0mmol/litre.\n\nThis recommendation is not intended to affect treatment with icosapent ethyl that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThere are currently no treatment options to reduce the risk of cardiovascular events in people taking statins who have controlled levels of LDL-C but raised levels of triglycerides. Icosapent ethyl is licensed for people taking statins who have raised triglycerides and a high risk of cardiovascular events, and who have either:\n\nestablished cardiovascular disease (secondary prevention), or\n\ndiabetes and at least one other cardiovascular risk factor (primary prevention).\n\nClinical trial evidence suggests that icosapent ethyl reduces the risk of cardiovascular events, compared with placebo, in people with raised fasting triglycerides (1.7\xa0mmol/litre or above) who are taking statins. The trial only included people with LDL-C levels above 1.04 mmol/litre and below or equal to 2.60\xa0mmol/litre.\n\nThe cost-effectiveness estimates for icosapent ethyl are uncertain. Icosapent ethyl is unlikely to be cost effective for primary prevention, so it is not recommended for this. But the most likely cost-effectiveness estimates for secondary prevention are within what NICE normally considers an acceptable use of NHS resources. So, icosapent ethyl is recommended for secondary prevention in people with LDL-C levels above 1.04\xa0mmol/litre and below or equal to 2.60\xa0mmol/litre.\n\nPeople must be taking a statin to have icosapent ethyl. People who cannot have statins are not covered by icosapent ethyl's marketing authorisation, so NICE cannot make any recommendations in this area.", 'Information about icosapent ethyl': "# Marketing authorisation indication\n\nIcosapent ethyl (Vazkepa, Amarin Corporation) is indicated 'to reduce the risk of cardiovascular events in adult statin-treated patients at high cardiovascular risk with elevated triglycerides (≥150\xa0mg/dL [1.7mmol/l]) and:\n\nestablished cardiovascular disease, or\n\ndiabetes, and at least on other cardiovascular risk factor'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for icosapent ethyl.\n\n# Price\n\nIcosapent ethyl costs £144.21 per pack of 120 capsules (excluding VAT; company submission). Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by Amarin, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway and comparator\n\n## People with elevated triglycerides who are having statins with or without ezetimibe would welcome a treatment option\n\nNHS England estimated that between 25% and 35% of people having statin therapy have elevated triglycerides. The patient and clinical experts explained there is an unmet need for this population. This is because there are no pharmaceutical treatments for people at risk of cardiovascular events who have elevated triglycerides despite having statins with or without ezetimibe. They explained the aim of treatment would be to reduce the risk of cardiovascular events. The patient expert commented that lifestyle changes, including diet and exercise, can help to reduce the risk of cardiovascular events. The patient expert noted the importance of having treatment options because current ways of reducing cardiovascular risk may not work for everyone. The committee concluded that people with elevated triglycerides who are having statins with or without ezetimibe would welcome a treatment option.\n\n## Statins with or without ezetimibe is an appropriate comparator\n\nThe marketing authorisation for icosapent ethyl says it should be used in addition to statin therapy. The company submission, which was based on the REDUCE‑IT trial (see section\xa03.6), also noted people could have ezetimibe in addition to statins. The clinical experts said that fibrates are not used to reduce the risk of cardiovascular events in people with moderately elevated triglycerides. They explained that fibrates are used by people with very high triglycerides to prevent pancreatitis, which is a different indication. The clinical experts confirmed that there are no treatments to reduce cardiovascular risk for people with elevated triglycerides who have statins with or without ezetimibe. Therefore, the committee agreed statins with or without ezetimibe was the appropriate comparator.\n\n## Icosapent ethyl is likely to be used mostly in a primary care setting\n\nThe company noted it expected icosapent ethyl to be used in a primary care setting. The clinical experts commented that icosapent ethyl might be used in secondary care but it would likely be used more in primary care. The committee concluded icosapent ethyl would likely be used mostly in a primary care setting.\n\n# Population\n\n## The population in the company's submission is narrower than the marketing authorisation in terms of LDL-C levels and is acceptable\n\nIcosapent ethyl's marketing authorisation does not specify age or low-density lipoprotein cholesterol (LDL‑C) thresholds (see section\xa02.1). However, the company only provided evidence for icosapent ethyl from the REDUCE‑IT trial. This included people aged 45 and older who had cardiovascular disease, and people aged 50 and older who had diabetes and at least 1 other cardiovascular risk factor (see section\xa03.5). The trial also only included people with LDL‑C levels above 1.04\xa0mmol/litre and below or equal to 2.60\xa0mmol/litre. A clinical expert noted that there are people younger than 45 who have cardiovascular disease and elevated fasting triglycerides in the NHS. They explained that many of these people have South Asian family backgrounds. The ERG commented that the treatment effect for icosapent ethyl varies by age, with a larger benefit observed in people under 65 (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.56 to 0.75) than in people aged 65 or older (HR 0.87, 95%\xa0CI 0.76 to 1.00). The company highlighted that these analyses did not include adjusting for potential confounders or multiple comparisons. The committee was aware that restricting by age may result in an equalities issue because age is a protected characteristic. The committee concluded that the company's submission for icosapent ethyl was narrower than the marketing authorisation and it was acceptable to use the LDL-C thresholds from REDUCE-IT. This would ensure its recommendation was based on the available evidence.\n\n## It is appropriate to consider the effects of icosapent ethyl only for the secondary prevention subgroup\n\nIn its original submission, the company provided evidence for 2 separate risk groups from the REDUCE‑IT trial: primary and secondary prevention. The primary prevention group included people aged 50 and older with type 1 or 2 diabetes and at least 1 additional cardiovascular risk factor. People in the secondary prevention group were aged 45 and older with established cardiovascular disease. The committee noted that\xa0NICE's technology appraisal guidance on alirocumab (TA393),\xa0evolocumab (TA394)\xa0and inclisiran (TA733) defined high risk of cardiovascular disease as a history of any of the following:\n\na previous cardiovascular event, including acute coronary syndrome (such as myocardial infarction or unstable angina needing hospitalisation)\n\nprevious coronary or other arterial revascularisation procedures\n\ncoronary heart disease\n\nischaemic stroke\n\nperipheral arterial disease.In response to the first consultation, the company provided analyses that focused only on the secondary prevention subgroup. The committee noted that icosapent ethyl was unlikely to be cost effective in the primary prevention subgroup, because the cost-effectiveness estimates presented at the first committee meeting were substantially higher than the range normally considered an acceptable use of NHS resources. It concluded that it was appropriate to focus on the effects of icosapent ethyl for the secondary prevention subgroup. This includes people with diabetes who have established cardiovascular disease.\n\n# Clinical evidence\n\n## The REDUCE-IT trial may not be generalisable to the NHS in England\n\nThe company provided clinical evidence from REDUCE‑IT, a randomised trial comparing icosapent ethyl with a mineral oil placebo. The trial included people who had statins with or without ezetimibe, fasting triglyceride levels of 1.53\xa0mmol/litre or more and below 5.64\xa0mmol/litre, and LDL-C levels of more than 1.04\xa0mmol/litre to 2.60\xa0mmol/litre. In the trial, 8,179 people were randomised and 29% were in the primary prevention group and 71% were in the secondary prevention group (see section\xa03.5). The primary endpoint was time from randomisation to the first occurrence of any component of the major adverse cardiovascular event (MACE) composite outcome. This comprised cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularisation and unstable angina. The ERG noted that REDUCE-IT did not include any people from the UK, which increases uncertainty around the generalisability of the results to the NHS in England. A clinical expert commented that the trial did not represent the ethnic diversity in England, because some family backgrounds were underrepresented. They noted that people with South Asian family backgrounds may benefit more from icosapent ethyl. The company compared the baseline characteristics of the secondary prevention subgroup with a similar population from Steen et al. 2016. This was a retrospective study of 183,565 people with or without atherosclerotic cardiovascular disease from The Health Improvement Network database in the UK. The company noted that BMI and systolic blood pressure were similar between REDUCE‑IT and Steen et al. However, the ERG noted that there were substantial differences between REDUCE-IT and Steen et al. that might modify the treatment effect. The mean age was higher in Steen et al. and the percentage of male patients was lower. There were also differences in comorbidities. In response to consultation, the company highlighted that the populations in England and REDUCE-IT had similar distributions by ethnic group. The company also stated that in REDUCE-IT, there was no interaction between the efficacy of icosapent ethyl in reducing the risk of cardiovascular events according to ethnicity ('white' HR 0.77, 95% CI 0.69 to 0.85, 'non-white' HR 0.60, 95% CI 0.43 to 0.83). It stated that an advisory board of 9 UK clinical experts considered the trial data would be generalisable to the UK population. The clinical adviser to NHS England noted that several treatments available in the NHS, such as SGLT2 inhibitors and GLP-1 agonists, were used by only a small proportion of people in REDUCE‑IT. The clinical adviser explained that the change in treatment landscape in the NHS in England since the trial began makes the generalisability of REDUCE‑IT to current practice uncertain. The company stated that the use of SGLT2 inhibitors and GLP-1 agonists in the trial was consistent with clinical practice at the time of the trial. It also noted that people who do not have diabetes would not necessarily be able to have these treatments. The committee concluded that REDUCE‑IT may not fully represent NHS clinical practice, which increases uncertainty around the generalisability of the results.\n\n## There is uncertainty in the trial results because icosapent ethyl's mechanism of action is not fully understood\n\nThe company stated that icosapent ethyl's mechanism of action is not fully understood. The company noted it appears to modulate the atherosclerosis pathway by lipid and non-lipid effects. It explained the primary lipid effect is to reduce triglyceride levels. It added that the non-lipid effects may include localised anti-inflammatory effects, regulation of lipid metabolism gene transcription, antithrombotic effects and plaque reduction. The clinical experts also commented that the mechanism of action is uncertain. They explained that the reduction in cardiovascular risk observed in REDUCE‑IT was larger than what would be expected from a reduction in triglycerides alone. It was also larger than that reported by an earlier trial (STRENGTH) of a drug with a similar mechanism of action to icosapent ethyl (see section\xa03.8). In response to consultation, the company stated that the mechanism of action is likely multifactorial and that icosapent ethyl can positively alter the development, progression and stabilisation of atherosclerotic plaque. It stated that triglyceride reduction only played a minor role in the reduction in the risk of cardiovascular events associated with icosapent ethyl. The company also noted that other related technologies that have been appraised by NICE, such as SGLT2 inhibitors, have uncertain mechanisms of action. The committee concluded that the mechanism of action for icosapent ethyl is not fully understood. This added uncertainty to the trial's results because the difference in benefit compared with STRENGTH had not been fully explained.\n\n## The treatment effect of icosapent ethyl is uncertain because of the potential negative effect of mineral oil placebo in REDUCE-IT\n\nThe placebo group in REDUCE‑IT had 4\xa0g of light mineral oil per day. Icosapent ethyl significantly reduced the first occurrence of the MACE outcome in the secondary prevention subgroup compared with placebo (HR 0.73, 95% CI 0.65 to 0.81). A professional group and the NHS England clinical adviser expressed concerns about the REDUCE‑IT results, in part because of the use of mineral oil. They commented that mineral oil may not be a true neutral oil and may have increased the risk of cardiovascular events in the placebo group. This would exaggerate the observed difference in cardiovascular events between the icosapent ethyl and placebo groups. The professional group and NHS England clinical adviser also commented that results of a similar trial, STRENGTH, did not show the same magnitude of benefit as REDUCE-IT. STRENGTH compared a combination of eicosapentaenoic acid and docosahexaenoic acid (which is similar to, but not the same as, icosapent ethyl) with a corn oil placebo. The ERG explained that a 2021 paper by Doi et al. comparing REDUCE‑IT with STRENGTH suggested the differences in results might be partially explained by differences in placebo comparators. But the ERG cautioned that there were other possible explanations, including that corn oil could decrease the risk of MACE or that there were underlying differences in patient characteristics between the trials. The ERG highlighted a systematic review by Olshansky et al. 2020 that concluded that it is likely that mineral oil at the quantities used as placebos does not significantly affect the conclusion of REDUCE-IT. However, the ERG noted that this systematic review had some limitations and one of the co-authors was employed by the company. In response to consultation, the company acknowledged that some parameters associated with cardiovascular risk increased in the placebo group of REDUCE-IT. However, it stated that it was uncertain if these changes were because of the natural history of the disease, regression to the mean, or negative effects of mineral oil. The company provided a comparison of cardiovascular outcomes trials from 2003 to 2019. The comparison found that 79% of studies reported increases in LDL-C after statin stabilisation, similar to what was observed in the placebo group of REDUCE-IT. In response to consultation the company also highlighted that the drug in STRENGTH was different to icosapent ethyl because of different proportions of docosahexaenoic acid and eicosapentaenoic acid. So, comparing the results from the 2 trials was not appropriate. The experts explained that among cardiovascular disease researchers and clinicians, there is an ongoing debate about mineral oil placebos and the impact on trial outcomes. The committee concluded that the relative effect of icosapent ethyl was uncertain because of the potential negative effect of the mineral oil placebo.\n\n## It is appropriate to consider scenarios for an estimated possible reduction in treatment effect from 1.5% to 3%\n\nAt the first meeting, the NHS England clinical adviser explained they expected to see analyses with the magnitude of treatment effect reduced by 7% to account for the estimated negative effect of mineral oil. This estimate was based on the 2021 paper by Doi et al. comparing the results of REDUCE-IT and STRENGTH. The committee was aware that the company provided the analyses done by the Food and Drug Administration (FDA) in the US to the European Medicines Agency based on the 3-point MACE outcome assuming that the potential negative effect of mineral oil on MACE events was between 0.3% and 3%. The committee also noted that the Doi et al. 2021 paper commented that there was an unexplained additional 13% benefit in REDUCE‑IT. In response to the first consultation, the company provided scenarios with the clinical effectiveness of icosapent ethyl reduced by 0.3%, 1%, 2% or 3% based on the analyses provided to the European Medicines Agency. The company considered that the range of 7% to 13% was not plausible because it was based on a single simulated Danish observational study. A clinical expert commented that it was difficult to quantify the potential negative effects of mineral oil and there was significant uncertainty. As such, they could not state which percentage reduction in treatment effect was more plausible. The committee was aware that the European public assessment report on icosapent ethyl notes that a 10% putative negative effect of mineral oil would be a worst-case scenario but likely an overestimation. In response to the second consultation, the company presented an analysis replicating a Cox regression model made by the FDA to examine the effects of high-sensitivity C-reactive protein and LDL‑C on the relative benefit of icosapent ethyl. It presented a propensity score matched approach to the Cox regression analysis to account for overlapping effects of the biomarkers. It also presented an analysis exploring the relationship between on-treatment serum active drug concentration and cardiovascular outcomes to explore the effects on cardiovascular risk that are independent of serum eicosapentaenoic acid levels. The company considers the results of these analyses to be confidential so they cannot be reported here. On the basis of these analyses, the company updated its base-case model to include a 1.5% reduced treatment effect for icosapent ethyl. Considering the company's analyses and the conclusion of the European Medicines Agency, the committee concluded that it would be appropriate to consider scenarios estimating a possible reduction in treatment effect from 1.5% to 3%.\n\n## Icosapent ethyl has manageable adverse events\n\nIn REDUCE‑IT, similar proportions of people having icosapent ethyl (81.8%) and placebo (81.3%) reported adverse events. The clinical experts noted that icosapent ethyl appears to be generally well tolerated, but they had some concerns around specific adverse events. In REDUCE‑IT, there were significant differences in the incidence of atrial fibrillation (5.3% icosapent ethyl, 3.9% placebo), bleeding-related events (11.8% icosapent ethyl, 9.9% placebo), constipation (5.4% icosapent ethyl, 3.6% placebo) and peripheral oedema (6.5% icosapent ethyl, 5.0% placebo). The committee noted that some fish oil products can be associated with unpleasant burps that may affect adherence (icosapent ethyl is derived from fish oil). The company stated that unpleasant burps had very little impact on treatment adherence. The committee noted the concerns about some adverse events, but concluded icosapent ethyl was generally well tolerated with manageable adverse events.\n\n# The economic model\n\n## The results from the company's model are uncertain\n\nThe company's model included 8\xa0health states: cardiovascular event-free, first event, post-first event, second event, post-second event, third or more event, post-third or more event, and death. The events in the model were based on the composite 5‑point MACE outcome from REDUCE‑IT (see section\xa03.6). The health states were populated by fitting parametric models to the Kaplan–Meier curves for first, second and third plus cardiovascular events from REDUCE‑IT using a partitioned survival approach. The model used a 1‑day cycle length and a lifetime horizon, equivalent to 36\xa0years. The company used baseline utility values from the literature (Stevanovic et al. 2016 and O'Reilly et al. 2011) and health state multipliers from NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification. The ERG noted several concerns with the model structure and that the company's partitioned survival approach to estimate the probability of having a cardiovascular event deviated from the modelling approach in related NICE appraisals. In recent hypercholesterolaemia and mixed dyslipidaemia appraisals, the economic models have often followed a Markov approach and used specific cardiovascular event types as health states. The ERG was concerned that the model structure assumed independence of endpoints, meaning the probability of having a second or third cardiovascular event was independent of the time of the previous events. It commented that the company's model did not explicitly model nonfatal cardiovascular events and used a 1-day cycle length. The committee commented that it was unusual that the company's entire model was based on REDUCE‑IT, rather than applying the relative treatment effect observed in the trial to a baseline risk estimated using routine datasets. In response to consultation, the company explained that its model was designed to align with REDUCE-IT, in which people progressed through health states in a specific order. It also commented that time from randomisation to a first, second or third plus event was used so there were no issues with crossover of events during the trial period. Beyond the trial period, the company noted that any extrapolation curves that crossed were considered clinically implausible and disregarded. The ERG considered that these comments were insufficient justification for the model structure and uncertainty remains. The company provided a comparison of the model-estimated survival and mortality from REDUCE-IT. The committee noted that the model appeared to overestimate mortality in both the placebo and icosapent ethyl groups at 5\xa0years. The committee concluded that the results of the company's model were uncertain because of the model structure and the discrepancy between model and trial outcomes.\n\n## Using the composite 5-point MACE outcome in the model increases uncertainty\n\nThe company's model used the same composite MACE outcome as REDUCE‑IT (see section\xa03.6). The ERG was concerned that the composite outcome could mask the treatment effect in relation to individual cardiovascular events. The ERG highlighted that in the intention to treat population, the hazard ratios for cardiovascular death (HR\xa00.80, 95% CI 0.66 to 0.98) and death from any cause (HR 0.87, 95%\xa0CI 0.74 to 1.02) were larger than that for the composite 5‑point MACE (HR\xa00.75, 95% CI 0.68 to 0.83). The company noted that although the composite outcome was used, the distribution of specific cardiovascular events was applied in the model. The company explained that the effect of icosapent ethyl on each specific event occurring as a first, second or third plus event was taken into account. However, the ERG commented that applying direct estimates of time to each event is not necessarily equivalent to combining time to composite event with the proportion of each event in the composite outcome. The clinical experts commented that using a composite MACE outcome is common for large clinical trials but one expert said that there was some debate about whether all components of the MACE should be used. The committee was concerned that the composite outcome might be double counting risk. It noted that revascularisations accounted for most second and third events (the exact values are considered confidential by the company and cannot be reported here). It also noted that coronary revascularisation could be an indicated procedure based on a preceding event, such as myocardial infarction. At its first meeting, the committee requested Kaplan–Meier curves and hazard ratios for each of the individual cardiovascular events. In response to consultation the company provided Kaplan–Meier curves and hazard ratios over time for each individual event type in the composite outcome. The ERG commented that in the Kaplan–Meier curves for cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, there appeared to be a lag in the separation of icosapent ethyl and placebo curves at around 1 to 2\xa0years. This might mean the composite outcome biases the treatment effect in favour of icosapent ethyl in the first 1 to 2\xa0years of treatment. The ERG also commented that when considering the hazard ratios over time, there are some differences between the individual events and the composite. The committee welcomed the additional information from the company but concluded that using the composite outcome in the model increased uncertainty.\n\n## It is implausible that there is no loss of treatment effect at treatment discontinuation\n\nThe company's base case assumed that the treatment effect for icosapent ethyl continued at the same level for the duration of the model with no loss of treatment effect at discontinuation. The company commented that similar technology appraisals did not include loss of treatment effect, including TA393, TA394 and TA733. The company provided an analysis of the treatment effect over time, which showed that it did not decrease during the follow-up period of REDUCE-IT. The clinical expert commented that given the absence of longer-term data it is difficult to determine the appropriateness of an assumption of treatment effect loss. However, the expert noted that related treatments for cardiovascular disease, such as statins, have long-term effects. The expert commented that the company's assumption of no loss of treatment effect was likely reasonable. However, the committee was concerned that treatment discontinuation was not linked to treatment effect in the icosapent ethyl model. At its first meeting, the committee noted that it would have preferred a method linking treatment effect and discontinuation by changing the hazard ratio to 1 at an appropriate time after people stopped icosapent ethyl. In response to consultation, the company commented that the clinical efficacy curves accounted for efficacy lost because of discontinuation because they are based on the intention to treat population, which includes all patients in the icosapent ethyl trial, regardless of treatment discontinuation. The committee acknowledged this, but considered that if the proportion of patients continuing treatment reduced over the model time horizon, it would expect the average treatment effect to be lower than that captured in the trial. The committee noted that in the recent related appraisal of bempedoic acid with ezetimibe (TA694), the company's model assumed results achieved at 12\xa0weeks were maintained for the duration of the model's time horizon, or until treatment was stopped. It recognised that in TA393, the company had assumed 100% treatment continuation and compliance over the entire time horizon. The committee noted that this assumption likely would not be appropriate in this appraisal because many people had discontinued treatment by the end of follow-up in REDUCE‑IT (the value is considered confidential by the company and cannot be reported here). The company highlighted that follow-up was longer in REDUCE-IT and so it would be expected that more people would discontinue treatment. The committee noted that assumptions of complete continuation and no loss of treatment effect were also used in TA733. The committee commented that the icosapent ethyl appraisal had different considerations to those previous appraisals. It considered that there was large uncertainty around the assumption that the treatment effect observed over the REDUCE-IT trial period would continue for the entire modelled time horizon if more people discontinued treatment over time. The committee concluded that it was implausible that the treatment effect would not reduce at any point after discontinuation.\n\n## It is plausible that the treatment effect may be lost after 10 years if treatment is discontinued\n\nThe company's base case did not apply a loss of treatment effect. However, the company did provide 2 scenarios assuming that once a person discontinued treatment, after a period of either 10 or 20\xa0years, they would have equivalent clinical outcomes to people in the placebo group. The company explained that because of the model structure, when assuming that people who discontinue treatment follow the efficacy of the placebo group, it was assuming that all events that were avoided occur at discontinuation, which was not clinically plausible. The committee agreed that the way in which the loss of treatment effect had been modelled was potentially biased against icosapent ethyl. This was mainly because it was implausible that all avoided events would occur at treatment discontinuation, but also because the efficacy curves for people staying on treatment included some people who had stopped treatment in the trial. The ERG's base-case included the company's scenario where people stopping icosapent ethyl would have the same clinical efficacy as the placebo group after 10\xa0years. For people continuing treatment, the assumption was that the treatment effect would remain constant over the model time horizon. The committee acknowledged the limitations with the modelled scenarios but considered it reasonable to accept the scenario in which people stopping icosapent ethyl would lose treatment effect after 10\xa0years and those continuing would maintain the treatment effect. However, it acknowledged that the true cost-effectiveness results would likely be lower than in the scenarios presented, had the loss of treatment effect been modelled more appropriately.\n\n## The company's model has uncertainties so the comparison with the validation model is also uncertain\n\nBecause of the ERG's concerns with the company's model, the company provided a microsimulation model for validation. The validation model was originally developed for the US setting but was adapted to the UK NHS setting by using the same costs, utilities and background mortality as the company's model. The validation model also used cardiovascular event data from REDUCE-IT. The company provided a comparison of its model with the validation model. The validation model explicitly modelled individual nonfatal cardiovascular events, had a cycle length of 6\xa0months and assumed people experienced a disutility associated with an acute event for 18\xa0months after an event, after which they experienced a post-event utility. The company also provided a 30‑year comparison of the expected number of first, second and third events, people discontinuing icosapent ethyl, and people alive in the company's and validation models. It noted the models had different structures but produced similar clinical estimates. The committee noted there were still uncertainties about the company's model structure (see section\xa03.11) and how treatment effect after discontinuation was modelled (see section\xa03.13). The ERG also noted that it was unclear to what extent the validation model should be used to inform decisions in the company's model. The committee concluded that the company's model remained uncertain and therefore the comparison with the validation model was uncertain.\n\n# Cost-effectiveness estimates\n\n## Because of the uncertainty an acceptable ICER is towards the lower end of the range normally considered a cost-effective use of NHS resources\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of the high level of uncertainty in the clinical and economic evidence, the committee agreed that an acceptable ICER would be towards the lower end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained).\n\n## The most plausible ICER is between £21,750 and £24,821 per QALY gained\n\nAfter the second consultation, the company's base-case ICER for icosapent ethyl compared with a stable dose of statins with or without ezetimibe was £20,000 per QALY gained for the secondary prevention group. The company's base case assumed no loss of treatment effect for icosapent ethyl but did include a 1.5% treatment effect reduction to account for the possible effects of the mineral oil placebo. The ERG's base case included a loss of treatment effect for those discontinuing after 10 years but did not include a reduction in treatment effect for the mineral oil placebo. The ERG's base-case ICER was £21,062 per QALY gained. The ERG presented scenario analyses including a 0%, 1.5%, 3% or 7% treatment effect reduction to adjust for the possible effect of mineral oil. It also presented scenario analyses including a loss of treatment effect on discontinuation after 5 or 10\xa0years, or not at all. The committee considered that the scenarios including a reduction of treatment effect of 1.5% and 3% (see section\xa03.9) and a loss of treatment effect on discontinuation at 10\xa0years (see section\xa03.14) were the most plausible scenarios. However, it considered that the ICERs that included a loss of treatment effect on discontinuation were likely too high, because of the way this had been modelled. So, the committee also considered a scenario with a 3% reduction in treatment effect and no loss of treatment effect on discontinuation. Therefore, the committee considered that the most plausible ICER was between £21,750 and £24,821 per QALY gained.\n\n# Other factors\n\n## The committee considered potential equality issues in its decision making\n\nA patient organisation and clinical expert raised several potential equalities issues. They noted that people with Black, Asian and minority ethnic family backgrounds are more likely to have elevated triglycerides. The patient organisation also commented that people living in England's most deprived areas are almost 4 times more likely to die prematurely from cardiovascular disease than those in the least deprived. It also explained that compared with the general population, people with severe mental illness are more likely to develop and die from preventable conditions, including cardiovascular disease. It also noted that people with learning disabilities are at increased risk of developing cardiovascular disease. The clinical expert noted that some religions have restrictions on fish products. The committee considered these to be important issues. The committee concluded that its recommendation for icosapent ethyl would apply to all patients and that the recommendation would not affect people protected by the equality legislation any differently.\n\n## End of life criteria do not apply\n\nNICE's advice about life-extending treatments for people with a short life expectancy did not apply.\n\n## The committee has not seen evidence of additional benefits that are not captured in the cost-effectiveness analysis\n\nThe clinical experts noted that icosapent ethyl may be considered innovative because it appears to work on a disease pathway that is not fully understood. The committee concluded that it had not seen evidence of additional benefits associated with icosapent ethyl over those already included in the QALY calculations.\n\n# Conclusion\n\n## Icosapent ethyl is recommended for reducing the risk of cardiovascular events in people with elevated triglycerides\n\nThe committee noted uncertainty in the clinical effectiveness evidence for icosapent ethyl because of the mineral oil placebo in the REDUCE-IT trial (see section\xa03.8). It also noted concerns about the generalisability of the trial results to the NHS in England (see section\xa03.6). It was concerned about the company's modelling approach (see section\xa03.11), including how the treatment effect after discontinuation was modelled (see section\xa03.13) and the composite outcome (see section\xa03.12). Nevertheless, the most plausible ICER was towards the lower end of the range of what NICE normally considers a cost-effective use of NHS resources. Therefore, the committee recommended icosapent ethyl for reducing the risk of cardiovascular events in people with raised fasting triglycerides (1.7\xa0mmol/litre or more) who are having statins and have established cardiovascular disease. Established cardiovascular disease is defined in line with the definition of high-risk cardiovascular disease in NICE's technology appraisal guidance on alirocumab, evolocumab and inclisiran (see section\xa03.5). Icosapent ethyl is recommended for people with LDL-C levels above 1.04 mmol/litre and below or equal to 2.60\xa0mmol/litre, in line with the clinical evidence from REDUCE-IT (see section\xa03.4)."}	https://www.nice.org.uk/guidance/ta805	Evidence-based recommendations on icosapent ethyl (Vazkepa) with statin therapy for reducing the risk of cardiovascular events in adults with raised triglycerides.
f0453d18731518b9d44db28e314eaaff1cb2b11a	nice	Roxadustat for treating symptomatic anaemia in chronic kidney disease	Roxadustat for treating symptomatic anaemia in chronic kidney disease Evidence-based recommendations on roxadustat (Evrenzo) for treating symptomatic anaemia associated with chronic kidney disease in adults. # Recommendations Roxadustat is recommended as an option for treating symptomatic anaemia associated with chronic kidney disease (CKD) in adults only if: they have stage 3 to 5 CKD with no iron deficiency and they are not on dialysis at the start of treatment and the company provides roxadustat according to the commercial arrangement. This recommendation is not intended to affect treatment with roxadustat that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Treatment for symptomatic anaemia associated with chronic kidney disease includes erythropoiesis stimulating agents (ESAs). Roxadustat is an alternative to ESAs. A clinical trial comparing roxadustat with darbepoetin alfa (an ESA) shows that roxadustat works as well as darbepoetin alfa. The cost effectiveness estimates for roxadustat are within what NICE normally considers an acceptable use of NHS resources. So roxadustat is recommended.# Information about roxadustat # Marketing authorisation indication Roxadustat (Evrenzo, Astellas Pharma) 'is indicated for treatment of adult patients with symptomatic anaemia associated with chronic kidney disease (CKD)'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for roxadustat. # Price The list prices of roxadustat are: £59.24 per 12‑tablet pack, each tablet contains 20 mg of roxadustat (excluding VAT; BNF online, accessed December 2021) £148.11 per 12‑tablet pack, each tablet contains 50 mg of roxadustat (excluding VAT; BNF online, accessed December 2021) £207.35 per 12‑tablet pack, each tablet contains 70 mg of roxadustat (excluding VAT; BNF online, accessed December 2021) £296.21 per 12‑tablet pack, each tablet contains 100 mg of roxadustat (excluding VAT; BNF online, accessed December 2021) £444.32 per 12‑tablet pack, each tablet contains 150 mg of roxadustat (excluding VAT; BNF online, accessed December 2021).The company has a commercial arrangement. This makes roxadustat available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Astellas Pharma, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Anaemia associated with chronic kidney disease is associated with extreme fatigue and reduced quality of life Anaemia is a serious condition defined by abnormally low levels of haemoglobin (Hb) or too few red blood cells in the blood. This reduces the ability of blood to carry oxygen around the body. Erythropoietin, a hormone produced by the kidneys in response to low oxygen levels, stimulates the bone marrow to produce red blood cells. However, kidneys that are not working properly make less erythropoietin, so anaemia is common in people with chronic kidney disease (CKD). CKD is characterised by the progressive loss of kidney function and is generally categorised into 5 stages based on decreasing kidney function. The prevalence and severity of anaemia increase as kidney disease worsens (6% of people with stage 1 CKD have anaemia compared with 34% and 43% of people with stage 4 and 5 CKD, respectively). People with CKD already face substantial challenges that affect their quality of life. Symptoms of CKD include fatigue, itching, swelling and sleep problems. These can affect many aspects of normal life and people's capacity to stay in work. Also, people with CKD experience stress and difficulties coming to terms with the diagnosis of an incurable, progressive disease and making difficult decisions about treatment, including dialysis. Anaemia further affects their quality of life. The patient expert explained that the symptoms of untreated anaemia are severe and disabling. For example, some people cannot drive, work, or even walk because of the extreme fatigue associated with anaemia. As a result, this can affect mental health. The patient expert added that people going into dialysis need relief from anaemia-associated fatigue to make decisions about their treatment and manage their life around dialysis. The committee concluded that anaemia can be associated with extreme fatigue and has a considerable effect on quality of life for people with CKD. ## People with anaemia in CKD would welcome an oral alternative to injectable erythropoiesis stimulating agents Anaemia is carefully monitored in people with CKD. NICE's guideline on chronic kidney disease: assessment and management recommends maintaining Hb between 100 g/litre and 120 g/litre for adults and avoiding Hb levels above 120 g/litre because of an increased risk of death and serious cardiovascular adverse events. Anaemia associated with CKD may be treated with iron therapy, erythropoiesis stimulating agents (ESAs), or both. NICE's guideline recommends that ESA treatment not be started without also managing iron deficiency. The clinical experts confirmed that people with anaemia must have sufficient iron levels (iron replete) before starting treatment with ESAs. Iron therapy can be given orally or intravenously depending on the severity of CKD, dialysis status or previous response to treatment. Treatment with ESAs is offered to adults, children and young people with anaemia who are likely to benefit in terms of quality of life and physical function. NICE's guideline on chronic kidney disease recommends a Hb level of 110 g/litre or lower for starting anaemia treatment. Clinical experts indicated that the level of haemoglobin at which it is appropriate to start treatment with ESAs is individualised, but they are likely to start treatment at Hb levels lower than 95 g/litre to 105 g/litre. The committee discussed whether ESAs were interchangeable and could be considered equally effective (a 'class effect'). The clinical experts explained that while some differences exist in the frequency of administration, the effectiveness of ESAs was similar. The committee concluded that ESAs could be considered as a class. Current ESAs are injectable analogues of erythropoietin that can be given subcutaneously, intravenously, or through the haemodialysis machine. For people who are not on haemodialysis, including those on peritoneal dialysis, ESAs are typically self-administered. People have training to learn how to self-inject and to dispose of sharps. However, many people with anaemia find injecting themselves unpleasant and difficult, while some have to rely on others to give them their injections. Many people manage subcutaneous injections because of the high prevalence of people with diabetes on insulin among people with CKD and anaemia. In general, the patient and clinical experts noted that ESAs are well-established products that improve quality of life for people with anaemia. The patient expert highlighted that treatment-related adverse events are important to patients. They noted that people may be less likely to take medications that might have adverse effects that can affect quality of life. The committee concluded that people with anaemia would welcome an oral treatment if it is safe, particularly those who find it difficult to inject ESAs. ## The company's positioning of roxadustat in the treatment pathway is appropriate Roxadustat has a marketing authorisation for treating symptomatic anaemia associated with CKD in adults. The company positioned roxadustat as an alternative to ESAs for treating symptomatic anaemia associated with stage 3 to 5 CKD in people with no iron deficiency and who are not on dialysis at the start of treatment. It added that roxadustat would only be offered to people who are not on dialysis (including peritoneal dialysis), but people starting roxadustat would be able to continue treatment if they went on to dialysis. Also, switching from ESAs to roxadustat for people who are on dialysis and whose anaemia is stable on ESAs should only be considered if there is a valid clinical reason. This is because of cardiovascular disease safety concerns based on advice from the European Medicines Agency and the Medicines and Healthcare products Regulatory Agency (MHRA). Also, there is no clinical trial evidence of switching treatment from ESAs to roxadustat in people with anaemia associated with CKD who are not on dialysis. Clinical experts stated that they would start ESA treatment based on the presence of anaemia symptoms if people had sufficient iron levels. They added that anaemia associated with stage 1 or 2 CKD is usually effectively treated with iron therapy alone, while ESAs are reserved for stage 3 to 5 CKD. They also confirmed that because intravenous iron and some ESAs are administered through the dialysis machine, the main benefit of roxadustat as an oral treatment would be for treating anaemia in people not on dialysis. The clinical experts explained the importance of avoiding blood transfusion because of the potential impact of developing antibodies that may affect the success of future kidney transplants. The committee was aware that some people cannot have treatment with ESAs because of chronic inflammation, cancer, adverse reactions, anaemia that does not respond adequately to ESAs or because they are not able to self-inject. However, the company had not presented any evidence for roxadustat in people whose anaemia cannot be treated with ESAs. The committee concluded that the position of roxadustat in the treatment pathway broadly represented where it would be used in clinical practice. # Clinical effectiveness ## DOLOMITES is the only clinical trial that reflects the decision problem The company identified 4 multicentre, randomised controlled trials of roxadustat in people with anaemia and stage 3 to 5 CKD who were not on dialysis at the start of treatment. Three trials (ALPS, ANDES, and OLYMPUS) compared roxadustat with placebo, while the fourth study (DOLOMITES) compared roxadustat with darbepoetin alfa, an ESA. The DOLOMITES study was a phase 3, open-label, non-inferiority trial in 28 countries including the UK. It included people with symptomatic anaemia and stage 3, 4 or 5 CKD who were not on dialysis and had Hb levels less than 105 g/litre at the start of treatment. Although lower than the 110 g/litre threshold recommended in NICE's guideline on chronic kidney disease for starting anaemia treatment, the committee recalled that this reflects UK practice (see section 3.2). The DOLOMITES trial excluded people who could not take ESAs, had cancer, had anaemia caused by conditions other than CKD or who had chronic inflammatory conditions that could impact erythropoiesis (making red blood cells). It also excluded people who had ESAs, intravenous iron, or a red blood cell transfusion 12, 6 and 8 weeks before study randomisation, respectively. The primary end point was Hb response after 24 weeks of treatment, defined as: An Hb level of 110 g/litre or more and change from baseline Hb of 10 g/litre or more in people with Hb greater than 80 g/litre at baseline without rescue therapy. Change from baseline Hb of 20 g/litre or more in people with Hb of 80 g/litre or less at baseline without rescue therapy.DOLOMITES was designed as a non-inferiority trial, with no plan to test the primary end point for superiority. Secondary outcomes included change from baseline in Hb level, low-density lipoprotein cholesterol and mean arterial pressure, time to first hypertension event and intravenous iron infusion, and health-related quality-of-life measures such as the SF‑36, EQ‑5D‑5L visual analogue scale (VAS) and the Functional Assessment of Cancer Therapy – Anemia (FACT‑An) scale. With respect to baseline characteristics, 95% to 96% of people in the DOLOMITES trial were described as being white, compared with about 87% in clinical practice. The company confirmed that the roxadustat trials had different requirements for iron repletion. As a result, about half of the people in the DOLOMITES trial had sufficient iron levels compared with clinical practice, when iron repletion is needed to start treatment with ESA. The committee noted that both roxadustat and darbepoetin alfa arms included similar proportions of people who did not have sufficient iron levels. The company stated that oral iron was encouraged in the roxadustat arm of the DOLOMITES trial both for supporting erythropoiesis and as the first-line treatment for iron deficiency. But in the darbepoetin alfa arm either oral or intravenous iron could be given for iron deficiency according to local practice. The company did not present any evidence for people who cannot take ESAs. The committee concluded that DOLOMITES is the only trial that reflects the decision problem, and it is likely to be generalisable to NHS clinical practice. ## Roxadustat is non-inferior compared with darbepoetin alfa The company defined non-inferiority as the lower limit of the 2‑sided 95% confidence interval (non-inferiority margin) being greater than -15% difference in the proportion of people whose anaemia responded to treatment between roxadustat and darbepoetin alfa. Results from the DOLOMITES trial showed that after 24 weeks, 256 people (90%) randomised to have roxadustat and 213 people (78%) randomised to have darbepoetin alfa achieved the primary end point. The difference was 12% (95% confidence interval 5.7% to 17.4%) and non-inferiority was met. All measures of quality of life (SF‑36, EQ‑5D‑5L VAS and FACT‑An) and all other secondary end points were non-inferior for roxadustat compared with darbepoetin alfa, while a decreased need for intravenous iron was superior. The trial presented no results on length of life. The committee agreed that roxadustat is non-inferior compared with darbepoetin alfa. ## The company's revised approach using only DOLOMITES trial data is acceptable To compare roxadustat with ESAs as a class, the company initially combined data from the roxadustat arms of the darbepoetin alfa-controlled DOLOMITES and all placebo-controlled trials to estimate clinical parameters for roxadustat. Data for darbepoetin alfa as proxy for the clinical effectiveness of all ESAs was based on the DOLOMITES trial alone. The company considered combining the roxadustat arms to be appropriate. However, it could not explain to the committee's satisfaction how it had done this. The ERG was concerned that the company's pooling approach removed the benefits of randomisation of the trials. Therefore, the results of the pooled analyses were likely to be biased. The committee agreed with the ERG that using combined roxadustat data did not outweigh the benefits of using the head-to-head trial data from the DOLOMITES trial. It considered that the company's approach to combining roxadustat data was not appropriate. The committee appreciated the importance of using data, when available, in the absence of potentially less biased approaches. However, for decision making, the committee preferred analyses only using data from DOLOMITES. After consultation, the company updated its base case to use only DOLOMITES trial data to determine the clinical effectiveness of roxadustat and darbepoetin alfa. The ERG confirmed that the company applied the change correctly. The committee concluded that the company's revised approach using only DOLOMITES trial data was acceptable for decision making. # Cost effectiveness ## The company's economic model broadly reflects anaemia and is acceptable for decision making The company used a cohort health-state transition model to estimate the cost effectiveness of roxadustat compared with ESAs, with effectiveness measured in quality-adjusted life years (QALYs). The company assumed that roxadustat improves quality of life but does not make people live any longer compared with ESAs. The model included 8 health states based on Hb level categories (that is, below 70 g/litre, 70 to 79.9 g/litre, 80 to 89.9 g/litre, 90 to 99.9 g/litre, 100 to 109.9 g/litre, 110 to 119.9 g/litre, 120 to 129.9 g/litre and 130 g/litre and above) and a death health state. The company stated that it chose the 8 Hb categories from 2 published studies: a microsimulation cost-effectiveness model of Hb level targets for treating anaemia in the US (Yarnoff et al. 2016) and an observational study assessing the relationship between Hb level and health-related quality of life (Finklestein et al. 2009). The company initially based the probability of being in each health state on the pooled roxadustat trials data. But, it changed to DOLOMITES trial only data after the first committee meeting. Hb levels determined treatment dose, the proportion of people having iron therapy, iron therapy dose and the frequency of red blood cell transfusions. It modelled the impact of dialysis on survival and health-related quality of life implicitly. It did the same for the impact of treatment-related adverse events on survival and health-related quality of life. The company acknowledged that it did not include renal transplant. It stated that it modelled adverse events based on anaemia treatment and not for each health state because of insufficient data. The model included a 25‑year time horizon, which the company considered to cover lifetime length. The ERG was concerned that the company had not fully justified the Hb categories used to define health states. For instance, Yarnoff et al. took the Hb categories directly from another study of transfusion burden in anaemia in the US (Lawler et al. 2010) without further justification. Finkelstein et al. showed that the impact of Hb increases only for levels below 110 g/litre, 110 to below 120 g/litre, 120 to below 130 g/litre and 130 g/litre and above. It was unclear to the ERG why and how each health state would differ in terms of health-related quality of life, costs, and survival. For example, the model by Yarnoff et al. models quality-of-life impact through Hb levels, but this modelling does not confirm that a change of 10 g/litre in Hb has a meaningful effect on quality of life. The patient expert highlighted that people with anaemia are not aware of changes in Hb levels. They further explained that people notice improvements in quality of life, such as feeling less tired, when their Hb levels increased above 90 g/litre. At the second committee meeting, 1 clinical expert advised that increases of 10 g/litre in Hb do not show noticeable differences in quality of life. The ERG noted that during the company's own model validation, experts indicated that a model with health states based on Hb levels below, within and above the NICE guideline target range might reflect the condition. The target Hb range in the NICE guideline is 100 g/litre to 120 g/L (see section 3.2). One of the clinical experts attending the first committee meeting agreed. The committee, at its first meeting, concluded that having 8 health states overcomplicates the model and there is not enough data for each health state to identify differences between them. The company did not revise its model to include fewer health states after the first committee meeting. So it was unclear to the committee whether reducing the number of health states would have an impact on the cost-effectiveness estimates. The committee concluded that the company's economic model broadly reflects anaemia being based on Hb, but including 8 health states may overcomplicate the model. ## Transition probabilities between health states are uncertain In its model, the company distributed people across Hb health states over the lifetime time horizon. The company initially based the probability of being in each health state for the first cycle of the model on the pooled roxadustat trials. Because each cycle in the model is 3 months, the company used the data from the first 12 weeks of the pooled roxadustat trials to distribute people across the Hb health states in the first cycle. The company used a multinomial logistic regression model to distribute people after the first cycle. The regression model included several covariates such as treatment type (placebo, ESA or roxadustat), time (log), history of cardiovascular disease at baseline, history of type 2 diabetes at baseline, unique study identifier (ALPS, ANDES, OLYMPUS, and DOLOMITES), and an interaction between treatment type and time. The committee questioned why the company had chosen to include an interaction between treatment type and time. It noted that the company had not presented it with results from a model excluding this interaction. After consultation, the company revised its modelling approach to use only DOLOMITES trial data to inform the distribution of people across health states over the lifetime horizon. Also, it stated that all available DOLOMITES trial data was included in the regression model for long-term extrapolation, including data from people who had up to 104 weeks of roxadustat treatment. The ERG was concerned that the company had not provided enough details of the methodology behind the regression model based on DOLOMITES only trial data. This included the statistical analysis plan for the regression model, diagnostic plots or how the additional long-term DOLOMITES data was incorporated. The committee noted that the long-term extrapolations were uncertain and considered that the effects seen in the DOLOMITES trial might not last indefinitely over the 25‑year time horizon. So, at the second committee meeting, the committee preferred the scenario analysis when roxadustat and ESA have equal efficacy in month 25 of the model (that is, immediately after the end of the DOLOMITES trial). The committee concluded that the transition probabilities between health states estimated by the company remained uncertain because of the insufficient information on the regression model. # Utility values ## The company's revised base case using a multiplicative approach to estimate health-state utilities is acceptable The company estimated health-state utilities using general population utility values adjusted for age and sex and subtracting disutility for CKD, type of dialysis (haemodialysis and peritoneal dialysis), Hb level, and treatment-related adverse events. It sourced the general population utilities and disutilities for CKD, type of dialysis and adverse events from literature or NICE's technology appraisal guidance on tolvaptan for autosomal dominant polycystic kidney disease (TA358). Acting on the committee's preference to use a single source of data, for the Hb level utility reductions, the company obtained the utility values from the DOLOMITES trial data. This used the EQ‑5D‑5L instrument cross-walked to EQ‑5D‑3L levels values. It then used a generalised linear mixed model to estimate utility values for each Hb level controlling for history of cardiovascular disease and presence or absence of type 2 diabetes at baseline. The company initially assumed that the utility reductions are additive based on previous studies that also used this approach (for example, Yarnoff et al. 2010 and Glenngard et al. 2018). However, the ERG highlighted that the company did not explore any alternative approaches to health-state utility estimation such as multiplicative, or minimum or maximum values. The literature suggests that a multiplicative approach might be preferable when multiple factors can affect overall utility. The committee noted that with high disutility values, using an additive approach would lead to implausibly low health-state utility values in some cases. It stated that it would prefer health-state utilities estimated using a multiplicative approach. After consultation the company updated its base case to include a multiplicative approach to estimate health-state utilities. The ERG confirmed that the company applied the change correctly. The committee concluded that the company's revised approach was acceptable for decision making. ## The company's approach to modelling harms and costs of Hb level over 120 g/litre is uncertain, but the impact on cost effectiveness is likely to be low The company used utility reductions for CKD, dialysis and adverse events from published sources and estimated utility reductions for each Hb level based on roxadustat trial data (see section 3.9). The committee noted that the sources for disutilities for CKD, type of dialysis and adverse events dated as far back as 1999. It was unclear whether these values reflect current values or whether they were generalisable to CKD because they were taken from TA358 on polycystic kidney disease (see section 3.9). The committee also considered that the utility reductions applied by the company were high (for example, a utility reduction of 0.35 for a mild stroke, which is the same as the utility reduction applied for people who were on haemodialysis). The patient expert added that it is unlikely for dialysis to reduce utility to that extent. This is because people are aware that dialysis is a treatment approach that extends life compared with an adverse event such as stroke, which is irreversible and disabling and can potentially make people ineligible for kidney transplant. At the first meeting, the committee recalled regulatory advice to avoid sustained Hb levels greater than 120 g/litre, because of an increased risk of cardiovascular disease. It noted that the company did not reflect this in its modelling. The committee was particularly concerned that the company included lower roxadustat doses and costs, reduced iron and blood transfusion use, and did not include disutility and costs for Hb levels over 120 g/litre in the model. It considered that this modelling would overestimate the cost effectiveness of treatment with roxadustat. The committee concluded that the utility reductions for type of dialysis and Hb level do not reflect patient and clinical experience. After consultation, the company included a scenario analysis exploring the impact of capturing harms and costs for higher Hb levels. It did so by including Hb‑specific event probabilities for stroke, heart attack and vascular access thrombosis. The company sourced the probability of stroke caused by Hb levels from published literature, but used the same value for heart attack and vascular access thrombosis in the absence of published data for these events. The ERG and the committee were unclear whether the harms and costs of these events were applied to Hb levels over 120 g/litre or 130 g/litre. The committee considered it good practice to apply the harms and costs to Hb levels over 120 g/litre. It indicated that it preferred this assumption be included in the base case, rather than as a scenario analysis. Also, it highlighted that the company had not adequately captured the consequences of Hb levels over 120 g/litre because it did not include all relevant harms and costs. Also, the committee recalled there were few disincentives in the model for Hb going above the target range. It concluded that the company's approach to modelling harms and costs of Hb levels over 120 g/litre was uncertain, but it considered that the impact on cost effectiveness was likely to be low. # Costs in the economic model ## Costs of hospitalisations should be based on hospitalisation rates measured directly from the DOLOMITES trial The company modelled frequency of hospitalisations indirectly based on adverse events seen in the roxadustat trials, rather than directly based on frequency of hospitalisations. It did so to avoid double counting the costs and quality-of-life effects associated with hospitalisations and adverse events. Also, the company indicated that there was not enough data to model hospitalisations based on Hb level and that roxadustat was not expected to affect hospitalisation rates. This is despite the company showing different rates of hospitalisations between roxadustat (58%) and darbepoetin alfa (52%) in the DOLOMITES trial. The ERG highlighted that the company's approach was not in line with NICE's guide to the methods of technology appraisal, which states that indirect (surrogate) outcomes should be used only when direct outcomes are not available. It added that the company should explore both expected and unexpected effects associated with roxadustat. The committee recognised that it is possible for the company to model hospitalisations directly and avoid double counting, because the company knows which hospitalisations were because of adverse events. The committee understood that hospitalisations from causes other than adverse events made up about a third of all hospitalisations and emphasised the need to measure hospitalisations directly. After consultation, the company provided additional justification for modelling hospitalisations indirectly based on adverse events. It calculated and presented the incident rate ratios for hospitalisations from adverse events and other causes, which showed that there were no significant differences in hospitalisations between roxadustat and ESA. The committee accepted that there were no significant differences in hospitalisations between roxadustat and ESA and considered that their inclusion was likely to have a small impact on cost effectiveness. However, it preferred that the company's approach had been in line with NICE guidance. The committee concluded that the costs of hospitalisations should be based on hospitalisation rates measured directly from the DOLOMITES trial. ## The company's revised base case should include additional adverse events The company chose major adverse cardiovascular events as the only adverse events in its economic model. It included stroke, heart attack and vascular access thrombosis. It considered these more important than other adverse events because they can lead to death and reduce health-related quality of life, have a high prevalence in people with CKD, and contribute to high healthcare resource use. The company indicated that its own 3 experts agreed with its choice of adverse events. It considered other adverse events to have no impact on model outcomes because they had a low incidence or similar rates between the roxadustat and darbepoetin alfa arms. However, the ERG noted that some adverse events differed in incidence by 2% to 4% between roxadustat and darbepoetin alfa: peripheral oedema (15% compared with 12%) hyperkalaemia (12% compared with 14%) nausea (11% compared with 9%) hyperphosphatemia (9% compared with 5%) muscle spasms (8% compared with 5%) dyspnoea (7% compared with 4%) headache (7% compared with 4%) insomnia (6% compared with 3%).The patient expert indicated that specific adverse events such as insomnia, headache and nausea are important for patients because they can affect quality of life and whether people will take roxadustat as intended. At the first committee meeting, the company presented exploratory analyses including additional adverse events that occurred in more than 3% of the DOLOMITES population and were of grade 3 or higher severity. These included cardiac failure, pneumonia, and hypertension. It considered that these adverse events had a minor impact on the cost effectiveness of roxadustat. Despite this, the committee considered that the company model should have included a wider range of adverse events, particularly those that are important to patients and could impact quality of life. After consultation, the company provided additional justification to exclude adverse events from the modelling. It showed that the rates of adverse events that were of grade 3 or higher severity in DOLOMITES were similar between roxadustat and darbepoetin alfa. However, the committee recalled that certain adverse events such as nausea and headache affect quality of life even at grade 2 severity. The patient expert reiterated that adverse events are important because they can affect adherence to treatment. They added that if patients stop taking their anaemia medication because of adverse events then this would reduce their Hb levels and in turn affect their quality of life. The committee understood that rates of adverse events of grade 2 or higher severity were similar between roxadustat and darbepoetin alfa. So it considered that their exclusion from the modelling was likely to have a small impact on cost effectiveness. However, it considered it good practice to explore the impact of all relevant adverse events and concluded that the company's revised base case should have included additional adverse events. ## The estimated costs of roxadustat in the company's revised approach are appropriate The company estimated costs of roxadustat based on body weight, Hb levels, and 2 separate treatment phases (correction and maintenance) to account for dose changes made in clinical practice. Starting doses are based on weight, and dose changes are based on response to treatment and changes in Hb levels. The correction phase lasted up to 3 months from starting treatment and corresponded with the first cycle of the model. The maintenance phase started immediately after the correction phase. The company initially estimated the average roxadustat dosage for each Hb level in the correction phase based on data including body weight from people in all roxadustat trials. However, after consultation, the company estimated roxadustat dosages for the correction phase only from the DOLOMITES trial data. For the maintenance phase, it extrapolated the average weekly dose using a generalised linear mixed model and controlled for history of cardiovascular disease and presence of type 2 diabetes at baseline. The company confirmed at the first committee meeting that it had not assumed treatment stops in the economic model, despite the DOLOMITES trial having a stopping rule for roxadustat for Hb levels above 130 g/litre. Clinical experts indicated that the decision whether to stop treatment depends on how well anaemia is managed. They stated that they would titrate the dose of roxadustat down if Hb levels reached around 125 g/litre so that Hb levels stay within a safe range (that is, between 100 g/litre and 120 g/litre) rather than stopping treatment (see section 3.8). After consultation, the company revised its base case to include a stopping rule for roxadustat at Hb levels over 130 g/litre. It applied the stopping rule only to roxadustat treatment costs in this health state, because Hb levels over 130 g/litre are not associated with a utility benefit in the model. However, the ERG was concerned that this adjustment implicitly assumed that the stopping rule affects only roxadustat costs and not its clinical effectiveness or other model parameters. The committee found the application of the stopping rule uncertain because roxadustat would not be completely stopped in clinical practice. Instead the dosage would be adjusted or temporarily withheld until Hb levels reach the target range according to the instructions in the summary of product characteristics for roxadustat and clinical expert feedback. However, the committee concluded that the estimated costs of roxadustat in the company's revised approach are appropriate because they are based only on the DOLOMITES trial data. ## The overall costs of ESAs are uncertain, but the company's revised approach is appropriate The prices of ESAs reflect confidential arrangements between companies and the NHS. The company estimated costs of ESAs using the same approach as for the costs of roxadustat (see section 3.13). It used only data from the DOLOMITES trial to determine the average weekly doses for the correction and maintenance phases. In line with clinical guidance and practice, the company assumed a class effect (see section 3.2) and included all 5 ESAs available in the UK in the model. To determine equivalent doses between ESAs, the company used darbepoetin alfa as a reference and applied a 'dose conversion' factor for each ESA based on their weekly dose from the BNF. The company took the list price of the different types of ESA from the BNF. It estimated the proportions of people with anaemia having each ESA from TUNE, an unpublished observational retrospective study of medical records in the UK population. However, the company acknowledged that there is uncertainty around the distribution of ESAs in clinical practice because there are no clear or reliable sources to inform this parameter. Clinical experts pointed out that some hospitals or NHS trusts purchase and prescribe only 1 type of ESA, rather than a basket of different types of ESAs as used in the company model. The company included drug administration costs for 20% of people who have ESAs. One clinical expert confirmed that people do incur costs associated with ESA administration and that the proportion of people estimated by the company is reasonable. After consultation, the company revised its modelling approach to include administration costs for people on peritoneal dialysis. However, it did not include a stopping rule for ESAs when Hb levels exceed those recommended by the regulators (120 g/litre; MHRA recombinant human erythropoietins: new advice for prescribing). The company indicated that it considered the ESA dosing data from DOLOMITES to reflect clinical practice and any stopping rules. This is because the dosing of darbepoetin alfa was based on its summary of product characteristics, which already includes dose adjustments and temporary stops if Hb levels exceed 120 g/litre. The committee agreed that the stopping rule for ESAs was already accounted for in the dosage data from DOLOMITES. It concluded that the company's revised approach was acceptable for decision making, but the overall costs of ESAs are uncertain. # Cost-effectiveness estimates ## The company did not address all of the committee's preferred assumptions, but the likely impact on cost effectiveness is small The committee discussed the company's base case, revised after consultation. It noted how the company attempted to address its preferences from its first meeting, namely: Using only DOLOMITES trial data for clinical effectiveness estimates for roxadustat and ESAs (see section 3.6). Clarifying that health-state transition probabilities are based on 36‑week data from DOLOMITES and also include some 104‑week follow-up data (see section 3.8). Health-state utilities estimated using a multiplicative approach (see section 3.9). Health states that reflect the harms and costs of having Hb levels over 120 g/litre (see section 3.10). ESA administration costs for people who start having peritoneal dialysis. Roxadustat costs that reflect the DOLOMITES trial (see section 3.13). A model that reflects the stopping rule in DOLOMITES and other regulatory recommendations for safety (see section 3.8 and section 3.13).The ERG acknowledged that the company's revised base case incorporates its and the committee's preferred assumptions. So it considered its preferred base case the same as the company's revised base case. The ERG's analysis also included the confidential NHS Commercial Medicines Unit price for each ESA. However, the ERG highlighted that the company's revised base case excluded some committee preferred assumptions such as: Providing full justification for using 8 health states or using fewer health states (see section 3.7). Justifying and providing full details of the regression model used to extrapolate beyond the trial period (see section 3.8). Including hospitalisation costs based on hospitalisation rates measured directly from the DOLOMITES trial (see section 3.11). Including additional adverse events that impact adherence to treatment and health-related quality of life (see section 3.12).The committee did not agree with the updated preferences for the harms and costs of Hb levels over 120 g/litre in the company's revised base case (see section 3.10). It also considered that the exclusion of its preferred assumptions highlighted by the ERG increased the uncertainty of the cost-effectiveness estimate. However, it noted that the impact of including the harms and costs of Hb levels over 120 g/litre and its remaining preferred assumptions in the revised base case was likely to be small. The committee was willing to accept this uncertainty specifically for this appraisal. But, it considered it good practice to adequately capture the harms and costs of Hb levels over 120 g/litre, and to include or explore all its preferred assumptions in the base case for future hypoxia-inducible factor inhibitors similar to roxadustat. The committee concluded that the company had not addressed all its preferred assumptions adequately but considered the likely impact on cost effectiveness to be small. ## The ICERs for roxadustat are within what NICE considers an acceptable use of NHS resources Applying confidential discounts for ESAs, and considering its preferences, the committee noted that the ERG's and company's incremental cost-effectiveness estimates (ICERs) were within what NICE considers an acceptable use of NHS resources. Because of the confidential discounts for ESAs, the ICERs or incremental costs cannot be reported here. The committee was satisfied that roxadustat is similarly effective to ESA and that overall, the costs are similar. # Innovation ## Roxadustat has a novel mechanism of action, but has not shown superiority to ESAs, and all benefits are captured in the modelling The committee noted that roxadustat is a first-in-class oral hypoxia-inducible factor prolyl hydroxylase inhibitor, which provides an additional treatment for anaemia associated with CKD. However, it was aware that roxadustat was shown only to be non-inferior to current treatment. The patient expert indicated that roxadustat's oral administration is a step-change compared with injectable ESAs, even though this might affect whether people will take roxadustat as intended. Having an oral alternative might reduce costs associated with ESA administration and reduce the need for cold-chain storage and special sharps disposals. Roxadustat might also simplify management of anaemia by reducing the need for iron transfusions. The committee recalled that the company already included fewer iron infusions and costs of ESA administration costs in its economic model (see section 3.13). So, the committee concluded that roxadustat did not meet NICE's criteria to be considered an innovative treatment. # Conclusion ## Roxadustat is recommended as an option for treating symptomatic anaemia associated with chronic kidney disease The committee was satisfied that roxadustat is similarly effective to ESAs and that overall, the costs are similar. So, it was able to recommend roxadustat as an option for treating symptomatic anaemia associated with chronic kidney disease.	{'Recommendations': 'Roxadustat is recommended as an option for treating symptomatic anaemia associated with chronic kidney disease (CKD) in adults only if:\n\nthey have stage 3 to 5 CKD with no iron deficiency and\n\nthey are not on dialysis at the start of treatment and\n\nthe company provides roxadustat according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with roxadustat that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment for symptomatic anaemia associated with chronic kidney disease includes erythropoiesis stimulating agents (ESAs). Roxadustat is an alternative to ESAs.\n\nA clinical trial comparing roxadustat with darbepoetin alfa (an ESA) shows that roxadustat works as well as darbepoetin alfa.\n\nThe cost effectiveness estimates for roxadustat are within what NICE normally considers an acceptable use of NHS resources. So roxadustat is recommended.', 'Information about roxadustat': "# Marketing authorisation indication\n\nRoxadustat (Evrenzo, Astellas Pharma) 'is indicated for treatment of adult patients with symptomatic anaemia associated with chronic kidney disease (CKD)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for roxadustat.\n\n# Price\n\nThe list prices of roxadustat are:\n\n£59.24 per 12‑tablet pack, each tablet contains 20\xa0mg of roxadustat (excluding VAT; BNF online, accessed December 2021)\n\n£148.11 per 12‑tablet pack, each tablet contains 50\xa0mg of roxadustat (excluding VAT; BNF online, accessed December 2021)\n\n£207.35 per 12‑tablet pack, each tablet contains 70\xa0mg of roxadustat (excluding VAT; BNF online, accessed December 2021)\n\n£296.21 per 12‑tablet pack, each tablet contains 100\xa0mg of roxadustat (excluding VAT; BNF online, accessed December 2021)\n\n£444.32 per 12‑tablet pack, each tablet contains 150\xa0mg of roxadustat (excluding VAT; BNF online, accessed December 2021).The company has a commercial arrangement. This makes roxadustat available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Astellas Pharma, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Anaemia associated with chronic kidney disease is associated with extreme fatigue and reduced quality of life\n\nAnaemia is a serious condition defined by abnormally low levels of haemoglobin (Hb) or too few red blood cells in the blood. This reduces the ability of blood to carry oxygen around the body. Erythropoietin, a hormone produced by the kidneys in response to low oxygen levels, stimulates the bone marrow to produce red blood cells. However, kidneys that are not working properly make less erythropoietin, so anaemia is common in people with chronic kidney disease (CKD). CKD is characterised by the progressive loss of kidney function and is generally categorised into 5\xa0stages based on decreasing kidney function. The prevalence and severity of anaemia increase as kidney disease worsens (6% of people with stage\xa01 CKD have anaemia compared with 34% and 43% of people with stage\xa04 and\xa05 CKD, respectively). People with CKD already face substantial challenges that affect their quality of life. Symptoms of CKD include fatigue, itching, swelling and sleep problems. These can affect many aspects of normal life and people's capacity to stay in work. Also, people with CKD experience stress and difficulties coming to terms with the diagnosis of an incurable, progressive disease and making difficult decisions about treatment, including dialysis. Anaemia further affects their quality of life. The patient expert explained that the symptoms of untreated anaemia are severe and disabling. For example, some people cannot drive, work, or even walk because of the extreme fatigue associated with anaemia. As a result, this can affect mental health. The patient expert added that people going into dialysis need relief from anaemia-associated fatigue to make decisions about their treatment and manage their life around dialysis. The committee concluded that anaemia can be associated with extreme fatigue and has a considerable effect on quality of life for people with CKD.\n\n## People with anaemia in CKD would welcome an oral alternative to injectable erythropoiesis stimulating agents\n\nAnaemia is carefully monitored in people with CKD. NICE's guideline on chronic kidney disease: assessment and management recommends maintaining Hb between 100\xa0g/litre and 120\xa0g/litre for adults and avoiding Hb levels above 120\xa0g/litre because of an increased risk of death and serious cardiovascular adverse events. Anaemia associated with CKD may be treated with iron therapy, erythropoiesis stimulating agents (ESAs), or both. NICE's guideline recommends that ESA treatment not be started without also managing iron deficiency. The clinical experts confirmed that people with anaemia must have sufficient iron levels (iron replete) before starting treatment with ESAs. Iron therapy can be given orally or intravenously depending on the severity of CKD, dialysis status or previous response to treatment. Treatment with ESAs is offered to adults, children and young people with anaemia who are likely to benefit in terms of quality of life and physical function. NICE's guideline on chronic kidney disease recommends a Hb level of 110\xa0g/litre or lower for starting anaemia treatment. Clinical experts indicated that the level of haemoglobin at which it is appropriate to start treatment with ESAs is individualised, but they are likely to start treatment at Hb levels lower than 95\xa0g/litre to 105\xa0g/litre. The committee discussed whether ESAs were interchangeable and could be considered equally effective (a 'class effect'). The clinical experts explained that while some differences exist in the frequency of administration, the effectiveness of ESAs was similar. The committee concluded that ESAs could be considered as a class. Current ESAs are injectable analogues of erythropoietin that can be given subcutaneously, intravenously, or through the haemodialysis machine. For people who are not on haemodialysis, including those on peritoneal dialysis, ESAs are typically self-administered. People have training to learn how to self-inject and to dispose of sharps. However, many people with anaemia find injecting themselves unpleasant and difficult, while some have to rely on others to give them their injections. Many people manage subcutaneous injections because of the high prevalence of people with diabetes on insulin among people with CKD and anaemia. In general, the patient and clinical experts noted that ESAs are well-established products that improve quality of life for people with anaemia. The patient expert highlighted that treatment-related adverse events are important to patients. They noted that people may be less likely to take medications that might have adverse effects that can affect quality of life. The committee concluded that people with anaemia would welcome an oral treatment if it is safe, particularly those who find it difficult to inject ESAs.\n\n## The company's positioning of roxadustat in the treatment pathway is appropriate\n\nRoxadustat has a marketing authorisation for treating symptomatic anaemia associated with CKD in adults. The company positioned roxadustat as an alternative to ESAs for treating symptomatic anaemia associated with stage\xa03 to 5 CKD in people with no iron deficiency and who are not on dialysis at the start of treatment. It added that roxadustat would only be offered to people who are not on dialysis (including peritoneal dialysis), but people starting roxadustat would be able to continue treatment if they went on to dialysis. Also, switching from ESAs to roxadustat for people who are on dialysis and whose anaemia is stable on ESAs should only be considered if there is a valid clinical reason. This is because of cardiovascular disease safety concerns based on advice from the European Medicines Agency and the Medicines and Healthcare products Regulatory Agency (MHRA). Also, there is no clinical trial evidence of switching treatment from ESAs to roxadustat in people with anaemia associated with CKD who are not on dialysis. Clinical experts stated that they would start ESA treatment based on the presence of anaemia symptoms if people had sufficient iron levels. They added that anaemia associated with stage\xa01 or\xa02 CKD is usually effectively treated with iron therapy alone, while ESAs are reserved for stage\xa03 to\xa05 CKD. They also confirmed that because intravenous iron and some ESAs are administered through the dialysis machine, the main benefit of roxadustat as an oral treatment would be for treating anaemia in people not on dialysis. The clinical experts explained the importance of avoiding blood transfusion because of the potential impact of developing antibodies that may affect the success of future kidney transplants. The committee was aware that some people cannot have treatment with ESAs because of chronic inflammation, cancer, adverse reactions, anaemia that does not respond adequately to ESAs or because they are not able to self-inject. However, the company had not presented any evidence for roxadustat in people whose anaemia cannot be treated with ESAs. The committee concluded that the position of roxadustat in the treatment pathway broadly represented where it would be used in clinical practice.\n\n# Clinical effectiveness\n\n## DOLOMITES is the only clinical trial that reflects the decision problem\n\nThe company identified 4 multicentre, randomised controlled trials of roxadustat in people with anaemia and stage\xa03 to\xa05 CKD who were not on dialysis at the start of treatment. Three trials (ALPS, ANDES, and OLYMPUS) compared roxadustat with placebo, while the fourth study (DOLOMITES) compared roxadustat with darbepoetin alfa, an ESA. The DOLOMITES study was a phase\xa03, open-label, non-inferiority trial in 28\xa0countries including the UK. It included people with symptomatic anaemia and stage\xa03, 4 or 5 CKD who were not on dialysis and had Hb levels less than 105\xa0g/litre at the start of treatment. Although lower than the 110\xa0g/litre threshold recommended in NICE's guideline on chronic kidney disease for starting anaemia treatment, the committee recalled that this reflects UK practice (see section\xa03.2). The DOLOMITES trial excluded people who could not take ESAs, had cancer, had anaemia caused by conditions other than CKD or who had chronic inflammatory conditions that could impact erythropoiesis (making red blood cells). It also excluded people who had ESAs, intravenous iron, or a red blood cell transfusion 12, 6 and 8\xa0weeks before study randomisation, respectively. The primary end point was Hb response after 24\xa0weeks of treatment, defined as:\n\nAn Hb level of 110\xa0g/litre or more and change from baseline Hb of 10\xa0g/litre or more in people with Hb greater than 80\xa0g/litre at baseline without rescue therapy.\n\nChange from baseline Hb of 20\xa0g/litre or more in people with Hb of 80\xa0g/litre or less at baseline without rescue therapy.DOLOMITES was designed as a non-inferiority trial, with no plan to test the primary end point for superiority. Secondary outcomes included change from baseline in Hb level, low-density lipoprotein cholesterol and mean arterial pressure, time to first hypertension event and intravenous iron infusion, and health-related quality-of-life measures such as the SF‑36, EQ‑5D‑5L visual analogue scale (VAS) and the Functional Assessment of Cancer Therapy – Anemia (FACT‑An) scale. With respect to baseline characteristics, 95% to 96% of people in the DOLOMITES trial were described as being white, compared with about 87% in clinical practice. The company confirmed that the roxadustat trials had different requirements for iron repletion. As a result, about half of the people in the DOLOMITES trial had sufficient iron levels compared with clinical practice, when iron repletion is needed to start treatment with ESA. The committee noted that both roxadustat and darbepoetin alfa arms included similar proportions of people who did not have sufficient iron levels. The company stated that oral iron was encouraged in the roxadustat arm of the DOLOMITES trial both for supporting erythropoiesis and as the first-line treatment for iron deficiency. But in the darbepoetin alfa arm either oral or intravenous iron could be given for iron deficiency according to local practice. The company did not present any evidence for people who cannot take ESAs. The committee concluded that DOLOMITES is the only trial that reflects the decision problem, and it is likely to be generalisable to NHS clinical practice.\n\n## Roxadustat is non-inferior compared with darbepoetin alfa\n\nThe company defined non-inferiority as the lower limit of the 2‑sided 95% confidence interval (non-inferiority margin) being greater than -15% difference in the proportion of people whose anaemia responded to treatment between roxadustat and darbepoetin alfa. Results from the DOLOMITES trial showed that after 24\xa0weeks, 256\xa0people (90%) randomised to have roxadustat and 213\xa0people (78%) randomised to have darbepoetin alfa achieved the primary end point. The difference was 12% (95% confidence interval 5.7% to 17.4%) and non-inferiority was met. All measures of quality of life (SF‑36, EQ‑5D‑5L VAS and FACT‑An) and all other secondary end points were non-inferior for roxadustat compared with darbepoetin alfa, while a decreased need for intravenous iron was superior. The trial presented no results on length of life. The committee agreed that roxadustat is non-inferior compared with darbepoetin alfa.\n\n## The company's revised approach using only DOLOMITES trial data is acceptable\n\nTo compare roxadustat with ESAs as a class, the company initially combined data from the roxadustat arms of the darbepoetin alfa-controlled DOLOMITES and all placebo-controlled trials to estimate clinical parameters for roxadustat. Data for darbepoetin alfa as proxy for the clinical effectiveness of all ESAs was based on the DOLOMITES trial alone. The company considered combining the roxadustat arms to be appropriate. However, it could not explain to the committee's satisfaction how it had done this. The ERG was concerned that the company's pooling approach removed the benefits of randomisation of the trials. Therefore, the results of the pooled analyses were likely to be biased. The committee agreed with the ERG that using combined roxadustat data did not outweigh the benefits of using the head-to-head trial data from the DOLOMITES trial. It considered that the company's approach to combining roxadustat data was not appropriate. The committee appreciated the importance of using data, when available, in the absence of potentially less biased approaches. However, for decision making, the committee preferred analyses only using data from DOLOMITES. After consultation, the company updated its base case to use only DOLOMITES trial data to determine the clinical effectiveness of roxadustat and darbepoetin alfa. The ERG confirmed that the company applied the change correctly. The committee concluded that the company's revised approach using only DOLOMITES trial data was acceptable for decision making.\n\n# Cost effectiveness\n\n## The company's economic model broadly reflects anaemia and is acceptable for decision making\n\nThe company used a cohort health-state transition model to estimate the cost effectiveness of roxadustat compared with ESAs, with effectiveness measured in quality-adjusted life years (QALYs). The company assumed that roxadustat improves quality of life but does not make people live any longer compared with ESAs. The model included 8 health states based on Hb level categories (that is, below 70\xa0g/litre, 70 to 79.9\xa0g/litre, 80 to 89.9\xa0g/litre, 90 to 99.9\xa0g/litre, 100 to 109.9\xa0g/litre, 110 to 119.9\xa0g/litre, 120 to 129.9\xa0g/litre and 130\xa0g/litre and above) and a death health state. The company stated that it chose the 8 Hb categories from 2 published studies: a microsimulation cost-effectiveness model of Hb level targets for treating anaemia in the US (Yarnoff et al. 2016) and an observational study assessing the relationship between Hb level and health-related quality of life (Finklestein et al. 2009). The company initially based the probability of being in each health state on the pooled roxadustat trials data. But, it changed to DOLOMITES trial only data after the first committee meeting. Hb levels determined treatment dose, the proportion of people having iron therapy, iron therapy dose and the frequency of red blood cell transfusions. It modelled the impact of dialysis on survival and health-related quality of life implicitly. It did the same for the impact of treatment-related adverse events on survival and health-related quality of life. The company acknowledged that it did not include renal transplant. It stated that it modelled adverse events based on anaemia treatment and not for each health state because of insufficient data. The model included a 25‑year time horizon, which the company considered to cover lifetime length. The ERG was concerned that the company had not fully justified the Hb categories used to define health states. For instance, Yarnoff et al. took the Hb categories directly from another study of transfusion burden in anaemia in the US (Lawler et al. 2010) without further justification. Finkelstein et al. showed that the impact of Hb increases only for levels below 110\xa0g/litre, 110 to below 120\xa0g/litre, 120 to below 130\xa0g/litre and 130\xa0g/litre and above. It was unclear to the ERG why and how each health state would differ in terms of health-related quality of life, costs, and survival. For example, the model by Yarnoff et al. models quality-of-life impact through Hb levels, but this modelling does not confirm that a change of 10\xa0g/litre in Hb has a meaningful effect on quality of life. The patient expert highlighted that people with anaemia are not aware of changes in Hb levels. They further explained that people notice improvements in quality of life, such as feeling less tired, when their Hb levels increased above 90\xa0g/litre. At the second committee meeting, 1\xa0clinical expert advised that increases of 10\xa0g/litre in Hb do not show noticeable differences in quality of life. The ERG noted that during the company's own model validation, experts indicated that a model with health states based on Hb levels below, within and above the NICE guideline target range might reflect the condition. The target Hb range in the NICE guideline is 100\xa0g/litre to 120\xa0g/L (see section\xa03.2). One of the clinical experts attending the first committee meeting agreed. The committee, at its first meeting, concluded that having 8 health states overcomplicates the model and there is not enough data for each health state to identify differences between them. The company did not revise its model to include fewer health states after the first committee meeting. So it was unclear to the committee whether reducing the number of health states would have an impact on the cost-effectiveness estimates. The committee concluded that the company's economic model broadly reflects anaemia being based on Hb, but including 8 health states may overcomplicate the model.\n\n## Transition probabilities between health states are uncertain\n\nIn its model, the company distributed people across Hb health states over the lifetime time horizon. The company initially based the probability of being in each health state for the first cycle of the model on the pooled roxadustat trials. Because each cycle in the model is 3\xa0months, the company used the data from the first 12\xa0weeks of the pooled roxadustat trials to distribute people across the Hb health states in the first cycle. The company used a multinomial logistic regression model to distribute people after the first cycle. The regression model included several covariates such as treatment type (placebo, ESA or roxadustat), time (log[time+1]), history of cardiovascular disease at baseline, history of type\xa02 diabetes at baseline, unique study identifier (ALPS, ANDES, OLYMPUS, and DOLOMITES), and an interaction between treatment type and time. The committee questioned why the company had chosen to include an interaction between treatment type and time. It noted that the company had not presented it with results from a model excluding this interaction. After consultation, the company revised its modelling approach to use only DOLOMITES trial data to inform the distribution of people across health states over the lifetime horizon. Also, it stated that all available DOLOMITES trial data was included in the regression model for long-term extrapolation, including data from people who had up to 104\xa0weeks of roxadustat treatment. The ERG was concerned that the company had not provided enough details of the methodology behind the regression model based on DOLOMITES only trial data. This included the statistical analysis plan for the regression model, diagnostic plots or how the additional long-term DOLOMITES data was incorporated. The committee noted that the long-term extrapolations were uncertain and considered that the effects seen in the DOLOMITES trial might not last indefinitely over the 25‑year time horizon. So, at the second committee meeting, the committee preferred the scenario analysis when roxadustat and ESA have equal efficacy in month\xa025 of the model (that is, immediately after the end of the DOLOMITES trial). The committee concluded that the transition probabilities between health states estimated by the company remained uncertain because of the insufficient information on the regression model.\n\n# Utility values\n\n## The company's revised base case using a multiplicative approach to estimate health-state utilities is acceptable\n\nThe company estimated health-state utilities using general population utility values adjusted for age and sex and subtracting disutility for CKD, type of dialysis (haemodialysis and peritoneal dialysis), Hb level, and treatment-related adverse events. It sourced the general population utilities and disutilities for CKD, type of dialysis and adverse events from literature or NICE's technology appraisal guidance on tolvaptan for autosomal dominant polycystic kidney disease (TA358). Acting on the committee's preference to use a single source of data, for the Hb level utility reductions, the company obtained the utility values from the DOLOMITES trial data. This used the EQ‑5D‑5L instrument cross-walked to EQ‑5D‑3L levels values. It then used a generalised linear mixed model to estimate utility values for each Hb level controlling for history of cardiovascular disease and presence or absence of type\xa02 diabetes at baseline. The company initially assumed that the utility reductions are additive based on previous studies that also used this approach (for example, Yarnoff et al. 2010 and Glenngard et al. 2018). However, the ERG highlighted that the company did not explore any alternative approaches to health-state utility estimation such as multiplicative, or minimum or maximum values. The literature suggests that a multiplicative approach might be preferable when multiple factors can affect overall utility. The committee noted that with high disutility values, using an additive approach would lead to implausibly low health-state utility values in some cases. It stated that it would prefer health-state utilities estimated using a multiplicative approach. After consultation the company updated its base case to include a multiplicative approach to estimate health-state utilities. The ERG confirmed that the company applied the change correctly. The committee concluded that the company's revised approach was acceptable for decision making.\n\n## The company's approach to modelling harms and costs of Hb level over 120\xa0g/litre is uncertain, but the impact on cost effectiveness is likely to be low\n\nThe company used utility reductions for CKD, dialysis and adverse events from published sources and estimated utility reductions for each Hb level based on roxadustat trial data (see section\xa03.9). The committee noted that the sources for disutilities for CKD, type of dialysis and adverse events dated as far back as 1999. It was unclear whether these values reflect current values or whether they were generalisable to CKD because they were taken from TA358 on polycystic kidney disease (see section\xa03.9). The committee also considered that the utility reductions applied by the company were high (for example, a utility reduction of 0.35 for a mild stroke, which is the same as the utility reduction applied for people who were on haemodialysis). The patient expert added that it is unlikely for dialysis to reduce utility to that extent. This is because people are aware that dialysis is a treatment approach that extends life compared with an adverse event such as stroke, which is irreversible and disabling and can potentially make people ineligible for kidney transplant. At the first meeting, the committee recalled regulatory advice to avoid sustained Hb levels greater than 120\xa0g/litre, because of an increased risk of cardiovascular disease. It noted that the company did not reflect this in its modelling. The committee was particularly concerned that the company included lower roxadustat doses and costs, reduced iron and blood transfusion use, and did not include disutility and costs for Hb levels over 120\xa0g/litre in the model. It considered that this modelling would overestimate the cost effectiveness of treatment with roxadustat. The committee concluded that the utility reductions for type of dialysis and Hb level do not reflect patient and clinical experience. After consultation, the company included a scenario analysis exploring the impact of capturing harms and costs for higher Hb levels. It did so by including Hb‑specific event probabilities for stroke, heart attack and vascular access thrombosis. The company sourced the probability of stroke caused by Hb levels from published literature, but used the same value for heart attack and vascular access thrombosis in the absence of published data for these events. The ERG and the committee were unclear whether the harms and costs of these events were applied to Hb levels over 120\xa0g/litre or 130\xa0g/litre. The committee considered it good practice to apply the harms and costs to Hb levels over 120\xa0g/litre. It indicated that it preferred this assumption be included in the base case, rather than as a scenario analysis. Also, it highlighted that the company had not adequately captured the consequences of Hb levels over 120\xa0g/litre because it did not include all relevant harms and costs. Also, the committee recalled there were few disincentives in the model for Hb going above the target range. It concluded that the company's approach to modelling harms and costs of Hb levels over 120\xa0g/litre was uncertain, but it considered that the impact on cost effectiveness was likely to be low.\n\n# Costs in the economic model\n\n## Costs of hospitalisations should be based on hospitalisation rates measured directly from the DOLOMITES trial\n\nThe company modelled frequency of hospitalisations indirectly based on adverse events seen in the roxadustat trials, rather than directly based on frequency of hospitalisations. It did so to avoid double counting the costs and quality-of-life effects associated with hospitalisations and adverse events. Also, the company indicated that there was not enough data to model hospitalisations based on Hb level and that roxadustat was not expected to affect hospitalisation rates. This is despite the company showing different rates of hospitalisations between roxadustat (58%) and darbepoetin alfa (52%) in the DOLOMITES trial. The ERG highlighted that the company's approach was not in line with NICE's guide to the methods of technology appraisal, which states that indirect (surrogate) outcomes should be used only when direct outcomes are not available. It added that the company should explore both expected and unexpected effects associated with roxadustat. The committee recognised that it is possible for the company to model hospitalisations directly and avoid double counting, because the company knows which hospitalisations were because of adverse events. The committee understood that hospitalisations from causes other than adverse events made up about a third of all hospitalisations and emphasised the need to measure hospitalisations directly. After consultation, the company provided additional justification for modelling hospitalisations indirectly based on adverse events. It calculated and presented the incident rate ratios for hospitalisations from adverse events and other causes, which showed that there were no significant differences in hospitalisations between roxadustat and ESA. The committee accepted that there were no significant differences in hospitalisations between roxadustat and ESA and considered that their inclusion was likely to have a small impact on cost effectiveness. However, it preferred that the company's approach had been in line with NICE guidance. The committee concluded that the costs of hospitalisations should be based on hospitalisation rates measured directly from the DOLOMITES trial.\n\n## The company's revised base case should include additional adverse events\n\nThe company chose major adverse cardiovascular events as the only adverse events in its economic model. It included stroke, heart attack and vascular access thrombosis. It considered these more important than other adverse events because they can lead to death and reduce health-related quality of life, have a high prevalence in people with CKD, and contribute to high healthcare resource use. The company indicated that its own 3 experts agreed with its choice of adverse events. It considered other adverse events to have no impact on model outcomes because they had a low incidence or similar rates between the roxadustat and darbepoetin alfa arms. However, the ERG noted that some adverse events differed in incidence by 2% to 4% between roxadustat and darbepoetin alfa:\n\nperipheral oedema (15% compared with 12%)\n\nhyperkalaemia (12% compared with 14%)\n\nnausea (11% compared with 9%)\n\nhyperphosphatemia (9% compared with 5%)\n\nmuscle spasms (8% compared with 5%)\n\ndyspnoea (7% compared with 4%)\n\nheadache (7% compared with 4%)\n\ninsomnia (6% compared with 3%).The patient expert indicated that specific adverse events such as insomnia, headache and nausea are important for patients because they can affect quality of life and whether people will take roxadustat as intended. At the first committee meeting, the company presented exploratory analyses including additional adverse events that occurred in more than 3% of the DOLOMITES population and were of grade\xa03 or higher severity. These included cardiac failure, pneumonia, and hypertension. It considered that these adverse events had a minor impact on the cost effectiveness of roxadustat. Despite this, the committee considered that the company model should have included a wider range of adverse events, particularly those that are important to patients and could impact quality of life. After consultation, the company provided additional justification to exclude adverse events from the modelling. It showed that the rates of adverse events that were of grade\xa03 or higher severity in DOLOMITES were similar between roxadustat and darbepoetin alfa. However, the committee recalled that certain adverse events such as nausea and headache affect quality of life even at grade\xa02 severity. The patient expert reiterated that adverse events are important because they can affect adherence to treatment. They added that if patients stop taking their anaemia medication because of adverse events then this would reduce their Hb levels and in turn affect their quality of life. The committee understood that rates of adverse events of grade\xa02 or higher severity were similar between roxadustat and darbepoetin alfa. So it considered that their exclusion from the modelling was likely to have a small impact on cost effectiveness. However, it considered it good practice to explore the impact of all relevant adverse events and concluded that the company's revised base case should have included additional adverse events.\n\n## The estimated costs of roxadustat in the company's revised approach are appropriate\n\nThe company estimated costs of roxadustat based on body weight, Hb levels, and 2 separate treatment phases (correction and maintenance) to account for dose changes made in clinical practice. Starting doses are based on weight, and dose changes are based on response to treatment and changes in Hb levels. The correction phase lasted up to 3\xa0months from starting treatment and corresponded with the first cycle of the model. The maintenance phase started immediately after the correction phase. The company initially estimated the average roxadustat dosage for each Hb level in the correction phase based on data including body weight from people in all roxadustat trials. However, after consultation, the company estimated roxadustat dosages for the correction phase only from the DOLOMITES trial data. For the maintenance phase, it extrapolated the average weekly dose using a generalised linear mixed model and controlled for history of cardiovascular disease and presence of type\xa02 diabetes at baseline. The company confirmed at the first committee meeting that it had not assumed treatment stops in the economic model, despite the DOLOMITES trial having a stopping rule for roxadustat for Hb levels above 130\xa0g/litre. Clinical experts indicated that the decision whether to stop treatment depends on how well anaemia is managed. They stated that they would titrate the dose of roxadustat down if Hb levels reached around 125\xa0g/litre so that Hb levels stay within a safe range (that is, between 100\xa0g/litre and 120\xa0g/litre) rather than stopping treatment (see section\xa03.8). After consultation, the company revised its base case to include a stopping rule for roxadustat at Hb levels over 130\xa0g/litre. It applied the stopping rule only to roxadustat treatment costs in this health state, because Hb levels over 130\xa0g/litre are not associated with a utility benefit in the model. However, the ERG was concerned that this adjustment implicitly assumed that the stopping rule affects only roxadustat costs and not its clinical effectiveness or other model parameters. The committee found the application of the stopping rule uncertain because roxadustat would not be completely stopped in clinical practice. Instead the dosage would be adjusted or temporarily withheld until Hb levels reach the target range according to the instructions in the summary of product characteristics for roxadustat and clinical expert feedback. However, the committee concluded that the estimated costs of roxadustat in the company's revised approach are appropriate because they are based only on the DOLOMITES trial data.\n\n## The overall costs of ESAs are uncertain, but the company's revised approach is appropriate\n\nThe prices of ESAs reflect confidential arrangements between companies and the NHS. The company estimated costs of ESAs using the same approach as for the costs of roxadustat (see section\xa03.13). It used only data from the DOLOMITES trial to determine the average weekly doses for the correction and maintenance phases. In line with clinical guidance and practice, the company assumed a class effect (see section\xa03.2) and included all 5 ESAs available in the UK in the model. To determine equivalent doses between ESAs, the company used darbepoetin alfa as a reference and applied a 'dose conversion' factor for each ESA based on their weekly dose from the BNF. The company took the list price of the different types of ESA from the BNF. It estimated the proportions of people with anaemia having each ESA from TUNE, an unpublished observational retrospective study of medical records in the UK population. However, the company acknowledged that there is uncertainty around the distribution of ESAs in clinical practice because there are no clear or reliable sources to inform this parameter. Clinical experts pointed out that some hospitals or NHS trusts purchase and prescribe only 1 type of ESA, rather than a basket of different types of ESAs as used in the company model. The company included drug administration costs for 20% of people who have ESAs. One clinical expert confirmed that people do incur costs associated with ESA administration and that the proportion of people estimated by the company is reasonable. After consultation, the company revised its modelling approach to include administration costs for people on peritoneal dialysis. However, it did not include a stopping rule for ESAs when Hb levels exceed those recommended by the regulators (120\xa0g/litre; MHRA recombinant human erythropoietins: new advice for prescribing). The company indicated that it considered the ESA dosing data from DOLOMITES to reflect clinical practice and any stopping rules. This is because the dosing of darbepoetin alfa was based on its summary of product characteristics, which already includes dose adjustments and temporary stops if Hb levels exceed 120\xa0g/litre. The committee agreed that the stopping rule for ESAs was already accounted for in the dosage data from DOLOMITES. It concluded that the company's revised approach was acceptable for decision making, but the overall costs of ESAs are uncertain.\n\n# Cost-effectiveness estimates\n\n## The company did not address all of the committee's preferred assumptions, but the likely impact on cost effectiveness is small\n\nThe committee discussed the company's base case, revised after consultation. It noted how the company attempted to address its preferences from its first meeting, namely:\n\nUsing only DOLOMITES trial data for clinical effectiveness estimates for roxadustat and ESAs (see section\xa03.6).\n\nClarifying that health-state transition probabilities are based on 36‑week data from DOLOMITES and also include some 104‑week follow-up data (see section\xa03.8).\n\nHealth-state utilities estimated using a multiplicative approach (see section 3.9).\n\nHealth states that reflect the harms and costs of having Hb levels over 120\xa0g/litre (see section 3.10).\n\nESA administration costs for people who start having peritoneal dialysis.\n\nRoxadustat costs that reflect the DOLOMITES trial (see section 3.13).\n\nA model that reflects the stopping rule in DOLOMITES and other regulatory recommendations for safety (see section\xa03.8 and section\xa03.13).The ERG acknowledged that the company's revised base case incorporates its and the committee's preferred assumptions. So it considered its preferred base case the same as the company's revised base case. The ERG's analysis also included the confidential NHS Commercial Medicines Unit price for each ESA. However, the ERG highlighted that the company's revised base case excluded some committee preferred assumptions such as:\n\nProviding full justification for using 8 health states or using fewer health states (see section\xa03.7).\n\nJustifying and providing full details of the regression model used to extrapolate beyond the trial period (see section\xa03.8).\n\nIncluding hospitalisation costs based on hospitalisation rates measured directly from the DOLOMITES trial (see section 3.11).\n\nIncluding additional adverse events that impact adherence to treatment and health-related quality of life (see section\xa03.12).The committee did not agree with the updated preferences for the harms and costs of Hb levels over 120\xa0g/litre in the company's revised base case (see section\xa03.10). It also considered that the exclusion of its preferred assumptions highlighted by the ERG increased the uncertainty of the cost-effectiveness estimate. However, it noted that the impact of including the harms and costs of Hb levels over 120\xa0g/litre and its remaining preferred assumptions in the revised base case was likely to be small. The committee was willing to accept this uncertainty specifically for this appraisal. But, it considered it good practice to adequately capture the harms and costs of Hb levels over 120\xa0g/litre, and to include or explore all its preferred assumptions in the base case for future hypoxia-inducible factor inhibitors similar to roxadustat. The committee concluded that the company had not addressed all its preferred assumptions adequately but considered the likely impact on cost effectiveness to be small.\n\n## The ICERs for roxadustat are within what NICE considers an acceptable use of NHS resources\n\nApplying confidential discounts for ESAs, and considering its preferences, the committee noted that the ERG's and company's incremental cost-effectiveness estimates (ICERs) were within what NICE considers an acceptable use of NHS resources. Because of the confidential discounts for ESAs, the ICERs or incremental costs cannot be reported here. The committee was satisfied that roxadustat is similarly effective to ESA and that overall, the costs are similar.\n\n# Innovation\n\n## Roxadustat has a novel mechanism of action, but has not shown superiority to ESAs, and all benefits are captured in the modelling\n\nThe committee noted that roxadustat is a first-in-class oral hypoxia-inducible factor prolyl hydroxylase inhibitor, which provides an additional treatment for anaemia associated with CKD. However, it was aware that roxadustat was shown only to be non-inferior to current treatment. The patient expert indicated that roxadustat's oral administration is a step-change compared with injectable ESAs, even though this might affect whether people will take roxadustat as intended. Having an oral alternative might reduce costs associated with ESA administration and reduce the need for cold-chain storage and special sharps disposals. Roxadustat might also simplify management of anaemia by reducing the need for iron transfusions. The committee recalled that the company already included fewer iron infusions and costs of ESA administration costs in its economic model (see section\xa03.13). So, the committee concluded that roxadustat did not meet NICE's criteria to be considered an innovative treatment.\n\n# Conclusion\n\n## Roxadustat is recommended as an option for treating symptomatic anaemia associated with chronic kidney disease\n\nThe committee was satisfied that roxadustat is similarly effective to ESAs and that overall, the costs are similar. So, it was able to recommend roxadustat as an option for treating symptomatic anaemia associated with chronic kidney disease."}	https://www.nice.org.uk/guidance/ta807	Evidence-based recommendations on roxadustat (Evrenzo) for treating symptomatic anaemia associated with chronic kidney disease in adults.
ba217d8e137205e3f29a3bf57eaeda467308fd3f	nice	Risankizumab for treating active psoriatic arthritis after inadequate response to DMARDs	Risankizumab for treating active psoriatic arthritis after inadequate response to DMARDs Evidence-based recommendations on risankizumab (Skyrizi) for treating active psoriatic arthritis in adults. # Recommendations Risankizumab, alone or with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults whose disease has not responded well enough to disease-modifying antirheumatic drugs (DMARDs) or who cannot tolerate them. It is recommended only if they have: peripheral arthritis with 3 or more tender joints and 3 or more swollen joints moderate to severe psoriasis (a body surface area of at least 3% affected by plaque psoriasis and a Psoriasis Area and Severity Index score greater than 10) had 2 conventional DMARDs and at least 1 biological DMARD.Risankizumab is recommended only if the company provides it according to the commercial arrangement. Assess the response to risankizumab from 16 weeks. Stop risankizumab if psoriatic arthritis has not responded adequately using the Psoriatic Arthritis Response Criteria (PsARC; an adequate response is an improvement in at least 2 of the 4 criteria, 1 of which must be joint tenderness or swelling score, with no worsening in any of the 4 criteria). If PsARC response does not support continuing treatment but there is a PASI 75 response, a dermatologist should decide whether continuing treatment is appropriate based on skin response. If risankizumab is one of a range of suitable treatments, including guselkumab, choose the least expensive (taking into account administration costs, dosage, price per dose and commercial arrangements). Take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the PsARC, and make any adjustments needed. Take into account how skin colour could affect the PASI score and make any adjustments needed. These recommendations are not intended to affect treatment with risankizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations People with psoriatic arthritis that is not controlled well enough with 2 conventional DMARDs are usually offered biological DMARDs. People whose disease has not responded to a biological DMARD and who also have moderate to severe psoriasis may be offered guselkumab, an IL‑23 modulator already recommended by NICE. Risankizumab is also an IL‑23 modulator. Clinical evidence shows that risankizumab is effective for active psoriatic arthritis compared with placebo. Risankizumab has not been compared directly with other biological DMARDs for psoriatic arthritis. But the results of an indirect comparison suggest that it is as effective as guselkumab, particularly for skin and joint symptoms, and likely has similar safety. Risankizumab has similar costs to guselkumab for people with moderate to severe psoriasis who have had 2 conventional DMARDs and at least 1 biological DMARD. So, risankizumab is recommended as an option for treating active psoriatic arthritis in this group.# Information about risankizumab # Marketing authorisation indication Risankizumab (Skyrizi, AbbVie) 'alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis in adults who have had an inadequate response or who have been intolerant to one or more disease-modifying antirheumatic drugs (DMARDs)'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for risankizumab. # Price The cost of a 150 mg pre-filled disposable injection of risankizumab is £3,326.09 (excluding VAT; BNF online, accessed May 2022). The company has a commercial arrangement. This makes risankizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Decision problem ## The company's decision problem is relevant to clinical practice Risankizumab is licensed for treating active psoriatic arthritis in adults who have had an inadequate response or who have been intolerant to 1 or more disease-modifying antirheumatic drugs (DMARDs). The company's decision problem was narrower than risankizumab's marketing authorisation. It positioned risankizumab for people who also have moderate to severe psoriasis and have previously had 2 conventional and at least 1 biological DMARD. The proposed population was consistent with NICE's technology appraisal guidance on guselkumab. Risankizumab and guselkumab are both IL‑23 modulators. The company presented a comparison with guselkumab, which the committee considered was consistent with the criteria for a cost-comparison appraisal (see section 3.6). The committee noted that NICE has recommended many treatments other than guselkumab for psoriatic arthritis. But, because guselkumab is the only treatment recommended for this specific subgroup it is an appropriate comparator for a cost-comparison appraisal. The committee concluded that the company's decision problem was relevant to clinical practice. # Clinical effectiveness ## Risankizumab is more effective than placebo Risankizumab has been studied in 3 randomised controlled trials including a total of 1,592 adults with active psoriatic arthritis. These trials compared risankizumab with placebo. The KEEPsAKE 2 trial (n=443) is the focus of the company's evidence submission because 46.5% of participants had previously had a biological DMARD. In the KEEPsAKE 2 trial, risankizumab showed statistically significant improvements in primary and secondary endpoints compared with placebo: a higher proportion had an American College of Rheumatology (ACR) 20 response at 16 weeks and 24 weeks, and a higher proportion had a Psoriasis Area and Severity Index (PASI) 90 response at 24 weeks. The committee concluded that risankizumab was more effective than placebo. ## The company's network meta-analyses are suitable for decision making The company did a series of network meta-analyses (NMAs) on PASI response rates, ACR response rates and safety outcomes. These compared risankizumab with guselkumab. The ERG was satisfied with the search strategy, the methodological quality of the included trials and the methodology used for the NMAs. The committee accepted the ERG's view, concluding that the NMAs provided by the company were suitable for decision making. ## Risankizumab provides similar ACR and PASI response rates to guselkumab The NMAs showed no significant differences between risankizumab and guselkumab for any of the ACR (20, 50, 70) and PASI (50, 75, 90, 100) outcomes. Also, there were no significant differences in adverse events rates. The ERG advised that the lack of significant differences does not imply clinical equivalence and that the wide confidence intervals around the point estimates suggest uncertainty. The committee noted this uncertainty. But, it agreed that their effectiveness is likely to be comparable. This is because the point estimates were close to 1 (or 0) for the main efficacy outcomes at 24 weeks and the drugs have the same mechanism of action. ## The trial results are generalisable to the population in the company's decision problem The ERG highlighted several limitations with the NMA. The company positioned risankizumab for also treating moderate to severe psoriasis in people who have had 2 conventional DMARDs and at least 1 biological DMARD. A pre-specified subgroup of the trial had all previously had a biological DMARD. However, in this subgroup only 51.0% had also had 2 conventional DMARDs. In addition, only a small proportion of the previous biological DMARD subgroup had moderate to severe psoriasis (the exact figures are considered confidential by the company and cannot be reported here). However, the committee recalled that when appraising guselkumab it had accepted the assumption that efficacy specific to people who had a biological DMARD was generalisable to that of people who also had 2 conventional DMARDS. Also, that modelling was appropriate regardless of disease severity. The committee agreed that the trial results were generalisable to the population in the company's decision problem. # Cost comparison ## It is appropriate to assess response to risankizumab at 16 weeks NICE's technology appraisal guidance on guselkumab recommends that response to treatment should be assessed from 16 weeks and stopped at 24 weeks if there is an inadequate Psoriatic Arthritis Response Criteria (PsARC) response. The summary of product characteristics for guselkumab specifies considering stopping treatment if no response is shown at 24 weeks. In its base case, the company modelled assessing PsARC response at 24 weeks for both treatments, aligned with the recommendation for guselkumab. However, the summary of product characteristics for risankizumab states that 'consideration should be given to discontinuing treatment in patients who have shown no response after 16 weeks of treatment'. The company also submitted a scenario modelling response assessment at 16 weeks. The committee recalled that there was strong clinical support in the appraisal of guselkumab for assessing response at 16 weeks. Also, that this is more aligned with clinical practice of using other biologic therapies for this condition. The committee considered it was appropriate to assess response to risankizumab at 16 weeks, in line with the summary of product characteristics. ## The total costs associated with risankizumab are similar to or lower than those associated with guselkumab The company presented a cost-comparison analysis that modelled the total costs of risankizumab and guselkumab over 5 years. The base case assumes that the only difference between the 2 treatment options arises from costs associated with drug acquisition. Additional scenario analyses explored the impact of variable drug administration and monitoring costs. It also assumed clinical equivalence between the 2 treatment options, based on evidence from the NMA outlined in section 3.3. The base case assumed treatment response was assessed at 24 weeks and applied a 16.5% annual probability of discontinuing treatment after initial assessment of response, for both risankizumab and guselkumab. This was in line with the modelling for the guselkumab appraisal for this indication. A scenario explored the impact of assessing response at 16 weeks. Taking into account the patient access scheme discounts, the total costs associated with risankizumab were similar to or lower than those associated with guselkumab. This was whether response was assessed at 16 weeks or 24 weeks (the exact results cannot be reported here because the discounts are confidential). ## Risankizumab is recommended as an option for treating active psoriatic arthritis The committee concluded that the criteria for a positive cost comparison were met because: risankizumab provided similar overall health benefits to guselkumab, and the total costs associated with risankizumab were similar or lower than the total costs associated with guselkumab.The committee therefore recommended risankizumab as an option for treating active psoriatic arthritis in adults. It concluded that the recommendations for risankizumab should be consistent with the company's proposal and NICE's technology appraisal guidance on guselkumab, that is, only if the person has: peripheral arthritis with 3 or more tender joints and 3 or more swollen joints moderate to severe psoriasis (a body surface area of at least 3% affected by plaque psoriasis and a PASI score greater than 10) had 2 conventional DMARDs and at least 1 biological DMARD.The response to risankizumab should be assessed from 16 weeks. If psoriatic arthritis has not responded adequately using the PsARC (an adequate response is an improvement in at least 2 of the 4 criteria, 1 of which must be joint tenderness or swelling score, with no worsening in any of the 4 criteria), risankizumab should be stopped. If PsARC response does not support continuing treatment but there is a PASI 75 response, a dermatologist should decide whether continuing treatment is appropriate based on skin response. ## Clinicians should take into account factors that may affect PsARC and PASI and make any clinical adjustments needed The committee noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the PsARC. It concluded that this should be taken into account when using the PsARC. The committee was also aware that the PASI might underestimate disease severity in people with darker skin. The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.	{'Recommendations': 'Risankizumab, alone or with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults whose disease has not responded well enough to disease-modifying antirheumatic drugs (DMARDs) or who cannot tolerate them. It is recommended only if they have:\n\nperipheral arthritis with 3 or more tender joints and 3 or more swollen joints\n\nmoderate to severe psoriasis (a body surface area of at least 3% affected by plaque psoriasis and a Psoriasis Area and Severity Index [PASI] score greater than 10)\n\nhad 2\xa0conventional DMARDs and at least 1\xa0biological DMARD.Risankizumab is recommended only if the company provides it according to the commercial arrangement.\n\nAssess the response to risankizumab from 16\xa0weeks. Stop risankizumab if psoriatic arthritis has not responded adequately using the Psoriatic Arthritis Response Criteria (PsARC; an adequate response is an improvement in at least 2 of the 4\xa0criteria, 1 of which must be joint tenderness or swelling score, with no worsening in any of the 4\xa0criteria). If PsARC response does not support continuing treatment but there is a PASI\xa075 response, a dermatologist should decide whether continuing treatment is appropriate based on skin response.\n\nIf risankizumab is one of a range of suitable treatments, including guselkumab, choose the least expensive (taking into account administration costs, dosage, price per dose and commercial arrangements).\n\nTake into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the PsARC, and make any adjustments needed.\n\nTake into account how skin colour could affect the PASI score and make any adjustments needed.\n\nThese recommendations are not intended to affect treatment with risankizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPeople with psoriatic arthritis that is not controlled well enough with 2\xa0conventional DMARDs are usually offered biological DMARDs. People whose disease has not responded to a biological DMARD and who also have moderate to severe psoriasis may be offered guselkumab, an IL‑23 modulator already recommended by NICE. Risankizumab is also an IL‑23 modulator.\n\nClinical evidence shows that risankizumab is effective for active psoriatic arthritis compared with placebo. Risankizumab has not been compared directly with other biological DMARDs for psoriatic arthritis. But the results of an indirect comparison suggest that it is as effective as guselkumab, particularly for skin and joint symptoms, and likely has similar safety.\n\nRisankizumab has similar costs to guselkumab for people with moderate to severe psoriasis who have had 2\xa0conventional DMARDs and at least 1\xa0biological DMARD. So, risankizumab is recommended as an option for treating active psoriatic arthritis in this group.', 'Information about risankizumab': "# Marketing authorisation indication\n\nRisankizumab (Skyrizi, AbbVie) 'alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis in adults who have had an inadequate response or who have been intolerant to one or more disease-modifying antirheumatic drugs (DMARDs)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for risankizumab.\n\n# Price\n\nThe cost of a 150\xa0mg pre-filled disposable injection of risankizumab is £3,326.09 (excluding VAT; BNF online, accessed May 2022). The company has a commercial arrangement. This makes risankizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Decision problem\n\n## The company's decision problem is relevant to clinical practice\n\nRisankizumab is licensed for treating active psoriatic arthritis in adults who have had an inadequate response or who have been intolerant to 1 or more disease-modifying antirheumatic drugs (DMARDs). The company's decision problem was narrower than risankizumab's marketing authorisation. It positioned risankizumab for people who also have moderate to severe psoriasis and have previously had 2\xa0conventional and at least 1\xa0biological DMARD. The proposed population was consistent with NICE's technology appraisal guidance on guselkumab. Risankizumab and guselkumab are both IL‑23 modulators. The company presented a comparison with guselkumab, which the committee considered was consistent with the criteria for a cost-comparison appraisal (see section\xa03.6). The committee noted that NICE has recommended many treatments other than guselkumab for psoriatic arthritis. But, because guselkumab is the only treatment recommended for this specific subgroup it is an appropriate comparator for a cost-comparison appraisal. The committee concluded that the company's decision problem was relevant to clinical practice.\n\n# Clinical effectiveness\n\n## Risankizumab is more effective than placebo\n\nRisankizumab has been studied in 3\xa0randomised controlled trials including a total of 1,592 adults with active psoriatic arthritis. These trials compared risankizumab with placebo. The KEEPsAKE\xa02 trial (n=443) is the focus of the company's evidence submission because 46.5% of participants had previously had a biological DMARD. In the KEEPsAKE\xa02 trial, risankizumab showed statistically significant improvements in primary and secondary endpoints compared with placebo: a higher proportion had an American College of Rheumatology (ACR)\xa020 response at 16\xa0weeks and 24\xa0weeks, and a higher proportion had a Psoriasis Area and Severity Index (PASI)\xa090 response at 24\xa0weeks. The committee concluded that risankizumab was more effective than placebo.\n\n## The company's network meta-analyses are suitable for decision making\n\nThe company did a series of network meta-analyses (NMAs) on PASI response rates, ACR response rates and safety outcomes. These compared risankizumab with guselkumab. The ERG was satisfied with the search strategy, the methodological quality of the included trials and the methodology used for the NMAs. The committee accepted the ERG's view, concluding that the NMAs provided by the company were suitable for decision making.\n\n## Risankizumab provides similar ACR and PASI response rates to guselkumab\n\nThe NMAs showed no significant differences between risankizumab and guselkumab for any of the ACR (20, 50, 70) and PASI (50, 75, 90, 100) outcomes. Also, there were no significant differences in adverse events rates. The ERG advised that the lack of significant differences does not imply clinical equivalence and that the wide confidence intervals around the point estimates suggest uncertainty. The committee noted this uncertainty. But, it agreed that their effectiveness is likely to be comparable. This is because the point estimates were close to 1 (or 0) for the main efficacy outcomes at 24\xa0weeks and the drugs have the same mechanism of action.\n\n## The trial results are generalisable to the population in the company's decision problem\n\nThe ERG highlighted several limitations with the NMA. The company positioned risankizumab for also treating moderate to severe psoriasis in people who have had 2 conventional DMARDs and at least 1 biological DMARD. A pre-specified subgroup of the trial had all previously had a biological DMARD. However, in this subgroup only 51.0% had also had 2\xa0conventional DMARDs. In addition, only a small proportion of the previous biological DMARD subgroup had moderate to severe psoriasis (the exact figures are considered confidential by the company and cannot be reported here). However, the committee recalled that when appraising guselkumab it had accepted the assumption that efficacy specific to people who had a biological DMARD was generalisable to that of people who also had 2\xa0conventional DMARDS. Also, that modelling was appropriate regardless of disease severity. The committee agreed that the trial results were generalisable to the population in the company's decision problem.\n\n# Cost comparison\n\n## It is appropriate to assess response to risankizumab at 16 weeks\n\nNICE's technology appraisal guidance on guselkumab recommends that response to treatment should be assessed from 16\xa0weeks and stopped at 24\xa0weeks if there is an inadequate Psoriatic Arthritis Response Criteria (PsARC) response. The summary of product characteristics for guselkumab specifies considering stopping treatment if no response is shown at 24\xa0weeks. In its base case, the company modelled assessing PsARC response at 24\xa0weeks for both treatments, aligned with the recommendation for guselkumab. However, the summary of product characteristics for risankizumab states that 'consideration should be given to discontinuing treatment in patients who have shown no response after 16\xa0weeks of treatment'. The company also submitted a scenario modelling response assessment at 16\xa0weeks. The committee recalled that there was strong clinical support in the appraisal of guselkumab for assessing response at 16\xa0weeks. Also, that this is more aligned with clinical practice of using other biologic therapies for this condition. The committee considered it was appropriate to assess response to risankizumab at 16\xa0weeks, in line with the summary of product characteristics.\n\n## The total costs associated with risankizumab are similar to or lower than those associated with guselkumab\n\nThe company presented a cost-comparison analysis that modelled the total costs of risankizumab and guselkumab over 5\xa0years. The base case assumes that the only difference between the 2\xa0treatment options arises from costs associated with drug acquisition. Additional scenario analyses explored the impact of variable drug administration and monitoring costs. It also assumed clinical equivalence between the 2\xa0treatment options, based on evidence from the NMA outlined in section\xa03.3. The base case assumed treatment response was assessed at 24\xa0weeks and applied a 16.5% annual probability of discontinuing treatment after initial assessment of response, for both risankizumab and guselkumab. This was in line with the modelling for the guselkumab appraisal for this indication. A scenario explored the impact of assessing response at 16\xa0weeks. Taking into account the patient access scheme discounts, the total costs associated with risankizumab were similar to or lower than those associated with guselkumab. This was whether response was assessed at 16\xa0weeks or 24\xa0weeks (the exact results cannot be reported here because the discounts are confidential).\n\n## Risankizumab is recommended as an option for treating active psoriatic arthritis\n\nThe committee concluded that the criteria for a positive cost comparison were met because:\n\nrisankizumab provided similar overall health benefits to guselkumab, and\n\nthe total costs associated with risankizumab were similar or lower than the total costs associated with guselkumab.The committee therefore recommended risankizumab as an option for treating active psoriatic arthritis in adults. It concluded that the recommendations for risankizumab should be consistent with the company's proposal and NICE's technology appraisal guidance on guselkumab, that is, only if the person has:\n\nperipheral arthritis with 3 or more tender joints and 3 or more swollen joints\n\nmoderate to severe psoriasis (a body surface area of at least 3% affected by plaque psoriasis and a PASI score greater than 10)\n\nhad 2\xa0conventional DMARDs and at least 1\xa0biological DMARD.The response to risankizumab should be assessed from 16\xa0weeks. If psoriatic arthritis has not responded adequately using the PsARC (an adequate response is an improvement in at least 2 of the 4 criteria, 1 of which must be joint tenderness or swelling score, with no worsening in any of the 4\xa0criteria), risankizumab should be stopped. If PsARC response does not support continuing treatment but there is a PASI\xa075 response, a dermatologist should decide whether continuing treatment is appropriate based on skin response.\n\n## Clinicians should take into account factors that may affect PsARC and PASI and make any clinical adjustments needed\n\nThe committee noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the PsARC. It concluded that this should be taken into account when using the PsARC. The committee was also aware that the PASI might underestimate disease severity in people with darker skin. The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate."}	https://www.nice.org.uk/guidance/ta803	Evidence-based recommendations on risankizumab (Skyrizi) for treating active psoriatic arthritis in adults.
4de2f36b47574b4ca90111bd7ff68b01f7aabe02	nice	Fenfluramine for treating seizures associated with Dravet syndrome	Fenfluramine for treating seizures associated with Dravet syndrome Evidence-based recommendations on fenfluramine (Fintepla) for treating seizures associated with Dravet syndrome in people aged 2 and older. # Recommendations Fenfluramine is recommended as an add‑on to other antiseizure medicines for treating seizures associated with Dravet syndrome in people aged 2 years and older, only if: seizures have not been controlled after trying 2 or more antiseizure medicines the frequency of convulsive seizures is checked every 6 months, and fenfluramine is stopped if it has not fallen by at least 30% compared with the 6 months before starting treatment the company provides fenfluramine according to the commercial arrangement. This recommendation is not intended to affect treatment with fenfluramine that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For children and young people, this decision should be made jointly by the clinician and the child or young person, or their parents or carers. Why the committee made these recommendations Treatment for Dravet syndrome often starts with a single antiseizure drug such as sodium valproate. Other treatments can then be added if seizures are not well controlled. In practice, standard care often involves a combination of 3 antiseizure medicines. Clinicians may offer add-on therapies such as cannabidiol with clobazam, or fenfluramine. Clinical trial evidence shows that fenfluramine, when added to standard care medicines, reduces the number of convulsive seizures people have. And it may be more effective than cannabidiol plus clobazam in reducing the number of seizures when used with 2 other antiseizure medicines. There is some evidence that adding fenfluramine improves quality of life for people with Dravet syndrome and their carers compared with standard care medicines alone. The cost-effectiveness estimates are within the range NICE considers an acceptable use of NHS resources. There is evidence that there are also likely to be benefits from fenfluramine beyond what was in the economic model. These include reducing how long seizures last for, fewer non-convulsive seizures, and quality of life benefits. So fenfluramine is recommended.# Information about fenfluramine # Marketing authorisation indication Fenfluramine (Fintepla, Zogenix) is licensed for 'the treatment of seizures associated with Dravet syndrome as an add-on therapy to other anti-seizure medicines for patients 2 years of age and older'. # Dosage in the marketing authorisation Fenfluramine is taken orally. It can be used with or without stiripentol. Because of how fenfluramine is metabolised, the recommended maintenance dose after titration is 0.7 mg/kg/day (maximum 26 mg/day) for people not taking stiripentol, and 0.4 mg/kg/day for people taking stiripentol (maximum 17 mg/day). See details of the dosage schedule in the summary of product characteristics for fenfluramine. # Price The list price of fenfluramine is £901.44 per 60 ml bottle, £1,802.88 per 120 ml bottle and £5,408.65 per 360 ml bottle (BNF online accessed February 2022). The company has a commercial arrangement. This makes fenfluramine available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Zogenix, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Disease background ## Dravet syndrome severely affects a person's quality of life, and that of their family and carers Dravet syndrome is a severe, lifelong and genetic form of epilepsy. It usually presents in the first year of life with recurrent, prolonged convulsive seizures. As well as severe seizures, children have developmental delays and learning disabilities. Comorbidities are common and include autism, attention deficit hyperactivity disorder (ADHD), and difficulties with speech, mobility, eating, behaviour and sleep. A carer expert explained that the high seizure burden and comorbidities have a serious effect on families. They noted that looking after a child with Dravet syndrome is life-changing: 'you can never rest' and are 'on high alert at all times as a carer'. People with the disease often need round-the-clock care and help with almost all aspects of daily life. Families and carers may find looking after people with Dravet syndrome demanding, preventing them from leading normal lives. The anxiety that a child with Dravet syndrome may have status epilepticus and the risk of sudden unexpected death in epilepsy (SUDEP) substantially affects the mental wellbeing of all family members. There is also a high unmet need because the condition is resistant to standard care treatments in 90% of people with Dravet syndrome. The committee concluded that Dravet syndrome severely affects the person's quality of life and that of their family and carers. # Managing Dravet syndrome in the NHS and positioning fenfluramine in the treatment pathway ## Standard care for Dravet syndrome includes a first-line antiseizure drug then first and second add-on therapies NICE's guideline on epilepsies in children, young people and adults recommends the antiseizure drug sodium valproate as the first-line treatment option for Dravet syndrome. A clinical expert noted that first-line sodium valproate is standard care and that topiramate, which was included in the 2012 NICE guideline on epilepsy, is now less used first line. If sodium valproate is not effective or tolerated, clobazam or stiripentol can be added. NICE's technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Dravet syndrome recommends cannabidiol plus clobazam in people aged 2 and older. The committee noted that cannabidiol plus clobazam is an option as a second add‑on, but it does not work for everyone and the combination is not always tolerated. However, it understood that NICE's guidance on cannabidiol concluded that the positioning of cannabidiol plus clobazam after 2 treatments in the treatment pathway was appropriate. ## Stiripentol can be used as a first or second add-on treatment The clinical experts noted that Dravet syndrome is one of the epilepsy syndromes most resistant to antiseizure drugs. People with the condition often need add‑on treatments. A combination of 3 drugs often provides the best seizure control, most commonly sodium valproate, stiripentol and clobazam. The clinical experts noted that stiripentol is an important part of standard care and is usually used at the early stage of disease, particularly for children. They also explained that, although stiripentol is licensed to be used with clobazam, in practice stiripentol is usually used in children newly diagnosed with Dravet syndrome and added to sodium valproate as the first add‑on therapy. This is because the combination of sodium valproate and clobazam (another option for first add‑on, see section 3.2) often causes drowsiness. Clobazam may or may not then be added as a second add‑on after stiripentol. Alternatively, stiripentol may be used as a second add‑on if clobazam is the first add‑on to sodium valproate. The committee concluded that stiripentol is part of standard care and could be used either as a first or second add‑on therapy to other standard antiseizure drugs for treating seizures in Dravet syndrome. ## The treatment sequence for add-on therapies after first-line antiseizure drugs is individualised to the person The clinical experts noted that often the new add‑on treatment will not immediately replace the previous treatment. The goal is to control seizures with as few medications as possible. Rather, the new treatment is added sequentially to assess its impact, usually over about 3 months to allow sufficient titration and monitoring. When adding cannabidiol, which requires treatment with clobazam, clinicians do not add both drugs at the same time, because it is difficult to identify which drug was associated with adverse effects (or benefits). An existing treatment may be tapered down slowly before removing it if the condition responds to a newly added treatment. The choice of what treatment to add or remove is individualised to the person. The carer expert explained that they would not continue a treatment if it does not work because of the burden of taking medicines and potential adverse effects. The committee concluded that the sequence of adding treatments to antiseizure drugs is individualised in clinical practice. ## The company's positioning of fenfluramine as a second add-on treatment is appropriate The clinical experts noted that, while fenfluramine can be offered as an add‑on drug at any point in the pathway according to its licence and with or without clobazam, it would be offered in NHS clinical practice after stiripentol, clobazam, or both, as a second add‑on treatment. They also noted that both stiripentol and clobazam might be stopped if fenfluramine is added and effective. The committee agreed that the company's positioning of fenfluramine as a second add‑on treatment in the treatment pathway is appropriate. ## Comparators at the second add-on position in the treatment pathway include cannabidiol plus clobazam and other standard care drugs The company focused its submission on the comparison between fenfluramine and cannabidiol plus clobazam as a second add‑on treatment. It explained that this was because cannabidiol plus clobazam is the only therapy with enough data, and is currently accepted as clinically and cost effective. The clinical experts explained that, as a second add‑on, cannabidiol plus clobazam is a relevant comparator to fenfluramine. The committee agreed but noted that there are other options for a second add‑on treatment in the pathway (see section 3.3 and section 3.4). For people who cannot tolerate cannabidiol plus clobazam, drugs comprising standard care are the appropriate comparator, which might include stiripentol. The committee concluded that the company's positioning of fenfluramine as a second add‑on compared with cannabidiol plus clobazam is appropriate. However, the continued use of other drugs that comprise standard care is also a relevant comparator for people who cannot take cannabidiol or clobazam. # Clinical effectiveness evidence ## Fenfluramine is an effective treatment for Dravet syndrome in the short term compared with placebo The company submitted evidence from 2 phase 3, double-blind, placebo-controlled randomised controlled trials, Study 1 and Study 1504. In these studies fenfluramine as an add‑on to standard care drugs was compared with placebo in children and young people with Dravet syndrome aged between 2 and 18 years. Study 1 (n=119) excluded patients taking stiripentol and assessed the efficacy of fenfluramine at 2 dosages: 0.2 mg/kg/day (this dosage is not licensed and was assessed in the trial for dose–response relationship) and 0.7 mg/kg/day. Study 1504 (n=87) needed patients to be taking stiripentol and assessed the efficacy of fenfluramine 0.4 mg/kg/day. Study 1 and Study 1504 had follow-up periods of 14 weeks and 15 weeks, respectively. The primary end point of both trials was percentage change in convulsive seizure frequency per 28 days during the treatment period compared with baseline. Evidence showed that, among patients not taking stiripentol in Study 1, fenfluramine 0.7 mg/kg/day and 0.2 mg/kg/day were associated with a 62.3% (95% confidence interval ‑48 to ‑73%, p<0.001), and 32.4% (95% CI: ‑6 to ‑51%, p=0.02) greater reduction than placebo, respectively. For patients taking stiripentol (Study 1504), fenfluramine 0.4 mg/kg/day was associated with a 54% (95% CI: ‑67 to ‑36%, p<0.001) greater reduction than placebo. Both trials reported on change in mean convulsive seizure-free days per 28 days from baseline as a secondary end point. Results suggested that fenfluramine is associated with a greater increase in convulsive seizure-free days than placebo across all dosages (this data is confidential and cannot be reported here). Both trials assessed quality of life in patients using the Pediatric Quality of Life Inventory (PedsQL) and reported on changes from baseline in PedsQL scores associated with different dosages. Study 1 (in people not taking stiripentol) showed that, at 14‑week follow up, both fenfluramine 0.7 mg/kg/day and 0.2 mg/kg/day were associated with a greater improvement from baseline in PedsQL than placebo. Mean scores were (standard deviation): 5.9 (15.1), p=0.02 and 6.8 (11.2), p=0.003 for fenfluramine 0.7 mg/kg/day and 0.2 mg/kg/day, respectively; and -1.6 (10.4) for placebo. However, results of Study 1504 (in people taking stiripentol) showed that, at 15‑week follow up, changes from baseline in mean total PedsQL score were not statistically different (alpha level = 0.05 ) between fenfluramine 0.4 mg/kg/day and placebo (mean : -0.9 compared with -0.3 , p=0.0618). Results for carers' quality of life appeared to be in the same direction of treatment effect (this data is confidential and cannot be reported here). The committee concluded that fenfluramine is more effective than placebo in reducing convulsive seizure frequencies in people with Dravet syndrome in the short term. ## Fenfluramine may be more effective than cannabidiol plus clobazam in reducing convulsive seizure frequencies No trials directly compared fenfluramine with cannabidiol plus clobazam. So the company did a network meta-analysis to assess the effectiveness of different dosages of fenfluramine (Study 1: 0.2 mg/kg/day and 0.7 mg/kg/day; Study 1504: 0.4 mg/kg/day) and cannabidiol plus clobazam (10 mg/kg/day and 20 mg/kg/day plus clobazam) relative to placebo. The network meta-analysis was done for both the primary and secondary outcomes of Study 1 and Study 1504. The ERG noted there were differences in the use of standard care drugs including clobazam across trials. The network meta-analysis assessed percentage change from baseline in convulsive seizure frequency in 28 days compared with placebo, which was the primary end point of Study 1 and Study 1504 and informed the economic model. The ERG noted that, while the results showed that all doses of fenfluramine and cannabidiol plus clobazam were more effective than placebo in reducing convulsive seizure frequency per 28 days, there was no difference between fenfluramine and cannabidiol plus clobazam in this analysis. During the first meeting, the committee noted that this analysis did not show a difference between fenfluramine and cannabidiol plus clobazam. It also noted that it would prefer to see the absolute changes from baseline associated with different dosages of fenfluramine and cannabidiol plus clobazam. During the consultation, the company explained that data for absolute changes from baseline for cannabidiol plus clobazam is not publicly available, so it was not able to do this analysis. The company instead presented an indirect treatment comparison between fenfluramine, cannabidiol, and placebo on the outcome of percentage change from baseline in convulsive seizure frequency over 28 days using the Bucher method. This additional analysis included data publicly available from 4 trials of cannabidiol plus clobazam (results of the analysis are confidential and cannot be reported here). The committee noted that the comparisons between fenfluramine and different dosages of cannabidiol plus clobazam were mixed but largely favoured fenfluramine. Carer and clinical experts explained during the second meeting that Dravet syndrome is a heterogeneous condition, reflected in the range of seizure frequency and intensity. They said that the differences in results reflected the natural variation in the condition and are expected. The committee noted that the mixed results may be partly because of the small sample sizes in the trials as well as heterogeneity. It questioned why the company did not pool the 2 cannabidiol plus clobazam trials with the same dosing in this additional analysis on the primary end point. The company explained that it was because the committee had requested analysis of the absolute change in convulsive seizure frequency for cannabidiol plus clobazam from baseline compared with fenfluramine during its first meeting, given the uncertainties in the network meta-analysis of the primary end point. However, the company had no access to such data for cannabidiol plus clobazam. So the company did not combine the cannabidiol plus clobazam trials with the same or different dosages, so that the differences in treatment effect on the primary end point between specific dosages of fenfluramine and specific dosages of cannabidiol plus clobazam can be seen. The company also explained that the 2 cannabidiol plus clobazam trials with the maximum recommended dosing for cannabidiol plus clobazam (20 mg/kg/day) reported different treatment effects for the primary end point. The ERG noted that the heterogeneity across trials may be another reason not to pool trials for analysis. The committee acknowledged that, overall, the evidence suggested superiority of fenfluramine compared with cannabidiol plus clobazam but noted that there was high uncertainty given the heterogeneity across trials. # Stopping treatment ## The stopping rule of 30% seizure reduction at 6 months is the most clinically appropriate response criteria The marketing authorisation for fenfluramine does not specify a stopping rule. At the first committee meeting, the company proposed that fenfluramine should be stopped after 6 months if the frequency of convulsive seizures had not reduced by at least 30% from baseline. This is in line with the first assessment time set out in the stopping rule in NICE's technology appraisal guidance on cannabidiol with clobazam. The clinical experts said that because seizures can cluster in people with Dravet syndrome, at least 6 months would be needed to assess response to treatment. People with Dravet syndrome are seen every 6 months in clinical practice. In the first meeting, the committee concluded that stopping rules at 6 months and every 6 months thereafter was appropriate. During the second meeting, the committee questioned whether this stopping rule would fully capture any waning of the treatment effect, for example, if there is a slight deterioration in treatment effect but still some benefit in seizure control compared with baseline. The clinical experts explained that, if some deterioration in response is seen in practice, treatment is not immediately stopped. They said that clinicians would usually consider all the medicines someone is taking and taper one off when another is added. The clinical experts also explained that clinicians would continue if fenfluramine seizure frequency reduced by 30% compared with baseline. A 30% reduction is the minimum to continue although a 50% reduction would be a clearer indicator of benefit. The patient and carer experts noted that parents would not keep their child on treatment if it is not working. They added that duration and severity of seizures is also important and could be reduced by treatment, which could have a large benefit for patients and carers. The committee discussed stopping fenfluramine in relation to waning of treatment effect in the model. The company did not assume waning of treatment effect in its model. It explained that no waning of treatment effect was assumed beyond the first 6 months. The company presented results from Study 1503 (n=330) to support the long-term treatment effect of fenfluramine, which had data from up to 3 years. Study 1503 included people who satisfactorily completed Study 1 and Study 1504, with a mean daily dosage between 0.3 mg/kg/day and 0.7 mg/kg/day for 70% of people (Study 1503 Fintepla.eu). Results indicated that the treatment effect on percentage change in convulsive seizure frequency per 28 days relative to baseline was largely maintained at 3-year follow up. The clinical expert noted that the inclusion criteria reflected clinical practice. They also noted that they did not see waning of treatment effect in practice and, if there is any, waning of treatment effect would appear in the first year of treatment. The committee appreciated that only people for whom fenfluramine was working would continue having it in practice. The company explained that the model also implemented ongoing treatment discontinuation probabilities as seen in Study 1503. Discontinuations seen in Study 1503 included stopping for all reasons, including loss of efficacy, as well as adverse events over the lifetime in the model. Evidence from Study 1503 indicated a 0.7% discontinuation probability for fenfluramine and a similar probability of 0.8% for cannabidiol plus clobazam per 28‑day cycle. The committee concluded that it was appropriate for waning to be excluded from the model. The committee appreciated that a stopping rule based on a less than 30% reduction in seizure frequency at 6 months might be applied in the model. However, it felt that this may not reflect all stopping caused by lack of efficacy because it knew that discontinuations were ongoing in Study 1503, including discontinuations caused by lack of efficacy in the longer-term follow up. The committee considered that there was some uncertainty in the company's stopping rule at 6 months, which assumed that a 30% reduction in seizure frequency at this timepoint already accounted for all loss of treatment effect in the model and was the most clinically appropriate threshold. The company presented a revised model which considered an alternative scenario using a stopping rule of a 50% reduction in seizures at 6 months. The clinical experts explained that a 30% reduction in seizures at 6 months is the minimum they would expect from a new treatment, but that it was unclear whether a 50% stopping rule at 6 months was a better threshold. They said that a 50% reduction in seizure frequency would not be a sensitive enough response criterion to take into account the potential benefit of reducing extremely severe seizures. And they said that a more moderate reduction in seizures (that is, between 30% and 50%) could still mean a valuable reduction in both severity of seizures and hospitalisations in people with Dravet syndrome. A 30% stopping rule would also align with the current stopping criteria for cannabidiol. The committee concluded that the stopping rule of at least 30% reduction in seizure frequency at 6 months was the most appropriate. # Modelling approach ## The company's modelling structure is appropriate for decision making and overall the results are valid The company presented a revised individual-patient state-transition model to estimate the cost effectiveness of fenfluramine during the consultation after discussions with the ERG and NICE. The model consisted of 3 health states: alive, on treatment; alive, treatment discontinued; and dead. Patient profiles including age, body weight, number of convulsive seizures per cycle, number of convulsive-free days per cycle, concomitant medication (receiving stiripentol or not), and mortality risk were then assigned to individual patients. The model was run twice, once using baseline characteristic data from Study 1 without stiripentol and another using data from Study 1504 with stiripentol. The results were then combined and weighted based on an estimate of 58% of the population having stiripentol and 42% not having stiripentol, as informed by the European DISCUSS survey with UK data on carers of people with Dravet syndrome. The clinical experts noted that 58% of the population having stiripentol was largely in line with clinical practice in the NHS. For the merged population, the company's model focused on the comparison against cannabidiol plus clobazam as the second add‑on therapies in the treatment pathway. The ERG noted that several validity issues raised at the first committee meeting were resolved during consultation, and that overall the model results were valid. However, it noted that, because of the design of the model, the company provided separate model files for scenario analyses and validating them would take longer than usual. For the same reasons, the ERG was not able run its preferred analyses. The ERG had noted an error in the updated base case of the company's model related to discontinuation probabilities. The company corrected its base case so that the discontinuation probabilities in the model for the trial titration and maintenance phases were the same as those in the company's submission, and equal for both treatments. The committee concluded that the company's model structure was appropriate for decision making, and overall the results were valid. ## The merged population is appropriate for decision making During the first meeting, the committee noted that the cost-effectiveness estimates were substantially higher when stiripentol was used than when it was not, and asked for the reasons to be explored. During consultation, the company provided disaggregated results for the merged population: for the Study 1 population without stiripentol, and for the Study 1504 population with stiripentol. It explained that in Study 1 no one was taking stiripentol. So when people stopped fenfluramine or cannabidiol plus clobazam they reverted to standard care that was cheaper than standard care in Study 1504, which included stiripentol, which is an expensive drug. Consequently, the ongoing costs in Study 1 were much lower than in Study 1504. The committee also noted that fenfluramine 0.4 mg/kg/day with stiripentol in Study 1504 resulted in a smaller incremental cost than fenfluramine 0.7 mg/kg/day without stiripentol in Study 1. Taking account of the quality-adjusted life year (QALY) differences between the 2 studies, the company explained that the net effect of stiripentol was to reduce the incremental cost-effectiveness ratio (ICER) in Study 1504 compared with Study 1. The ERG agreed with the company's explanation during the second meeting. The committee noted the difference in cost-effectiveness estimates when stiripentol is used compared with when it is not used in the company's base case. It recalled that stiripentol is not a treatment modifier for fenfluramine. The committee considered that grouping the population based on stiripentol use may be artificial and not feasible for clinical practice. This was because the treatment sequence for add‑on therapies to control seizure frequencies is individualised to the patient (see section 3.4), and because stiripentol is used as either a first or second add‑on treatment in the usual combination of 3 drugs to control seizure frequencies (see section 3.3). The committee was also aware that this grouping was not supported by the clinical evidence available. Taking into account the unmet need (see section 3.1), the complexities of the condition, and the individualised and unique treatment sequencing of adding treatments to first‑line antiseizure drugs across patients, the committee concluded that the merged population is appropriate for decision making. ## Basing the model on convulsive seizure-free days may be reasonable but there are uncertainties in the relationship between convulsive seizure frequency and seizure days The company's network meta-analysis assessed the change (mean percentage reduction) in the frequency of convulsive seizures per 28 days from baseline compared with placebo for the fenfluramine and cannabidiol plus clobazam arms. The company reported that there was no information on the number of days people had convulsive seizures from the cannabidiol trials. It therefore assumed that the change (the mean percentage reduction) in the frequency of convulsive seizures per 28 days from baseline compared with placebo, as informed by the network meta-analysis, was the same as the change in days people had convulsive seizures per 28 days from baseline compared with placebo. The company then calculated seizure-free days by subtracting the seizure days from 28 days per cycle. The ERG noted that, although there is a relationship between having fewer convulsive seizures and having fewer days with convulsive seizures in the 28‑day cycle, the relationship was unlikely to be linear. During the first meeting, the committee noted that there were uncertainties in both the company's and ERG's approaches in deriving the relationship between the reduction in convulsive seizure frequencies and reduction in days having convulsive seizures. The committee concluded that basing the model on convulsive seizure frequency instead of convulsive seizure‑free days would avoid the problem of determining the most appropriate relationship between them and the uncertainties. During consultation, the company explained that it modelled seizure-free days to adequately capture the impact of Dravet syndrome and therapies on patients and carers. The carer expert noted that both convulsive seizure frequency and seizure-free days are important. The carer expert explained that seizure freedom is relevant because with even just one night with no seizures, for example, the patient and their carers do not wake up exhausted. They have not needed to wake up to time a seizure and decide whether to administer rescue medication or call an ambulance during the night. In response to the consultation, the company did a regression analysis to estimate the proportionality between the percentage change in convulsive seizure frequency and the percentage change in convulsive seizure days. This analysis was of patient-level and combined data from all arms of Study 1 and Study 1504. The result indicated that the relationship was not 1:1 but close to linear (the data is confidential and cannot be reported here). The company used this assumption for both the fenfluramine and cannabidiol arms in the updated model. The committee appreciated that having fewer convulsive seizures and fewer days with convulsive seizures are both important for patient and carers, but that fewer days with convulsive seizures may be more meaningful for them. The committee concluded that basing the model on convulsive seizure-free days was reasonable but noted that this was an uncertainty in the model. ## The strength of the relationship between convulsive seizure frequency and mortality is not clear The company assumed in its base case that mortality is linked to the frequency of convulsive seizures. Total mortality in the model included background and seizure-related mortality: SUDEP, status epilepticus deaths and accidental deaths. The clinical expert noted that the association between convulsive seizure frequency and status epilepticus-related and accidental deaths is seen regardless of seizure cause. However, the clinical expert noted that the exact cause of SUDEP is unknown. The ongoing convulsive seizure frequency is a risk factor for SUDEP in Dravet syndrome although the relationship between reduction in convulsive seizure frequency and reduction in mortality is uncertain. There is little data on the association between convulsive seizure frequency and risk of SUDEP in Dravet syndrome. The company used Cooper et al. (2016), which is a retrospective uncontrolled cohort study including 100 children and young people with Dravet syndrome. Cooper et al. reports the incidence of Dravet-specific SUDEP and total mortality over a median follow up of 10 years. Because Cooper et al. did not report on the relationship between convulsive seizure frequency and SUDEP, the company took the risk estimates for SUDEP by seizure frequency from a case–control study of adults with general epilepsy (Nilsson et al. 1999). Because the SUDEP rate in Dravet syndrome reported by Cooper et al. was much higher than that in general epilepsy, the company calibrated the SUDEP rate reported by Nilsson et al. to the expected SUDEP rate from Cooper et al. using a multiplier of 8.38. During the first meeting, the ERG considered that strong assumptions were needed to link convulsive seizure frequency with SUDEP in Dravet syndrome. It was also concerned about the implausible estimates resulting from extrapolating. Given that there was no evidence of fenfluramine extending life, the ERG preferred to remove the link between seizure frequency and mortality, that is, to not assume in the model that treatment with fenfluramine prolongs life. People with Dravet syndrome have many comorbidities, which may also confound the association between frequency of seizures and death. The committee acknowledged that there may be an association between convulsive seizures and SUDEP. It also understood that the increased risk of death would not be necessarily reversed by treatment. So the committee concluded during the first meeting that it would prefer to see scenario analyses testing different strengths of relationship between convulsive seizure frequency and SUDEP, including analyses in which fenfluramine did not prolong life. During consultation, the company said that its survival curve based on Cooper et al. (SUDEP and status epilepticus-related mortality) and other published literature and expert opinion (accident-related mortality) was in line with the mortality expected in Dravet syndrome in the UK, and that this was confirmed by UK clinicians. The company also provided scenario analyses exploring the relationship between convulsive seizure frequency and SUDEP, but not for removing the link entirely from the model. The company argued that it would be unreasonable to remove the possibility of a mortality benefit from the model because of the lack of evidence from clinical trials. This is because Dravet syndrome is a rare condition and it is not possible for clinical trials to be powered enough to detect the difference in the risk of mortality between interventions. It also argued that modelling the relationship between convulsive seizure frequency and mortality was in line with clinical expectations. The 2 alternative scenarios the company provided assumed: the same mortality in Dravet syndrome as in the general epilepsy population mortality in Dravet syndrome to be calibrated midway between the company's base-case estimate in Dravet syndrome (Cooper et al. 2016) and general epilepsy mortality (Nilsson et al. 1999). The company explained that both scenarios were likely to underestimate the actual risk of death in the model and may be biased against fenfluramine. The committee recalled that fenfluramine is likely more effective than cannabidiol plus clobazam in reducing convulsive seizure frequencies (see section 3.9). The ERG noted that the company's scenario analyses had a large impact on the cost-effectiveness estimate. During the second meeting, the committee noted that the company's overall survival projection in the model was in line with the literature and seemed reasonable. It noted that assuming that mortality in Dravet syndrome was a midpoint calibration between the Cooper et al. study and general epilepsy might be more probable than assuming it was the same as in the general epilepsy population. The committee recognised that convulsive seizure frequency is likely to be related to mortality in Dravet syndrome. However, it noted that it had not been presented with enough evidence to suggest an association between reduced convulsive seizure frequency and reduced risk of mortality in Dravet syndrome with fenfluramine treatment. Taking into account that Dravet syndrome is a rare condition, and the evidence available, the committee concluded that there may be a relationship between the reduced convulsive seizure frequency and mortality in Dravet syndrome but that the strength of this relationship was unclear. ## The impact of excluding non-convulsive seizures from the model is not clear The company explained that it excluded non‑convulsive seizures from its model because it is difficult to measure them, being less noticeable and harder to record. It said that, had it included non‑convulsive seizures, it is likely it would have improved fenfluramine's cost effectiveness compared with standard care drugs. To support this, the company cited a study (Gunning et al. 2020) comparing cannabidiol plus clobazam with placebo, which reported that cannabidiol plus clobazam may reduce the frequency of total seizures and convulsive seizures compared with placebo. The company explained that, because fenfluramine was likely to reduce convulsive seizure frequency compared with cannabidiol plus clobazam (see section 3.9), it was likely that fenfluramine would reduce non‑conclusive seizure frequency compared with cannabidiol plus clobazam as well. However, the ERG considered that including non‑convulsive seizures could worsen cost effectiveness for fenfluramine and that there was uncertainty. This was because cannabidiol plus clobazam was compared with placebo instead of fenfluramine in Gunning et al. 2020. The clinical experts noted that non‑convulsive seizures have a significant impact on day-to-day life, but acknowledged the difficulties in measuring them, particularly in adults who may be in residential care. Given the uncertainties, the committee concluded that the impact of excluding non‑convulsive care in the model is unclear and took this into account during decision making. ## Using real-world dosing evidence for fenfluramine and cannabidiol is appropriate for this appraisal The company presented real‑world evidence from studies that showed the average dosing of fenfluramine (see section 2.2) and cannabidiol (see section 3.9). The evidence suggested that the average dose for each treatment was below the licensed maximum dose. The clinical experts said that they titrate the treatment to a dose that reduces seizures while minimising the adverse effects of treatment. They added that most patients would not reach the maximum licensed dose. They said doses could start high but then be reduced if the patient had adverse effects, to a dose that still controlled seizures. In the preconsultation version of the company's model, the company used a dosage of 12 mg/kg/day for cannabidiol, which was in line with the dosage used in NICE's technology appraisal guidance on cannabidiol with clobazam. After consultation, the company argued that the typical maintenance dosage used in the UK was likely to be higher, and changed to a dosage of 15 mg/kg/day in its updated model. It justified this with the following: Evidence from a study on slow titration of cannabidiol add-on in drug-resistant epilepsies (D'Onofrio et al. 2020), which was done in France and included 48 people. It looked at slow titrations to improve safety without affecting the efficacy of cannabidiol. It showed that median dosages increased from 10 mg/kg/day to 18 mg/kg/day in people with Dravet syndrome from month 1 to month 6. Evidence from a study of 6 people with Dravet syndrome in 1 centre in the UK, which reported an average cannabidiol dose of 13.3 mg/kg/day over 7.5 months (Desai et al. 2021). The latest published data from an open-label extension study of add-on cannabidiol in patients with Dravet syndrome (n=315; Scheffer et al. 2021), which reported a median modal dose of over 20 mg/kg/day for a mean duration of 627 days. The company's clinical experts said that the average dose in the UK was 15 mg/kg/day or higher.The company said that there was no evidence of a significant difference in efficacy in the real‑world studies compared with the trials. But it did not present the results of the studies in detail to enable the committee to assess this. The committee noted that the evidence from the open-label study was likely to be an overestimate because it was titrated for tolerability, and optimal efficacy was achieved at a lower dose. The committee noted that the study from the UK was very small so considered it supportive evidence for the French study. The clinical experts at the meeting noted that, particularly for children, 15 mg/kg/day seemed accurate. While the committee did not consider the evidence for the exact dosage of cannabidiol in the UK to be particularly clear, it was relatively confident from the French study, with support from the small UK-based study and clinical input, that the average UK dosage is higher than 12 mg/kg/day. It concluded that using a dose of 15 mg/kg/day of cannabidiol in the model was reasonable. The committee noted that the evidence for the real‑world use of cannabidiol was predominantly from France, with a smaller amount of supportive evidence from the UK. The evidence for fenfluramine was from real‑world use in Germany and Italy, and an international open-label extension study in which the mean daily dose for fenfluramine was 0.32 mg/kg/day with stiripentol and 0.40 mg/kg/day without stiripentol. The clinical experts said that there was no reason to expect that patients in the UK would be treated differently to patients in Europe because genetically they would be similar, and Dravet syndrome is managed in the same way as it is managed in the UK. The committee noted that using the real‑world expected dose for both treatment and comparator had a considerable impact on the ICER but considered it would better reflect the cost of these treatments to the NHS. The committee noted that, while it would prefer not to disconnect the effects from the drug from the amount of drug given, it considered this to be an exceptional situation. It noted that treatments to reduce seizures are not used in the same way as other treatments that aim to reach the maximum tolerable dose. And it heard from clinical experts that the dose used would be a balance between seizure reductions and adverse effects of treatment. In this case, the committee concluded that it was reasonable to use the real‑world evidence presented by the company to determine the dosages of both treatments in the model. # Adverse events ## Fenfluramine is associated with manageable adverse events but there is uncertainty in modelling The company excluded from its model treatment‑emergent adverse events on the basis that the incidence was low and similar across fenfluramine and placebo arms. The company made a pragmatic assumption that adverse events would be similar for cannabidiol so excluded them from the model. The company also provided evidence supporting the assumption that there is little difference in the incidence of treatment-emergent adverse events between fenfluramine and cannabidiol plus clobazam. However, the ERG noted that in Study 1, 12.5% of people having fenfluramine 0.7 mg/kg/day stopped treatment because of adverse events, compared with none in the placebo arm. While the ERG agreed that the impact in the model was likely to be small, the clinical expert considered that the impact of adverse events should be included in the model. During consultation, the company explained that the monitoring for adverse events was fully captured in routine management, and that additional costs related to monitoring were appropriately captured in the model as well. The ERG noted that the impact of adverse events and additional monitoring were not reflected in event costs or corresponding disutilities, although this was likely to have a minor impact on the cost-effectiveness estimate. The committee concluded that fenfluramine was associated with manageable adverse events, although there was uncertainty in its modelling, and it took this into account in its decision making. # Utility values in the economic model ## Incorporating carers' quality of life in the model is appropriate but this should be done by applying a carer disutility The company estimated that 1.8 carers (2 carers minus 0.2 to account for sharing) would apply to all patients. Carer utility was added to the patient utility to obtain the overall quality of life in the model. However, the ERG noted that the company's model removes the carer's utility when the patient dies, which overestimates the impact of mortality because the carer does not die with the patient. The clinical and carer experts noted that comorbidities and learning disabilities need care, which was not a direct function of seizure frequency. They explained that remaining alert for a seizure has a significant impact on a carer's quality of life. They also noted that many people with Dravet syndrome are cared for in the family home, with a big impact on parents and siblings, and that at least one parent needed to give up work. The ERG considered that applying a carer decrement (disutility), as in NICE's technology appraisal guidance on cannabidiol with clobazam, rather than adding a carer utility may address these problems. The ERG explored this approach by applying 1.8 carers, but only to people with the highest seizure frequencies (more than 8 seizures a month). The company argued that the ERG's approach was based on arbitrary categories and was not appropriate for a model based on carer-level data from clinical trials. The company also noted that individual carer-level data shows that seizure‑free days also affect carers' quality of life. During the first meeting, the committee concluded that there was no agreed way to incorporate carer utilities in the model. However, it was concerned that the company's approach was not implemented appropriately because it included implausible assumptions for carers' utilities. During the consultation, the company explained that it set carer utility at zero when the patients dies in its base case. The company also provided a scenario analysis retaining the carer's utilities when the patient dies, but at the lowest quality-of-life estimate for carers when the patient was alive. The ERG commented that this assumption was debatable but had a large impact on the cost-effectiveness estimate. If applying carers' utilities when the patient dies, the ERG preferred to retain the carer utility in the model at the highest quality-of-life estimate the carer experienced when the patient was alive. However, it was unable to implement this analysis. The committee was concerned that the company's technique for including carer utility – whereby carers are modelled to die at the same time as the patient – is unusual and would result in biased results. The committee understood that there was no consensus method when incorporating carers' quality of life in a model, but, mathematically, the carer disutility approach may be more appropriate in this case. The committee concluded that it was appropriate to incorporate carers' quality of life in the model but said this should be done by applying a carer disutility. In response, the company revised its model to incorporate carer disutility and presented it alongside a scenario analysis showing the impact of using both approaches. Using the carer disutility approach had a large impact on the ICER. The committee noted that both approaches had limitations and that the true ICER may lie between both approaches. But it concluded that using the disutility approach had more face validity because it did not result in the unexpected assumption that carers would die at the same time as the patient. # Cost-effectiveness estimate ## The ICERs are within the range considered cost effective and take into account the committee's preferred assumptions NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, decisions about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. There is a patient access scheme for the comparator treatment cannabidiol. Therefore costs and ICERs are confidential and cannot be presented. When the committee's preferred assumptions were taken into account, the ICER was within the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). The committee's preferred assumptions included the following assumptions and approaches: Correcting the error for discontinuations as identified and adopted by the ERG (see section 3.13). Using the merged population including people taking and not taking stiripentol (see section 3.14). Basing the model on convulsive seizure-free days (see section 3.15 and section 3.16). A relationship between convulsive seizure frequency and mortality in Dravet syndrome (see section 3.17). Using real‑world dosing evidence for fenfluramine and cannabidiol (see section 3.20 and section 3.21). Incorporating carer's quality of life into the model by applying carer disutility (see section 3.23 and section 3.24). # Other factors ## Equality issues No equality issues relevant to the committee's preliminary recommendations were raised. ## There are likely to be additional benefits of fenfluramine not captured in the model A clinical expert said that they considered fenfluramine to be a step change in managing Dravet syndrome because the same benefits have not been seen in trials of other drugs. A carer expert said fenfluramine has significantly improved their quality of life. They also noted that fenfluramine can improve a child's intellectual development because fewer seizures means, for example, that they can make progress in their speech. During the second meeting, the committee noted that there may be potential benefits of fenfluramine which were not captured in the modelling. These included, for example, the benefit of fenfluramine in reducing the duration of convulsive seizures (see section 3.10), the benefits on non‑convulsive seizures (see section 3.19) and the benefit on the quality of life of the siblings of children or young people with Dravet syndrome (see section 3.23). The company also highlighted that its model is likely to be conservative because it does not capture the value of: -ther motor functional (for example walking) and executive function improvements the potential for fewer discontinuations and adverse events with fenfluramine that fenfluramine is likely to be used in a higher proportion of adults, which is likely to improve cost effectiveness compared with the uncapped dosing of cannabidiol.The committee concluded that that there are likely to be additional benefits of fenfluramine that were not captured in the model. ## Fenfluramine is recommended The committee acknowledged that Dravet syndrome has a substantial effect on the quality of life of people with the condition, and their families and carers. It noted that the clinical evidence suggested fenfluramine is clinically effective in reducing the number of convulsive seizures, and that it may be more effective than cannabidiol plus clobazam in reducing convulsive seizure frequency. There were some uncertainties around the assumptions in the model. However, the committee considered that the most plausible ICER for fenfluramine compared with cannabidiol plus clobazam was likely to be within the range normally considered an effective use of NHS resources. So, fenfluramine is recommended as an add‑on to 2 other antiseizure medicines for treating seizures associated with Dravet syndrome in people aged 2 years and older in the NHS.	{'Recommendations': 'Fenfluramine is recommended as an add‑on to other antiseizure medicines for treating seizures associated with Dravet syndrome in people aged 2\xa0years and older, only if:\n\nseizures have not been controlled after trying 2 or more antiseizure medicines\n\nthe frequency of convulsive seizures is checked every 6\xa0months, and fenfluramine is stopped if it has not fallen by at least 30% compared with the 6\xa0months before starting treatment\n\nthe company provides fenfluramine according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with fenfluramine that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For children and young people, this decision should be made jointly by the clinician and the child or young person, or their parents or carers.\n\nWhy the committee made these recommendations\n\nTreatment for Dravet syndrome often starts with a single antiseizure drug such as sodium valproate. Other treatments can then be added if seizures are not well controlled. In practice, standard care often involves a combination of 3\xa0antiseizure medicines. Clinicians may offer add-on therapies such as cannabidiol with clobazam, or fenfluramine.\n\nClinical trial evidence shows that fenfluramine, when added to standard care medicines, reduces the number of convulsive seizures people have. And it may be more effective than cannabidiol plus clobazam in reducing the number of seizures when used with 2 other antiseizure medicines. There is some evidence that adding fenfluramine improves quality of life for people with Dravet syndrome and their carers compared with standard care medicines alone.\n\nThe cost-effectiveness estimates are within the range NICE considers an acceptable use of NHS resources. There is evidence that there are also likely to be benefits from fenfluramine beyond what was in the economic model. These include reducing how long seizures last for, fewer non-convulsive seizures, and quality of life benefits. So fenfluramine is recommended.', 'Information about fenfluramine': "# Marketing authorisation indication\n\nFenfluramine (Fintepla, Zogenix) is licensed for 'the treatment of seizures associated with Dravet syndrome as an add-on therapy to other anti-seizure medicines for patients 2\xa0years of age and older'.\n\n# Dosage in the marketing authorisation\n\nFenfluramine is taken orally. It can be used with or without stiripentol. Because of how fenfluramine is metabolised, the recommended maintenance dose after titration is 0.7\xa0mg/kg/day (maximum 26\xa0mg/day) for people not taking stiripentol, and 0.4\xa0mg/kg/day for people taking stiripentol (maximum 17\xa0mg/day). See details of the dosage schedule in the summary of product characteristics for fenfluramine.\n\n# Price\n\nThe list price of fenfluramine is £901.44 per 60\xa0ml bottle, £1,802.88 per 120\xa0ml bottle and £5,408.65 per 360\xa0ml bottle (BNF online accessed February 2022). The company has a commercial arrangement. This makes fenfluramine available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Zogenix, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Disease background\n\n## Dravet syndrome severely affects a person's quality of life, and that of their family and carers\n\nDravet syndrome is a severe, lifelong and genetic form of epilepsy. It usually presents in the first year of life with recurrent, prolonged convulsive seizures. As well as severe seizures, children have developmental delays and learning disabilities. Comorbidities are common and include autism, attention deficit hyperactivity disorder (ADHD), and difficulties with speech, mobility, eating, behaviour and sleep. A carer expert explained that the high seizure burden and comorbidities have a serious effect on families. They noted that looking after a child with Dravet syndrome is life-changing: 'you can never rest' and are 'on high alert at all times as a carer'. People with the disease often need round-the-clock care and help with almost all aspects of daily life. Families and carers may find looking after people with Dravet syndrome demanding, preventing them from leading normal lives. The anxiety that a child with Dravet syndrome may have status epilepticus and the risk of sudden unexpected death in epilepsy (SUDEP) substantially affects the mental wellbeing of all family members. There is also a high unmet need because the condition is resistant to standard care treatments in 90% of people with Dravet syndrome. The committee concluded that Dravet syndrome severely affects the person's quality of life and that of their family and carers.\n\n# Managing Dravet syndrome in the NHS and positioning fenfluramine in the treatment pathway\n\n## Standard care for Dravet syndrome includes a first-line antiseizure drug then first and second add-on therapies\n\nNICE's guideline on epilepsies in children, young people and adults recommends the antiseizure drug sodium valproate as the first-line treatment option for Dravet syndrome. A clinical expert noted that first-line sodium valproate is standard care and that topiramate, which was included in the 2012 NICE guideline on epilepsy, is now less used first line. If sodium valproate is not effective or tolerated, clobazam or stiripentol can be added. NICE's technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Dravet syndrome recommends cannabidiol plus clobazam in people aged 2\xa0and older. The committee noted that cannabidiol plus clobazam is an option as a second add‑on, but it does not work for everyone and the combination is not always tolerated. However, it understood that NICE's guidance on cannabidiol concluded that the positioning of cannabidiol plus clobazam after 2\xa0treatments in the treatment pathway was appropriate.\n\n## Stiripentol can be used as a first or second add-on treatment\n\nThe clinical experts noted that Dravet syndrome is one of the epilepsy syndromes most resistant to antiseizure drugs. People with the condition often need add‑on treatments. A combination of 3\xa0drugs often provides the best seizure control, most commonly sodium valproate, stiripentol and clobazam. The clinical experts noted that stiripentol is an important part of standard care and is usually used at the early stage of disease, particularly for children. They also explained that, although stiripentol is licensed to be used with clobazam, in practice stiripentol is usually used in children newly diagnosed with Dravet syndrome and added to sodium valproate as the first add‑on therapy. This is because the combination of sodium valproate and clobazam (another option for first add‑on, see section\xa03.2) often causes drowsiness. Clobazam may or may not then be added as a second add‑on after stiripentol. Alternatively, stiripentol may be used as a second add‑on if clobazam is the first add‑on to sodium valproate. The committee concluded that stiripentol is part of standard care and could be used either as a first or second add‑on therapy to other standard antiseizure drugs for treating seizures in Dravet syndrome.\n\n## The treatment sequence for add-on therapies after first-line antiseizure drugs is individualised to the person\n\nThe clinical experts noted that often the new add‑on treatment will not immediately replace the previous treatment. The goal is to control seizures with as few medications as possible. Rather, the new treatment is added sequentially to assess its impact, usually over about 3\xa0months to allow sufficient titration and monitoring. When adding cannabidiol, which requires treatment with clobazam, clinicians do not add both drugs at the same time, because it is difficult to identify which drug was associated with adverse effects (or benefits). An existing treatment may be tapered down slowly before removing it if the condition responds to a newly added treatment. The choice of what treatment to add or remove is individualised to the person. The carer expert explained that they would not continue a treatment if it does not work because of the burden of taking medicines and potential adverse effects. The committee concluded that the sequence of adding treatments to antiseizure drugs is individualised in clinical practice.\n\n## The company's positioning of fenfluramine as a second add-on treatment is appropriate\n\nThe clinical experts noted that, while fenfluramine can be offered as an add‑on drug at any point in the pathway according to its licence and with or without clobazam, it would be offered in NHS clinical practice after stiripentol, clobazam, or both, as a second add‑on treatment. They also noted that both stiripentol and clobazam might be stopped if fenfluramine is added and effective. The committee agreed that the company's positioning of fenfluramine as a second add‑on treatment in the treatment pathway is appropriate.\n\n## Comparators at the second add-on position in the treatment pathway include cannabidiol plus clobazam and other standard care drugs\n\nThe company focused its submission on the comparison between fenfluramine and cannabidiol plus clobazam as a second add‑on treatment. It explained that this was because cannabidiol plus clobazam is the only therapy with enough data, and is currently accepted as clinically and cost effective. The clinical experts explained that, as a second add‑on, cannabidiol plus clobazam is a relevant comparator to fenfluramine. The committee agreed but noted that there are other options for a second add‑on treatment in the pathway (see section 3.3 and section\xa03.4). For people who cannot tolerate cannabidiol plus clobazam, drugs comprising standard care are the appropriate comparator, which might include stiripentol. The committee concluded that the company's positioning of fenfluramine as a second add‑on compared with cannabidiol plus clobazam is appropriate. However, the continued use of other drugs that comprise standard care is also a relevant comparator for people who cannot take cannabidiol or clobazam.\n\n# Clinical effectiveness evidence\n\n## Fenfluramine is an effective treatment for Dravet syndrome in the short term compared with placebo\n\nThe company submitted evidence from 2 phase\xa03, double-blind, placebo-controlled randomised controlled trials, Study\xa01 and Study\xa01504. In these studies fenfluramine as an add‑on to standard care drugs was compared with placebo in children and young people with Dravet syndrome aged between 2 and 18\xa0years. Study\xa01 (n=119) excluded patients taking stiripentol and assessed the efficacy of fenfluramine at 2\xa0dosages: 0.2\xa0mg/kg/day (this dosage is not licensed and was assessed in the trial for dose–response relationship) and 0.7\xa0mg/kg/day. Study\xa01504 (n=87) needed patients to be taking stiripentol and assessed the efficacy of fenfluramine 0.4\xa0mg/kg/day. Study\xa01 and Study\xa01504 had follow-up periods of 14\xa0weeks and 15\xa0weeks, respectively. The primary end\xa0point of both trials was percentage change in convulsive seizure frequency per 28\xa0days during the treatment period compared with baseline. Evidence showed that, among patients not taking stiripentol in Study\xa01, fenfluramine 0.7\xa0mg/kg/day and 0.2\xa0mg/kg/day were associated with a 62.3% (95% confidence interval [CI] ‑48 to\xa0‑73%, p<0.001), and 32.4% (95%\xa0CI: ‑6 to\xa0‑51%, p=0.02) greater reduction than placebo, respectively. For patients taking stiripentol (Study\xa01504), fenfluramine 0.4\xa0mg/kg/day was associated with a 54% (95%\xa0CI: ‑67 to\xa0‑36%, p<0.001) greater reduction than placebo.\n\nBoth trials reported on change in mean convulsive seizure-free days per 28\xa0days from baseline as a secondary end\xa0point. Results suggested that fenfluramine is associated with a greater increase in convulsive seizure-free days than placebo across all dosages (this data is confidential and cannot be reported here). Both trials assessed quality of life in patients using the Pediatric Quality of Life Inventory (PedsQL) and reported on changes from baseline in PedsQL scores associated with different dosages. Study\xa01 (in people not taking stiripentol) showed that, at 14‑week follow up, both fenfluramine 0.7\xa0mg/kg/day and 0.2\xa0mg/kg/day were associated with a greater improvement from baseline in PedsQL than placebo. Mean scores were (standard deviation): 5.9 (15.1), p=0.02 and 6.8 (11.2), p=0.003 for fenfluramine 0.7\xa0mg/kg/day and 0.2\xa0mg/kg/day, respectively; and -1.6 (10.4) for placebo. However, results of Study\xa01504 (in people taking stiripentol) showed that, at 15‑week follow up, changes from baseline in mean total PedsQL score were not statistically different (alpha level = 0.05 [2‑sided]) between fenfluramine 0.4\xa0mg/kg/day and placebo (mean [standard deviation]: -0.9 [11.8] compared with -0.3 [12.4], p=0.0618). Results for carers' quality of life appeared to be in the same direction of treatment effect (this data is confidential and cannot be reported here). The committee concluded that fenfluramine is more effective than placebo in reducing convulsive seizure frequencies in people with Dravet syndrome in the short term.\n\n## Fenfluramine may be more effective than cannabidiol plus clobazam in reducing convulsive seizure frequencies\n\nNo trials directly compared fenfluramine with cannabidiol plus clobazam. So the company did a network meta-analysis to assess the effectiveness of different dosages of fenfluramine (Study\xa01: 0.2\xa0mg/kg/day and 0.7\xa0mg/kg/day; Study\xa01504: 0.4\xa0mg/kg/day) and cannabidiol plus clobazam (10\xa0mg/kg/day and 20\xa0mg/kg/day plus clobazam) relative to placebo. The network meta-analysis was done for both the primary and secondary outcomes of Study\xa01 and Study\xa01504. The ERG noted there were differences in the use of standard care drugs including clobazam across trials. The network meta-analysis assessed percentage change from baseline in convulsive seizure frequency in 28\xa0days compared with placebo, which was the primary end\xa0point of Study\xa01 and Study\xa01504 and informed the economic model. The ERG noted that, while the results showed that all doses of fenfluramine and cannabidiol plus clobazam were more effective than placebo in reducing convulsive seizure frequency per 28\xa0days, there was no difference between fenfluramine and cannabidiol plus clobazam in this analysis. During the first meeting, the committee noted that this analysis did not show a difference between fenfluramine and cannabidiol plus clobazam. It also noted that it would prefer to see the absolute changes from baseline associated with different dosages of fenfluramine and cannabidiol plus clobazam. During the consultation, the company explained that data for absolute changes from baseline for cannabidiol plus clobazam is not publicly available, so it was not able to do this analysis. The company instead presented an indirect treatment comparison between fenfluramine, cannabidiol, and placebo on the outcome of percentage change from baseline in convulsive seizure frequency over 28\xa0days using the Bucher method. This additional analysis included data publicly available from 4\xa0trials of cannabidiol plus clobazam (results of the analysis are confidential and cannot be reported here). The committee noted that the comparisons between fenfluramine and different dosages of cannabidiol plus clobazam were mixed but largely favoured fenfluramine. Carer and clinical experts explained during the second meeting that Dravet syndrome is a heterogeneous condition, reflected in the range of seizure frequency and intensity. They said that the differences in results reflected the natural variation in the condition and are expected. The committee noted that the mixed results may be partly because of the small sample sizes in the trials as well as heterogeneity. It questioned why the company did not pool the 2\xa0cannabidiol plus clobazam trials with the same dosing in this additional analysis on the primary end point. The company explained that it was because the committee had requested analysis of the absolute change in convulsive seizure frequency for cannabidiol plus clobazam from baseline compared with fenfluramine during its first meeting, given the uncertainties in the network meta-analysis of the primary end point. However, the company had no access to such data for cannabidiol plus clobazam. So the company did not combine the cannabidiol plus clobazam trials with the same or different dosages, so that the differences in treatment effect on the primary end point between specific dosages of fenfluramine and specific dosages of cannabidiol plus clobazam can be seen. The company also explained that the 2\xa0cannabidiol plus clobazam trials with the maximum recommended dosing for cannabidiol plus clobazam (20\xa0mg/kg/day) reported different treatment effects for the primary end point. The ERG noted that the heterogeneity across trials may be another reason not to pool trials for analysis. The committee acknowledged that, overall, the evidence suggested superiority of fenfluramine compared with cannabidiol plus clobazam but noted that there was high uncertainty given the heterogeneity across trials.\n\n# Stopping treatment\n\n## The stopping rule of 30% seizure reduction at 6\xa0months is the most clinically appropriate response criteria\n\nThe marketing authorisation for fenfluramine does not specify a stopping rule. At the first committee meeting, the company proposed that fenfluramine should be stopped after 6\xa0months if the frequency of convulsive seizures had not reduced by at least 30% from baseline. This is in line with the first assessment time set out in the stopping rule in NICE's technology appraisal guidance on cannabidiol with clobazam. The clinical experts said that because seizures can cluster in people with Dravet syndrome, at least 6\xa0months would be needed to assess response to treatment. People with Dravet syndrome are seen every 6\xa0months in clinical practice. In the first meeting, the committee concluded that stopping rules at 6\xa0months and every 6\xa0months thereafter was appropriate. During the second meeting, the committee questioned whether this stopping rule would fully capture any waning of the treatment effect, for example, if there is a slight deterioration in treatment effect but still some benefit in seizure control compared with baseline. The clinical experts explained that, if some deterioration in response is seen in practice, treatment is not immediately stopped. They said that clinicians would usually consider all the medicines someone is taking and taper one off when another is added. The clinical experts also explained that clinicians would continue if fenfluramine seizure frequency reduced by 30% compared with baseline. A 30% reduction is the minimum to continue although a 50% reduction would be a clearer indicator of benefit. The patient and carer experts noted that parents would not keep their child on treatment if it is not working. They added that duration and severity of seizures is also important and could be reduced by treatment, which could have a large benefit for patients and carers.\n\nThe committee discussed stopping fenfluramine in relation to waning of treatment effect in the model. The company did not assume waning of treatment effect in its model. It explained that no waning of treatment effect was assumed beyond the first 6\xa0months. The company presented results from Study\xa01503 (n=330) to support the long-term treatment effect of fenfluramine, which had data from up to 3\xa0years. Study\xa01503 included people who satisfactorily completed Study\xa01 and Study\xa01504, with a mean daily dosage between 0.3\xa0mg/kg/day and 0.7\xa0mg/kg/day for 70% of people (Study\xa01503 Fintepla.eu). Results indicated that the treatment effect on percentage change in convulsive seizure frequency per 28\xa0days relative to baseline was largely maintained at 3-year follow up. The clinical expert noted that the inclusion criteria reflected clinical practice. They also noted that they did not see waning of treatment effect in practice and, if there is any, waning of treatment effect would appear in the first year of treatment. The committee appreciated that only people for whom fenfluramine was working would continue having it in practice. The company explained that the model also implemented ongoing treatment discontinuation probabilities as seen in Study\xa01503. Discontinuations seen in Study\xa01503 included stopping for all reasons, including loss of efficacy, as well as adverse events over the lifetime in the model. Evidence from Study\xa01503 indicated a 0.7% discontinuation probability for fenfluramine and a similar probability of 0.8% for cannabidiol plus clobazam per 28‑day cycle. The committee concluded that it was appropriate for waning to be excluded from the model.\n\nThe committee appreciated that a stopping rule based on a less than 30% reduction in seizure frequency at 6\xa0months might be applied in the model. However, it felt that this may not reflect all stopping caused by lack of efficacy because it knew that discontinuations were ongoing in Study\xa01503, including discontinuations caused by lack of efficacy in the longer-term follow up. The committee considered that there was some uncertainty in the company's stopping rule at 6\xa0months, which assumed that a 30% reduction in seizure frequency at this timepoint already accounted for all loss of treatment effect in the model and was the most clinically appropriate threshold. The company presented a revised model which considered an alternative scenario using a stopping rule of a 50% reduction in seizures at 6\xa0months. The clinical experts explained that a 30% reduction in seizures at 6\xa0months is the minimum they would expect from a new treatment, but that it was unclear whether a 50% stopping rule at 6\xa0months was a better threshold. They said that a 50% reduction in seizure frequency would not be a sensitive enough response criterion to take into account the potential benefit of reducing extremely severe seizures. And they said that a more moderate reduction in seizures (that is, between 30% and 50%) could still mean a valuable reduction in both severity of seizures and hospitalisations in people with Dravet syndrome. A 30% stopping rule would also align with the current stopping criteria for cannabidiol. The committee concluded that the stopping rule of at least 30% reduction in seizure frequency at 6\xa0months was the most appropriate.\n\n# Modelling approach\n\n## The company's modelling structure is appropriate for decision making and overall the results are valid\n\nThe company presented a revised individual-patient state-transition model to estimate the cost effectiveness of fenfluramine during the consultation after discussions with the ERG and NICE. The model consisted of 3\xa0health states: alive, on treatment; alive, treatment discontinued; and dead. Patient profiles including age, body weight, number of convulsive seizures per cycle, number of convulsive-free days per cycle, concomitant medication (receiving stiripentol or not), and mortality risk were then assigned to individual patients. The model was run twice, once using baseline characteristic data from Study\xa01 without stiripentol and another using data from Study\xa01504 with stiripentol. The results were then combined and weighted based on an estimate of 58% of the population having stiripentol and 42% not having stiripentol, as informed by the European DISCUSS survey with UK data on carers of people with Dravet syndrome. The clinical experts noted that 58% of the population having stiripentol was largely in line with clinical practice in the NHS. For the merged population, the company's model focused on the comparison against cannabidiol plus clobazam as the second add‑on therapies in the treatment pathway. The ERG noted that several validity issues raised at the first committee meeting were resolved during consultation, and that overall the model results were valid. However, it noted that, because of the design of the model, the company provided separate model files for scenario analyses and validating them would take longer than usual. For the same reasons, the ERG was not able run its preferred analyses. The ERG had noted an error in the updated base case of the company's model related to discontinuation probabilities. The company corrected its base case so that the discontinuation probabilities in the model for the trial titration and maintenance phases were the same as those in the company's submission, and equal for both treatments. The committee concluded that the company's model structure was appropriate for decision making, and overall the results were valid.\n\n## The merged population is appropriate for decision making\n\nDuring the first meeting, the committee noted that the cost-effectiveness estimates were substantially higher when stiripentol was used than when it was not, and asked for the reasons to be explored. During consultation, the company provided disaggregated results for the merged population: for the Study\xa01 population without stiripentol, and for the Study\xa01504 population with stiripentol. It explained that in Study\xa01 no one was taking stiripentol. So when people stopped fenfluramine or cannabidiol plus clobazam they reverted to standard care that was cheaper than standard care in Study\xa01504, which included stiripentol, which is an expensive drug. Consequently, the ongoing costs in Study\xa01 were much lower than in Study\xa01504. The committee also noted that fenfluramine 0.4\xa0mg/kg/day with stiripentol in Study\xa01504 resulted in a smaller incremental cost than fenfluramine 0.7\xa0mg/kg/day without stiripentol in Study\xa01. Taking account of the quality-adjusted life year (QALY) differences between the 2\xa0studies, the company explained that the net effect of stiripentol was to reduce the incremental cost-effectiveness ratio (ICER) in Study\xa01504 compared with Study\xa01. The ERG agreed with the company's explanation during the second meeting. The committee noted the difference in cost-effectiveness estimates when stiripentol is used compared with when it is not used in the company's base case. It recalled that stiripentol is not a treatment modifier for fenfluramine. The committee considered that grouping the population based on stiripentol use may be artificial and not feasible for clinical practice. This was because the treatment sequence for add‑on therapies to control seizure frequencies is individualised to the patient (see section\xa03.4), and because stiripentol is used as either a first or second add‑on treatment in the usual combination of 3 drugs to control seizure frequencies (see section\xa03.3). The committee was also aware that this grouping was not supported by the clinical evidence available. Taking into account the unmet need (see section\xa03.1), the complexities of the condition, and the individualised and unique treatment sequencing of adding treatments to first‑line antiseizure drugs across patients, the committee concluded that the merged population is appropriate for decision making.\n\n## Basing the model on convulsive seizure-free days may be reasonable but there are uncertainties in the relationship between convulsive seizure frequency and seizure days\n\nThe company's network meta-analysis assessed the change (mean percentage reduction) in the frequency of convulsive seizures per 28\xa0days from baseline compared with placebo for the fenfluramine and cannabidiol plus clobazam arms. The company reported that there was no information on the number of days people had convulsive seizures from the cannabidiol trials. It therefore assumed that the change (the mean percentage reduction) in the frequency of convulsive seizures per 28\xa0days from baseline compared with placebo, as informed by the network meta-analysis, was the same as the change in days people had convulsive seizures per 28\xa0days from baseline compared with placebo. The company then calculated seizure-free days by subtracting the seizure days from 28\xa0days per cycle. The ERG noted that, although there is a relationship between having fewer convulsive seizures and having fewer days with convulsive seizures in the 28‑day cycle, the relationship was unlikely to be linear. During the first meeting, the committee noted that there were uncertainties in both the company's and ERG's approaches in deriving the relationship between the reduction in convulsive seizure frequencies and reduction in days having convulsive seizures. The committee concluded that basing the model on convulsive seizure frequency instead of convulsive seizure‑free days would avoid the problem of determining the most appropriate relationship between them and the uncertainties. During consultation, the company explained that it modelled seizure-free days to adequately capture the impact of Dravet syndrome and therapies on patients and carers. The carer expert noted that both convulsive seizure frequency and seizure-free days are important. The carer expert explained that seizure freedom is relevant because with even just one night with no seizures, for example, the patient and their carers do not wake up exhausted. They have not needed to wake up to time a seizure and decide whether to administer rescue medication or call an ambulance during the night.\n\nIn response to the consultation, the company did a regression analysis to estimate the proportionality between the percentage change in convulsive seizure frequency and the percentage change in convulsive seizure days. This analysis was of patient-level and combined data from all arms of Study\xa01 and Study\xa01504. The result indicated that the relationship was not 1:1 but close to linear (the data is confidential and cannot be reported here). The company used this assumption for both the fenfluramine and cannabidiol arms in the updated model. The committee appreciated that having fewer convulsive seizures and fewer days with convulsive seizures are both important for patient and carers, but that fewer days with convulsive seizures may be more meaningful for them. The committee concluded that basing the model on convulsive seizure-free days was reasonable but noted that this was an uncertainty in the model.\n\n## The strength of the relationship between convulsive seizure frequency and mortality is not clear\n\nThe company assumed in its base case that mortality is linked to the frequency of convulsive seizures. Total mortality in the model included background and seizure-related mortality: SUDEP, status epilepticus deaths and accidental deaths. The clinical expert noted that the association between convulsive seizure frequency and status epilepticus-related and accidental deaths is seen regardless of seizure cause. However, the clinical expert noted that the exact cause of SUDEP is unknown. The ongoing convulsive seizure frequency is a risk factor for SUDEP in Dravet syndrome although the relationship between reduction in convulsive seizure frequency and reduction in mortality is uncertain. There is little data on the association between convulsive seizure frequency and risk of SUDEP in Dravet syndrome. The company used Cooper et al. (2016), which is a retrospective uncontrolled cohort study including 100\xa0children and young people with Dravet syndrome. Cooper et al. reports the incidence of Dravet-specific SUDEP and total mortality over a median follow up of 10\xa0years. Because Cooper et al. did not report on the relationship between convulsive seizure frequency and SUDEP, the company took the risk estimates for SUDEP by seizure frequency from a case–control study of adults with general epilepsy (Nilsson et al. 1999). Because the SUDEP rate in Dravet syndrome reported by Cooper et al. was much higher than that in general epilepsy, the company calibrated the SUDEP rate reported by Nilsson et al. to the expected SUDEP rate from Cooper et al. using a multiplier of 8.38. During the first meeting, the ERG considered that strong assumptions were needed to link convulsive seizure frequency with SUDEP in Dravet syndrome. It was also concerned about the implausible estimates resulting from extrapolating. Given that there was no evidence of fenfluramine extending life, the ERG preferred to remove the link between seizure frequency and mortality, that is, to not assume in the model that treatment with fenfluramine prolongs life. People with Dravet syndrome have many comorbidities, which may also confound the association between frequency of seizures and death. The committee acknowledged that there may be an association between convulsive seizures and SUDEP. It also understood that the increased risk of death would not be necessarily reversed by treatment. So the committee concluded during the first meeting that it would prefer to see scenario analyses testing different strengths of relationship between convulsive seizure frequency and SUDEP, including analyses in which fenfluramine did not prolong life.\n\nDuring consultation, the company said that its survival curve based on Cooper et al. (SUDEP and status epilepticus-related mortality) and other published literature and expert opinion (accident-related mortality) was in line with the mortality expected in Dravet syndrome in the UK, and that this was confirmed by UK clinicians. The company also provided scenario analyses exploring the relationship between convulsive seizure frequency and SUDEP, but not for removing the link entirely from the model. The company argued that it would be unreasonable to remove the possibility of a mortality benefit from the model because of the lack of evidence from clinical trials. This is because Dravet syndrome is a rare condition and it is not possible for clinical trials to be powered enough to detect the difference in the risk of mortality between interventions. It also argued that modelling the relationship between convulsive seizure frequency and mortality was in line with clinical expectations. The 2 alternative scenarios the company provided assumed:\n\nthe same mortality in Dravet syndrome as in the general epilepsy population\n\nmortality in Dravet syndrome to be calibrated midway between the company's base-case estimate in Dravet syndrome (Cooper et al. 2016) and general epilepsy mortality (Nilsson et al. 1999). The company explained that both scenarios were likely to underestimate the actual risk of death in the model and may be biased against fenfluramine. The committee recalled that fenfluramine is likely more effective than cannabidiol plus clobazam in reducing convulsive seizure frequencies (see section\xa03.9). The ERG noted that the company's scenario analyses had a large impact on the cost-effectiveness estimate. During the second meeting, the committee noted that the company's overall survival projection in the model was in line with the literature and seemed reasonable. It noted that assuming that mortality in Dravet syndrome was a midpoint calibration between the Cooper et al. study and general epilepsy might be more probable than assuming it was the same as in the general epilepsy population. The committee recognised that convulsive seizure frequency is likely to be related to mortality in Dravet syndrome. However, it noted that it had not been presented with enough evidence to suggest an association between reduced convulsive seizure frequency and reduced risk of mortality in Dravet syndrome with fenfluramine treatment. Taking into account that Dravet syndrome is a rare condition, and the evidence available, the committee concluded that there may be a relationship between the reduced convulsive seizure frequency and mortality in Dravet syndrome but that the strength of this relationship was unclear.\n\n## The impact of excluding non-convulsive seizures from the model is not clear\n\nThe company explained that it excluded non‑convulsive seizures from its model because it is difficult to measure them, being less noticeable and harder to record. It said that, had it included non‑convulsive seizures, it is likely it would have improved fenfluramine's cost effectiveness compared with standard care drugs. To support this, the company cited a study (Gunning et al. 2020) comparing cannabidiol plus clobazam with placebo, which reported that cannabidiol plus clobazam may reduce the frequency of total seizures and convulsive seizures compared with placebo. The company explained that, because fenfluramine was likely to reduce convulsive seizure frequency compared with cannabidiol plus clobazam (see section\xa03.9), it was likely that fenfluramine would reduce non‑conclusive seizure frequency compared with cannabidiol plus clobazam as well. However, the ERG considered that including non‑convulsive seizures could worsen cost effectiveness for fenfluramine and that there was uncertainty. This was because cannabidiol plus clobazam was compared with placebo instead of fenfluramine in Gunning et al. 2020. The clinical experts noted that non‑convulsive seizures have a significant impact on day-to-day life, but acknowledged the difficulties in measuring them, particularly in adults who may be in residential care. Given the uncertainties, the committee concluded that the impact of excluding non‑convulsive care in the model is unclear and took this into account during decision making.\n\n## Using real-world dosing evidence for fenfluramine and cannabidiol is appropriate for this appraisal\n\nThe company presented real‑world evidence from studies that showed the average dosing of fenfluramine (see section\xa02.2) and cannabidiol (see section\xa03.9). The evidence suggested that the average dose for each treatment was below the licensed maximum dose. The clinical experts said that they titrate the treatment to a dose that reduces seizures while minimising the adverse effects of treatment. They added that most patients would not reach the maximum licensed dose. They said doses could start high but then be reduced if the patient had adverse effects, to a dose that still controlled seizures. In the preconsultation version of the company's model, the company used a dosage of 12\xa0mg/kg/day for cannabidiol, which was in line with the dosage used in NICE's technology appraisal guidance on cannabidiol with clobazam. After consultation, the company argued that the typical maintenance dosage used in the UK was likely to be higher, and changed to a dosage of 15\xa0mg/kg/day in its updated model. It justified this with the following:\n\nEvidence from a study on slow titration of cannabidiol add-on in drug-resistant epilepsies (D'Onofrio et al. 2020), which was done in France and included 48\xa0people. It looked at slow titrations to improve safety without affecting the efficacy of cannabidiol. It showed that median dosages increased from 10\xa0mg/kg/day to 18\xa0mg/kg/day in people with Dravet syndrome from month 1 to month 6.\n\nEvidence from a study of 6\xa0people with Dravet syndrome in 1\xa0 centre in the UK, which reported an average cannabidiol dose of 13.3\xa0mg/kg/day over 7.5\xa0months (Desai et al. 2021).\n\nThe latest published data from an open-label extension study of add-on cannabidiol in patients with Dravet syndrome (n=315; Scheffer et al. 2021), which reported a median modal dose of over 20\xa0mg/kg/day for a mean duration of 627\xa0days.\n\nThe company's clinical experts said that the average dose in the UK was 15\xa0mg/kg/day or higher.The company said that there was no evidence of a significant difference in efficacy in the real‑world studies compared with the trials. But it did not present the results of the studies in detail to enable the committee to assess this. The committee noted that the evidence from the open-label study was likely to be an overestimate because it was titrated for tolerability, and optimal efficacy was achieved at a lower dose. The committee noted that the study from the UK was very small so considered it supportive evidence for the French study. The clinical experts at the meeting noted that, particularly for children, 15\xa0mg/kg/day seemed accurate. While the committee did not consider the evidence for the exact dosage of cannabidiol in the UK to be particularly clear, it was relatively confident from the French study, with support from the small UK-based study and clinical input, that the average UK dosage is higher than 12\xa0mg/kg/day. It concluded that using a dose of 15\xa0mg/kg/day of cannabidiol in the model was reasonable.\n\nThe committee noted that the evidence for the real‑world use of cannabidiol was predominantly from France, with a smaller amount of supportive evidence from the UK. The evidence for fenfluramine was from real‑world use in Germany and Italy, and an international open-label extension study in which the mean daily dose for fenfluramine was 0.32\xa0mg/kg/day with stiripentol and 0.40\xa0mg/kg/day without stiripentol. The clinical experts said that there was no reason to expect that patients in the UK would be treated differently to patients in Europe because genetically they would be similar, and Dravet syndrome is managed in the same way as it is managed in the UK. The committee noted that using the real‑world expected dose for both treatment and comparator had a considerable impact on the ICER but considered it would better reflect the cost of these treatments to the NHS. The committee noted that, while it would prefer not to disconnect the effects from the drug from the amount of drug given, it considered this to be an exceptional situation. It noted that treatments to reduce seizures are not used in the same way as other treatments that aim to reach the maximum tolerable dose. And it heard from clinical experts that the dose used would be a balance between seizure reductions and adverse effects of treatment. In this case, the committee concluded that it was reasonable to use the real‑world evidence presented by the company to determine the dosages of both treatments in the model.\n\n# Adverse events\n\n## Fenfluramine is associated with manageable adverse events but there is uncertainty in modelling\n\nThe company excluded from its model treatment‑emergent adverse events on the basis that the incidence was low and similar across fenfluramine and placebo arms. The company made a pragmatic assumption that adverse events would be similar for cannabidiol so excluded them from the model. The company also provided evidence supporting the assumption that there is little difference in the incidence of treatment-emergent adverse events between fenfluramine and cannabidiol plus clobazam. However, the ERG noted that in Study\xa01, 12.5% of people having fenfluramine 0.7\xa0mg/kg/day stopped treatment because of adverse events, compared with none in the placebo arm. While the ERG agreed that the impact in the model was likely to be small, the clinical expert considered that the impact of adverse events should be included in the model. During consultation, the company explained that the monitoring for adverse events was fully captured in routine management, and that additional costs related to monitoring were appropriately captured in the model as well. The ERG noted that the impact of adverse events and additional monitoring were not reflected in event costs or corresponding disutilities, although this was likely to have a minor impact on the cost-effectiveness estimate. The committee concluded that fenfluramine was associated with manageable adverse events, although there was uncertainty in its modelling, and it took this into account in its decision making.\n\n# Utility values in the economic model\n\n## Incorporating carers' quality of life in the model is appropriate but this should be done by applying a carer disutility\n\nThe company estimated that 1.8\xa0carers (2\xa0carers minus 0.2 to account for sharing) would apply to all patients. Carer utility was added to the patient utility to obtain the overall quality of life in the model. However, the ERG noted that the company's model removes the carer's utility when the patient dies, which overestimates the impact of mortality because the carer does not die with the patient. The clinical and carer experts noted that comorbidities and learning disabilities need care, which was not a direct function of seizure frequency. They explained that remaining alert for a seizure has a significant impact on a carer's quality of life. They also noted that many people with Dravet syndrome are cared for in the family home, with a big impact on parents and siblings, and that at least one parent needed to give up work. The ERG considered that applying a carer decrement (disutility), as in NICE's technology appraisal guidance on cannabidiol with clobazam, rather than adding a carer utility may address these problems. The ERG explored this approach by applying\xa01.8 carers, but only to people with the highest seizure frequencies (more than 8\xa0seizures a month). The company argued that the ERG's approach was based on arbitrary categories and was not appropriate for a model based on carer-level data from clinical trials. The company also noted that individual carer-level data shows that seizure‑free days also affect carers' quality of life. During the first meeting, the committee concluded that there was no agreed way to incorporate carer utilities in the model. However, it was concerned that the company's approach was not implemented appropriately because it included implausible assumptions for carers' utilities.\n\nDuring the consultation, the company explained that it set carer utility at zero when the patients dies in its base case. The company also provided a scenario analysis retaining the carer's utilities when the patient dies, but at the lowest quality-of-life estimate for carers when the patient was alive. The ERG commented that this assumption was debatable but had a large impact on the cost-effectiveness estimate. If applying carers' utilities when the patient dies, the ERG preferred to retain the carer utility in the model at the highest quality-of-life estimate the carer experienced when the patient was alive. However, it was unable to implement this analysis. The committee was concerned that the company's technique for including carer utility – whereby carers are modelled to die at the same time as the patient – is unusual and would result in biased results. The committee understood that there was no consensus method when incorporating carers' quality of life in a model, but, mathematically, the carer disutility approach may be more appropriate in this case. The committee concluded that it was appropriate to incorporate carers' quality of life in the model but said this should be done by applying a carer disutility. In response, the company revised its model to incorporate carer disutility and presented it alongside a scenario analysis showing the impact of using both approaches. Using the carer disutility approach had a large impact on the ICER. The committee noted that both approaches had limitations and that the true ICER may lie between both approaches. But it concluded that using the disutility approach had more face validity because it did not result in the unexpected assumption that carers would die at the same time as the patient.\n\n# Cost-effectiveness estimate\n\n## The ICERs are within the range considered cost effective and take into account the committee's preferred assumptions\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, decisions about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. There is a patient access scheme for the comparator treatment cannabidiol. Therefore costs and ICERs are confidential and cannot be presented. When the committee's preferred assumptions were taken into account, the ICER was within the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). The committee's preferred assumptions included the following assumptions and approaches:\n\nCorrecting the error for discontinuations as identified and adopted by the ERG (see section\xa03.13).\n\nUsing the merged population including people taking and not taking stiripentol (see section\xa03.14).\n\nBasing the model on convulsive seizure-free days (see section\xa03.15 and section\xa03.16).\n\nA relationship between convulsive seizure frequency and mortality in Dravet syndrome (see section\xa03.17).\n\nUsing real‑world dosing evidence for fenfluramine and cannabidiol (see section\xa03.20 and section\xa03.21).\n\nIncorporating carer's quality of life into the model by applying carer disutility (see section\xa03.23 and section\xa03.24).\n\n# Other factors\n\n## Equality issues\n\nNo equality issues relevant to the committee's preliminary recommendations were raised.\n\n## There are likely to be additional benefits of fenfluramine not captured in the model\n\nA clinical expert said that they considered fenfluramine to be a step change in managing Dravet syndrome because the same benefits have not been seen in trials of other drugs. A carer expert said fenfluramine has significantly improved their quality of life. They also noted that fenfluramine can improve a child's intellectual development because fewer seizures means, for example, that they can make progress in their speech. During the second meeting, the committee noted that there may be potential benefits of fenfluramine which were not captured in the modelling. These included, for example, the benefit of fenfluramine in reducing the duration of convulsive seizures (see section\xa03.10), the benefits on non‑convulsive seizures (see section\xa03.19) and the benefit on the quality of life of the siblings of children or young people with Dravet syndrome (see section\xa03.23). The company also highlighted that its model is likely to be conservative because it does not capture the value of:\n\nother motor functional (for example walking) and executive function improvements\n\nthe potential for fewer discontinuations and adverse events with fenfluramine\n\nthat fenfluramine is likely to be used in a higher proportion of adults, which is likely to improve cost effectiveness compared with the uncapped dosing of cannabidiol.The committee concluded that that there are likely to be additional benefits of fenfluramine that were not captured in the model.\n\n## Fenfluramine is recommended\n\nThe committee acknowledged that Dravet syndrome has a substantial effect on the quality of life of people with the condition, and their families and carers. It noted that the clinical evidence suggested fenfluramine is clinically effective in reducing the number of convulsive seizures, and that it may be more effective than cannabidiol plus clobazam in reducing convulsive seizure frequency. There were some uncertainties around the assumptions in the model. However, the committee considered that the most plausible ICER for fenfluramine compared with cannabidiol plus clobazam was likely to be within the range normally considered an effective use of NHS resources. So, fenfluramine is recommended as an add‑on to 2 other antiseizure medicines for treating seizures associated with Dravet syndrome in people aged 2\xa0years and older in the NHS."}	https://www.nice.org.uk/guidance/ta808	Evidence-based recommendations on fenfluramine (Fintepla) for treating seizures associated with Dravet syndrome in people aged 2 and older.
89244ffa02d131d5ca3f17bed57cef5753efc52e	nice	Pneumonia in adults: diagnosis and management	Pneumonia in adults: diagnosis and management This guideline was developed before the COVID-19 pandemic. It covers diagnosing and managing pneumonia in adults who do not have COVID-19. It aims to improve accurate assessment and diagnosis of pneumonia to help guide antibiotic prescribing and ensure that people receive the right treatment. # Introduction Pneumonia is an infection of the lung tissue. When a person has pneumonia the air sacs in their lungs become filled with microorganisms, fluid and inflammatory cells and their lungs are not able to work properly. Diagnosis of pneumonia is based on symptoms and signs of an acute lower respiratory tract infection, and can be confirmed by a chest X‑ray showing new shadowing that is not due to any other cause (such as pulmonary oedema or infarction). In this guideline pneumonia is classified as community‑acquired or hospital‑acquired, based on different microbial causes and patient factors, which need different management strategies. Every year between 0.5% and 1% of adults in the UK will have community‑acquired pneumonia. It is diagnosed in 5–12% of adults who present to GPs with symptoms of lower respiratory tract infection, and 22–42% of these are admitted to hospital, where the mortality rate is between 5% and 14%. Between 1.2% and 10% of adults admitted to hospital with community‑acquired pneumonia are managed in an intensive care unit, and for these patients the risk of dying is more than 30%. More than half of pneumonia‑related deaths occur in people older than 84 years. At any time 1.5% of hospital inpatients in England have a hospital‑acquired respiratory infection, more than half of which are hospital‑acquired pneumonia and are not associated with intubation. Hospital‑acquired pneumonia is estimated to increase hospital stay by about 8 days and has a reported mortality rate that ranges from 30–70%. Variations in clinical management and outcome occur across the UK. The guideline is needed because pneumonia is common and has a high mortality rate. The British Thoracic Society (2009) has published guidance on the management of community-acquired pneumonia in adults, but there is a lack of evidence‑based guidance on the management of hospital‑acquired pneumonia. For both types of pneumonia there is variation in care and areas of uncertainty for best practice, and these are the main focus of this guideline. This guideline provides recommendations for the diagnosis of pneumonia, and aspects of management of community‑acquired pneumonia in adults. However, it does not provide recommendations on areas of care where best practice is already established, such as diagnosis using chest X‑ray. It does not cover bronchiectasis complicated by pneumonia, or patients who acquire pneumonia while intubated or in an intensive care unit, who are immunocompromised, or in whom management of pneumonia is an expected part of end‑of‑life care. For guidance on antibiotic treatment of pneumonia, see NICE's guidelines on pneumonia (community-acquired): antimicrobial prescribing and pneumonia (hospital-acquired): antimicrobial prescribing.# Recommendations The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Terms used in this guideline ## Clinical diagnosis of community-acquired pneumonia Diagnosis based on symptoms and signs of lower respiratory tract infection in a patient who, in the opinion of the GP and in the absence of a chest X‑ray, is likely to have community‑acquired pneumonia. This might be because of the presence of focal chest signs, illness severity or other features. ## Community-acquired pneumonia Pneumonia that is acquired outside hospital. Pneumonia that develops in a nursing home resident is included in this definition. When managed in hospital the diagnosis is usually confirmed by chest X‑ray. ## Hospital-acquired pneumonia Pneumonia that develops 48 hours or more after hospital admission and that was not incubating at hospital admission. When managed in hospital the diagnosis is usually confirmed by chest X‑ray. For the purpose of this guideline, pneumonia that develops in hospital after intubation (ventilator‑associated pneumonia) is excluded from this definition. ## Lower respiratory tract infection An acute illness (present for 21 days or less), usually with cough as the main symptom, and with at least 1 other lower respiratory tract symptom (such as fever, sputum production, breathlessness, wheeze or chest discomfort or pain) and no alternative explanation (such as sinusitis or asthma). Pneumonia, acute bronchitis and exacerbation of chronic obstructive airways disease are included in this definition. ## Mortality risk The percentage likelihood of death occurring in a patient in the next 30 days. ## Severity assessment A judgement by the managing clinician as to the likelihood of adverse outcomes in a patient. This is based on a combination of clinical understanding and knowledge in addition to a mortality risk score. The difference between categories of severity and mortality risk can be important. Typically the mortality risk score will match the severity assessment. However, there may be situations where the mortality score does not accurately predict mortality risk and clinical judgement is needed. An example might be a patient with a low mortality risk score who has an unusually low oxygen level, who would be considered to have a severe illness. # Presentation with lower respiratory tract infection For people presenting with symptoms of lower respiratory tract infection in primary care, consider a point of care C‑reactive protein test if after clinical assessment a diagnosis of pneumonia has not been made and it is not clear whether antibiotics should be prescribed. Use the results of the C‑reactive protein test to guide antibiotic prescribing in people without a clinical diagnosis of pneumonia as follows: Do not routinely offer antibiotic therapy if the C‑reactive protein concentration is less than 20 mg/litre. Consider a delayed antibiotic prescription (a prescription for use at a later date if symptoms worsen) if the C‑reactive protein concentration is between 20 mg/litre and 100 mg/litre. Offer antibiotic therapy if the C‑reactive protein concentration is greater than 100 mg/litre. # Community-acquired pneumonia ## Severity assessment in primary care When a clinical diagnosis of community-acquired pneumonia is made in primary care, determine whether patients are at low, intermediate or high risk of death using the CRB65 score (see box 1). Box 1 CRB65 score for mortality risk assessment in primary care CRB65 score is calculated by giving 1 point for each of the following prognostic features: confusion (abbreviated Mental Test score 8 or less, or new disorientation in person, place or time). For guidance on delirium, see the NICE guideline on delirium. raised respiratory rate (30 breaths per minute or more) low blood pressure (diastolic 60 mmHg or less, or systolic less than 90 mmHg) age 65 years or more. Lim WS, van der Eerden MM, Laing R, et al. (2003) Defining community‑acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 58: 377–82 Patients are stratified for risk of death as follows: : low risk (less than 1% mortality risk) -r 2: intermediate risk (1‑10% mortality risk) -r 4: high risk (more than 10% mortality risk). Use clinical judgement in conjunction with the CRB65 score to inform decisions about whether patients need hospital assessment as follows: consider home‑based care for patients with a CRB65 score of 0 consider hospital assessment for all other patients, particularly those with a CRB65 score of 2 or more. ## Severity assessment in hospital When a diagnosis of community-acquired pneumonia is made at presentation to hospital, determine whether patients are at low, intermediate or high risk of death using the CURB65 score (see box 2). Box 2 CURB65 score for mortality risk assessment in hospital CURB65 score is calculated by giving 1 point for each of the following prognostic features: confusion (abbreviated Mental Test score 8 or less, or new disorientation in person, place or time). For guidance on delirium, see the NICE guideline on delirium raised blood urea nitrogen (over 7 mmol/litre) raised respiratory rate (30 breaths per minute or more) low blood pressure (diastolic 60 mmHg or less, or systolic less than 90 mmHg) age 65 years or more. Patients are stratified for risk of death as follows: -r 1: low risk (less than 3% mortality risk) : intermediate risk (3‑15% mortality risk) to 5: high risk (more than 15% mortality risk). Lim WS, van der Eerden MM, Laing R, et al. (2003) Defining community‑acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 58: 377–82 Use clinical judgement in conjunction with the CURB65 score to guide the management of community‑acquired pneumonia, as follows: consider home‑based care for patients with a CURB65 score of 0 or 1 consider hospital‑based care for patients with a CURB65 score of 2 or more consider intensive care assessment for patients with a CURB65 score of 3 or more. Stratify patients presenting with community‑acquired pneumonia into those with low‑, moderate‑ or high‑severity disease. The grade of severity will usually correspond to the risk of death. ## Microbiological tests Do not routinely offer microbiological tests to patients with low‑severity community‑acquired pneumonia. For patients with moderate‑ or high‑severity community‑acquired pneumonia: take blood and sputum cultures and consider pneumococcal and legionella urinary antigen tests. ## Timely diagnosis and treatment Put in place processes to allow diagnosis (including X‑rays) and treatment of community‑acquired pneumonia within 4 hours of presentation to hospital. ## Antibiotic therapy See the NICE guideline on pneumonia (community-acquired): antimicrobial prescribing for recommendations on antibiotic therapy. Deleted. Deleted. Deleted. Deleted. Deleted. Deleted. Deleted. Deleted. ## Glucocorticoid treatment Do not routinely offer a glucocorticoid to patients with community‑acquired pneumonia unless they have other conditions for which glucocorticoid treatment is indicated. ## Monitoring in hospital Consider measuring a baseline C‑reactive protein concentration in patients with community‑acquired pneumonia on admission to hospital, and repeat the test if clinical progress is uncertain after 48 to 72 hours. ## Safe discharge from hospital Do not routinely discharge patients with community‑acquired pneumonia if in the past 24 hours they have had 2 or more of the following findings: temperature higher than 37.5°C respiratory rate 24 breaths per minute or more heart rate over 100 beats per minute systolic blood pressure 90 mmHg or less -xygen saturation under 90% on room air abnormal mental status inability to eat without assistance. Consider delaying discharge for patients with community‑acquired pneumonia if their temperature is higher than 37.5°C. ## Patient information Explain to patients with community‑acquired pneumonia that after starting treatment their symptoms should steadily improve, although the rate of improvement will vary with the severity of the pneumonia, and most people can expect that by: week: fever should have resolved weeks: chest pain and sputum production should have substantially reduced weeks: cough and breathlessness should have substantially reduced months: most symptoms should have resolved but fatigue may still be present months: most people will feel back to normal. Advise patients with community‑acquired pneumonia to consult their healthcare professional if they feel that their condition is deteriorating or not improving as expected. # Hospital-acquired pneumonia ## Antibiotic therapy See the NICE guideline on pneumonia (hospital-acquired): antimicrobial prescribing for recommendations on antibiotic therapy for hospital-acquired pneumonia. Deleted. Deleted. Deleted.# Research recommendations The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. # Urine antigen testing In moderate‑ to high‑severity community‑acquired pneumonia does using legionella and pneumococcal urinary antigen testing in addition to other routine tests improve outcomes? ## Why this is important Current practice and evidence suggest that giving a combination of antibiotics to patients with moderate‑ to high‑severity community‑acquired pneumonia reduces mortality. However, no randomised controlled trial has looked at using urinary antigen testing to target treatment. If effective, such targeted treatment could improve antibiotic stewardship, increase compliance and potentially reduce costs. # C-reactive protein-guided antibiotic duration In patients hospitalised with moderate‑ to high‑severity community‑acquired pneumonia, does using C‑reactive protein monitoring in addition to clinical observation to guide antibiotic duration safely reduce the total duration of antibiotic therapy compared with a fixed empirical antibiotic course? ## Why this is important The recommended duration of antibiotic therapy for adults hospitalised with moderate‑ to high‑severity community‑acquired pneumonia is based on evidence of very low quality; no relevant clinical trials were identified by NICE. The burden of community‑acquired pneumonia is large, and its treatment accounts for a high proportion of antibiotic use in hospitals. Overuse of antibiotics is associated with antimicrobial resistance, which is a national and global priority. # Continuous positive pressure ventilation What is the clinical effectiveness of continuous positive pressure ventilation compared with usual care in patients with community‑acquired pneumonia and type I respiratory failure without a history of chronic obstructive pulmonary disease? ## Why this is important Type I respiratory failure is a common feature of pneumonia. Mild type I respiratory failure is easily corrected with low levels of supplemental oxygen, whereas severe life‑threatening hypoxemia needs immediate intubation and invasive ventilation. Research into whether continuous positive pressure ventilation improves gas exchange and subsequent outcomes, such as mortality, could help improve care for patients with respiratory failure between these extremes. # Hospital-acquired pneumonia Can rapid microbiological diagnosis of hospital‑acquired pneumonia reduce the use of extended-spectrum antibiotic therapy, without adversely affecting outcomes? ## Why this is important Data are limited on the microbiology of hospital‑acquired pneumonia to guide antibiotic therapy. Hospital‑acquired infections can be caused by highly resistant pathogens that need treatment with extended‑spectrum antibiotics (for example, extended‑spectrum penicillins, third‑generation cephalosporins, aminoglycosides, carbapenems, linezolid, vancomycin, or teicoplanin), as recommended by British Society of Antimicrobial Chemotherapy guidance. Because routine microbial tests lack sensitivity and take 24–48 hours to identify a causative pathogen, patient characteristics are used to guide antibiotic choice. However, this may lead to unnecessary use of extended‑spectrum antibiotics in patients infected with non‑resistant organisms, and inappropriate use of first‑line antibiotics (such as beta‑lactam stable penicillins, macrolides or doxycycline) in patients infected with resistant organisms. Rapid diagnostic tests to identify causative bacterial pathogens and determine whether they are resistant to antibiotics may have a role in guiding antibiotic choice for postoperative hospital‑acquired pneumonia. To limit population variability and include high‑risk patients spending time in intensive care, studies should include postoperative patients from different surgical specialties.	{'Introduction': "Pneumonia is an infection of the lung tissue. When a person has pneumonia the air sacs in their lungs become filled with microorganisms, fluid and inflammatory cells and their lungs are not able to work properly. Diagnosis of pneumonia is based on symptoms and signs of an acute lower respiratory tract infection, and can be confirmed by a chest X‑ray showing new shadowing that is not due to any other cause (such as pulmonary oedema or infarction). In this guideline pneumonia is classified as community‑acquired or hospital‑acquired, based on different microbial causes and patient factors, which need different management strategies.\n\nEvery year between 0.5% and 1%\xa0of adults in the UK will have community‑acquired pneumonia. It is diagnosed in 5–12%\xa0of adults who present to GPs with symptoms of lower respiratory tract infection, and 22–42%\xa0of these are admitted to hospital, where the mortality rate is between 5% and 14%. Between 1.2% and 10%\xa0of adults admitted to hospital with community‑acquired pneumonia are managed in an intensive care unit, and for these patients the risk of dying is more than 30%. More than half of pneumonia‑related deaths occur in people older than 84\xa0years.\n\nAt any time 1.5%\xa0of hospital inpatients in England have a hospital‑acquired respiratory infection, more than half of which are hospital‑acquired pneumonia and are not associated with intubation. Hospital‑acquired pneumonia is estimated to increase hospital stay by about 8\xa0days and has a reported mortality rate that ranges from 30–70%. Variations in clinical management and outcome occur across the UK.\n\nThe guideline is needed because pneumonia is common and has a high mortality rate. The\xa0 British Thoracic Society (2009) has published guidance on the management of\xa0community-acquired pneumonia in adults, but there is a lack of evidence‑based guidance on the management of hospital‑acquired pneumonia. For both types of pneumonia there is variation in care and areas of uncertainty for best practice, and these are the main focus of this guideline.\n\nThis guideline provides recommendations for the diagnosis of pneumonia, and aspects of management of community‑acquired pneumonia in adults. However, it does not provide recommendations on areas of care where best practice is already established, such as diagnosis using chest X‑ray. It does not cover bronchiectasis complicated by pneumonia, or patients who acquire pneumonia while intubated or in an intensive care unit, who are immunocompromised, or in whom management of pneumonia is an expected part of end‑of‑life care. For guidance on antibiotic treatment of pneumonia, see NICE's guidelines on pneumonia (community-acquired): antimicrobial prescribing\xa0and pneumonia (hospital-acquired): antimicrobial prescribing.", 'Recommendations': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Terms used in this guideline\n\n## Clinical diagnosis of community-acquired pneumonia\n\nDiagnosis based on symptoms and signs of lower respiratory tract infection in a patient who, in the opinion of the GP and in the absence of a chest X‑ray, is likely to have community‑acquired pneumonia. This might be because of the presence of focal chest signs, illness severity or other features.\n\n## Community-acquired pneumonia\n\nPneumonia that is acquired outside hospital. Pneumonia that develops in a nursing home resident is included in this definition. When managed in hospital the diagnosis is usually confirmed by chest X‑ray.\n\n## Hospital-acquired pneumonia\n\nPneumonia that develops 48\xa0hours or more after hospital admission and that was not incubating at hospital admission. When managed in hospital the diagnosis is usually confirmed by chest X‑ray. For the purpose of this guideline, pneumonia that develops in hospital after intubation (ventilator‑associated pneumonia) is excluded from this definition.\n\n## Lower respiratory tract infection\n\nAn acute illness (present for 21\xa0days or less), usually with cough as the main symptom, and with at least 1\xa0other lower respiratory tract symptom (such as fever, sputum production, breathlessness, wheeze or chest discomfort or pain) and no alternative explanation (such as sinusitis or asthma). Pneumonia, acute bronchitis and exacerbation of chronic obstructive airways disease are included in this definition.\n\n## Mortality risk\n\nThe percentage likelihood of death occurring in a patient in the next 30\xa0days.\n\n## Severity assessment\n\nA judgement by the managing clinician as to the likelihood of adverse outcomes in a patient. This is based on a combination of clinical understanding and knowledge in addition to a mortality risk score. The difference between categories of severity and mortality risk can be important. Typically the mortality risk score will match the severity assessment. However, there may be situations where the mortality score does not accurately predict mortality risk and clinical judgement is needed. An example might be a patient with a low mortality risk score who has an unusually low oxygen level, who would be considered to have a severe illness.\n\n# Presentation with lower respiratory tract infection\n\nFor people presenting with symptoms of lower respiratory tract infection in primary care, consider a point of care C‑reactive protein test if after clinical assessment a diagnosis of pneumonia has not been made and it is not clear whether antibiotics should be prescribed. Use the results of the C‑reactive protein test to guide antibiotic prescribing in people without a clinical diagnosis of pneumonia as follows:\n\nDo not routinely offer antibiotic therapy if the C‑reactive protein concentration is less than 20\xa0mg/litre.\n\nConsider a delayed antibiotic prescription (a prescription for use at a later date if symptoms worsen) if the C‑reactive protein concentration is between 20\xa0mg/litre and 100\xa0mg/litre.\n\nOffer antibiotic therapy if the C‑reactive protein concentration is greater than 100\xa0mg/litre.\n\n# Community-acquired pneumonia\n\n## Severity assessment in primary care\n\nWhen a clinical diagnosis of community-acquired pneumonia is made in primary care, determine whether patients are at low, intermediate or high risk of death using the CRB65 score (see box\xa01).\n\nBox 1 CRB65 score for mortality risk assessment in primary care\n\nCRB65 score is calculated by giving 1\xa0point for each of the following prognostic features:\n\nconfusion (abbreviated Mental Test score 8\xa0or less, or new disorientation in person, place or time). For guidance on delirium, see the NICE guideline on delirium.\n\nraised respiratory rate (30 breaths per minute or more)\n\nlow blood pressure (diastolic 60\xa0mmHg or less, or systolic less than 90\xa0mmHg)\n\nage 65\xa0years or more.\n\nLim WS, van der Eerden MM, Laing R, et al. (2003) Defining community‑acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 58: 377–82\n\nPatients are stratified for risk of death as follows:\n\n: low risk (less than 1% mortality risk)\n\nor 2: intermediate risk (1‑10% mortality risk)\n\nor 4: high risk (more than 10% mortality risk).\n\nUse clinical judgement in conjunction with the CRB65 score to inform decisions about whether patients need hospital assessment as follows:\n\nconsider home‑based care for patients with a CRB65 score of 0\n\nconsider hospital assessment for all other patients, particularly those with a CRB65 score of 2 or more.\n\n## Severity assessment in hospital\n\nWhen a diagnosis of community-acquired pneumonia is made at presentation to hospital, determine whether patients are at low, intermediate or high risk of death using the CURB65 score (see box\xa02).\n\nBox 2 CURB65 score for mortality risk assessment in hospital\n\nCURB65 score is calculated by giving 1\xa0point for each of the following prognostic features:\n\nconfusion (abbreviated Mental Test score 8\xa0or less, or new disorientation in person, place or time). For guidance on delirium, see the NICE guideline on delirium\n\nraised blood urea nitrogen (over 7\xa0mmol/litre)\n\nraised respiratory rate (30\xa0breaths per minute or more)\n\nlow blood pressure (diastolic 60\xa0mmHg or less, or systolic less than 90\xa0mmHg)\n\nage 65\xa0years or more.\n\nPatients are stratified for risk of death as follows:\n\nor 1: low risk (less than 3%\xa0mortality risk)\n\n: intermediate risk (3‑15%\xa0mortality risk)\n\nto 5: high risk (more than 15%\xa0mortality risk).\n\nLim WS, van der Eerden MM, Laing R, et al. (2003) Defining community‑acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 58: 377–82\n\nUse clinical judgement in conjunction with the CURB65 score to guide the management of community‑acquired pneumonia, as follows:\n\nconsider home‑based care for patients with a CURB65 score of 0\xa0or\xa01\n\nconsider hospital‑based care for patients with a CURB65 score of 2\xa0or more\n\nconsider intensive care assessment for patients with a CURB65 score of 3\xa0or more.\n\nStratify patients presenting with community‑acquired pneumonia into those with low‑, moderate‑ or high‑severity disease. The grade of severity will usually correspond to the risk of death.\n\n## Microbiological tests\n\nDo not routinely offer microbiological tests to patients with low‑severity community‑acquired pneumonia.\n\nFor patients with moderate‑ or high‑severity community‑acquired pneumonia:\n\ntake blood and sputum cultures and\n\nconsider pneumococcal and legionella urinary antigen tests.\n\n## Timely diagnosis and treatment\n\nPut in place processes to allow diagnosis (including X‑rays) and treatment of community‑acquired pneumonia within 4\xa0hours of presentation to hospital.\n\n## Antibiotic therapy\n\nSee the\xa0NICE guideline on pneumonia (community-acquired): antimicrobial prescribing for recommendations on antibiotic therapy.\n\nDeleted.\n\nDeleted.\n\nDeleted.\n\nDeleted.\n\nDeleted.\n\nDeleted.\n\nDeleted.\n\nDeleted.\n\n## Glucocorticoid treatment\n\nDo not routinely offer a glucocorticoid to patients with community‑acquired pneumonia unless they have other conditions for which glucocorticoid treatment is indicated.\n\n## Monitoring in hospital\n\nConsider measuring a baseline C‑reactive protein concentration in patients with community‑acquired pneumonia on admission to hospital, and repeat the test if clinical progress is uncertain after 48\xa0to 72\xa0hours.\n\n## Safe discharge from hospital\n\nDo not routinely discharge patients with community‑acquired pneumonia if in the past 24\xa0hours they have had 2\xa0or more of the following findings:\n\ntemperature higher than\xa037.5°C\n\nrespiratory rate 24\xa0breaths per minute or more\n\nheart rate over 100\xa0beats per minute\n\nsystolic blood pressure 90\xa0mmHg or less\n\noxygen saturation under 90%\xa0on room air\n\nabnormal mental status\n\ninability to eat without assistance.\n\nConsider delaying discharge for patients with community‑acquired pneumonia if their temperature is higher than 37.5°C.\n\n## Patient information\n\nExplain to patients with community‑acquired pneumonia that after starting treatment their symptoms should steadily improve, although the rate of improvement will vary with the severity of the pneumonia, and most people can expect that by:\n\nweek: fever should have resolved\n\nweeks: chest pain and sputum production should have substantially reduced\n\nweeks: cough and breathlessness should have substantially reduced\n\nmonths: most symptoms should have resolved but fatigue may still be present\n\nmonths: most people will feel back to normal.\n\nAdvise patients with community‑acquired pneumonia to consult their healthcare professional if they feel that their condition is deteriorating or not improving as expected.\n\n# Hospital-acquired pneumonia\n\n## Antibiotic therapy\n\nSee the\xa0NICE guideline on pneumonia (hospital-acquired): antimicrobial prescribing for recommendations on antibiotic therapy for hospital-acquired pneumonia.\n\nDeleted.\n\nDeleted.\n\nDeleted.", 'Research recommendations': 'The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Urine antigen testing\n\nIn moderate‑\xa0to high‑severity community‑acquired pneumonia does using legionella and pneumococcal urinary antigen testing in addition to other routine tests improve outcomes?\n\n## Why this is important\n\nCurrent practice and evidence suggest that giving a combination of antibiotics to patients with moderate‑\xa0to high‑severity community‑acquired pneumonia reduces mortality. However, no randomised controlled trial has looked at using urinary antigen testing to target treatment. If effective, such targeted treatment could improve antibiotic stewardship, increase compliance and potentially reduce costs.\n\n# C-reactive protein-guided antibiotic duration\n\nIn patients hospitalised with moderate‑\xa0to high‑severity community‑acquired pneumonia, does using C‑reactive protein monitoring in addition to clinical observation to guide antibiotic duration safely reduce the total duration of antibiotic therapy compared with a fixed empirical antibiotic course?\n\n## Why this is important\n\nThe recommended duration of antibiotic therapy for adults hospitalised with moderate‑\xa0to high‑severity community‑acquired pneumonia is based on evidence of very low quality; no relevant clinical trials were identified by NICE. The burden of community‑acquired pneumonia is large, and its treatment accounts for a high proportion of antibiotic use in hospitals. Overuse of antibiotics is associated with antimicrobial resistance, which is a national and global priority.\n\n# Continuous positive pressure ventilation\n\nWhat is the clinical effectiveness of continuous positive pressure ventilation compared with usual care in patients with community‑acquired pneumonia and type I respiratory failure without a history of chronic obstructive pulmonary disease?\n\n## Why this is important\n\nType I respiratory failure is a common feature of pneumonia. Mild type I respiratory failure is easily corrected with low levels of supplemental oxygen, whereas severe life‑threatening hypoxemia needs immediate intubation and invasive ventilation. Research into whether continuous positive pressure ventilation improves gas exchange and subsequent outcomes, such as mortality, could help improve care for patients with respiratory failure between these extremes.\n\n# Hospital-acquired pneumonia\n\nCan rapid microbiological diagnosis of hospital‑acquired pneumonia reduce the use of extended-spectrum antibiotic therapy, without adversely affecting outcomes?\n\n## Why this is important\n\nData are limited on the microbiology of hospital‑acquired pneumonia to guide antibiotic therapy. Hospital‑acquired infections can be caused by highly resistant pathogens that need treatment with extended‑spectrum antibiotics (for example, extended‑spectrum penicillins, third‑generation cephalosporins, aminoglycosides, carbapenems, linezolid, vancomycin, or teicoplanin), as recommended by British Society of Antimicrobial Chemotherapy guidance. Because routine microbial tests lack sensitivity and take 24–48\xa0hours to identify a causative pathogen, patient characteristics are used to guide antibiotic choice. However, this may lead to unnecessary use of extended‑spectrum antibiotics in patients infected with non‑resistant organisms, and inappropriate use of first‑line antibiotics (such as beta‑lactam stable penicillins, macrolides or doxycycline) in patients infected with resistant organisms.\n\nRapid diagnostic tests to identify causative bacterial pathogens and determine whether they are resistant to antibiotics may have a role in guiding antibiotic choice for postoperative hospital‑acquired pneumonia.\n\nTo limit population variability and include high‑risk patients spending time in intensive care, studies should include postoperative patients from different surgical specialties.'}	https://www.nice.org.uk/guidance/cg191	This guideline was developed before the COVID-19 pandemic. It covers diagnosing and managing pneumonia in adults who do not have COVID-19. It aims to improve accurate assessment and diagnosis of pneumonia to help guide antibiotic prescribing and ensure that people receive the right treatment.
b78cc77e0be5d01702840e4d2149db1216fc5002	nice	Social, emotional and mental wellbeing in primary and secondary education	Social, emotional and mental wellbeing in primary and secondary education This guideline covers ways to support social, emotional and mental wellbeing in children and young people in primary and secondary education (key stages 1 to 5), and people 25 years and under with special educational needs or disability in further education colleges. It aims to promote good social, emotional and psychological health to protect children and young people against behavioural and health problems. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. Recommendations relating to parents or carers might be less relevant to older young people, especially those in post-16 education settings and may need to be interpreted accordingly. For the purposes of this guideline, the term 'school' covers schools, colleges, further education providers and other educational settings. # Whole-school approach Adopt a whole-school approach to support positive social, emotional and mental wellbeing of staff, children and young people (including people with a neurodiverse condition) in primary and secondary education. Ensure that the school has a culture, ethos and practice that strengthens relational approaches and inclusion, and that recognises the importance of psychological safety. Review the school's policies and procedures regularly to make sure that they promote social, emotional and mental wellbeing positively and consistently. This should include making them consistent with relational approaches to social, emotional and mental wellbeing. Review regularly the school's accessibility plan, medical conditions policy and approach to understanding behaviour, taking into account neurodiversity and communication needs. Also take into account the value of trauma-informed approaches and parental co-production. Consider monitoring and evaluating the impact and effectiveness of the whole-school approach as part of a school improvement strategy. ## Supporting the whole-school approach Support the whole-school approach by: having an outward-facing approach to the community and to engaging with local communities and groups strengthening links to external agencies that can provide additional support, such as local children's health and care services and relevant voluntary and community sector organisations having shared principles for engagement between education and mental health services, for example agreeing referral pathways promoting the involvement of education providers in wider local strategic decision making about children and young people's mental health having ways of feeding back to parents and carers. Ensure that school governance structures support the whole-school approach and that school leadership is actively involved in supporting the whole-school approach. Make the responsibility for social, emotional and mental wellbeing curriculum content part of the remit of school leadership (including governance). ## Supporting staff Ensure that staff have continuing professional development to support both their own wellbeing and the implementation of the school's approach. This could include training in emotional literacy, trauma, neurodiversity, communication needs and relational approaches. Signpost staff to quality-assured local and national resources to support their wellbeing in line with the Department for Education's education staff wellbeing charter. Support staff in their pastoral roles by providing protected time for supervision and continuing professional development. Make peer supervision available for teachers and other school staff to enable them to have space and support to discuss issues and reflect on practice. Ensure that all teachers can recognise children and young people's pastoral needs, and that they understand the wider context of the pupils' lived experiences and how they interact with their environment. Provide them with additional training or support if needed. Ensure that all information held by the school related to the local early help offer is kept up to date. ## Involving families and pupils Involve parents and carers in designing and implementing the whole‑school approach. Involve children and young people in discussing and agreeing whole‑school approaches and communicate with them regularly about decisions, so they understand how their views inform practice. Take into account the opinions of all members of the school community. This may mean making adjustments to address neurodiversity and communication needs. ## Implementing the whole-school approach Designate a lead person to determine what is needed to successfully implement universal curriculum interventions. The lead should also be the go-to person for advice on the most appropriate educational resources for any intervention. The lead person should be someone in a leadership post who has strategic responsibilities and oversight of social, emotional and mental wellbeing across the school. When implementing whole-school approaches, take into account the core values that the school culture and practice are built on, and the psychological safety of pupils, staff members and leadership. For example, this could involve developing a school culture and ethos in which children, young people and staff feel safe to make and learn from mistakes. Adopt a 'graduated response' (or 'step up–step down') approach to support (moving between universal and targeted support as relevant) as an integral part of the whole-school approach alongside broader universal approaches. Ensure that staff understand this approach and have the right support to implement it (see the recommendations on targeted support). ## Local support Local public health departments, and children and young people's mental health services, should proactively gather and be responsive to the views and concerns of schools and colleges in their area about children and young people's social, emotional and mental wellbeing. Local authorities should compile, and keep up to date, a directory of the local services that promote children and young people's social emotional and mental wellbeing and are available to support schools in their area. This should include: what the services can offer local mental health and special educational needs and disability (SEND) services, including services that might be less well known details of how to access the services. Take risk factors for poor social, emotional and mental wellbeing into account when developing the Joint Strategic Needs Assessment. This should include the contribution that schools can make to improving social, emotional and mental wellbeing and take into account schools' impact on learning and life chances (see the recommendations on identification and risk factors). The local integrated care system and schools should work together to identify opportunities for joint practice to support the social, emotional and mental wellbeing of children and young people, for example agreeing principles for when and how to share information. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on whole-school approach . Full details of the evidence and the committee's discussion are in evidence review A: whole-school approaches. Loading. Please wait. # Universal curriculum content Ensure that the curriculum for all pupils includes evidence-based, culturally appropriate information about social, emotional and mental wellbeing to develop children and young people's knowledge and skills as part of the whole-school approach. Take account of the Department for Education's relationships education, relationships and sex education, and health education guidance when selecting or developing universal curriculum content. Use an approach that builds on children and young people's previous learning (for example, a spiral curriculum) when planning and delivering a curriculum intervention for all pupils. Integrate relevant activities into all aspects of education to reinforce the curriculum offer about social, emotional and mental wellbeing and skills. Use non-judgemental 'strengths-based' approaches to support children and young people's social, emotional and mental wellbeing. These are approaches to improve or develop their: self-worth (for example, self-esteem, empowerment, self-care) skills (for example, problem solving skills, social skills, communication skills) resilience (for example, coping skills and strategies, perseverance). Use universal interventions that align with the whole-school approach, for example 'child- (or young person) to-trusted-adult' support. Consider universal interventions informed by mindfulness or cognitive behavioural approaches (including trauma-focused cognitive behavioural approaches) for all children and young people. These should be delivered by trained staff who can teach children and young people how to use the approach and support them when they do. Consider including regular rhythmic physical activity in the universal curriculum. If it is included, ensure that there is time and space available for this. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on universal curriculum content . Full details of the evidence and the committee's discussion are in: evidence review B: universal curriculum approaches evidence review C: qualitative evidence synthesis for universal curriculum approaches. Loading. Please wait. # Identifying children and young people at risk of poor social, emotional and mental wellbeing ## Identification and risk factors When considering whether a child or young person has risk factors for poor social, emotional and mental wellbeing, take into account: the number, duration and complexity of risk and protective factors, their cumulative effects and interactions between them that the effects of risk and protective factors, or combinations of factors, might differ across life stages that they may have unidentified or unmet educational needs, for example special educational needs or disabilities that impact on their ability to access education.For a list of risk and protective factors, see table 1 in the Department for Education's mental health and behaviour in schools guidance. Be aware that the list is not exhaustive. Base the identification of children and young people at risk of poor social, emotional and mental wellbeing on information from a variety of sources, for example observation, self-report and consideration of their early life experiences. Be aware that some children and young people will internalise their distress and will therefore be more difficult to identify. Assess children and young people identified as at risk and decide whether to monitor their social, emotional and mental wellbeing or to offer them targeted support (see the recommendations on tools and techniques). Take into account any existing assessments, for example from educational psychologists or child and adolescent mental health services. When identifying risk in children and young people with disabilities or special educational needs, ensure that staff understand the graduated response to need as specified in the current Department of Health and Social Care and Department for Education's special educational needs and disability (SEND) code of practice, and that they can respond with relevant interventions. If necessary, they should seek input from specialised external agencies. ## Tools and techniques If using a tool or technique to assess a child or young person who has been identified as at risk of poor social, emotional or mental wellbeing, consider using one that is validated (see Public Health England's guidance on measuring mental wellbeing in children and young people). When selecting a tool or technique to assess social, emotional and mental wellbeing, take into account: the child or young person's needs, wishes and feelings the purpose of the assessment how the tool or technique fits with the school culture and ethos contextual factors, such as the child or young person's chronological or developmental age or ethnicity and any communication needs (being aware that assessment tools are context specific and vary in quality). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on identifying children and young people at risk of poor social, emotional and mental wellbeing . Full details of the evidence and the committee's discussion are in: evidence review D: risk factors for poor social, emotional and mental wellbeing evidence review E: qualitative review for risk factors for poor social, emotional and mental wellbeing evidence review F: risk factors for poor social, emotional and mental wellbeing. Loading. Please wait. # Targeted support Have clear guidance on how to identify individual children and young people and groups of people for targeted support based on their specific needs (see the section on identifying children and young people at risk of poor social, emotional and mental wellbeing). Offer targeted individual or group support to children and young people who have been identified as needing additional social, emotional or mental health support. Use trained, experienced practitioners who are competent to provide the support. Any support should be culturally sensitive and take into account possible neurodiversity, communication needs and other needs of the child or young person. Actively involve the parents or carers of the child or young person when deciding whether to offer targeted support (but think about whether the young person is competent to give their consent or there are reasons not to involve the parents or carers). Discuss with them any support that is being proposed and make sure that they understand it and agree with it. Explain the targeted support to the child or young person and involve them in decisions about the support offered to them, including when and where it is offered. Where appropriate and possible, obtain their agreement before starting the support. Take into account the range of individual needs and risks when putting together a group for targeted group support, including the developmental age and cultural background of the pupils it is being delivered to. Promote a range of targeted support, including peer-to-peer support, that allows children and young people to express difficult feelings and talk about their experiences. Aim to minimise the risk of any unintended adverse consequences and stigma and proactively normalise seeking support. Take care not to reinforce bullying by singling people out for support. Ensure that all targeted support is delivered collaboratively with any other external agencies or services, the professional network around the child or young person and any support that the child or young person is already receiving. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on targeted support . Full details of the evidence and the committee's discussion are in: evidence review G: targeted social and emotional support evidence review H: targeted mental health support. Loading. Please wait. # Support with school-related transitions and other life changes ## All transitions and life changes Train staff to recognise the wide-ranging impacts of transitions and life changes on children and young people's social, emotional and mental wellbeing, taking into account that they may differ between individuals, for example because of cultural background, age and gender. This includes recognising both planned (for example, moving between schools or classes) and unanticipated life changes, and the different ways that a child or young person typically expresses their mental health problems and responds to trauma. ## Transitions between schools and classes or leaving education Plan and offer tailored interventions to prepare children and young people for educational transitions and for leaving education completely. This includes: Establishing a relationship with the child or young person and their parent or carer. Gathering the child or young person's views about their transition. Supporting the child or young person to feel ready for the transition, for example understanding how they will get to and from the new school or job. Sharing with the new class or school and staff information about the child or young person that will help them. The information should be positive and not set out to victimise or stigmatise them, and it should be shared in line with the National Data Guardian's Caldicott principles. Identifying and communicating with the professional and personal network around the child or young person, if there is one, as part of good transition support.Also follow these principles for any managed moves (in which a child or young person is placed in a new school by the local authority or by school-to-school voluntary agreement). Support the child or young person at the time of the educational transition to cope with the loss of important relationships caused by the transition. Enhance children and young people's sense of belonging in the new school or class, for example by organising a peer mentor or buddy for them (see recommendation 1.4.6). ## After transitions between schools Check on an ongoing basis to see whether the child or young person is settling in and thriving after moving to a new education setting. Offer them tailored support if necessary. Check more regularly if the child or young person is at a higher risk of poor social, emotional and mental wellbeing. Promote peer mentoring between a child or young person entering a new education setting and a peer who has training in mentoring (see recommendation 1.4.6). ## Significant life changes Address needs identified by children or young people (or their parents or carers) going through significant life changes, mental health problems or mental illness. This should involve the special educational needs and disabilities coordinator (SENCo) or designated safeguarding lead and other agencies if necessary. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on transitions . Full details of the evidence and the committee's discussion are in evidence review I: interventions to support children and young people during periods of transition. Loading. Please wait. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local Act Personal Care and Support Jargon Buster. ## Adverse childhood experiences Highly stressful, and potentially traumatic, events or situations that occur during childhood or adolescence. They can be a single event, or prolonged threats to, and breaches of, the child or young person's safety, security, trust or bodily integrity. ## Early help Providing support as soon as a problem emerges, at any point in a child's life. For example, see the Early Intervention Foundation. ## Psychological safety The belief that one is in a safe place and will not be punished or humiliated for speaking up with ideas, questions, concerns or mistakes. ## Punitive behaviour management systems An approach to classroom or school management that focuses on establishing clear expectations for appropriate behaviour, monitoring behaviour, and then reinforcing appropriate behaviour and redirecting or sanctioning inappropriate behaviour. ## Relational approaches Approaches that emphasise connection, belonging and the teaching of effective conflict resolution skills. These approaches assume that behaviour is a means of communication and that behaviour that challenges can be a sign of unmet emotional needs. Relational approaches approach behaviour with curiosity rather than judgement. They are grounded in psychological theory and support children to build their self-regulation skills. They take account of context and the child or young person's lived experiences. ## Rhythmic physical activity Any kind of activity that is based on a steady and prominent beat. During rhythmic activities individuals participate in rhythmic body movement, for example rebounding on a trampoline or moving to a beat. ## Spiral curriculum A course of study in which pupils study the same topics in ever-increasing complexity throughout their time at school to reinforce previous lessons. ## Targeted support Support aimed at individuals or groups who have been identified as being at greater risk of poor social, emotional and mental wellbeing. ## Trauma-informed approaches Approaches to support children and young people who suffer with trauma or mental health problems and whose troubled behaviour is a barrier to learning. ## Trusted adults Adults that children and young people can turn to in times of worry, stress or crisis. ## Universal curriculum content Curriculum content that is for everyone. ## Whole-school approach For the purposes of this guideline, 'whole-school' also covers colleges, further education providers and other educational settings. A whole-school approach defines the entire school community as a single unit and involves coordinated action between 3 interrelated components: curriculum, teaching and learning school ethos and environment family and community partnership. The 8 principles to promoting a whole-school and college approach to mental health andwellbeing are set out in Department for Education and Public Health England's guidance on promoting children and young people's mental health and wellbeing.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Early signs of poor social, emotional and mental wellbeing What are the early signs of social, emotional and mental wellbeing issues, including in children and young people who are internalising it? a) What early factors predict poor social, emotional and mental wellbeing? b) How do children and young people with poor social, emotional and mental wellbeing describe their thoughts and feelings at early onset stage? c) What are the barriers and facilitators to identifying children and young people at risk of poor social, emotional and mental wellbeing at school? For a short explanation of why the committee made the recommendation for research, see the rationale section on identifying children and young people at risk of poor social, emotional and mental wellbeing . Full details of the evidence and the committee's discussion are in: evidence review D: risk factors for poor social, emotional and mental wellbeing evidence review E: qualitative review for risk factors for poor social, emotional and mental wellbeing evidence review F: risk factors for poor social, emotional and mental wellbeing. Loading. Please wait. ## Intersecting social, cultural and personal factors What is the role of intersecting social, cultural and personal factors in developing poor social, emotional and mental wellbeing? For a short explanation of why the committee made the recommendation for research, see the rationale section on identifying children and young people at risk of poor social, emotional and mental wellbeing . Full details of the evidence and the committee's discussion are in: evidence review D: risk factors for poor social, emotional and mental wellbeing evidence review E: qualitative review for risk factors for poor social, emotional and mental wellbeing evidence review F: risk factors for poor social, emotional and mental wellbeing. Loading. Please wait. ## Targeted support What is the effectiveness (including long-term effectiveness) and cost effectiveness of targeted group or individual interventions for children and young people who have been identified as needing additional mental health support, and does it vary by ethnicity, socioeconomic status or other cultural and personal factors? For a short explanation of why the committee made the recommendation for research, see the rationale section on targeted support . Full details of the evidence and the committee's discussion are in: evidence review G: targeted social and emotional support evidence review H: targeted mental health support. Loading. Please wait. ## Effectiveness of interventions What components of interventions or approaches to promote social, emotional and mental wellbeing are effective and cost effective? For a short explanation of why the committee made the recommendation for research, see the rationale section on whole-school approach . Full details of the evidence and the committee's discussion are in: evidence review G: targeted social and emotional support evidence review H: targeted mental health support. Loading. Please wait. ## System leadership and service delivery How can practitioners, institutions and organisations work together to improve systems leadership that impacts collectively on positive outcomes for children and young people's social, emotional and mental wellbeing? For a short explanation of why the committee made the recommendation for research, see the rationale section on whole-school approach . Full details of the evidence and the committee's discussion are in evidence review A: whole-school approaches. Loading. Please wait. # Other recommendations for research ## Children and young people with special educational needs Are children and young people with special educational needs at higher risk of poor social, emotional and mental wellbeing? For a short explanation of why the committee made the recommendation for research, see the rationale section on identifying children and young people at risk of poor social, emotional and mental wellbeing . Full details of the evidence and the committee's discussion are in: evidence review D: risk factors for poor social, emotional and mental wellbeing evidence review E: qualitative review for risk factors for poor social, emotional and mental wellbeing evidence review F: risk factors for poor social, emotional and mental wellbeing. Loading. Please wait. ## Harms and unintended consequences What are the possible harms and unintended consequences of targeted group or individual interventions for children and young people who have been identified as needing additional mental health support? For a short explanation of why the committee made the recommendation for research, see the rationale section on targeted support . Full details of the evidence and the committee's discussion are in: evidence review G: targeted social and emotional support evidence review H: targeted mental health support. Loading. Please wait. ## Targeted support What are parents' and carers' views on targeted group or individual interventions for children and young people who have been identified as needing additional mental health support? For a short explanation of why the committee made the recommendation for research, see the rationale section on targeted support . Full details of the evidence and the committee's discussion are in: evidence review G: targeted social and emotional support evidence review H: targeted mental health support. Loading. Please wait. ## Views on transitions to secondary school What are the views and experiences of children about moving to secondary school? For a short explanation of why the committee made the recommendation for research, see the rationale section on support with school-related transitions and other life changes . Full details of the evidence and the committee's discussion are in evidence review I: interventions to support children and young people during periods of transition. Loading. Please wait. ## Support for transitions What do children and young people, including those from underserved populations, find useful to support life changes in the context of their education? For a short explanation of why the committee made the recommendation for research, see the rationale section on support with school-related transitions and other life changes . Full details of the evidence and the committee's discussion are in evidence review I: interventions to support children and young people during periods of transition. Loading. Please wait. ## Impact of COVID-19 What is the medium-to long-term impact of the COVID-19 pandemic on children and young people's social, emotional and mental wellbeing? For a short explanation of why the committee made the recommendation for research, see the rationale section on identifying children and young people at risk of poor social, emotional and mental wellbeing . Full details of the evidence and the committee's discussion are in: evidence review D: risk factors for poor social, emotional and mental wellbeing evidence review E: qualitative review for risk factors for poor social, emotional and mental wellbeing evidence review F: risk factors for poor social, emotional and mental wellbeing. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice or services. # Whole-school approach Recommendations 1.1.1 to 1.1.22 ## Why the committee made the recommendations The committee agreed that the inclusion health agenda (for example, see the Office for Health Improvement and Disparities inclusion health: applying all our health) and tackling inequalities were central to this guideline. When implementing the guideline, schools and wider system partners would need to pay particular attention to marginalised or excluded groups, both in terms of their involvement and in terms of tailoring the recommendations to meet the needs of those groups. The committee made special consideration of the needs of children and young people with learning difficulties and special educational needs and disabilities (SEND). They agreed to place neurodiversity at the heart of their considerations and received expert testimony on the topic to inform their discussions. Professionals from special schools were represented on the committee, and the focus group work with children and young people that NICE commissioned included people from schools with high rates of SEND and from special schools and pupil referral units. The committee discussed the benefits of implementing a whole-school approach for children and young people's social, emotional and mental wellbeing, including preventing the onset of poor outcomes and supporting those with identified needs. They agreed that this could have implications far beyond school environments, for example on employability and anti-social behaviours. The quantitative studies included various whole-school approaches with different combinations of components and various aims, although the strongest evidence was about bullying. They showed some benefit and no harms or adverse consequences. The qualitative evidence showed that pupils and teachers valued whole-school approaches and believed that they had a positive effect on school culture. Overall, the committee agreed that there was some evidence to support the effectiveness of whole-school approaches. There was evidence about the acceptability of whole-school approaches and what made them more or less likely to work, and the committee had more confidence in the findings from these studies than the quantitative ones. This evidence was supported by their expertise and experience and by the testimony of invited expert witnesses. The committee heard expert testimony about relational approaches being more effective than using purely punitive behaviour management systems for managing social, emotional and mental wellbeing in children and young people. Together with this and their own experience and expertise, they agreed that embedding a relational approach in the overall culture and ethos of the school was the basis of a successful whole-school approach, and this would need to be reflected consistently in school policies and procedures. Reviewing policies regularly would help to ensure that this happens. Although the committee were not able to set a specific timeframe for review because there was no evidence, they agreed that annually would be reasonable. They also agreed that leadership was key to embedding this approach and that the leadership needed to come from a senior person. They discussed that this might fit well with the role of the designated school mental health lead. However, because this is a developing role, they agreed it would be premature to specify this. Additionally, having heard expert testimony about trauma-informed approaches in schools, the committee encouraged a shift towards these approaches to understand and therefore manage behaviour. The committee regarded the whole-school approach as a framework that other interventions can slot into. They noted that interventions such as targeted support have a better chance of success if schools actively engage with local agencies. They also agreed that, to be effective, a whole-school approach needed monitoring and evaluating to make sure the approach was working. The committee also noted that it would be more useful if future research focused on the effective components of interventions or approaches (see the recommendation for research on effectiveness of interventions). The committee agreed that school leader support and governance was crucial for a whole-school approach to work and that the whole-school approach needed ongoing engagement with school staff, parents and carers, and the wider community. An effective whole-school approach would also lead to improved integration with external agencies, including mental health services and local public health departments. This is essential to ensure that schools can play an active role in decision making on the local transformation plan for children and young people's mental health. The committee agreed on the importance of collaboration between schools and other services that were not school based but that had an impact on children and young people's social, emotional and mental wellbeing. They noted that, in their experience, schools did not always have mechanisms in place for working with key local services. They agreed that further research was needed to explore how agencies could work together (see the recommendation for research on system leadership and service delivery). The committee discussed the key role of staff in the whole-school approach. They agreed that staff needed to feel supported in their own wellbeing to be able to create an environment that fostered wellbeing in children and young people. Ways to do this include continuing professional development and formal and informal support. Staff need to be able to recognise the pastoral needs of the children and young people they work with, and to understand how these are influenced by their wider life experiences. This can help them to relate better to the child or young person, and to other people who may be involved in their care. Understanding behaviour as a means of communication could help with this. They identified that staff need time and support for pastoral training. The committee noted that there are national and local resources that staff can use to help them manage their own wellbeing. The resources can also help staff keep up to date with local agencies that could help with children and young people's mental health through the early help offer. The evidence supported the committee's view that the school's communication with parents, carers and families is important. The committee agreed that the whole‑school approach worked better if parents, carers and families were involved with the planning of it. Focus group research commissioned by NICE to explore children and young people's perspectives on the draft recommendations identified several important ways of successfully implementing whole-school approaches. Based on the findings of the focus groups, the committee recognised the importance of involving children and young people and capturing their views when agreeing on approaches, including views from minority and seldom-heard groups. This focus group research also identified the importance of effective communication between school staff and children and young people. The committee recognised the need for excellent communication channels between these groups when implementing universal interventions. They also highlighted the importance of taking into account children and young people's views, how much time there was in the curriculum and resourcing, teacher understanding of the interventions and parental engagement for the successful implementation of universal interventions. These factors were identified from the evidence base and the committee's own experiences. The committee discussed the challenges of implementing a whole-school approach. Based on the expert testimony they had heard and on their own expertise and experience in setting up, supporting and evaluating whole-school approaches, they agreed that there were key things they could recommend that would make the implementation smoother. This included the importance of creating a school environment that was a safe space for both teachers and children and young people and where they would not be punished or penalised for mistakes or for speaking up. Also, after hearing from experts, the committee highlighted the significance of core values and strong leadership when implementing a relational whole-school approach. The committee agreed that if the universal curriculum was managed and planned by a specific person it would be better coordinated across the school and could be kept up to date more easily. This person would need to be a senior leader who was able to influence school policy. This coordination could also lead to a more streamlined approach to moving children and young people into and out of targeted interventions (a graduated or 'step up–step down' approach) when universal content was not meeting their social, emotional and mental wellbeing needs. The committee discussed how the whole-school approach could be influenced by the wider local and national context. They agreed that local authorities, especially local public health teams and children and young people's mental health services, had a responsibility to respond to broader needs that schools identified and engage with schools and colleges. Local authorities and health partners also needed to consider the risk factors for poor social, emotional and mental wellbeing when gathering and analysing health data and planning the local response, for example through the Joint Strategic Needs Assessment. The committee noted that schools often found it difficult to understand what was on offer locally that could support their children and young people, for example occupational therapy or speech and language therapy. Even if they knew about the services, they might not know how to refer children and young people into them. The committee agreed that local authorities and care systems would be best placed to address this. ## How the recommendations might affect practice The recommendations reinforce current best practice. They are based on existing processes that most, if not all, schools should be following. However, the committee recognised that adopting and maintaining a whole-school approach needs significant additional time, ongoing leadership and dedicated resourcing. For example, school staff may need more protected time to engage with pupils and local agencies and to undertake relevant training. This could partly be delivered as part of a school's ongoing continuing professional development, for example in inset days. Return to recommendations # Universal curriculum content Recommendations 1.2.1 to 1.2.8 ## Why the committee made the recommendations The committee looked at a substantial amount of evidence about the effectiveness of universal curriculum-content interventions to improve social, emotional and mental wellbeing in primary and secondary education. Although they noted that much of the evidence was limited in terms of the confidence they could have in its findings, it supported their experience that universal curriculum-content interventions help promote the skills needed for good social, emotional and mental wellbeing. It also supported statutory guidance about what should be covered in the universal curriculum. They also considered a smaller amount of qualitative data of mixed quality. Because the qualitative evidence was from only a few studies and its findings were not useful for making recommendations, it was used only to contextualise the recommendations rather than to provide a basis for them. The committee agreed that lessons from universal curriculum content should be cumulative and should be integrated into other school subjects and activities to consolidate children and young people's understanding. The committee also agreed that using a 'strengths-based' approach to support children and young people's social, emotional and mental wellbeing would help to remove the fear of failure and would bring a focus on providing skills that children and young people would be able to use in the future. Some evidence also showed that mindfulness interventions had benefits in developing social, emotional and mental skills in both primary and secondary school children and young people, and for academic outcomes in secondary school pupils. Cognitive behavioural approaches increased social and emotional skills and reduced anxiety in primary school children. However, the committee noted that trauma-focused cognitive behavioural approaches may be more appropriate for children and young people who have previously experienced trauma. Evidence from expert testimony highlighted the value of regular rhythmic physical activity, such as running, bouncing or cross-training, in helping children and young people manage their social, emotional and mental wellbeing. They agreed that these interventions would be most useful in schools where there was a good fit with the whole-school approach. Social connectedness was highlighted by the committee as a key factor for good social, emotional and mental wellbeing in children and young people in the context of the COVID-19 pandemic. The committee agreed that this encouraged the use of support by both peers and trusted adults. ## How the recommendations might affect practice The recommendations reinforce current best practice because they are based on existing processes that schools should generally be following, such as using a spiral curriculum and promoting the spiritual, moral, cultural, mental and physical development of pupils. There may be an impact on financial resources and day‑to‑day staffing for the training and peer support needed to deliver these interventions, but this may be partly covered as part of the staff's continuing professional development programme. Additional time may be needed to establish good communication channels between staff and pupils, to help pupils and the trusted adult develop their relationship and to train teachers on the benefits of interventions. Return to recommendations # Identifying children and young people at risk of poor social, emotional and mental wellbeing Recommendations 1.3.1 to 1.3.6 ## Why the committee made the recommendations The committee looked at a substantial amount of quantitative evidence on several potential risk factors for poor social, emotional and mental wellbeing in primary and secondary education. They agreed that most of the evidence was of reasonable quality. They recognised that many of the individual risk factors could indicate other underlying causes such as unidentified or unmet educational needs. They also considered qualitative evidence from a single study. However, they did not believe that this evidence was strong enough to base recommendations on it. The committee highlighted that the cumulative effect and interactions of multiple risk and protective factors were a much better indicator of poor social, emotional and mental wellbeing than single factors, and that the presence of a single risk factor did not in itself indicate poor social, emotional and mental wellbeing. They agreed that assessment needed to be based on both the number and the complexity of the risk factors, and that evidence needed to be gathered from a wide variety of sources. They agreed that it was unclear how interactions between various social and personal factors contributed to that cumulative effect (see the recommendation for research on intersecting social, cultural and personal factors). Evidence also showed that adverse childhood experiences are a key factor associated with increased prevalence of poor social, emotional and mental wellbeing. The committee agreed that although the presence of 1 or 2 adverse childhood events should not be seen as a pre-determined risk for poor social, emotional and mental wellbeing, it was a sign that assessment was needed to decide whether to intervene or to monitor the child or young person's wellbeing. The committee recognised that children and young people with neurodiverse conditions (such as autism or attention deficit hyperactivity disorder) and those with special educational needs or disabilities were key populations. Therefore, it was important to take their individual needs into account and to engage with relevant agencies. They noted a lack of evidence about whether children and young people with special educational needs were at a higher risk of poor social, emotional and mental wellbeing and made a recommendation for research about this (see the section on other recommendations for research). The committee agreed that an exhaustive list of risk and protective factors was not available, but that the Department for Education's guidance on mental health and behaviour in schools made a good start. They noted that it was last updated in 2018 and therefore did not include the effects of COVID-19 as a risk factor (at the time of publication of this guideline). From their expertise and experience, the committee stated that lack of awareness and training for staff members was a key barrier to identifying children and young people at risk. They agreed that staff needed to be aware of how poor social, emotional and mental wellbeing may present so that they are able to identify issues. They also need to be aware that sometimes these issues can mask unrecognised special educational needs and it is important to understand how to respond to this. The committee noted that much of this is set out in statutory guidance. They recognised that further research is needed into how poor social, emotional and mental wellbeing can be identified in children and young people, especially those who internalise their distress, and what the barriers are to school staff recognising it (see the recommendation for research on early signs of poor social, emotional and mental wellbeing). They discussed the impact of the COVID-19 pandemic on children and young people's social, emotional and mental wellbeing and agreed that the medium- to long-term effects of this are not yet clear, but need to be investigated (see the section on other recommendations for research). The committee saw evidence from 1 study about tools for assessing social, emotional and mental wellbeing in children and young people, but it was not directly relevant to this guideline. However, they agreed that as a committee they had substantial expertise and experience in this area. On this basis, although they could not recommend specific tools because of a lack of evidence, they identified important factors that should be considered when selecting a tool. Staff need to be clear on what it is they are aiming to assess, because different tools measure different aspects of wellbeing. Tools are context specific and their appropriateness will be determined by situational factors, such as the chronological or developmental age of the child or young person. The committee also agreed that it was preferable to use validated tools, although they recognised that sometimes that may not be possible. ## How the recommendations might affect practice School-based practitioners routinely undertake many of these tasks and monitor children and young people's risk factors as part of their pastoral role. However, there may be an increase in the number of children and young people being observed, assessed and offered interventions. This may have cost implications if the extra workload falls on school staff. The committee agreed that many of the tasks will be part of the already planned rollout of the mental health support team and educational mental health practitioners. However, it should be noted that currently there are only plans for mental health support teams to reach 25% of the country and no commitment or resourcing to extend this beyond 2023/2024. Although school-based professionals are likely to have some awareness of poor social, emotional and mental wellbeing, there may be costs to train staff on identifying it, and on using trauma-informed approaches. Return to recommendations # Targeted support Recommendations 1.4.1 to 1.4.8 ## Why the committee made the recommendations The committee discussed evidence on delivering targeted support for children and young people in secondary and further education who have been identified as needing mental health support (for example, because of symptoms of depression or anxiety). The committee had low confidence in the findings of the quantitative evidence, even though there were quite a lot of studies. There was some better evidence from qualitative studies about the acceptability of targeted support, and the committee had more confidence in these findings. These studies included individual or group interventions that were delivered by school specialists (such as school counsellors) or external specialists (such as psychologists). Interventions lasted an average of 8 to 12 weeks. This evidence showed that targeted individual or group interventions were effective at reducing emotional distress and could also prevent a first diagnosis of depression. The committee therefore agreed that these were appropriate for pupils identified as needing social, emotional and mental health support. They agreed that although the evidence was from secondary schools, it was also likely to be relevant to primary settings. They were unable to assess from the evidence the comparative effectiveness of group and individual interventions on mental health. Nor were they able to assess the long-term impacts of these interventions or how they varied by population characteristics (see the recommendation for research on targeted support) or their potential harms and unintended consequences (see the other recommendation for research section on harms and unintended consequences). The studies used varying criteria to determine whether a pupil would need targeted support, for example if they had symptoms of depression or anxiety based on clinical assessment or assessment tools. In practice, pupils are often identified by their externalising behaviours, and those with internalising behaviours can often be missed. The committee agreed that it is important to base referrals for targeted support on individual needs and to have clear guidance about this. The evidence supported the committee's view that communication between schools and parents, carers and families is important for the success of targeted interventions. Families and parents or carers can influence their child's social, emotional and mental health behaviours, so the committee considered it was important that the school engages with parents and carers when considering targeted support. They agreed that further research could clarify what was important to parents in this regard (see other recommendations for research section on targeted support). Specialists who provide targeted social, emotional or mental health support may be employed by the school or be external. The committee agreed that it is the school's responsibility to ensure that specialists have the relevant training and experience. They were also aware of existing advice on using counsellors in schools (see the Department for Education's guidance on counselling in schools: a blueprint for the future). The committee were clear that for targeted support to be successful the pupil needs to be engaged and involved. They discussed the importance of getting their agreement (or that of their families and carers), not only because this is good practice, but also to help the pupil feel involved in the process. The evidence suggested that when planning targeted support, it is important to consider any potential unintended consequences of the support. This supported the committee's view that care needs to be taken to avoid negative labelling or stigmatising pupils when selecting them for targeted support. For example, if a pupil is known to leave lessons for a counselling session, classmates or teachers might treat them differently and they could be at increased risk of bullying. They may become withdrawn or defiant as a result and increase the behaviour that the intervention is intended to address. The evidence also highlighted that a group intervention may normalise undesirable behaviours. For example, groups that include pupils who are part of an existing friendship group known for behaviours that challenge may be difficult to work with. This is because of the potential for friendship status and 'membership rights' in the group to be a priority for the pupils rather than working to improve their social, emotional and mental health. The committee agreed that other factors such as developmental age and cultural background were also important to take into account when planning the membership of group interventions. Focus group research commissioned by NICE to explore children and young people's perspectives on the draft recommendations identified the importance of peer-to-peer support. However, the committee recognised the need to offer a range of support (including peer-to-peer support). This was because evidence in the wider literature on peer-to-peer support indicates that there is a danger that it can perpetuate bullying. Furthermore, the committee highlighted the importance of environment when delivering targeted interventions, because children and young people need to feel safe and comfortable to talk through difficult feelings. ## How the recommendations might affect practice The recommendations reinforce current best practice. They are based on existing processes that all schools should be following, so they are unlikely to have a considerable resource impact. Time and money may be needed to set up suitable environments for delivering interventions. Training and time may also be needed to ensure that school staff are able to monitor children and young people's wellbeing for signs of adverse reactions to receiving targeted support. Return to recommendations # Support with school-related transitions and other life changes Recommendations 1.5.1 to 1.5.7 ## Why the committee made the recommendations The committee discussed evidence on children and young people who are preparing for or undergoing a transition. Although there was a reasonable number of studies about the effectiveness of interventions to make transitions easier, the quality of the evidence was relatively low. However, the committee agreed with the evidence that transition interventions gave useful support. They also considered some higher quality evidence from qualitative studies about the acceptability of these interventions that helped them to make recommendations. The studies included several types of transitions, including moving to a new school or going through a life event such as parental divorce, as well as support for children and young people from a refugee background. Because of the different types of transition identified, the committee agreed that there was a need for support based on individual needs. They discussed how to tailor interventions so that they meet the child or young person's needs and acknowledged that teachers might need additional training for this. The evidence suggested that when planning for transitions it is important to consider any potential unintended consequences. This supported the committee's view that care needs to be taken to avoid negative labelling or stigmatising pupils, for example when sharing information with a new school. They discussed the lack of research about what children and young people themselves find useful during transitions, especially those from underserved populations (see the other recommendations for research section on support for transitions). The committee discussed managed moves (in which a child or young person is placed in a new school by the local authority or by school-to-school voluntary agreement) and agreed that the principles for these were the same as for general transitions. The committee did not see any evidence about children's experiences of school transitions but agreed that future research was needed to fill this gap (see the other recommendations for research section on views on transitions to secondary school). The evidence supported the committee's experience that communication and engagement between schools and parents, carers and families are important in managing transitions and life changes. This is also consistent with the committee's view that engaging with pupils and their parents or carers is an important part of a whole-school approach. The qualitative evidence on practical supports, such as travel advice, buddy systems and orientation sessions, was also supported by the committee experience that these are useful practical steps. Based on their expertise, the committee concluded that ongoing monitoring was beneficial in ensuring that the child or young person continues to progress and that the transition arrangements are effective over the whole of the child or young person's education. This is especially the case if they are at higher risk of poor social, emotional and mental wellbeing. Focus group research commissioned by NICE to explore children and young people's perspectives on the draft recommendations identified the importance of peer mentoring during transition periods to promote good social, emotional and mental wellbeing. The committee agreed with the value of peer mentoring for children and young people entering a new school, particularly from older pupils who have been appropriately trained as mentors. The committee discussed significant life changes in the context of the school environment and agreed that although these often could not be planned for (for example, a sudden bereavement), the school had a key role in supporting children and young people through these events and in arranging external support for the child or young person if it is needed. This included supporting children and young people through the loss of key relationships with school staff when they moved classes or schools. They agreed it was important to understand how children and young people could be supported through this (see the other recommendations for research section on support for transitions). ## How the recommendations might affect practice or services The committee agreed that supporting children and young people through transitions to new classes, schools or out of education was part of the general responsibilities of the school. As part of their pastoral role, teachers and other school staff would be trained to engage with pupils and identify those who were not thriving. They noted that agencies outside the school could also provide important services that the school was unable to provide. The recommendations highlight the value of peer mentoring for pupils transitioning to a new school. Additional time may be needed to train older pupils on how to effectively mentor new students. Return to recommendations# Context Primary and secondary schools help children and young people learn social, emotional and mental skills through both the taught and the wider curriculum (such as activities outside the classroom). Schools can provide the supportive, caring and nurturing environment that supports positive social, emotional and mental wellbeing. They are also important settings in which to identify and provide early intervention for children and young people at increased risk of mental ill health. Schools have statutory duties to establish environments where children and young people are supported and can fully engage. These duties encourage schools to support personal development, mental health and wellbeing. Many schools follow a whole-school approach to social, emotional and mental wellbeing (see the Department for Education's research and analysis on supporting mental health in schools and colleges). This approach goes beyond learning and teaching to include school culture, ethos and environment. It involves engaging with children and young people, their parents and carers, teacher and school leaders and outside agencies. Social, emotional and mental wellbeing may be promoted in curriculum subjects such as personal, social, health and economic education and be embedded more broadly through a school's commitment to the spiritual, moral, social and cultural development of their pupils. Key challenges for schools include: knowing what approaches improve student outcomes in a specific school setting accommodating effective teaching of social, emotional and mental wellbeing in a crowded curriculum. Schools use various methods to identify children and young people who may benefit from targeted interventions to support their approach to social, emotional and mental wellbeing. This may include information from other practitioners such as a speech and language therapist or special educational needs and disability coordinator.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nRecommendations relating to parents or carers might be less relevant to older young people, especially those in post-16 education settings and may need to be interpreted accordingly.\n\nFor the purposes of this guideline, the term 'school' covers schools, colleges, further education providers and other educational settings.\n\n# Whole-school approach\n\nAdopt a whole-school approach to support positive social, emotional and mental wellbeing of staff, children and young people (including people with a neurodiverse condition) in primary and secondary education.\n\nEnsure that the school has a culture, ethos and practice that strengthens relational approaches and inclusion, and that recognises the importance of psychological safety.\n\nReview the school's policies and procedures regularly to make sure that they promote social, emotional and mental wellbeing positively and consistently. This should include making them consistent with relational approaches to social, emotional and mental wellbeing.\n\nReview regularly the school's accessibility plan, medical conditions policy and approach to understanding behaviour, taking into account neurodiversity and communication needs. Also take into account the value of trauma-informed approaches and parental co-production.\n\nConsider monitoring and evaluating the impact and effectiveness of the whole-school approach as part of a school improvement strategy.\n\n## Supporting the whole-school approach\n\nSupport the whole-school approach by:\n\nhaving an outward-facing approach to the community and to engaging with local communities and groups\n\nstrengthening links to external agencies that can provide additional support, such as local children's health and care services and relevant voluntary and community sector organisations\n\nhaving shared principles for engagement between education and mental health services, for example agreeing referral pathways\n\npromoting the involvement of education providers in wider local strategic decision making about children and young people's mental health\n\nhaving ways of feeding back to parents and carers.\n\nEnsure that school governance structures support the whole-school approach and that school leadership is actively involved in supporting the whole-school approach. Make the responsibility for social, emotional and mental wellbeing curriculum content part of the remit of school leadership (including governance).\n\n## Supporting staff\n\nEnsure that staff have continuing professional development to support both their own wellbeing and the implementation of the school's approach. This could include training in emotional literacy, trauma, neurodiversity, communication needs and relational approaches.\n\nSignpost staff to quality-assured local and national resources to support their wellbeing in line with the Department for Education's education staff wellbeing charter.\n\nSupport staff in their pastoral roles by providing protected time for supervision and continuing professional development.\n\nMake peer supervision available for teachers and other school staff to enable them to have space and support to discuss issues and reflect on practice.\n\nEnsure that all teachers can recognise children and young people's pastoral needs, and that they understand the wider context of the pupils' lived experiences and how they interact with their environment. Provide them with additional training or support if needed.\n\nEnsure that all information held by the school related to the local early help offer is kept up to date.\n\n## Involving families and pupils\n\nInvolve parents and carers in designing and implementing the whole‑school approach.\n\nInvolve children and young people in discussing and agreeing whole‑school approaches and communicate with them regularly about decisions, so they understand how their views inform practice. Take into account the opinions of all members of the school community. This may mean making adjustments to address neurodiversity and communication needs.\n\n## Implementing the whole-school approach\n\nDesignate a lead person to determine what is needed to successfully implement universal curriculum interventions. The lead should also be the go-to person for advice on the most appropriate educational resources for any intervention. The lead person should be someone in a leadership post who has strategic responsibilities and oversight of social, emotional and mental wellbeing across the school.\n\nWhen implementing whole-school approaches, take into account the core values that the school culture and practice are built on, and the psychological safety of pupils, staff members and leadership. For example, this could involve developing a school culture and ethos in which children, young people and staff feel safe to make and learn from mistakes.\n\nAdopt a 'graduated response' (or 'step up–step down') approach to support (moving between universal and targeted support as relevant) as an integral part of the whole-school approach alongside broader universal approaches. Ensure that staff understand this approach and have the right support to implement it (see the recommendations on targeted support).\n\n## Local support\n\nLocal public health departments, and children and young people's mental health services, should proactively gather and be responsive to the views and concerns of schools and colleges in their area about children and young people's social, emotional and mental wellbeing.\n\nLocal authorities should compile, and keep up to date, a directory of the local services that promote children and young people's social emotional and mental wellbeing and are available to support schools in their area. This should include:\n\nwhat the services can offer\n\nlocal mental health and special educational needs and disability (SEND) services, including services that might be less well known\n\ndetails of how to access the services.\n\nTake risk factors for poor social, emotional and mental wellbeing into account when developing the Joint Strategic Needs Assessment. This should include the contribution that schools can make to improving social, emotional and mental wellbeing and take into account schools' impact on learning and life chances (see the recommendations on identification and risk factors).\n\nThe local integrated care system and schools should work together to identify opportunities for joint practice to support the social, emotional and mental wellbeing of children and young people, for example agreeing principles for when and how to share information.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on whole-school approach\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: whole-school approaches.\n\nLoading. Please wait.\n\n# Universal curriculum content\n\nEnsure that the curriculum for all pupils includes evidence-based, culturally appropriate information about social, emotional and mental wellbeing to develop children and young people's knowledge and skills as part of the whole-school approach.\n\nTake account of the Department for Education's relationships education, relationships and sex education, and health education guidance when selecting or developing universal curriculum content.\n\nUse an approach that builds on children and young people's previous learning (for example, a spiral curriculum) when planning and delivering a curriculum intervention for all pupils.\n\nIntegrate relevant activities into all aspects of education to reinforce the curriculum offer about social, emotional and mental wellbeing and skills.\n\nUse non-judgemental 'strengths-based' approaches to support children and young people's social, emotional and mental wellbeing. These are approaches to improve or develop their:\n\nself-worth (for example, self-esteem, empowerment, self-care)\n\nskills (for example, problem solving skills, social skills, communication skills)\n\nresilience (for example, coping skills and strategies, perseverance).\n\nUse universal interventions that align with the whole-school approach, for example 'child- (or young person) to-trusted-adult' support.\n\nConsider universal interventions informed by mindfulness or cognitive behavioural approaches (including trauma-focused cognitive behavioural approaches) for all children and young people. These should be delivered by trained staff who can teach children and young people how to use the approach and support them when they do.\n\nConsider including regular rhythmic physical activity in the universal curriculum. If it is included, ensure that there is time and space available for this.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on universal curriculum content\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review B: universal curriculum approaches\n\nevidence review C: qualitative evidence synthesis for universal curriculum approaches.\n\nLoading. Please wait.\n\n# Identifying children and young people at risk of poor social, emotional and mental wellbeing\n\n## Identification and risk factors\n\nWhen considering whether a child or young person has risk factors for poor social, emotional and mental wellbeing, take into account:\n\nthe number, duration and complexity of risk and protective factors, their cumulative effects and interactions between them\n\nthat the effects of risk and protective factors, or combinations of factors, might differ across life stages\n\nthat they may have unidentified or unmet educational needs, for example special educational needs or disabilities that impact on their ability to access education.For a list of risk and protective factors, see table 1 in the Department for Education's mental health and behaviour in schools guidance. Be aware that the list is not exhaustive.\n\nBase the identification of children and young people at risk of poor social, emotional and mental wellbeing on information from a variety of sources, for example observation, self-report and consideration of their early life experiences. Be aware that some children and young people will internalise their distress and will therefore be more difficult to identify.\n\nAssess children and young people identified as at risk and decide whether to monitor their social, emotional and mental wellbeing or to offer them targeted support (see the recommendations on tools and techniques). Take into account any existing assessments, for example from educational psychologists or child and adolescent mental health services.\n\nWhen identifying risk in children and young people with disabilities or special educational needs, ensure that staff understand the graduated response to need as specified in the current Department of Health and Social Care and Department for Education's special educational needs and disability (SEND) code of practice, and that they can respond with relevant interventions. If necessary, they should seek input from specialised external agencies.\n\n## Tools and techniques\n\nIf using a tool or technique to assess a child or young person who has been identified as at risk of poor social, emotional or mental wellbeing, consider using one that is validated (see Public Health England's guidance on measuring mental wellbeing in children and young people).\n\nWhen selecting a tool or technique to assess social, emotional and mental wellbeing, take into account:\n\nthe child or young person's needs, wishes and feelings\n\nthe purpose of the assessment\n\nhow the tool or technique fits with the school culture and ethos\n\ncontextual factors, such as the child or young person's chronological or developmental age or ethnicity and any communication needs (being aware that assessment tools are context specific and vary in quality).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on identifying children and young people at risk of poor social, emotional and mental wellbeing\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D: risk factors for poor social, emotional and mental wellbeing\n\nevidence review E: qualitative review for risk factors for poor social, emotional and mental wellbeing\n\nevidence review F: risk factors for poor social, emotional and mental wellbeing.\n\nLoading. Please wait.\n\n# Targeted support\n\nHave clear guidance on how to identify individual children and young people and groups of people for targeted support based on their specific needs (see the section on identifying children and young people at risk of poor social, emotional and mental wellbeing).\n\nOffer targeted individual or group support to children and young people who have been identified as needing additional social, emotional or mental health support. Use trained, experienced practitioners who are competent to provide the support. Any support should be culturally sensitive and take into account possible neurodiversity, communication needs and other needs of the child or young person.\n\nActively involve the parents or carers of the child or young person when deciding whether to offer targeted support (but think about whether the young person is competent to give their consent or there are reasons not to involve the parents or carers). Discuss with them any support that is being proposed and make sure that they understand it and agree with it.\n\nExplain the targeted support to the child or young person and involve them in decisions about the support offered to them, including when and where it is offered. Where appropriate and possible, obtain their agreement before starting the support.\n\nTake into account the range of individual needs and risks when putting together a group for targeted group support, including the developmental age and cultural background of the pupils it is being delivered to.\n\nPromote a range of targeted support, including peer-to-peer support, that allows children and young people to express difficult feelings and talk about their experiences.\n\nAim to minimise the risk of any unintended adverse consequences and stigma and proactively normalise seeking support. Take care not to reinforce bullying by singling people out for support.\n\nEnsure that all targeted support is delivered collaboratively with any other external agencies or services, the professional network around the child or young person and any support that the child or young person is already receiving.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on targeted support\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review G: targeted social and emotional support\n\nevidence review H: targeted mental health support.\n\nLoading. Please wait.\n\n# Support with school-related transitions and other life changes\n\n## All transitions and life changes\n\nTrain staff to recognise the wide-ranging impacts of transitions and life changes on children and young people's social, emotional and mental wellbeing, taking into account that they may differ between individuals, for example because of cultural background, age and gender. This includes recognising both planned (for example, moving between schools or classes) and unanticipated life changes, and the different ways that a child or young person typically expresses their mental health problems and responds to trauma.\n\n## Transitions between schools and classes or leaving education\n\nPlan and offer tailored interventions to prepare children and young people for educational transitions and for leaving education completely. This includes:\n\nEstablishing a relationship with the child or young person and their parent or carer.\n\nGathering the child or young person's views about their transition.\n\nSupporting the child or young person to feel ready for the transition, for example understanding how they will get to and from the new school or job.\n\nSharing with the new class or school and staff information about the child or young person that will help them. The information should be positive and not set out to victimise or stigmatise them, and it should be shared in line with the National Data Guardian's Caldicott principles.\n\nIdentifying and communicating with the professional and personal network around the child or young person, if there is one, as part of good transition support.Also follow these principles for any managed moves (in which a child or young person is placed in a new school by the local authority or by school-to-school voluntary agreement).\n\nSupport the child or young person at the time of the educational transition to cope with the loss of important relationships caused by the transition.\n\nEnhance children and young people's sense of belonging in the new school or class, for example by organising a peer mentor or buddy for them (see recommendation 1.4.6).\n\n## After transitions between schools\n\nCheck on an ongoing basis to see whether the child or young person is settling in and thriving after moving to a new education setting. Offer them tailored support if necessary. Check more regularly if the child or young person is at a higher risk of poor social, emotional and mental wellbeing.\n\nPromote peer mentoring between a child or young person entering a new education setting and a peer who has training in mentoring (see recommendation 1.4.6).\n\n## Significant life changes\n\nAddress needs identified by children or young people (or their parents or carers) going through significant life changes, mental health problems or mental illness. This should involve the special educational needs and disabilities coordinator (SENCo) or designated safeguarding lead and other agencies if necessary.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on transitions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: interventions to support children and young people during periods of transition.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local Act Personal Care and Support Jargon Buster.\n\n## Adverse childhood experiences\n\nHighly stressful, and potentially traumatic, events or situations that occur during childhood or adolescence. They can be a single event, or prolonged threats to, and breaches of, the child or young person's safety, security, trust or bodily integrity.\n\n## Early help\n\nProviding support as soon as a problem emerges, at any point in a child's life. For example, see the Early Intervention Foundation.\n\n## Psychological safety\n\nThe belief that one is in a safe place and will not be punished or humiliated for speaking up with ideas, questions, concerns or mistakes.\n\n## Punitive behaviour management systems\n\nAn approach to classroom or school management that focuses on establishing clear expectations for appropriate behaviour, monitoring behaviour, and then reinforcing appropriate behaviour and redirecting or sanctioning inappropriate behaviour.\n\n## Relational approaches\n\nApproaches that emphasise connection, belonging and the teaching of effective conflict resolution skills. These approaches assume that behaviour is a means of communication and that behaviour that challenges can be a sign of unmet emotional needs. Relational approaches approach behaviour with curiosity rather than judgement. They are grounded in psychological theory and support children to build their self-regulation skills. They take account of context and the child or young person's lived experiences.\n\n## Rhythmic physical activity\n\nAny kind of activity that is based on a steady and prominent beat. During rhythmic activities individuals participate in rhythmic body movement, for example rebounding on a trampoline or moving to a beat.\n\n## Spiral curriculum\n\nA course of study in which pupils study the same topics in ever-increasing complexity throughout their time at school to reinforce previous lessons.\n\n## Targeted support\n\nSupport aimed at individuals or groups who have been identified as being at greater risk of poor social, emotional and mental wellbeing.\n\n## Trauma-informed approaches\n\nApproaches to support children and young people who suffer with trauma or mental health problems and whose troubled behaviour is a barrier to learning.\n\n## Trusted adults\n\nAdults that children and young people can turn to in times of worry, stress or crisis.\n\n## Universal curriculum content\n\nCurriculum content that is for everyone.\n\n## Whole-school approach\n\nFor the purposes of this guideline, 'whole-school' also covers colleges, further education providers and other educational settings.\n\nA whole-school approach defines the entire school community as a single unit and involves coordinated action between 3 interrelated components:\n\ncurriculum, teaching and learning\n\nschool ethos and environment\n\nfamily and community partnership.\n\nThe 8\xa0principles to promoting a whole-school and college approach to mental health andwellbeing are set out in Department for Education and Public Health England's guidance on promoting children and young people's mental health and wellbeing.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Early signs of poor social, emotional and mental wellbeing\n\nWhat are the early signs of social, emotional and mental wellbeing issues, including in children and young people who are internalising it?\n\na) What early factors predict poor social, emotional and mental wellbeing?\n\nb) How do children and young people with poor social, emotional and mental wellbeing describe their thoughts and feelings at early onset stage?\n\nc) What are the barriers and facilitators to identifying children and young people at risk of poor social, emotional and mental wellbeing at school?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on identifying children and young people at risk of poor social, emotional and mental wellbeing\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D: risk factors for poor social, emotional and mental wellbeing\n\nevidence review E: qualitative review for risk factors for poor social, emotional and mental wellbeing\n\nevidence review F: risk factors for poor social, emotional and mental wellbeing.\n\nLoading. Please wait.\n\n## Intersecting social, cultural and personal factors\n\nWhat is the role of intersecting social, cultural and personal factors in developing poor social, emotional and mental wellbeing?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on identifying children and young people at risk of poor social, emotional and mental wellbeing\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0D: risk factors for poor social, emotional and mental wellbeing\n\nevidence review\xa0E: qualitative review for risk factors for poor social, emotional and mental wellbeing\n\nevidence review\xa0F: risk factors for poor social, emotional and mental wellbeing.\n\nLoading. Please wait.\n\n## Targeted support\n\nWhat is the effectiveness (including long-term effectiveness) and cost effectiveness of targeted group or individual interventions for children and young people who have been identified as needing additional mental health support, and does it vary by ethnicity, socioeconomic status or other cultural and personal factors?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on targeted support\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0G: targeted social and emotional support\n\nevidence review\xa0H: targeted mental health support.\n\nLoading. Please wait.\n\n## Effectiveness of interventions\n\nWhat components of interventions or approaches to promote social, emotional and mental wellbeing are effective and cost effective?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on whole-school approach\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0G: targeted social and emotional support\n\nevidence review\xa0H: targeted mental health support.\n\nLoading. Please wait.\n\n## System leadership and service delivery\n\nHow can practitioners, institutions and organisations work together to improve systems leadership that impacts collectively on positive outcomes for children and young people's social, emotional and mental wellbeing?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on whole-school approach\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: whole-school approaches.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Children and young people with special educational needs\n\nAre children and young people with special educational needs at higher risk of poor social, emotional and mental wellbeing?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on identifying children and young people at risk of poor social, emotional and mental wellbeing\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0D: risk factors for poor social, emotional and mental wellbeing\n\nevidence review\xa0E: qualitative review for risk factors for poor social, emotional and mental wellbeing\n\nevidence review\xa0F: risk factors for poor social, emotional and mental wellbeing.\n\nLoading. Please wait.\n\n## Harms and unintended consequences\n\nWhat are the possible harms and unintended consequences of targeted group or individual interventions for children and young people who have been identified as needing additional mental health support?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on targeted support\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0G: targeted social and emotional support\n\nevidence review\xa0H: targeted mental health support.\n\nLoading. Please wait.\n\n## Targeted support\n\nWhat are parents' and carers' views on targeted group or individual interventions for children and young people who have been identified as needing additional mental health support?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on targeted support\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0G: targeted social and emotional support\n\nevidence review\xa0H: targeted mental health support.\n\nLoading. Please wait.\n\n## Views on transitions to secondary school\n\nWhat are the views and experiences of children about moving to secondary school?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on support with school-related transitions and other life changes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: interventions to support children and young people during periods of transition.\n\nLoading. Please wait.\n\n## Support for transitions\n\nWhat do children and young people, including those from underserved populations, find useful to support life changes in the context of their education?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on support with school-related transitions and other life changes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: interventions to support children and young people during periods of transition.\n\nLoading. Please wait.\n\n## Impact of COVID-19\n\nWhat is the medium-to long-term impact of the COVID-19 pandemic on children and young people's social, emotional and mental wellbeing?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on identifying children and young people at risk of poor social, emotional and mental wellbeing\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0D: risk factors for poor social, emotional and mental wellbeing\n\nevidence review\xa0E: qualitative review for risk factors for poor social, emotional and mental wellbeing\n\nevidence review\xa0F: risk factors for poor social, emotional and mental wellbeing.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice or services.\n\n# Whole-school approach\n\nRecommendations 1.1.1 to 1.1.22\n\n## Why the committee made the recommendations\n\nThe committee agreed that the inclusion health agenda (for example, see the Office for Health Improvement and Disparities [previously Public Health England] inclusion health: applying all our health) and tackling inequalities were central to this guideline. When implementing the guideline, schools and wider system partners would need to pay particular attention to marginalised or excluded groups, both in terms of their involvement and in terms of tailoring the recommendations to meet the needs of those groups. The committee made special consideration of the needs of children and young people with learning difficulties and special educational needs and disabilities (SEND). They agreed to place neurodiversity at the heart of their considerations and received expert testimony on the topic to inform their discussions. Professionals from special schools were represented on the committee, and the focus group work with children and young people that NICE commissioned included people from schools with high rates of SEND and from special schools and pupil referral units.\n\nThe committee discussed the benefits of implementing a whole-school approach for children and young people's social, emotional and mental wellbeing, including preventing the onset of poor outcomes and supporting those with identified needs. They agreed that this could have implications far beyond school environments, for example on employability and anti-social behaviours. The quantitative studies included various whole-school approaches with different combinations of components and various aims, although the strongest evidence was about bullying. They showed some benefit and no harms or adverse consequences. The qualitative evidence showed that pupils and teachers valued whole-school approaches and believed that they had a positive effect on school culture. Overall, the committee agreed that there was some evidence to support the effectiveness of whole-school approaches. There was evidence about the acceptability of whole-school approaches and what made them more or less likely to work, and the committee had more confidence in the findings from these studies than the quantitative ones. This evidence was supported by their expertise and experience and by the testimony of invited expert witnesses.\n\nThe committee heard expert testimony about relational approaches being more effective than using purely punitive behaviour management systems for managing social, emotional and mental wellbeing in children and young people. Together with this and their own experience and expertise, they agreed that embedding a relational approach in the overall culture and ethos of the school was the basis of a successful whole-school approach, and this would need to be reflected consistently in school policies and procedures. Reviewing policies regularly would help to ensure that this happens. Although the committee were not able to set a specific timeframe for review because there was no evidence, they agreed that annually would be reasonable. They also agreed that leadership was key to embedding this approach and that the leadership needed to come from a senior person. They discussed that this might fit well with the role of the designated school mental health lead. However, because this is a developing role, they agreed it would be premature to specify this. Additionally, having heard expert testimony about trauma-informed approaches in schools, the committee encouraged a shift towards these approaches to understand and therefore manage behaviour.\n\nThe committee regarded the whole-school approach as a framework that other interventions can slot into. They noted that interventions such as targeted support have a better chance of success if schools actively engage with local agencies. They also agreed that, to be effective, a whole-school approach needed monitoring and evaluating to make sure the approach was working.\n\nThe committee also noted that it would be more useful if future research focused on the effective components of interventions or approaches (see the recommendation for research on effectiveness of interventions).\n\nThe committee agreed that school leader support and governance was crucial for a whole-school approach to work and that the whole-school approach needed ongoing engagement with school staff, parents and carers, and the wider community. An effective whole-school approach would also lead to improved integration with external agencies, including mental health services and local public health departments. This is essential to ensure that schools can play an active role in decision making on the local transformation plan for children and young people's mental health.\n\nThe committee agreed on the importance of collaboration between schools and other services that were not school based but that had an impact on children and young people's social, emotional and mental wellbeing. They noted that, in their experience, schools did not always have mechanisms in place for working with key local services. They agreed that further research was needed to explore how agencies could work together (see the recommendation for research on system leadership and service delivery).\n\nThe committee discussed the key role of staff in the whole-school approach. They agreed that staff needed to feel supported in their own wellbeing to be able to create an environment that fostered wellbeing in children and young people. Ways to do this include continuing professional development and formal and informal support.\n\nStaff need to be able to recognise the pastoral needs of the children and young people they work with, and to understand how these are influenced by their wider life experiences. This can help them to relate better to the child or young person, and to other people who may be involved in their care. Understanding behaviour as a means of communication could help with this. They identified that staff need time and support for pastoral training.\n\nThe committee noted that there are national and local resources that staff can use to help them manage their own wellbeing. The resources can also help staff keep up to date with local agencies that could help with children and young people's mental health through the early help offer.\n\nThe evidence supported the committee's view that the school's communication with parents, carers and families is important. The committee agreed that the whole‑school approach worked better if parents, carers and families were involved with the planning of it.\n\nFocus group research commissioned by NICE to explore children and young people's perspectives on the draft recommendations identified several important ways of successfully implementing whole-school approaches. Based on the findings of the focus groups, the committee recognised the importance of involving children and young people and capturing their views when agreeing on approaches, including views from minority and seldom-heard groups.\n\nThis focus group research also identified the importance of effective communication between school staff and children and young people. The committee recognised the need for excellent communication channels between these groups when implementing universal interventions. They also highlighted the importance of taking into account children and young people's views, how much time there was in the curriculum and resourcing, teacher understanding of the interventions and parental engagement for the successful implementation of universal interventions. These factors were identified from the evidence base and the committee's own experiences.\n\nThe committee discussed the challenges of implementing a whole-school approach. Based on the expert testimony they had heard and on their own expertise and experience in setting up, supporting and evaluating whole-school approaches, they agreed that there were key things they could recommend that would make the implementation smoother. This included the importance of creating a school environment that was a safe space for both teachers and children and young people and where they would not be punished or penalised for mistakes or for speaking up. Also, after hearing from experts, the committee highlighted the significance of core values and strong leadership when implementing a relational whole-school approach.\n\nThe committee agreed that if the universal curriculum was managed and planned by a specific person it would be better coordinated across the school and could be kept up to date more easily. This person would need to be a senior leader who was able to influence school policy. This coordination could also lead to a more streamlined approach to moving children and young people into and out of targeted interventions (a graduated or 'step up–step down' approach) when universal content was not meeting their social, emotional and mental wellbeing needs.\n\nThe committee discussed how the whole-school approach could be influenced by the wider local and national context. They agreed that local authorities, especially local public health teams and children and young people's mental health services, had a responsibility to respond to broader needs that schools identified and engage with schools and colleges. Local authorities and health partners also needed to consider the risk factors for poor social, emotional and mental wellbeing when gathering and analysing health data and planning the local response, for example through the Joint Strategic Needs Assessment.\n\nThe committee noted that schools often found it difficult to understand what was on offer locally that could support their children and young people, for example occupational therapy or speech and language therapy. Even if they knew about the services, they might not know how to refer children and young people into them. The committee agreed that local authorities and care systems would be best placed to address this.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current best practice. They are based on existing processes that most, if not all, schools should be following. However, the committee recognised that adopting and maintaining a whole-school approach needs significant additional time, ongoing leadership and dedicated resourcing. For example, school staff may need more protected time to engage with pupils and local agencies and to undertake relevant training. This could partly be delivered as part of a school's ongoing continuing professional development, for example in inset days.\n\nReturn to recommendations\n\n# Universal curriculum content\n\nRecommendations 1.2.1 to 1.2.8\n\n## Why the committee made the recommendations\n\nThe committee looked at a substantial amount of evidence about the effectiveness of universal curriculum-content interventions to improve social, emotional and mental wellbeing in primary and secondary education. Although they noted that much of the evidence was limited in terms of the confidence they could have in its findings, it supported their experience that universal curriculum-content interventions help promote the skills needed for good social, emotional and mental wellbeing. It also supported statutory guidance about what should be covered in the universal curriculum. They also considered a smaller amount of qualitative data of mixed quality. Because the qualitative evidence was from only a few studies and its findings were not useful for making recommendations, it was used only to contextualise the recommendations rather than to provide a basis for them.\n\nThe committee agreed that lessons from universal curriculum content should be cumulative and should be integrated into other school subjects and activities to consolidate children and young people's understanding.\n\nThe committee also agreed that using a 'strengths-based' approach to support children and young people's social, emotional and mental wellbeing would help to remove the fear of failure and would bring a focus on providing skills that children and young people would be able to use in the future.\n\nSome evidence also showed that mindfulness interventions had benefits in developing social, emotional and mental skills in both primary and secondary school children and young people, and for academic outcomes in secondary school pupils. Cognitive behavioural approaches increased social and emotional skills and reduced anxiety in primary school children. However, the committee noted that trauma-focused cognitive behavioural approaches may be more appropriate for children and young people who have previously experienced trauma.\n\nEvidence from expert testimony highlighted the value of regular rhythmic physical activity, such as running, bouncing or cross-training, in helping children and young people manage their social, emotional and mental wellbeing. They agreed that these interventions would be most useful in schools where there was a good fit with the whole-school approach.\n\nSocial connectedness was highlighted by the committee as a key factor for good social, emotional and mental wellbeing in children and young people in the context of the COVID-19 pandemic. The committee agreed that this encouraged the use of support by both peers and trusted adults.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current best practice because they are based on existing processes that schools should generally be following, such as using a spiral curriculum and promoting the spiritual, moral, cultural, mental and physical development of pupils. There may be an impact on financial resources and day‑to‑day staffing for the training and peer support needed to deliver these interventions, but this may be partly covered as part of the staff's continuing professional development programme.\n\nAdditional time may be needed to establish good communication channels between staff and pupils, to help pupils and the trusted adult develop their relationship and to train teachers on the benefits of interventions.\n\nReturn to recommendations\n\n# Identifying children and young people at risk of poor social, emotional and mental wellbeing\n\nRecommendations 1.3.1 to 1.3.6\n\n## Why the committee made the recommendations\n\nThe committee looked at a substantial amount of quantitative evidence on several potential risk factors for poor social, emotional and mental wellbeing in primary and secondary education. They agreed that most of the evidence was of reasonable quality. They recognised that many of the individual risk factors could indicate other underlying causes such as unidentified or unmet educational needs. They also considered qualitative evidence from a single study. However, they did not believe that this evidence was strong enough to base recommendations on it.\n\nThe committee highlighted that the cumulative effect and interactions of multiple risk and protective factors were a much better indicator of poor social, emotional and mental wellbeing than single factors, and that the presence of a single risk factor did not in itself indicate poor social, emotional and mental wellbeing. They agreed that assessment needed to be based on both the number and the complexity of the risk factors, and that evidence needed to be gathered from a wide variety of sources. They agreed that it was unclear how interactions between various social and personal factors contributed to that cumulative effect (see the recommendation for research on intersecting social, cultural and personal factors).\n\nEvidence also showed that adverse childhood experiences are a key factor associated with increased prevalence of poor social, emotional and mental wellbeing. The committee agreed that although the presence of 1 or 2 adverse childhood events should not be seen as a pre-determined risk for poor social, emotional and mental wellbeing, it was a sign that assessment was needed to decide whether to intervene or to monitor the child or young person's wellbeing. The committee recognised that children and young people with neurodiverse conditions (such as autism or attention deficit hyperactivity disorder) and those with special educational needs or disabilities were key populations. Therefore, it was important to take their individual needs into account and to engage with relevant agencies. They noted a lack of evidence about whether children and young people with special educational needs were at a higher risk of poor social, emotional and mental wellbeing and made a recommendation for research about this (see the section on other recommendations for research).\n\nThe committee agreed that an exhaustive list of risk and protective factors was not available, but that the Department for Education's guidance on mental health and behaviour in schools made a good start. They noted that it was last updated in 2018 and therefore did not include the effects of COVID-19 as a risk factor (at the time of publication of this guideline).\n\nFrom their expertise and experience, the committee stated that lack of awareness and training for staff members was a key barrier to identifying children and young people at risk. They agreed that staff needed to be aware of how poor social, emotional and mental wellbeing may present so that they are able to identify issues. They also need to be aware that sometimes these issues can mask unrecognised special educational needs and it is important to understand how to respond to this. The committee noted that much of this is set out in statutory guidance.\n\nThey recognised that further research is needed into how poor social, emotional and mental wellbeing can be identified in children and young people, especially those who internalise their distress, and what the barriers are to school staff recognising it (see the recommendation for research on early signs of poor social, emotional and mental wellbeing). They discussed the impact of the COVID-19 pandemic on children and young people's social, emotional and mental wellbeing and agreed that the medium- to long-term effects of this are not yet clear, but need to be investigated (see the section on other recommendations for research).\n\nThe committee saw evidence from 1\xa0study about tools for assessing social, emotional and mental wellbeing in children and young people, but it was not directly relevant to this guideline. However, they agreed that as a committee they had substantial expertise and experience in this area. On this basis, although they could not recommend specific tools because of a lack of evidence, they identified important factors that should be considered when selecting a tool. Staff need to be clear on what it is they are aiming to assess, because different tools measure different aspects of wellbeing. Tools are context specific and their appropriateness will be determined by situational factors, such as the chronological or developmental age of the child or young person. The committee also agreed that it was preferable to use validated tools, although they recognised that sometimes that may not be possible.\n\n## How the recommendations might affect practice\n\nSchool-based practitioners routinely undertake many of these tasks and monitor children and young people's risk factors as part of their pastoral role. However, there may be an increase in the number of children and young people being observed, assessed and offered interventions. This may have cost implications if the extra workload falls on school staff. The committee agreed that many of the tasks will be part of the already planned rollout of the mental health support team and educational mental health practitioners. However, it should be noted that currently there are only plans for mental health support teams to reach 25% of the country and no commitment or resourcing to extend this beyond 2023/2024.\n\nAlthough school-based professionals are likely to have some awareness of poor social, emotional and mental wellbeing, there may be costs to train staff on identifying it, and on using trauma-informed approaches.\n\nReturn to recommendations\n\n# Targeted support\n\nRecommendations 1.4.1 to 1.4.8\n\n## Why the committee made the recommendations\n\nThe committee discussed evidence on delivering targeted support for children and young people in secondary and further education who have been identified as needing mental health support (for example, because of symptoms of depression or anxiety). The committee had low confidence in the findings of the quantitative evidence, even though there were quite a lot of studies.\n\nThere was some better evidence from qualitative studies about the acceptability of targeted support, and the committee had more confidence in these findings. These studies included individual or group interventions that were delivered by school specialists (such as school counsellors) or external specialists (such as psychologists). Interventions lasted an average of 8 to 12\xa0weeks. This evidence showed that targeted individual or group interventions were effective at reducing emotional distress and could also prevent a first diagnosis of depression. The committee therefore agreed that these were appropriate for pupils identified as needing social, emotional and mental health support. They agreed that although the evidence was from secondary schools, it was also likely to be relevant to primary settings. They were unable to assess from the evidence the comparative effectiveness of group and individual interventions on mental health. Nor were they able to assess the long-term impacts of these interventions or how they varied by population characteristics (see the recommendation for research on targeted support) or their potential harms and unintended consequences (see the other recommendation for research section on harms and unintended consequences).\n\nThe studies used varying criteria to determine whether a pupil would need targeted support, for example if they had symptoms of depression or anxiety based on clinical assessment or assessment tools. In practice, pupils are often identified by their externalising behaviours, and those with internalising behaviours can often be missed. The committee agreed that it is important to base referrals for targeted support on individual needs and to have clear guidance about this.\n\nThe evidence supported the committee's view that communication between schools and parents, carers and families is important for the success of targeted interventions. Families and parents or carers can influence their child's social, emotional and mental health behaviours, so the committee considered it was important that the school engages with parents and carers when considering targeted support. They agreed that further research could clarify what was important to parents in this regard (see other recommendations for research section on targeted support).\n\nSpecialists who provide targeted social, emotional or mental health support may be employed by the school or be external. The committee agreed that it is the school's responsibility to ensure that specialists have the relevant training and experience. They were also aware of existing advice on using counsellors in schools (see the Department for Education's guidance on counselling in schools: a blueprint for the future).\n\nThe committee were clear that for targeted support to be successful the pupil needs to be engaged and involved. They discussed the importance of getting their agreement (or that of their families and carers), not only because this is good practice, but also to help the pupil feel involved in the process.\n\nThe evidence suggested that when planning targeted support, it is important to consider any potential unintended consequences of the support. This supported the committee's view that care needs to be taken to avoid negative labelling or stigmatising pupils when selecting them for targeted support. For example, if a pupil is known to leave lessons for a counselling session, classmates or teachers might treat them differently and they could be at increased risk of bullying. They may become withdrawn or defiant as a result and increase the behaviour that the intervention is intended to address.\n\nThe evidence also highlighted that a group intervention may normalise undesirable behaviours. For example, groups that include pupils who are part of an existing friendship group known for behaviours that challenge may be difficult to work with. This is because of the potential for friendship status and 'membership rights' in the group to be a priority for the pupils rather than working to improve their social, emotional and mental health. The committee agreed that other factors such as developmental age and cultural background were also important to take into account when planning the membership of group interventions.\n\nFocus group research commissioned by NICE to explore children and young people's perspectives on the draft recommendations identified the importance of peer-to-peer support. However, the committee recognised the need to offer a range of support (including peer-to-peer support). This was because evidence in the wider literature on peer-to-peer support indicates that there is a danger that it can perpetuate bullying. Furthermore, the committee highlighted the importance of environment when delivering targeted interventions, because children and young people need to feel safe and comfortable to talk through difficult feelings.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current best practice. They are based on existing processes that all schools should be following, so they are unlikely to have a considerable resource impact.\n\nTime and money may be needed to set up suitable environments for delivering interventions. Training and time may also be needed to ensure that school staff are able to monitor children and young people's wellbeing for signs of adverse reactions to receiving targeted support.\n\nReturn to recommendations\n\n# Support with school-related transitions and other life changes\n\nRecommendations 1.5.1 to 1.5.7\n\n## Why the committee made the recommendations\n\nThe committee discussed evidence on children and young people who are preparing for or undergoing a transition. Although there was a reasonable number of studies about the effectiveness of interventions to make transitions easier, the quality of the evidence was relatively low. However, the committee agreed with the evidence that transition interventions gave useful support. They also considered some higher quality evidence from qualitative studies about the acceptability of these interventions that helped them to make recommendations.\n\nThe studies included several types of transitions, including moving to a new school or going through a life event such as parental divorce, as well as support for children and young people from a refugee background. Because of the different types of transition identified, the committee agreed that there was a need for support based on individual needs. They discussed how to tailor interventions so that they meet the child or young person's needs and acknowledged that teachers might need additional training for this.\n\nThe evidence suggested that when planning for transitions it is important to consider any potential unintended consequences. This supported the committee's view that care needs to be taken to avoid negative labelling or stigmatising pupils, for example when sharing information with a new school. They discussed the lack of research about what children and young people themselves find useful during transitions, especially those from underserved populations (see the other recommendations for research section on support for transitions).\n\nThe committee discussed managed moves (in which a child or young person is placed in a new school by the local authority or by school-to-school voluntary agreement) and agreed that the principles for these were the same as for general transitions. The committee did not see any evidence about children's experiences of school transitions but agreed that future research was needed to fill this gap (see the other recommendations for research section on views on transitions to secondary school).\n\nThe evidence supported the committee's experience that communication and engagement between schools and parents, carers and families are important in managing transitions and life changes. This is also consistent with the committee's view that engaging with pupils and their parents or carers is an important part of a whole-school approach.\n\nThe qualitative evidence on practical supports, such as travel advice, buddy systems and orientation sessions, was also supported by the committee experience that these are useful practical steps.\n\nBased on their expertise, the committee concluded that ongoing monitoring was beneficial in ensuring that the child or young person continues to progress and that the transition arrangements are effective over the whole of the child or young person's education. This is especially the case if they are at higher risk of poor social, emotional and mental wellbeing.\n\nFocus group research commissioned by NICE to explore children and young people's perspectives on the draft recommendations identified the importance of peer mentoring during transition periods to promote good social, emotional and mental wellbeing. The committee agreed with the value of peer mentoring for children and young people entering a new school, particularly from older pupils who have been appropriately trained as mentors.\n\nThe committee discussed significant life changes in the context of the school environment and agreed that although these often could not be planned for (for example, a sudden bereavement), the school had a key role in supporting children and young people through these events and in arranging external support for the child or young person if it is needed. This included supporting children and young people through the loss of key relationships with school staff when they moved classes or schools. They agreed it was important to understand how children and young people could be supported through this (see the other recommendations for research section on support for transitions).\n\n## How the recommendations might affect practice or services\n\nThe committee agreed that supporting children and young people through transitions to new classes, schools or out of education was part of the general responsibilities of the school. As part of their pastoral role, teachers and other school staff would be trained to engage with pupils and identify those who were not thriving. They noted that agencies outside the school could also provide important services that the school was unable to provide. The recommendations highlight the value of peer mentoring for pupils transitioning to a new school. Additional time may be needed to train older pupils on how to effectively mentor new students.\n\nReturn to recommendations", 'Context': "Primary and secondary schools help children and young people learn social, emotional and mental skills through both the taught and the wider curriculum (such as activities outside the classroom). Schools can provide the supportive, caring and nurturing environment that supports positive social, emotional and mental wellbeing. They are also important settings in which to identify and provide early intervention for children and young people at increased risk of mental ill health.\n\nSchools have statutory duties to establish environments where children and young people are supported and can fully engage. These duties encourage schools to support personal development, mental health and wellbeing. Many schools follow a whole-school approach to social, emotional and mental wellbeing (see the Department for Education's research and analysis on supporting mental health in schools and colleges). This approach goes beyond learning and teaching to include school culture, ethos and environment. It involves engaging with children and young people, their parents and carers, teacher and school leaders and outside agencies.\n\nSocial, emotional and mental wellbeing may be promoted in curriculum subjects such as personal, social, health and economic education and be embedded more broadly through a school's commitment to the spiritual, moral, social and cultural development of their pupils. Key challenges for schools include:\n\nknowing what approaches improve student outcomes in a specific school setting\n\naccommodating effective teaching of social, emotional and mental wellbeing in a crowded curriculum.\n\nSchools use various methods to identify children and young people who may benefit from targeted interventions to support their approach to social, emotional and mental wellbeing. This may include information from other practitioners such as a speech and language therapist or special educational needs and disability coordinator."}	https://www.nice.org.uk/guidance/ng223	This guideline covers ways to support social, emotional and mental wellbeing in children and young people in primary and secondary education (key stages 1 to 5), and people 25 years and under with special educational needs or disability in further education colleges. It aims to promote good social, emotional and psychological health to protect children and young people against behavioural and health problems.
786790638f647b68f4a3dbb12ae8ceb5be26b3d3	nice	MiraQ for assessing graft flow during coronary artery bypass graft surgery	MiraQ for assessing graft flow during coronary artery bypass graft surgery Evidence-based recommendations on MiraQ for assessing graft flow during coronary artery bypass graft surgery. # Recommendations The MiraQ system is recommended as a cost saving option for assessing graft flow during coronary artery bypass graft surgery. Why the committee made these recommendations Clinical evidence shows that the MiraQ system is effective for assessing coronary artery bypass grafts and allows for grafts to be revised during surgery. This may reduce the frequency of graft occlusion and may reduce perioperative morbidity and mortality. The MiraQ system can lead to an estimated cost saving of £80.27 per person compared with clinical assessment. # The technology # Description of the technology The MiraQ cardiac system (MCQ0, Medistim ASA) uses ultrasound for the non-invasive assessment of graft blood flow during coronary artery bypass graft (CABG) surgery. It is intended for use in patients with coronary artery disease who are having CABG surgery. It measures 3 parameters of transit time flow (mean blood flow in ml/minute, pulsatility index and diastolic filling percentage) to assess graft blood flow and check patency. The MiraQ system measures transit time volume flow using specially designed probes. A microcomputer with a 19‑inch touch screen mounted on a moveable trolley is used to control the probes and store their outputs. The MiraQ system can use 2 types of probes to assess blood flow during CABG procedures (the PS and PQ). These differ in the number of recommended reuses and their method of sterilisation. Only the PS probe is considered in this guidance, because the PQ probe needs ethylene oxide sterilisation, which is not thought to be widely available in the NHS. The probes deliver a bidirectional ultrasound beam across a target vessel and the system analyses the returning signal to calculate the blood flow through the vessel at a default filter setting of 20 Hz. A real-time flow curve is displayed together with the mean blood flow in ml/minute, pulsatility index and diastolic filling percentage. This information can be used to determine whether flow through the graft and its anastomoses is acceptable. If not, then the graft can be explored to detect imperfections and revised as necessary to achieve acceptable blood flow. The cost of the MiraQ system stated in the sponsor's submission includes £32,000 for the VeriQ 2011 console, and £1,582 for each PS probe. These costs were updated in the 2017 revision of the cost model to £34,000 for the cardiac MCQ0 console and £1,481 for each probe. These costs were updated again in the 2021 revision of the cost model, because the MiraQ console and PS probe increased in price to £35,955 and £1,720, respectively. The annual maintenance cost (assuming a 10‑year life span) reduced from £1,800 to £1,369.80. The claimed benefits of the MiraQ system in the case for adoption presented by the manufacturer are: improved outcomes of revascularisation procedures by reducing the risk of early graft failure and adverse events reduced hospital stay for some patients by reducing the incidence of complications during and after surgery reduced numbers of repeat procedures and treatments for postoperative complications. # Current management Coronary artery disease is a common cause of symptoms, disability and death. It is caused by atherosclerosis, which leads to stenosis or occlusion of the coronary arteries. NICE's guideline on stable angina recommends that revascularisation of the blocked coronary arteries using CABG or percutaneous coronary interventions should be considered in people whose symptoms are not satisfactorily controlled by medical treatment. CABG aims to bypass narrowed or blocked segments of the coronary arteries using grafts. Grafts are usually constructed from lengths of the patient's own long saphenous vein or their internal mammary artery, although other vessels are also used. Cardiac surgeons use a variety of techniques to avoid technical imperfections during CABG, but assessment of graft flow is usually subjective. Techniques used vary according to the graft used, the surgical technique, and the surgeon's individual preference. They include the surgeon assessing resistance and perfusion beyond a graft by flushing fluid through it before restoring flow, and both observing and palpating grafts for pulsation when blood flow has been re-established. There are a number of methods for the objective assessment of the technical results and of blood flow. Transoesophageal echocardiography evaluates heart function after bypass by assessing regional left ventricular wall motion abnormalities, which can be compared with preoperative regional left ventricular function. Perioperative graft flow can be visualised in the operating theatre using conventional angiography or using indocyanine green fluorescence. NICE has produced interventional procedures guidance on intraoperative fluorescence angiography for the evaluation of coronary artery bypass graft. This guidance states that current evidence suggests that the procedure is safe enough for routine use in the evaluation of coronary artery bypass graft patency.# Clinical evidence # Summary of clinical evidence The key clinical outcomes for the MiraQ system presented in the decision problem were: incidence of graft failure time to graft failure peri and postoperative clinical events associated with graft failure (including mortality) frequency of the need for graft revision and changes in VeriQ measurements afterwards the need for repeat coronary revascularisation procedures long-term morbidity and mortality. The evidence for the clinical effectiveness of the MiraQ system was based on 2 retrospective observational studies that examined surgical outcomes, and one comparative study that compared parameter values from the VeriQ system against another flowmeter. The studies were conducted in hospitals in Europe and Canada; there were none in the UK. All patients in the studies were treated by coronary artery bypass graft (CABG) surgery. In a retrospective case study in Canada, Kieser et al. (2010) evaluated transit time flow measurement with the VeriQ system to detect technical errors in CABGs intra-operatively and to predict postoperative major adverse cardiac events. They assessed 1,000 arterial grafts in 336 consecutive patients. Three parameters of transit time flow (pulsatility index, flow and diastolic filling percentage) were measured in 990 (99%) of the grafts. A pulsatility index value of less than 5 was chosen as the principal measure of graft adequacy. In 82% of the patients (277 of 336), 93% of grafts (916 of 990) had a pulsatility index of less than or equal to 5. The remaining 74 (7%) grafts (in 59 patients, 18%) had a pulsatility index of greater than 5, but grafts were revised only when an abnormally high pulsatility index was accompanied by other indications of graft malfunction (abnormal electrocardiogram changes, regional wall motion abnormality on transoesophageal echocardiography or haemodynamic compromise). On this basis, 20 grafts (in 14 patients, 4%) that were suspected to be problematic were revised. For analysis of the findings, patients were divided into 2 groups: the 277 (82%) with at least one graft with a pulsatility index of less than 5, and 59 (18%) with at least one graft with a pulsatility index of greater than 5. Major adverse cardiac events (recurrent angina, perioperative myocardial infarction, postoperative angioplasty, re‑operation and/or perioperative death) occurred significantly more often in patients with a pulsatility index of greater than 5 (10 of 59, 17%) when compared with patients with a pulsatility index of less than 5 (15 of 277, 5.4%, p=0.005). Mortality following non-emergency surgery was significantly higher in the patient group with a pulsatility index of greater than 5 (5 of 54, 9%) than in the group with a pulsatility index of less than 5 (5 of 250, 2%, p=0.02). Becit et al. (2007) evaluated the effect on the surgical results of CABG of detecting graft dysfunction by intraoperative transit time flow measurement using the VeriQ system in a case–control study in Turkey. A pulsatility index of greater than 5 and diastolic filling percentage of less than 50% were used as the indicators of inadequate flow. The study compared the surgical outcomes for 2 matched series of consecutive patients whose operations were performed by the same surgeons. The study group (n=100) had transit time flow measurement during surgery and the control group (n=100) did not. Three per cent (9 of 303) of grafts in 9 (9%) patients in the study group were revised on the basis of abnormal transit time measurements, and after revision all flow values and flow patterns improved. No information was presented about graft revision in the control group. The incidence of intra-aortic balloon pump insertion for low cardiac output was significantly lower in the study group compared with the control group (1 of 100 versus 7 of 100, p<0.05). Also, perioperative myocardial infarction was significantly lower in the study group compared with the control group (0 of 100 versus 5 of 100, p<0.05). There was no statistically significant difference between the patient groups in intraoperative re-exploration for bleeding or deep sternal infection. Nordgaard et al. (2010) investigated the variation in pulsatility index measurement between 2 different flowmeters (VeriQ and Transonic) and examined whether increasing filtering of the flowmeter signals influenced flow curves and pulsatility index. The VeriQ and Transonic flowmeters have default filter settings of 20 Hz and 10 Hz respectively. Flow patterns in 19 patients recorded simultaneously by both flowmeters during CABG surgery were analysed. This showed that the VeriQ system provided systematically higher pulsatility index values than the Transonic device (mean ± standard deviation : 2.7±1.2 versus 1.8±0.6 respectively, p<0.001). Clinical evidence was also available from 26 studies on predecessor devices of the VeriQ system which were designed to evaluate the technical performance of devices, to compare them against the other methods of graft flow assessment such as intraoperative fluorescence imaging and postoperative X-ray angiography; and to assess the predictive value of abnormal transit time flow measurement on short and long-term clinical outcomes of CABG surgery. These were evaluated by the external assessment centre and, on balance, their opinion was that the studies showed that transit time flow measurements by the VeriQ system predecessor devices predicted short-term graft failure following CABG surgery and were easier to carry out than other methods. However, they also thought that assessing graft flow with transit time flow measurement alone may prompt unnecessary graft revision in some cases and there is inadequate evidence about whether transit time flow measurement predicts long-term patient survival. # Committee considerations The committee recognised that graft dysfunction is a major determinant of perioperative morbidity and mortality after CABG. It was advised that the majority of graft failures in the perioperative period are due to technical imperfections which, if recognised, might be corrected at the time of surgery. The committee noted that perioperative myocardial infarction resulting from graft failure may cause serious complications such as left ventricular dysfunction, ventricular arrhythmias and haemodynamic instability, which can necessitate prolonged intensive therapy unit stay. These complications may need interventions such as intra-aortic balloon pumping, coronary angiography and early reoperative CABG surgery. They may also lead to readmission to hospital. The committee considered that the available evidence supported the claim that transit time flow measured by the VeriQ system can identify grafts that have reduced flow as a result of technical imperfections. The committee recognised limitations in the available evidence. The main studies were observational, with potential for bias. The study by Kieser et al. (2010) investigated the VeriQ system on arterial grafts only, whereas in the NHS the majority of CABGs are vein grafts. Nevertheless, it judged that there was sufficient additional evidence relating to predecessor devices and sufficient expert advice to support the expectation that routinely revising all appropriate grafts on the basis of VeriQ measurements would result in reduced perioperative graft occlusions and consequent complications. The committee noted from the study by Nordgaard et al. (2010) that pulsatility index values from the VeriQ system may differ from those of other machines and are influenced by filter settings. However, these differences are systematic and expected to be predictable. The committee was advised that cardiac surgeons use a variety of methods to minimise and detect technical imperfections during CABG surgery but these may have limitations. On the basis of the evidence, it judged that the routine use of VeriQ, as an adjunct to other methods of assessment such as transoesophageal echocardiography, electrocardiography and clinical assessment, would be likely to detect technical problems in some grafts that appear to be satisfactory on clinical assessment alone. The committee noted that recent joint guidelines on myocardial revascularisation issued by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) have recommended graft evaluation by objective methods before leaving the operating theatre after CABG surgery. These guidelines refer to flow less than 20 ml/minute and a pulsatility index of greater than 5 as predicting technically inadequate grafts that need revision before leaving the operating theatre. The committee recognised that the clinical outcomes of CABG surgery have improved in the UK in the past 20 years and that complication rates are now very low. However it was advised that there is still a perioperative graft occlusion rate of 1% to 3%. The committee considered that the VeriQ system has potential to reduce this graft occlusion rate and so further reduce morbidity and mortality after CABG.# NHS considerations # System impact Approximately 22,500 isolated coronary artery bypass graft (CABG) operations are performed in the UK each year. In addition, a substantial proportion of patients having other cardiac surgery (for example, valve replacement surgery) have concomitant CABG. Based on this large number of patients, any reduction in graft occlusion rates by the MiraQ system during CABG surgery potentially offers significant cost savings to the NHS. The committee was informed that the MiraQ system is easy to use and does not significantly increase operative time. # Committee considerations As described in section 3, the committee judged that reduction in graft occlusion rates by MiraQ assessment and appropriate revision at the time of surgery could decrease complication rates. This could reduce the likelihood of subsequent interventions, prolonged intensive therapy unit and hospital stay, and readmission. Each of these reductions would result in significant resource savings.# Cost considerations # Cost evidence The economic evidence for the MiraQ system comprised a new cost analysis to assess the cost savings to the NHS of introducing the MiraQ system for assessing graft flow during coronary artery bypass graft (CABG) surgery, compared against clinical assessment. In the base-case analysis, the equipment cost for the MiraQ system was about £111 per procedure and the additional time for measuring flow in 3 grafts was 2.35 minutes. The equipment costs were based on the VeriQ 2011 console (purchase cost £32,000 with an anticipated life span of 10 years) and an average use of 1.7 probes per procedure (£1,582 per PS probe, which is recommended for up to 30 uses). The costs per patient were based on the purchase cost of a MiraQ system divided by 220 days' use per year over its life expectancy, including annual maintenance costs. Annual maintenance costs are payable from the end of year 2 at £1,800 per year. It was assumed that the annual maintenance costs for the remaining 8 years would be averaged over the 10‑year life expectancy of the equipment. All time costs in the model were based on the salaries of a CABG team comprising 2 cardiothoracic surgeons, 1 anaesthetist, 1 cardiac perfusionist and 2 cardiac nurses. The cost model evaluated the cost savings of using the MiraQ system compared with clinical assessment alone in assessing graft flow in all patients having CABG. The outcomes considered in the model are complications associated with the CABG surgery. The consequences of using the MiraQ system were based on results from 2 studies (Kieser et al. and Becit et al. ). In the base-case analysis, use of the MiraQ system was associated with an increase of 6.6% in the graft revision rate (a 2.3% increase in minor revisions and a 4.3% increase in major revisions). Costs were based on the time taken by the CABG team to perform the revisions. The cost of the time taken to perform a minor revision was estimated to be £11, and for major revisions, £180. The perioperative events included in the cost analysis were: incidence of postoperative myocardial infarction and the associated rehabilitation costs; use of intra-aortic balloon pumping; incidence and treatment costs of intraoperative re-exploration for bleeding; and incidence and treatment costs of deep sternal infection. The rates of these events for CABG with and without the MiraQ system were based on Becit et al. (2007). The base-case analysis compared a 0% postoperative myocardial infarction rate for patients assessed clinically and with VeriQ versus a 5% rate for patients who had clinical assessment alone. The treatment costs of postoperative myocardial infarction and associated rehabilitation costs were estimated to be £1,667 per patient. The cost of treatment by intra-aortic balloon pumping was estimated to be £2,657 per episode. The base-case analysis compared a 1% rate for intra-aortic balloon pumping for patients assessed clinically and with VeriQ versus a 7% rate for patients who had clinical assessment alone. There was no difference in the rate of intraoperative re-exploration of bleeding and incidence of deep sternal infection between the arms of the model. No adverse event costs as a result of using the VeriQ system were included in the model because none have been reported. The cost saving associated with the MiraQ system in the base case was £115 per patient based on purchase of a VeriQ 2011 console (£32,000), using a PS probe (£1,582 for 30 uses), and annual maintenance costs (£1,800) payable at the end of year 2. The sensitivity analysis based on the parameters and ranges identified by the manufacturer showed that estimates of cost saving for the MiraQ system are robust. The key drivers of the cost saving were the reduction in the rate of postoperative myocardial infarction and the reduction in use of intra-aortic balloon pumping associated with the use of the MiraQ system. The highest cost saving obtained in the sensitivity analysis was £323 per patient and was associated with 0% use of intra-aortic balloon pumping in patients assessed with the MiraQ system compared with a usage rate of 14% in patients assessed without the MiraQ system. The lowest cost saving, of £38 per patient, was obtained for a 2.5% postoperative myocardial infarction rate. The only case in which use of the MiraQ system was not cost saving (when the cost per patient was £45) was when there was no change in the usage rate of intra-aortic balloon pumping in either arm of the model (3.5%). The external assessment centre advised that this is a pessimistic view and that the MiraQ system is likely to be cost saving when used appropriately. # Committee considerations The committee considered that the assumptions made in the cost model were realistic and that the range of savings calculated for the use of MiraQ was likely to be realised in practice. The committee noted that the manufacturer's cost model did not include potential cost savings from reductions in intensive therapy unit stay and reduced readmission rates. The cost savings associated with the MiraQ system may therefore have been underestimated. The committee also noted that the manufacturer's estimated usage of the MiraQ system at 1 patient per day for 220 days per year was likely to be conservative. The committee was advised that on average 3 to 4 CABG operations are performed per day in a cardiac operating theatre in the UK. Increased annual use of a MiraQ system is expected to reduce the estimated equipment cost per procedure because the capital cost of the VeriQ system will be divided across more procedures. The committee considered that the reductions in perioperative myocardial infarction rate to zero and of intra-aortic balloon pump use from 7% to 1% when using the MiraQ system compared with clinical assessment alone in the base case were likely to be overestimates. This would tend to reduce the estimated cost savings of the MiraQ system. However, the committee noted that sensitivity analysis showed that if using the MiraQ system had no impact on the postoperative myocardial infarction rate or led to only a small change in intra-aortic balloon pumping rates (of less than 2%), the MiraQ system remained cost saving compared with clinical assessment alone, resulting in a saving to the NHS. # guidance review For the guidance review, the external assessment centre (EAC) revised the model to reflect 2017 costs (original guidance values are given in brackets). The main parameter changes were the cost of the MiraQ console £34,000 (£32,000) and probes £1,481 (£1,582) with 50 uses (30 uses). These costs resulted in a MiraQ system cost of about £141 (£111) per procedure. The cost of the time taken to perform a minor revision was estimated to be £24 (£11), and for major revisions, £396 (£180). Treatment costs of postoperative myocardial infarction and associated rehabilitation costs were estimated to be £2,031 (£1,667) per patient and treatment cost by intra-aortic balloon pumping was estimated to be £2,574 (£2,657) per episode. Base-case results for the 2017 revised model shows the cost saving associated with the MiraQ system was £141 (£115) per patient. Further details of the 2017 revised model are in the revised model summary. # guidance review For the 2022 guidance review, the EAC reviewed 87 studies that used the Medistim device (MiraQ or previous equivalent versions). It found that most of the evidence was based on single-arm studies with large in-between study heterogeneity. There was, therefore, not enough high-quality evidence to justify any changes to the guidance. The EAC revised the model to reflect 2021 costs and changes to the cost of the technology. This reduced the cost saving compared with clinical assessment from £141 to £80.27. The EAC found that there was no justification for updating the clinical parameters of the economic model. Further details of the revised model are in the cost update in the review decision from June 2022. # Conclusions The committee concluded that the available clinical and cost evidence supported the case for adopting the MiraQ system in the NHS for routine intraoperative graft flow assessment in patients having coronary artery bypass graft surgery.	{'Recommendations': 'The MiraQ system is recommended as a cost saving option for assessing graft flow during coronary artery bypass graft surgery.\n\nWhy the committee made these recommendations\n\nClinical evidence shows that the MiraQ system is effective for assessing coronary artery bypass grafts and allows for grafts to be revised during surgery. This may reduce the frequency of graft occlusion and may reduce perioperative morbidity and mortality.\n\nThe MiraQ system can lead to an estimated cost saving of £80.27 per person compared with clinical assessment. ', 'The technology': "# Description of the technology\n\nThe MiraQ cardiac system (MCQ0, Medistim ASA) uses ultrasound for the non-invasive assessment of graft blood flow during coronary artery bypass graft (CABG) surgery. It is intended for use in patients with coronary artery disease who are having CABG surgery. It measures 3\xa0parameters of transit time flow (mean blood flow in ml/minute, pulsatility index and diastolic filling percentage) to assess graft blood flow and check patency.\n\nThe MiraQ system measures transit time volume flow using specially designed probes. A microcomputer with a 19‑inch touch screen mounted on a moveable trolley is used to control the probes and store their outputs.\n\nThe MiraQ system can use 2 types of probes to assess blood flow during CABG procedures (the PS and PQ). These differ in the number of recommended reuses and their method of sterilisation. Only the PS probe is considered in this guidance, because the PQ probe needs ethylene oxide sterilisation, which is not thought to be widely available in the NHS. The probes deliver a bidirectional ultrasound beam across a target vessel and the system analyses the returning signal to calculate the blood flow through the vessel at a default filter setting of 20\xa0Hz. A real-time flow curve is displayed together with the mean blood flow in ml/minute, pulsatility index and diastolic filling percentage. This information can be used to determine whether flow through the graft and its anastomoses is acceptable. If not, then the graft can be explored to detect imperfections and revised as necessary to achieve acceptable blood flow.\n\nThe cost of the MiraQ system stated in the sponsor's submission includes £32,000 for the VeriQ 2011 console, and £1,582 for each PS probe. These costs were updated in the 2017 revision of the cost model to £34,000 for the cardiac MCQ0 console and £1,481 for each probe. These costs were updated again in the 2021 revision of the cost model, because the MiraQ console and PS probe increased in price to £35,955 and £1,720, respectively. The annual maintenance cost (assuming a 10‑year life span) reduced from £1,800 to £1,369.80. \n\nThe claimed benefits of the MiraQ system in the case for adoption presented by the manufacturer are:\n\nimproved outcomes of revascularisation procedures by reducing the risk of early graft failure and adverse events\n\nreduced hospital stay for some patients by reducing the incidence of complications during and after surgery\n\nreduced numbers of repeat procedures and treatments for postoperative complications.\n\n# Current management\n\nCoronary artery disease is a common cause of symptoms, disability and death. It is caused by atherosclerosis, which leads to stenosis or occlusion of the coronary arteries. NICE's guideline on stable angina recommends that revascularisation of the blocked coronary arteries using CABG or percutaneous coronary interventions should be considered in people whose symptoms are not satisfactorily controlled by medical treatment.\n\nCABG aims to bypass narrowed or blocked segments of the coronary arteries using grafts. Grafts are usually constructed from lengths of the patient's own long saphenous vein or their internal mammary artery, although other vessels are also used.\n\nCardiac surgeons use a variety of techniques to avoid technical imperfections during CABG, but assessment of graft flow is usually subjective. Techniques used vary according to the graft used, the surgical technique, and the surgeon's individual preference. They include the surgeon assessing resistance and perfusion beyond a graft by flushing fluid through it before restoring flow, and both observing and palpating grafts for pulsation when blood flow has been re-established.\n\nThere are a number of methods for the objective assessment of the technical results and of blood flow. Transoesophageal echocardiography evaluates heart function after bypass by assessing regional left ventricular wall motion abnormalities, which can be compared with preoperative regional left ventricular function. Perioperative graft flow can be visualised in the operating theatre using conventional angiography or using indocyanine green fluorescence. NICE has produced interventional procedures guidance on intraoperative fluorescence angiography for the evaluation of coronary artery bypass graft. This guidance states that current evidence suggests that the procedure is safe enough for routine use in the evaluation of coronary artery bypass graft patency.", 'Clinical evidence': '# Summary of clinical evidence\n\nThe key clinical outcomes for the MiraQ system presented in the decision problem were:\n\nincidence of graft failure\n\ntime to graft failure\n\nperi and postoperative clinical events associated with graft failure (including mortality)\n\nfrequency of the need for graft revision and changes in VeriQ measurements afterwards\n\nthe need for repeat coronary revascularisation procedures\n\nlong-term morbidity and mortality.\n\nThe evidence for the clinical effectiveness of the MiraQ system was based on 2 retrospective observational studies that examined surgical outcomes, and one comparative study that compared parameter values from the VeriQ system against another flowmeter. The studies were conducted in hospitals in Europe and Canada; there were none in the UK. All patients in the studies were treated by coronary artery bypass graft (CABG) surgery.\n\nIn a retrospective case study in Canada, Kieser et al. (2010) evaluated transit time flow measurement with the VeriQ system to detect technical errors in CABGs intra-operatively and to predict postoperative major adverse cardiac events. They assessed 1,000\xa0arterial grafts in 336 consecutive patients. Three parameters of transit time flow (pulsatility index, flow and diastolic filling percentage) were measured in 990 (99%) of the grafts. A pulsatility index value of less than 5 was chosen as the principal measure of graft adequacy. In 82% of the patients (277 of 336), 93% of grafts (916 of 990) had a pulsatility index of less than or equal to 5. The remaining 74 (7%) grafts (in 59 patients, 18%) had a pulsatility index of greater than 5, but grafts were revised only when an abnormally high pulsatility index was accompanied by other indications of graft malfunction (abnormal electrocardiogram [ECG] changes, regional wall motion abnormality on transoesophageal echocardiography or haemodynamic compromise). On this basis, 20 grafts (in 14 patients, 4%) that were suspected to be problematic were revised.\n\nFor analysis of the findings, patients were divided into 2 groups: the 277 (82%) with at least one graft with a pulsatility index of less than 5, and 59 (18%) with at least one graft with a pulsatility index of greater than 5. Major adverse cardiac events (recurrent angina, perioperative myocardial infarction, postoperative angioplasty, re‑operation and/or perioperative death) occurred significantly more often in patients with a pulsatility index of greater than 5 (10 of 59, 17%) when compared with patients with a pulsatility index of less than 5 (15 of 277, 5.4%, p=0.005). Mortality following non-emergency surgery was significantly higher in the patient group with a pulsatility index of greater than 5 (5 of 54, 9%) than in the group with a pulsatility index of less than 5 (5 of 250, 2%, p=0.02).\n\nBecit et al. (2007) evaluated the effect on the surgical results of CABG of detecting graft dysfunction by intraoperative transit time flow measurement using the VeriQ system in a case–control study in Turkey. A pulsatility index of greater than 5 and diastolic filling percentage of less than 50% were used as the indicators of inadequate flow. The study compared the surgical outcomes for 2 matched series of consecutive patients whose operations were performed by the same surgeons. The study group (n=100) had transit time flow measurement during surgery and the control group (n=100) did not. Three per cent (9 of 303) of grafts in 9 (9%) patients in the study group were revised on the basis of abnormal transit time measurements, and after revision all flow values and flow patterns improved. No information was presented about graft revision in the control group. The incidence of intra-aortic balloon pump insertion for low cardiac output was significantly lower in the study group compared with the control group (1 of 100 versus 7 of 100, p<0.05). Also, perioperative myocardial infarction was significantly lower in the study group compared with the control group (0 of 100 versus 5 of 100, p<0.05). There was no statistically significant difference between the patient groups in intraoperative re-exploration for bleeding or deep sternal infection.\n\nNordgaard et al. (2010) investigated the variation in pulsatility index measurement between 2 different flowmeters (VeriQ and Transonic) and examined whether increasing filtering of the flowmeter signals influenced flow curves and pulsatility index. The VeriQ and Transonic flowmeters have default filter settings of 20\xa0Hz and 10\xa0Hz respectively. Flow patterns in 19 patients recorded simultaneously by both flowmeters during CABG surgery were analysed. This showed that the VeriQ system provided systematically higher pulsatility index values than the Transonic device (mean ± standard deviation [SD]: 2.7±1.2 versus 1.8±0.6 respectively, p<0.001).\n\nClinical evidence was also available from 26 studies on predecessor devices of the VeriQ system which were designed to evaluate the technical performance of devices, to compare them against the other methods of graft flow assessment such as intraoperative fluorescence imaging and postoperative X-ray angiography; and to assess the predictive value of abnormal transit time flow measurement on short and long-term clinical outcomes of CABG surgery. These were evaluated by the external assessment centre and, on balance, their opinion was that the studies showed that transit time flow measurements by the VeriQ system predecessor devices predicted short-term graft failure following CABG surgery and were easier to carry out than other methods. However, they also thought that assessing graft flow with transit time flow measurement alone may prompt unnecessary graft revision in some cases and there is inadequate evidence about whether transit time flow measurement predicts long-term patient survival.\n\n# Committee considerations\n\nThe committee recognised that graft dysfunction is a major determinant of perioperative morbidity and mortality after CABG. It was advised that the majority of graft failures in the perioperative period are due to technical imperfections which, if recognised, might be corrected at the time of surgery.\n\nThe committee noted that perioperative myocardial infarction resulting from graft failure may cause serious complications such as left ventricular dysfunction, ventricular arrhythmias and haemodynamic instability, which can necessitate prolonged intensive therapy unit stay. These complications may need interventions such as intra-aortic balloon pumping, coronary angiography and early reoperative CABG surgery. They may also lead to readmission to hospital.\n\nThe committee considered that the available evidence supported the claim that transit time flow measured by the VeriQ system can identify grafts that have reduced flow as a result of technical imperfections.\n\nThe committee recognised limitations in the available evidence. The main studies were observational, with potential for bias. The study by Kieser et al. (2010) investigated the VeriQ system on arterial grafts only, whereas in the NHS the majority of CABGs are vein grafts. Nevertheless, it judged that there was sufficient additional evidence relating to predecessor devices and sufficient expert advice to support the expectation that routinely revising all appropriate grafts on the basis of VeriQ measurements would result in reduced perioperative graft occlusions and consequent complications.\n\nThe committee noted from the study by Nordgaard et al. (2010) that pulsatility index values from the VeriQ system may differ from those of other machines and are influenced by filter settings. However, these differences are systematic and expected to be predictable.\n\nThe committee was advised that cardiac surgeons use a variety of methods to minimise and detect technical imperfections during CABG surgery but these may have limitations. On the basis of the evidence, it judged that the routine use of VeriQ, as an adjunct to other methods of assessment such as transoesophageal echocardiography, electrocardiography and clinical assessment, would be likely to detect technical problems in some grafts that appear to be satisfactory on clinical assessment alone.\n\nThe committee noted that recent joint guidelines on myocardial revascularisation issued by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) have recommended graft evaluation by objective methods before leaving the operating theatre after CABG surgery. These guidelines refer to flow less than 20\xa0ml/minute and a pulsatility index of greater than 5 as predicting technically inadequate grafts that need revision before leaving the operating theatre.\n\nThe committee recognised that the clinical outcomes of CABG surgery have improved in the UK in the past 20\xa0years and that complication rates are now very low. However it was advised that there is still a perioperative graft occlusion rate of 1%\xa0to\xa03%. The committee considered that the VeriQ system has potential to reduce this graft occlusion rate and so further reduce morbidity and mortality after CABG.', 'NHS considerations': '# System impact\n\nApproximately 22,500 isolated coronary artery bypass graft (CABG) operations are performed in the UK each year. In addition, a substantial proportion of patients having other cardiac surgery (for example, valve replacement surgery) have concomitant CABG. Based on this large number of patients, any reduction in graft occlusion rates by the MiraQ system during CABG surgery potentially offers significant cost savings to the NHS.\n\nThe committee was informed that the MiraQ system is easy to use and does not significantly increase operative time.\n\n# Committee considerations\n\nAs described in section 3, the committee judged that reduction in graft occlusion rates by MiraQ assessment and appropriate revision at the time of surgery could decrease complication rates. This could reduce the likelihood of subsequent interventions, prolonged intensive therapy unit and hospital stay, and readmission. Each of these reductions would result in significant resource savings.', 'Cost considerations': "# Cost evidence\n\nThe economic evidence for the MiraQ system comprised a new cost analysis to assess the cost savings to the NHS of introducing the MiraQ system for assessing graft flow during coronary artery bypass graft (CABG) surgery, compared against clinical assessment.\n\nIn the base-case analysis, the equipment cost for the MiraQ system was about £111 per procedure and the additional time for measuring flow in 3 grafts was 2.35\xa0minutes. The equipment costs were based on the VeriQ 2011 console (purchase cost £32,000 with an anticipated life span of 10\xa0years) and an average use of 1.7\xa0probes per procedure (£1,582 per PS probe, which is recommended for up to 30 uses). The costs per patient were based on the purchase cost of a MiraQ system divided by 220\xa0days' use per year over its life expectancy, including annual maintenance costs. Annual maintenance costs are payable from the end of year\xa02 at £1,800 per year. It was assumed that the annual maintenance costs for the remaining 8\xa0years would be averaged over the 10‑year life expectancy of the equipment. All time costs in the model were based on the salaries of a CABG team comprising 2 cardiothoracic surgeons, 1 anaesthetist, 1 cardiac perfusionist and 2 cardiac nurses.\n\nThe cost model evaluated the cost savings of using the MiraQ system compared with clinical assessment alone in assessing graft flow in all patients having CABG. The outcomes considered in the model are complications associated with the CABG surgery.\n\nThe consequences of using the MiraQ system were based on results from 2 studies (Kieser et al. and Becit et al. ). In the base-case analysis, use of the MiraQ system was associated with an increase of 6.6% in the graft revision rate (a 2.3% increase in minor revisions and a 4.3% increase in major revisions). Costs were based on the time taken by the CABG team to perform the revisions. The cost of the time taken to perform a minor revision was estimated to be £11, and for major revisions, £180.\n\nThe perioperative events included in the cost analysis were: incidence of postoperative myocardial infarction and the associated rehabilitation costs; use of intra-aortic balloon pumping; incidence and treatment costs of intraoperative re-exploration for bleeding; and incidence and treatment costs of deep sternal infection. The rates of these events for CABG with and without the MiraQ system were based on Becit et al. (2007). The base-case analysis compared a 0% postoperative myocardial infarction rate for patients assessed clinically and with VeriQ versus a 5% rate for patients who had clinical assessment alone. The treatment costs of postoperative myocardial infarction and associated rehabilitation costs were estimated to be £1,667 per patient. The cost of treatment by intra-aortic balloon pumping was estimated to be £2,657 per episode. The base-case analysis compared a 1% rate for intra-aortic balloon pumping for patients assessed clinically and with VeriQ versus a 7% rate for patients who had clinical assessment alone. There was no difference in the rate of intraoperative re-exploration of bleeding and incidence of deep sternal infection between the arms of the model. No adverse event costs as a result of using the VeriQ system were included in the model because none have been reported.\n\nThe cost saving associated with the MiraQ system in the base case was £115 per patient based on purchase of a VeriQ 2011 console (£32,000), using a PS probe (£1,582 for 30 uses), and annual maintenance costs (£1,800) payable at the end of year 2.\n\nThe sensitivity analysis based on the parameters and ranges identified by the manufacturer showed that estimates of cost saving for the MiraQ system are robust. The key drivers of the cost saving were the reduction in the rate of postoperative myocardial infarction and the reduction in use of intra-aortic balloon pumping associated with the use of the MiraQ system. The highest cost saving obtained in the sensitivity analysis was £323 per patient and was associated with 0% use of intra-aortic balloon pumping in patients assessed with the MiraQ system compared with a usage rate of 14% in patients assessed without the MiraQ system. The lowest cost saving, of £38 per patient, was obtained for a 2.5% postoperative myocardial infarction rate. The only case in which use of the MiraQ system was not cost saving (when the cost per patient was £45) was when there was no change in the usage rate of intra-aortic balloon pumping in either arm of the model (3.5%). The external assessment centre advised that this is a pessimistic view and that the MiraQ system is likely to be cost saving when used appropriately.\n\n# Committee considerations\n\nThe committee considered that the assumptions made in the cost model were realistic and that the range of savings calculated for the use of MiraQ was likely to be realised in practice.\n\nThe committee noted that the manufacturer's cost model did not include potential cost savings from reductions in intensive therapy unit stay and reduced readmission rates. The cost savings associated with the MiraQ system may therefore have been underestimated.\n\nThe committee also noted that the manufacturer's estimated usage of the MiraQ system at 1 patient per day for 220\xa0days per year was likely to be conservative. The committee was advised that on average 3 to 4 CABG operations are performed per day in a cardiac operating theatre in the UK. Increased annual use of a MiraQ system is expected to reduce the estimated equipment cost per procedure because the capital cost of the VeriQ system will be divided across more procedures.\n\nThe committee considered that the reductions in perioperative myocardial infarction rate to zero and of intra-aortic balloon pump use from 7% to 1% when using the MiraQ system compared with clinical assessment alone in the base case were likely to be overestimates. This would tend to reduce the estimated cost savings of the MiraQ system. However, the committee noted that sensitivity analysis showed that if using the MiraQ system had no impact on the postoperative myocardial infarction rate or led to only a small change in intra-aortic balloon pumping rates (of less than 2%), the MiraQ system remained cost saving compared with clinical assessment alone, resulting in a saving to the NHS.\n\n# guidance review\n\nFor the guidance review, the external assessment centre (EAC) revised the model to reflect 2017 costs (original guidance values are given in brackets). The main parameter changes were the cost of the MiraQ console £34,000 (£32,000) and probes £1,481 (£1,582) with 50 uses (30 uses). These costs resulted in a MiraQ system cost of about £141 (£111) per procedure. The cost of the time taken to perform a minor revision was estimated to be £24 (£11), and for major revisions, £396 (£180). Treatment costs of postoperative myocardial infarction and associated rehabilitation costs were estimated to be £2,031 (£1,667) per patient and treatment cost by intra-aortic balloon pumping was estimated to be £2,574 (£2,657) per episode. Base-case results for the 2017 revised model shows the cost saving associated with the MiraQ system was £141 (£115) per patient. Further details of the 2017 revised model are in the revised model summary. \n\n# guidance review\n\nFor the 2022 guidance review, the EAC reviewed 87 studies that used the Medistim device (MiraQ or previous equivalent versions). It found that most of the evidence was based on single-arm studies with large in-between study heterogeneity. There was, therefore, not enough high-quality evidence to justify any changes to the guidance.\n\nThe EAC revised the model to reflect 2021 costs and changes to the cost of the technology. This reduced the cost saving compared with clinical assessment from £141 to £80.27. The EAC found that there was no justification for updating the clinical parameters of the economic model. Further details of the revised model are in the cost update in the review decision from June 2022.\xa0", 'Conclusions': 'The committee concluded that the available clinical and cost evidence supported the case for adopting the MiraQ system in the NHS for routine intraoperative graft flow assessment in patients having coronary artery bypass graft surgery.'}	https://www.nice.org.uk/guidance/mtg8	Evidence-based recommendations on MiraQ for assessing graft flow during coronary artery bypass graft surgery.
98bda46bbf4fa9bd118cc7c9decc26a9f77424d3	nice	Teduglutide for treating short bowel syndrome	Teduglutide for treating short bowel syndrome Evidence-based recommendations on teduglutide (Resvestive) for treating short bowel syndrome in people 1 year and above. # Recommendations Teduglutide is recommended, within its marketing authorisation, as an option for treating short bowel syndrome (SBS) in people 1 year and above. People's condition should be stable following a period of intestinal adaptation after surgery before having teduglutide. Teduglutide is recommended only if the company provides it according to the commercial arrangement. Why the committee made these recommendations Current treatment for SBS is parenteral support (giving nutrients and fluids intravenously) with best supportive care. Best supportive care includes antimotility and antisecretory medicines, fluid restriction and diet changes. Clinical trial evidence shows that teduglutide reduces the number of days a week people with SBS need parenteral support compared with placebo. However, how much it reduces this is uncertain because the trial design may not reflect NHS practice. Because of the uncertainties in the clinical evidence, the cost-effectiveness estimates are uncertain. However, even when accounting for the uncertainties, these estimates are below what NICE normally considers an acceptable use of NHS resources. Therefore, teduglutide is recommended.# Information about teduglutide # Marketing authorisation indication Teduglutide (Revestive, Takeda) is 'indicated for the treatment of patients aged 1 year and above with short bowel syndrome (SBS). Patients should be stable following a period of intestinal adaptation after surgery.' # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for teduglutide. # Price The list price of a 5 mg vial of teduglutide is £521.98. The list price of a 1.25 mg vial of teduglutide is £260.99 (excluding VAT; BNF online, accessed April 2022). The company has a commercial arrangement. This makes teduglutide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Takeda, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Short bowel syndrome is a chronic condition with limited treatment options Short bowel syndrome (SBS) is a chronic and potentially life-threatening condition characterised by reduced absorption of nutrients, water and electrolytes. SBS is commonly caused by surgery that has been needed to remove abnormal bowel. In adults, this surgery may be needed for a range of conditions, including mesenteric ischaemia, Crohn's disease and radiation enteritis. In children, it is often because of necrotising enterocolitis in premature babies, or other conditions such as volvulus or gastroschisis. Some children can be born with a short bowel. SBS can lead to intestinal failure. This is when the length of intestine remaining means the intestinal functions drops below the necessary level for absorption of nutrients, water and electrolytes. Intestinal failure is classified as type 3 when it is chronic and people need to have parenteral support over months or years. Current treatment for SBS includes parenteral support, in which nutrients and fluids are given intravenously for an average of 10 to 14 hours a day for between 2 and 7 days a week. Most people have parenteral support at home using a permanent intravenous tube. While parenteral support is life-saving, it is very time-consuming, highly complex and its complications can be life-threatening. These include blood infections, blood clots, and kidney and liver failure. Clinical and patient experts both noted that there are currently supply issues with parenteral support, and people with SBS are having to adapt their care to manage this. They also highlighted that administering parenteral support is complicated and challenging for people with SBS and their carers. They emphasised a need for new treatments that offer more normality for those affected by SBS. The committee concluded that SBS is a chronic condition with limited treatment options that can cause further adverse complications. ## People would welcome new treatment options for short bowel syndrome that reduce the number of days of parenteral support SBS is not only burdensome for the person with the condition, but for their carers too. This burden is often linked to the need to use parenteral support. Patient experts confirmed that parenteral support limits a normal life in many ways, including family, work and social life. Most people with SBS have parenteral support at home, and either administer this themselves or with a carer's assistance. Patient experts highlighted that this places a huge burden on people with SBS and their carers, because the responsibility of doing complicated procedures at home can be overwhelming. They feel that the impact on carers is often overlooked, and that many families have not had a night off from giving parenteral support in many years. Carers also often feel guilt when people with SBS experience complications such as blood infections because they feel that these would have been avoided if they had done their caring duties correctly. Clinical experts highlighted that there is potential for teduglutide to allow some people with SBS to wean off parenteral support completely, or at least reduce the number of nights per week when they need it. This would greatly increase the quality of life of both people with SBS and their carers. Both clinical and patient experts noted that there is an unmet need to reduce the time spent on parenteral support to increase the quality of life for people with SBS and their carers. The experts emphasised that this was a continuous burden, with little or no respite. They advised that any reduction in the number of nights of treatment would give people respite, which would give them and their family and carers some time to do other activities. Clinical experts explained that a person with SBS would usually have bespoke home parenteral nutrition formulations through compounded parenteral nutrition bags. However, because of the increased demand for parenteral support in England, some people do not have access to these formulations. Instead they are given standard preparations that are more complex to infuse and could result in reduced health. Clinical experts also highlighted that this is likely to incur a higher cost because people are prescribed multiple types of bags to replace what would usually be provided in their compounded parenteral nutrition. The committee agreed that the impact of parenteral support on people with SBS and their carers was high. It concluded that people would welcome new treatment options for SBS that reduce the number of days of parenteral support. # Treatment pathway and comparators ## Teduglutide is likely to be used once people become stable on parenteral support Teduglutide's marketing authorisation is for the treatment of SBS in people 1 year and above who are stable after a period of intestinal adaptation. The company's positioning of teduglutide was aligned with the marketing authorisation. This was highlighted as a decision point in the pathway after the adaptation phase. The adaptation phase is estimated to be up to 2 years in adults but can be longer in children. Clinical experts noted that they would want to use teduglutide for any child who needs routine parenteral support, and they would not want to wait more than 2 years to start treatment. They also highlighted that starting teduglutide might reduce the need for intestinal transplant because transplants would only be indicated for people in whom parenteral support is not working. The committee concluded that teduglutide was likely to be used for people with SBS once their parenteral support needs had been established and stabilised on a regular schedule. ## The only appropriate comparator for teduglutide is parenteral support combined with best supportive care For people with SBS, the company submission compared teduglutide with established clinical management including parenteral support with best supportive care (antimotility and antisecretory agents, fluid restriction and dietary optimisation). Further surgical procedures can be done after parenteral support stabilisation to attempt to increase the length of remaining bowel that is in direct continuity. However, because these are rarely done in practice, they were not included as a relevant comparator. Intestinal transplant can also be done if all other treatments fail. This is done in some children, but not routinely. Surgery was not considered a comparator in this appraisal, but avoiding the need for a transplant, which has lifelong consequences, could be a benefit of teduglutide. The committee concluded that parenteral support with best supportive care was the only appropriate comparator for teduglutide. # Clinical evidence ## The clinical trial evidence used in the company model is appropriate, but the patient support programme data is less certain The key clinical evidence for teduglutide came from 1 clinical trial and its long-term open-label extension study, and 1 non-interventional real-world study in adults with SBS: STEPS: a phase 3, multinational, randomised, double-blind, placebo-controlled 24‑week study and STEPS‑2: a 2‑year, open-label, multinational extension study for people who had screening or treatment in STEPS. PSP: a non-interventional patient support programme (PSP) in Australia.The company submitted clinical evidence for adults from an extension to STEPS‑2 and 1 further clinical trial and its extension that were not included in the economic model: STEPS‑3: an up to 1-year, open-label extension study for people in STEPS‑2 at 5 US sites. : a phase 3, multinational, randomised, double-blind, placebo-controlled, 24‑week study and 005: a 28‑week, open-label, multinational, extension study for people who had treatment with teduglutide or placebo in 004.The company decided not to include STEPS‑3 data in its model because the relevant cohort of patients only contained 5 people. 004 and 005 were not included because the results have weak external validity due to the restrictive parenteral support weaning algorithm used as part of the study protocol. The company also submitted evidence from 8 non-interventional real-world studies in adults which were not included in the model. The company submitted clinical evidence for children from 2 open-label studies and their extensions, but did not include this evidence in the economic model: C13: a phase 3, open-label, non-randomised, 12‑week study in the UK and US and SHP633‑303: its open-label, long-term extension. C14: a phase 3, multinational, open-label, non-randomised, 24‑week study and SHP633‑304: its open-label, multinational, long-term extension. No clinical data from studies in children was used in the modelling. The company's justification for this was that the trials in children had small sample sizes and non-continuous treatment across follow-on studies. The ERG was satisfied with the company's choice of clinical evidence used in the model. It agreed that STEPS was of good methodological quality. It highlighted the small sample size of STEPS‑3 and accepted that the weaning algorithm used in 004 and 005 was not closely matched to clinical practice. It also recognised the small sample numbers in C13, C14 and their extensions. The committee concluded that the clinical trial evidence chosen by the company for use in the model was appropriate. ## Results from trials in children show that teduglutide reduces parenteral support needs, but there are limitations in the trial design, which justifies the use of adult data for children The company provided efficacy data for children from 2 clinical trials and their long-term extensions. This data was provided to show that the efficacy of teduglutide in children is similar to and may even exceed its efficacy in adults. In C14, the primary outcome was the percentage of people who had a 20% to 100% reduction in parenteral volume from baseline at week 24. This was defined as a 'clinical response'. Reduction in days of parenteral support per week was measured as a secondary outcome. C14 found that more children with SBS had a clinical response on teduglutide compared with the standard care group (69% compared with 11%). Children having teduglutide also had a reduction in days of parenteral support per week from baseline, while those on standard care did not (1.3 days reduction compared with 0 days). The primary outcome for C13 was the reduction in days of parenteral support per week. The results of this are confidential and cannot be disclosed here. Reduction in parenteral support volume was measured as a secondary outcome. Results from C13 also showed reductions in parenteral volume from baseline at 12 weeks. Results from the extension studies are confidential and cannot be disclosed here. C13, C14 and their extensions were not included in the model because they had small sample sizes and the extensions had non-continuous treatment with teduglutide (see section 3.5). Instead, the company used adult data to inform both the adult and child base cases. The committee concluded that the results in children did indicate that teduglutide has clinical benefits for children, but they were not suitable for use in the model because of their limitations in study design. ## Clinical evidence from adult trials shows that teduglutide reduces parenteral support needs In STEPS, the primary outcome was the percentage of people with SBS who had a 20% to 100% reduction of parenteral volume from baseline at week 20 maintained to week 24. This was defined by the company as a 'clinical response'. A key outcome in both STEPS and STEPS-2 was the change in days per week of parenteral support from baseline. Both STEPS and STEPS‑2 assessed the safety of teduglutide. Outcomes considered from PSP were a 20% to 100% reduction in parenteral support volume from baseline ('clinical response') and change in days per week of parenteral support from baseline. The ERG noted the definition of 'clinical response' differed slightly between STEPS and PSP, but did not consider that it would affect the trial results. Both clinical and patient experts agreed that a reduction in days on parenteral support per week is more valuable to patients than reducing parenteral volume alone. People in the STEPS trial had an average number of days on parenteral support of 5.6 and 5.9 days (teduglutide and placebo arms respectively) before treatment. After treatment, significantly more people with SBS had a 1‑day or more reduction in weekly parenteral support on teduglutide over placebo (53.8% compared with 23.1%). The results from PSP are confidential and cannot be disclosed here. The committee concluded that the clinical evidence indicates that teduglutide reduces parenteral support needs in adults with SBS. ## The weaning algorithm in STEPS may have affected generalisability of the results in both arms People with SBS taking teduglutide can potentially reduce parenteral support and increase their oral diet through a process known as weaning. The STEPS trial used a weaning algorithm to decide if people with SBS should have their parenteral support reduced. A feature of the STEPS results is the apparent efficacy of placebo, with 23.1% of the placebo arm reducing their days of parenteral support by 1 day or more. The company commented that this is unrealistic, and that any reduction in days of parenteral support per week in the placebo arm were unlikely to be because of improved intestinal function. It emphasised that people entering STEPS had undergone parenteral support optimisation and stabilisation before starting teduglutide or placebo, so any differences in parenteral support over time in the placebo arm could not be explained by further optimisation of care. It suggested that the observed placebo effect is instead a result of the strict weaning algorithm used in the trial that was solely based on urine output. The ERG noted that the company's argument was plausible, and that changes in parenteral support do not rely on urine output alone in clinical practice. The company also stated that people in the placebo arm lost weight over the course of the trial and this indicates that they were not having adequate parenteral support. The committee queried whether this placebo effect reflected clinical practice. The clinical experts explained that in clinical practice clinicians do not know urine output on a day-to-day basis, and so weaning is less precise than in STEPS. They added that the weaning algorithm relying entirely on urine output was unrealistic and that maintaining weight should also be part of the weaning criteria. They clarified that while it may be possible for adults with SBS temporarily to reduce their parenteral support while having current standard care, this would not be sustainable if medical advice was followed correctly. This means that the placebo effect seen in STEPS did not reflect clinical practice. Conversely, the company also commented that the weaning algorithm used in STEPS in the teduglutide arm underestimated the extent to which parenteral support could be reduced, thereby underestimating the effect of teduglutide. The company's view was that the strict nature of this algorithm was therefore likely to underestimate the relative treatment effect of teduglutide compared with placebo. Also, the weaning algorithm constrained how quickly people were able to wean off parenteral support if they improved on teduglutide. The ERG highlighted that while the weaning algorithm is restrictive and may not reflect clinical practice, it was applied to both arms of the STEPS trial. Therefore, the internal validity of the results could be considered robust, but the absolute effects of teduglutide and placebo may not be valid. The ERG also received clinical feedback that adults on standard care were unlikely to reduce their parenteral support. The committee then explored whether teduglutide might allow some people with SBS to stop parenteral support altogether. Clinical experts commented that they would expect some people taking teduglutide to come off parenteral support entirely, and they have seen such cases in clinical practice. They stated that while some children may be able to wean off parenteral support naturally as their bowel matures and they grow, teduglutide allows them to improve faster and avoid both the clinical and social challenges associated with parenteral support. The committee considered whether it was more important to consider benefits relating to the clinical effectiveness of teduglutide independently, or in comparison with other treatments. The ERG agreed with the company's arguments relating to the impact of the weaning algorithm on the results. Clinical experts confirmed that people on standard care were unlikely to reduce their parenteral support. The committee was unable to come to a clear conclusion on the impact of the weaning algorithm on the trial results, but noted that placebo-controlled trials are usually appropriately designed to determine the true treatment effect of a new drug. It concluded that the weaning algorithm may have affected generalisability of the results from both arms of STEPS, which made the true relative treatment effect of teduglutide compared with placebo uncertain. ## The frequency of adverse events is broadly similar between teduglutide and placebo for adults The company provided safety evidence for adults, pooled from STEPS, STEPS‑2, 004 and 005. The ERG found that the pooling of safety data from these trials was appropriate. In the 24-week randomised trials, adults on teduglutide most commonly reported abdominal pain (38.5% compared with 27.1%), gastrointestinal stoma complications (37.8% compared with 13.6%), upper respiratory tract infections (27.5% compared with 13.6%) and abdominal distension (16.5% compared with 1.7%). The frequency and severity of these adverse events were broadly similar between the people having teduglutide and placebo, except for abdominal distension. The company commented that the observed adverse events were likely to be because of pro-absorptive and intestinotrophic effects of teduglutide, insufficient parenteral support weaning or the underlying nature of SBS. The ERG accepted this reasoning following advice from clinical experts. The committee concluded that the overall frequency and severity of adverse events resemble those of the placebo group. ## The safety profile of teduglutide in children is similar to adults The company also provided safety data for children, pooled from C13, SHP633‑303, C14 and SHP633‑304. The most common adverse events were vomiting (51.7%), pyrexia (43.8%), upper respiratory tract infection (41.6%), cough (33.7%) and device-related (central venous catheter) infection (29.2%). The ERG commented that the overall rates of adverse events were similar to adults, but respiratory infections, pyrexia, vomiting and catheter complications (including infections) were more common in children than in adults. The company stated that these adverse events would be expected to be more frequent in children. The committee commented that children are often admitted to hospital with catheter complications, because frequent diarrhoea can mean it is difficult for carers to always keep the catheter completely clean. The committee concluded that the safety profile of teduglutide is similar for adults and children. # Economic model ## The estimation of health-state transition probabilities within the model is a source of uncertainty, but is appropriate for decision making The economic model was developed using a Markov structure, comprising 9 health states defined by the days of parenteral support per week (from 7 days to parental support independence or to death). The company included a treatment stopping rule so that modelled teduglutide use would reflect its use in clinical practice as closely as possible. The summary of product characteristics recommends that treatment should be stopped if there is no overall improvement in the condition. It recommends that adults should have an evaluation after 6 months, with treatment continuation being reconsidered if there is no treatment benefit by 12 months. The model reflected this by assuming that those who had not had a reduction of at least 1 day of parenteral support per week at 12 months, compared with baseline, stop teduglutide. Once treatment is stopped, they immediately reverted to their baseline parenteral support state before teduglutide. Teduglutide is modelled to affect both cost and quality-adjusted life years (QALYs): Costs: Drug treatment (teduglutide) costs are increased. Costs associated with parenteral support, concomitant drugs, and complications linked to parenteral support are reduced. Incidence of adverse events are changed compared with standard care. QALYs: The number of days that people need parenteral support per week is reduced. This is modelled to improve the health-related quality of life of people with SBS and their carers. The incidence of complications associated with parenteral support are reduced. There are carer benefits.To calculate transition probabilities for teduglutide, the company pooled clinical data from the teduglutide arms of STEPS and STEPS‑2 and data from the PSP when estimating the reductions in parenteral support for the teduglutide group. It explained that it took this approach rather than using the relative treatment effect from the trial because the weaning algorithm in STEPS and STEPS‑2 underestimates parenteral support reductions for teduglutide (see section 3.8). The company supported this claim by doing an analysis comparing the percentage of people stopping parenteral support entirely while taking teduglutide between STEPS, PSP, and a combination of other real-world studies. The company also assumed that there is no change in parenteral support in the standard care arm and applied the STEPS baseline parenteral support requirement over the time horizon in the standard care arm of the model. The reasoning for this was that people need to have a stable parenteral support requirement before teduglutide, and reductions in parenteral support would not be expected in clinical practice without teduglutide (see section 3.3). The ERG confirmed that the model structure is appropriate. It advised that the company's explanation for underestimation of teduglutide effectiveness in the STEPS and STEPS‑2 trials was plausible, but that any comparison of effects between observational studies and randomised controlled trials should be interpreted with caution. The committee expressed some concern around the company's methodology for estimating transition probabilities. This was specifically related to breaking randomisation when pooling the real-world and teduglutide arm trial data while disregarding the relative treatment effect and placebo data from STEPS. The ERG stated that it had done a scenario analysis exploring the relative treatment effect of teduglutide from the STEPS data alone. This had a substantial upwards impact on the incremental cost-effectiveness ratio (ICER). But because it received clinical expert feedback that people having standard care would not be expected to reduce their parenteral support needs, the ERG considered this scenario to be conservative and did not incorporate it into its base case. At its first meeting, the committee concluded that the company's approach to modelling health-state transitions in both arms was a source of uncertainty and requested further scenario analyses. In response to these concerns, the company provided 2 scenarios: Using STEPS placebo arm data to calculate the first 6 months of transitions within the standard of care arm of the adult base case (only 6 months was considered by the company because it did not consider the placebo effect in STEPS to be sustainable long term). Using only data from STEPS or STEPS‑2 in the teduglutide arm of the adult base case, rather than pooling data from STEPS, STEPS‑2 and PSP.Both these scenarios had a modest upwards impact on the ICER. The ERG combined the 2 scenarios but stated that this was pessimistic and probably underestimated the benefit of teduglutide. The committee agreed that these scenarios resolved some uncertainty around the calculation of transition probabilities in the model. It concluded that the transition probabilities were a source of uncertainty but were appropriate for decision making. ## The assumptions and data sources are very similar between the models for adults and children No clinical study data from studies in children was used in the modelling (see section 3.5). The company considered that children would gain more benefit from teduglutide and so using adult data would give a conservative cost-effectiveness estimate for children. Clinical experts confirmed that children have more possibility for intestinal development and their SBS may be more responsive to treatment. The committee noted that offering teduglutide to children would reduce the likelihood of repeated line infections, because it is more difficult to avoid contamination of the catheter in children. The company decided to model the 2 populations separately. When modelling for children, treatment is allowed to continue beyond the age of 18. After the age of 18, adult model assumptions are applied to this population. The ERG agreed that the 2 populations should be considered separately. The assumptions and data sources are very similar between the models for adults and children. The differences in model assumptions to reflect children included: changing the starting age from 50 years to 6 years extending the time horizon from 50 years to 94 years using an alternative source of survival data (Pironi et al. 2011) longer hospital stays and more frequent hospitalisations (line fracture occlusion only) specialist visits a year, with additional testing (haematology, inflammatory markers, clinical biochemistry) reducing the vial used for delivery from 5 mg teduglutide to 1.25 mg teduglutide for children under 8 years old increasing the number of carers from 1 to 2.The cost-effectiveness results for children are much more favourable than for adults. The ERG clarified that this is because of the younger starting age and longer time horizon in the model for children. Teduglutide also reduces the costs associated with parenteral support (see section 3.11), and these 2 contributing factors mean that QALYs and cost benefits accrue for longer in the model. The committee concluded that the difference seen between the ICERs for adults and children are plausible. ## The choice of starting age is appropriate for use in the adult base case The company modelled adults and children separately. To do this, it used different starting ages for the 2 populations. The starting age for the adult base case was 50 years. The company's justification for using this age was that it was the average age of the STEPS trial population. The committee commented that it was unsure how much this age reflected the average age of adults with SBS in the clinical practice. As a result, the committee requested further justification for the company's choice of starting age and a set of scenarios with different plausible starting ages. The company responded that the mean age of adults with SBS from real-world studies ranged from 46 to 54. So, it did not change its base-case age of 50, but provided scenario analyses in which the starting age was reduced to 40 and 45 years. These scenario analyses resulted in lower ICERs. The ERG agreed with the company's choice of starting age and considered it appropriate to use in the adult base case. The committee concluded that the starting age of 50 was appropriate to use in the adult base case. ## The company's choice of the log-normal distribution to extrapolate overall survival in adults is acceptable There were very few deaths during the STEPS trial, so the company explained that it was not able to extrapolate overall survival for adults from this data. Instead, overall survival in the adult model is based on extrapolation of published Kaplan–Meier data for people with SBS on long-term parenteral support (Salazar et al. 2021). An alternative source of survival data is used for modelling overall survival in children (see section 3.12). The company chose to use the log-normal curve in its adult base case, based on both statistical fit and predicted hazard functions compared with Salazar et al. 2021. The survival probabilities were adjusted using life tables for England from the Office for National Statistics, to ensure extrapolations did not cause the mortality rate to fall below that of the general population. The ERG questioned if it was plausible for a proportion of people with SBS on long-term parenteral support to have the same mortality as the general population. The ERG explored this using an exponential curve because this retains mortality at a higher level than the general population for longer. However, it used the log-normal curve in its base case after accepting that it provides a better fit to the data than the exponential curve. Clinical experts commented that people with SBS have a near normal life expectancy once weaned off parenteral support. The committee therefore considered the company's assumptions around life expectancy for people on parenteral support to be acceptable. The committee concluded that the log-normal distribution was acceptable for extrapolating overall survival. ## The company's approach to modelling complications associated with parenteral support is acceptable for decision making Parenteral support can cause complications including intestinal failure associated liver disease (IFALD) and chronic kidney disease (CKD). In the company model, the risk of developing IFALD and CKD increases with days of parenteral support per week. The company explained that teduglutide reduces the incidence of these complications by reducing the number of days of parenteral support needed per week. Clinical experts agreed that teduglutide should reduce the risk of IFALD and CKD by reducing days of parenteral support and improving intestinal fluid absorption. The company did not model a mortality risk for IFALD and CKD. This was because clinical feedback stated that deaths because of these conditions in SBS are very rare, and the real-world data used to inform mortality already includes death from complications. The ERG highlighted that a lack of structural link in the model between the proportion of people with SBS living with complications and risk of death may lead to overestimation of IFALD and CKD over time. It stated that this could cause bias in both directions by overestimating costs and utility losses related to living with IFALD or CKD, and failing to capture the small, expected survival benefit for teduglutide. The committee concluded that the company's approach to modelling these complications was acceptable for decision making. ## The company's approach to modelling adverse events is appropriate for decision making The company considered 2 time periods when modelling adverse events, based on STEPS (first 6 months) and STEPS‑2 (after 6 months). When modelling adverse events in the teduglutide arm, observed adverse events in the teduglutide arm of STEPS were used to estimate a rate per person for the length of STEPS (6 months). This was then divided by 6 to get a per-cycle rate of individual adverse events. A similar method was used when modelling adverse events in the teduglutide arm from 6 months onwards, except the rate per person for the length of STEPS‑2 (24 months) was divided by 24 to obtain a per-cycle rate of individual adverse events. When modelling adverse events in the standard care arm, observed adverse events in the placebo arm of STEPS were used. These analyses showed that adverse event rates decreased substantially from 6 months onwards in people taking teduglutide (0.98 adverse events per cycle per person to 0.43 adverse events per cycle per person). The company stated that this was because people became more tolerant to teduglutide as treatment progressed. People on teduglutide also needed less parenteral support so any adverse events relating to this would be reduced in the teduglutide arm compared with the standard care arm. The ERG highlighted that there was no standard care safety data available beyond 6 months to validate these results. However, it was satisfied with the company's explanations of reduced adverse events in the teduglutide arm. Clinical experts agreed that they would expect the rate of adverse events to decrease over time with teduglutide, but only in people who had reductions in days of parenteral support per week. The committee concluded that the company's approach to modelling adverse events was appropriate for decision making. ## The company's approach to modelling the incidence and costs of line sepsis is appropriate for decision making Another complication of parenteral support is line sepsis. The company model assumes that health-state costs related to line sepsis increase with the number of days of parenteral support per week. The company explained that time spent on a catheter is recognised as being linked to sepsis incidence. Days of parenteral support per week is equivalent to days when the catheter will need to be manipulated to administer the treatment, and so it is appropriate to vary rates of line sepsis according to this in the model. The ERG commented that its understanding of catheter days is the number of days a catheter is inserted for access, not the number of days it is used for delivering parenteral support. However, it supported the plausibility of a relationship between the number of days of parenteral support per week and risk of line sepsis. Clinical experts agreed that they would expect the risk of line sepsis to be greater when parenteral support is administered more frequently. Also, they would expect some people on teduglutide to not need a central venous catheter at all, meaning related complications would be reduced. The committee concluded that the company's approach to modelling the incidence and costs of line sepsis is appropriate for decision making. # Utilities ## The health-state utilities from STEPS do not reflect the quality of life of people with SBS When considering impact on quality of life, patients and clinical experts both agreed that a reduction in days of parenteral support per week is the most relevant outcome of teduglutide treatment. STEPS used the SBS-quality-of-life scale, a disease-specific tool to measure quality of life in adults with SBS. People with SBS were asked to rate the influence of SBS on 17 items, including general wellbeing, leisure activities, work life and social life. The company stated that the health-related quality-of-life data collected in STEPS did not show statistically significant quality-of-life differences between teduglutide and standard care after 24 weeks of treatment. The company also argued that the STEPS health-related quality-of-life data showed an inconsistent relationship between days of parenteral support and health-state utilities. When the quality-of-life data was stratified and mapped to utility values, the highest utility values were seen for 4 days of parenteral support per week. The company explained that this lacked face validity because there was no gain in quality of life for fewer days per week of parenteral support. As a result, the company used values used in health-state vignettes (Ballinger et al. 2018) instead of the quality-of-life data from STEPS in its base case. It also assumed that carer utilities are related to days of parenteral support per week. The ERG accepted the company's use of the vignette utilities but explored uncertainty through various scenario analyses. It stated that the company's approach may exaggerate the quality-of-life benefits from reduction in days of parenteral support per week. However, clinical and patient experts agreed that a reduction of even 1 day of parenteral support per week can have a huge impact for people with SBS. This is because it allows for respite and gives time for normal activities for the person and their family and carers. The committee noted that using vignettes instead of trial data does not meet the NICE reference case. However, it agreed with the company and ERG that the use of vignette utilities was justified in this case. ## The company's approach to estimating carer disutility is appropriate for decision making Both adults and children with SBS commonly need caregivers for help with day-to-day tasks, complex medical procedures and emotional support. Carer utilities are linked to days of parenteral support per week in the modelling. The company's adult base case assumes that adults will have 1 carer, while its base case for children assumes 2 carers, based on the assumption that the child's parents would act as carers. Patient experts emphasised the challenging experience of being a carer for a person with SBS. They highlighted the amount of time taken to provide caregiving duties as well as the impact of the high responsibility and emotional burden of keeping people with SBS alive and well. They confirmed that the carer role for somebody with SBS had a huge impact on the carer's quality of life. Clinical experts confirmed that the expectation of carers was high, and they were often formally trained to be able to undertake care that was usually only done in hospitals. The ERG accepted the company's approach to modelling carer disutility. But it did specify that the carers' utilities derived from the UK caregiver survey do not provide support for an association between days of parenteral support per week and carer health-related quality of life. Clinical and patient experts highlighted that a reduction in days of parenteral support per week can have a huge impact on carers of people with SBS. The committee raised concerns that the company may have overestimated carer disutility by assuming children would have 2 carers rather than 1, which would favour teduglutide. It also questioned whether it was appropriate for all adults to have a caregiver. The company clarified that they had calculated adult caregiver requirements using results from a multinational survey that included the UK. In this survey, 21% of adults with SBS did not have a carer, 62% had 1 carer and 17% had 2 carers. From this, a weighted average of 0.96 carers per adult was calculated. The company also provided a scenario analysis in which the carer requirement was reduced from 1 as in the base case to 0.8 carers per adult. This had a small upward impact on the ICER. The ERG agreed with the assumption of 1 caregiver per adult but provided a scenario analysis in which carer disutility and home nurse costs were removed from the model entirely. The committee noted that it would be unrealistic to expect carer requirements to be removed entirely and acknowledged that both clinicians and patient groups supported the assumption that adults need a caregiver. It concluded that the company's approach to estimating carer disutility was appropriate for decision making. # Resource use and costs in the economic model ## Using the mean price of home parenteral nutrition available on the NHS is appropriate for decision making Parenteral support is provided by the NHS through the home parenteral nutrition (HPN) framework. The company estimated the resource use of HPN (consisting of parenteral support bags, catheter lock solution and costs for delivery and nursing) in its original submission based on resource use studies for both adults and children. It obtained prices using publicly available sources and expert input. There are several HPN providers in the HPN framework, each with different prices for the various components of HPN. These prices are confidential so cannot be disclosed here and were not available to the company at the start of the appraisal. According to the NICE methods guide, the price used should be transparent to the NHS and nationally available. When commercial discounts are to be considered, the lowest nationally available tender price should be used. Feedback from NHS England was that choosing the lowest cost HPN provider was unlikely to reflect the price paid across the NHS. The ERG provided ICERs using the lowest cost HPN provider, highest cost HPN provider and the mean price of all HPN providers to explore uncertainties around the true price of HPN in the NHS. When doing this, the ICERs ranged from cost-saving to cost-ineffective. The committee would have preferred for a weighted average of the different provider costs to have been used based on market share data but noted that this was not available. A patient expert highlighted that parenteral support provision and delivery is a very complex area and will differ according to individual needs. They also noted that supply issues add to the complexity. During the consultation period, multiple stakeholders also highlighted current issues with the HPN service, stating that the demand for parenteral support outweighs available supply. They highlighted that teduglutide could ease the parenteral support supply burden, addressing the current inequality and unfairness in the existing distribution of parenteral support. The committee considered the cost of parenteral support to be highly uncertain and noted the large impact on the cost-effectiveness results. After the first committee meeting, the top-level average cost of HPN in the NHS was provided to the company. The company updated its adult base-case analyses with this overall mean price of HPN and provided scenario analyses that varied the cost of parenteral support by plus or minus 20%. The ERG agreed that the mean price was the most appropriate price to use, but highlighted that the company's pricing for individual components of parenteral support were different to its own because the company was only provided with a top-level average. This meant that the company overestimated the price of some parts of the service, while underestimating others. The committee concluded that using the mean price of HPN was likely to be most appropriate for decision making, because it is unlikely that the lowest HPN price would be accessed by the entire population with SBS. ## Concomitant medication resource use and costs reflect NHS practice in both the company's and ERG's base cases When on parenteral support, people with SBS often take numerous concomitant medications, including proton pump inhibitors, antimotility agents (such as loperamide and codeine), fragmin and ondansetron. The company estimated the resource use of these concomitant medications following expert discussion and took their costs from the BNF. The ERG also provided scenario analyses exploring different dosing regimens and formulations for the concomitant medications in response to feedback from clinical experts before the committee meeting. During the committee meeting, clinical experts provided clarification around the resource use of concomitant medications for people on parenteral support in clinical practice: For adults and children: The company assumed proton pump inhibitors are given intravenously. Experts clarified that they are generally oral treatments, with only around 20% of adults and children with SBS having them intravenously. The company assumed that everyone gets daily fragmin, while experts confirmed that fragmin is only used in around 5% of adults and children with SBS. The company assumed that everyone gets daily Taurolock, while experts confirmed Taurolock is only used in about 50% of adults and children with SBS. For adults: The company assumed that codeine (an antimotility agent) is an intramuscular injection for SBS, whereas clinical experts confirmed it is always an oral treatment. The company assumed that all adults have ondansetron as a solution for injection. Clinical experts confirmed that it is used in a small proportion of adults (5%) and is usually an oral treatment. It is often offered to people with nausea and vomiting. For children: The company assumed that children have antimotility agents daily and assumed that loperamide and codeine were used equally in practice. Clinical experts confirmed that children need fewer antimotility agents when on teduglutide compared with standard care, and codeine is not generally used in children. The company assumed that all children have ondansetron as a solution for injection. Clinical experts confirmed that ondansetron is not generally used in children. When children become adults they may have different concomitant medication needs compared with people who develop SBS in adulthood.The clinical experts also confirmed that most concomitant medications are prescribed in primary care. Only intravenous proton pump inhibitors, ondansetron and Taurolock are available as secondary care prescriptions. The committee noted that there will be cost implications of this because of the different prices available to primary and secondary care providers. The company's original base case used higher dosing frequencies and different drug formulations than used in established clinical practice. The ERG's original base case differed from the company's in terms of assumptions surrounding associated medications. However, while the ERG's scenario analyses explored uncertainties around concomitant medication resource use, it also overestimated the use of concomitant medicines in clinical practice, and therefore the costs (which in the model offsets some of the costs of teduglutide). The ERG confirmed that ondansetron, intravenous proton pump inhibitors, codeine by injection and fragmin were major drivers of the cost-effectiveness results. The committee considered that neither the company's nor the ERG's base case accurately reflected the use of concomitant medications in the NHS. Addressing these overestimates would substantially increase the ICER. In response to this, the company amended its adult base-case analyses to reflect the feedback given by the clinical experts. The ERG agreed with the company's amendments to the concomitant medication assumptions, but also applied eMIT pricing to intravenous proton pump inhibitors and ondansetron because these are initially prescribed in a secondary care setting. The company highlighted that while these are prescribed in secondary care, the long-term use may be through a primary care service. The committee concluded that the concomitant medication assumptions used in the updated company and ERG adult base cases reflected NHS practice, giving a more realistic ICER for teduglutide. # Cost-effectiveness estimate ## Uncertainties associated with the cost-effectiveness estimates for adults were addressed by the company NICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICERs. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. At its first meeting, the committee recommended teduglutide for children despite uncertainties in the evidence, because the cost-effectiveness estimates were well below what NICE normally considers an acceptable use of NHS resources. However, the committee requested further clarification and analyses from the company for adults because the ICER was likely to be above an acceptable use of NHS resources when its preferences were incorporated. After changes made in response to consultation, the company's updated analyses for adults reflected the committee's preferences as follows: an updated base case for adults that aligns dosing and administration assumptions for concomitant medications with NHS practice scenario analyses considering different starting ages in the adult model, alongside justification for the starting age used scenario analyses applying the placebo arm data from STEPS rather than assuming a steady state for those not on teduglutide.The company also provided further justification for its adult carer requirement assumptions and increased its patient access scheme discount. The committee noted some uncertainties with the model inputs remained after its second meeting, namely: the generalisability of clinical-effectiveness results of both the teduglutide and placebo arms of STEPS (see section 3.8) the company's approach to estimating health-state transition probabilities for both the teduglutide and standard care arms (see section 3.11).The committee considered that the uncertainty about the generalisability of clinical-effectiveness results from both the teduglutide and placebo arms of STEPS, and other areas of uncertainty in the modelling, would mean that the ICER would have to be comfortably within the acceptable range of cost effectiveness before recommending teduglutide. The committee concluded that while uncertainty remained within the clinical evidence, the company had provided a sufficient response to resolve some of the uncertainties. ## Teduglutide is likely to be cost effective in both children and adults with SBS At its first meeting, the committee concluded that the company's and ERG's cost-effectiveness estimates for teduglutide in children with SBS were well below what NICE normally considers an acceptable use of NHS resources. Because of confidential commercial arrangements for teduglutide and comparator treatments, the cost-effectiveness results cannot be reported here. However, the committee needed further evidence and analysis relating to adults, and at its first meeting was unable to recommend teduglutide for adults. It considered that the ICER was highly dependent on the costs related to the concomitant medications given alongside parenteral support, and the original ICERs did not reflect concomitant medications given in NHS practice. When the company updated its base case in response to consultation to reflect the committee's preferred assumptions, and increased its patient access scheme discount, the ICER for adults was below an acceptable use of NHS resources (see section 3.21). Scenario analyses exploring the other areas of uncertainty (see section 3.22) did not increase the ICER above an acceptable use of NHS resources. Therefore, teduglutide is considered cost effective for children and adults with the current analyses. # Other factors There were no equality issues identified for teduglutide. ## There may be additional benefits of teduglutide that are not captured in the cost-effectiveness analysis The company considers teduglutide to be innovative because it represents a step change in the treatment of SBS, and existing treatment (parenteral support) only manages the symptoms of the disease. The ERG commented that the economic base case for teduglutide hinges on an evidence base with many uncertainties that cannot easily be resolved given the rarity and heterogeneity of SBS. The committee highlighted that there may be an uncaptured benefit to teduglutide in that it may prevent the need for intestinal transplant when parenteral support has not worked. The ERG noted that this was an important point to consider, but it was not possible to model this because of a lack of data on teduglutide's ability to reduce the need for intestinal transplant. The company stated that its base case for children is conservative because children may benefit more from teduglutide (see section 3.6). But the extent of this benefit is uncertain and may be countered by the fact that some children on standard care also have the potential to reduce their parenteral support needs (see section 3.8). The company also stated that their model only considers people with SBS to have improved quality of life when they reduce their parenteral support needs by 1 day or more. Because of this, people with SBS who reduce their weekly parenteral support volume, but not the number of days they have it across, are assumed to have no benefit. They highlighted that this is unlikely to be the case, because people with SBS will have a better quality of life when having parenteral support for fewer hours per day. Reduced hours of parenteral support per day means more flexibility and people can use the extra time to sleep or enjoy their usual activities. The company stated that these changes in lifestyle are not currently captured in the model. The committee concluded that there may be additional benefits of teduglutide that are not captured in the cost-effectiveness analysis. But the extent of these benefits is unclear because of uncertainties in the evidence. # Conclusion ## Teduglutide is recommended for treating short bowel syndrome in people aged 1 year or above Teduglutide is recommended for use in the NHS for treating SBS in people aged 1 year or above. The cost-effectiveness estimates for people with SBS were uncertain because of uncertainties within the clinical evidence. But they were highly likely to remain below what is considered an acceptable use of NHS resources, even when accounting for uncertainties.	{'Recommendations': "Teduglutide is recommended, within its marketing authorisation, as an option for treating short bowel syndrome (SBS) in people 1\xa0year and above. People's condition should be stable following a period of intestinal adaptation after surgery before having teduglutide. Teduglutide is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nCurrent treatment for SBS is parenteral support (giving nutrients and fluids intravenously) with best supportive care. Best supportive care includes antimotility and antisecretory medicines, fluid restriction and diet changes.\n\nClinical trial evidence shows that teduglutide reduces the number of days a week people with SBS need parenteral support compared with placebo. However, how much it reduces this is uncertain because the trial design may not reflect NHS practice.\n\nBecause of the uncertainties in the clinical evidence, the cost-effectiveness estimates are uncertain. However, even when accounting for the uncertainties, these estimates are below what NICE normally considers an acceptable use of NHS resources. Therefore, teduglutide is recommended.", 'Information about teduglutide': "# Marketing authorisation indication\n\nTeduglutide (Revestive, Takeda) is 'indicated for the treatment of patients aged 1\xa0year and above with short bowel syndrome (SBS). Patients should be stable following a period of intestinal adaptation after surgery.'\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for teduglutide.\n\n# Price\n\nThe list price of a 5\xa0mg vial of teduglutide is £521.98. The list price of a 1.25\xa0mg vial of teduglutide is £260.99 (excluding VAT; BNF online, accessed April 2022).\n\nThe company has a commercial arrangement. This makes teduglutide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Takeda, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Short bowel syndrome is a chronic condition with limited treatment options\n\nShort bowel syndrome (SBS) is a chronic and potentially life-threatening condition characterised by reduced absorption of nutrients, water and electrolytes. SBS is commonly caused by surgery that has been needed to remove abnormal bowel. In adults, this surgery may be needed for a range of conditions, including mesenteric ischaemia, Crohn's disease and radiation enteritis. In children, it is often because of necrotising enterocolitis in premature babies, or other conditions such as volvulus or gastroschisis. Some children can be born with a short bowel. SBS can lead to intestinal failure. This is when the length of intestine remaining means the intestinal functions drops below the necessary level for absorption of nutrients, water and electrolytes. Intestinal failure is classified as type\xa03 when it is chronic and people need to have parenteral support over months or years. Current treatment for SBS includes parenteral support, in which nutrients and fluids are given intravenously for an average of 10 to 14\xa0hours a day for between 2 and 7\xa0days a week. Most people have parenteral support at home using a permanent intravenous tube. While parenteral support is life-saving, it is very time-consuming, highly complex and its complications can be life-threatening. These include blood infections, blood clots, and kidney and liver failure. Clinical and patient experts both noted that there are currently supply issues with parenteral support, and people with SBS are having to adapt their care to manage this. They also highlighted that administering parenteral support is complicated and challenging for people with SBS and their carers. They emphasised a need for new treatments that offer more normality for those affected by SBS. The committee concluded that SBS is a chronic condition with limited treatment options that can cause further adverse complications.\n\n## People would welcome new treatment options for short bowel syndrome that reduce the number of days of parenteral support\n\nSBS is not only burdensome for the person with the condition, but for their carers too. This burden is often linked to the need to use parenteral support. Patient experts confirmed that parenteral support limits a normal life in many ways, including family, work and social life. Most people with SBS have parenteral support at home, and either administer this themselves or with a carer's assistance. Patient experts highlighted that this places a huge burden on people with SBS and their carers, because the responsibility of doing complicated procedures at home can be overwhelming. They feel that the impact on carers is often overlooked, and that many families have not had a night off from giving parenteral support in many years. Carers also often feel guilt when people with SBS experience complications such as blood infections because they feel that these would have been avoided if they had done their caring duties correctly. Clinical experts highlighted that there is potential for teduglutide to allow some people with SBS to wean off parenteral support completely, or at least reduce the number of nights per week when they need it. This would greatly increase the quality of life of both people with SBS and their carers. Both clinical and patient experts noted that there is an unmet need to reduce the time spent on parenteral support to increase the quality of life for people with SBS and their carers. The experts emphasised that this was a continuous burden, with little or no respite. They advised that any reduction in the number of nights of treatment would give people respite, which would give them and their family and carers some time to do other activities. Clinical experts explained that a person with SBS would usually have bespoke home parenteral nutrition formulations through compounded parenteral nutrition bags. However, because of the increased demand for parenteral support in England, some people do not have access to these formulations. Instead they are given standard preparations that are more complex to infuse and could result in reduced health. Clinical experts also highlighted that this is likely to incur a higher cost because people are prescribed multiple types of bags to replace what would usually be provided in their compounded parenteral nutrition. The committee agreed that the impact of parenteral support on people with SBS and their carers was high. It concluded that people would welcome new treatment options for SBS that reduce the number of days of parenteral support.\n\n# Treatment pathway and comparators\n\n## Teduglutide is likely to be used once people become stable on parenteral support\n\nTeduglutide's marketing authorisation is for the treatment of SBS in people 1\xa0year and above who are stable after a period of intestinal adaptation. The company's positioning of teduglutide was aligned with the marketing authorisation. This was highlighted as a decision point in the pathway after the adaptation phase. The adaptation phase is estimated to be up to 2\xa0years in adults but can be longer in children. Clinical experts noted that they would want to use teduglutide for any child who needs routine parenteral support, and they would not want to wait more than 2\xa0years to start treatment. They also highlighted that starting teduglutide might reduce the need for intestinal transplant because transplants would only be indicated for people in whom parenteral support is not working. The committee concluded that teduglutide was likely to be used for people with SBS once their parenteral support needs had been established and stabilised on a regular schedule.\n\n## The only appropriate comparator for teduglutide is parenteral support combined with best supportive care\n\nFor people with SBS, the company submission compared teduglutide with established clinical management including parenteral support with best supportive care (antimotility and antisecretory agents, fluid restriction and dietary optimisation). Further surgical procedures can be done after parenteral support stabilisation to attempt to increase the length of remaining bowel that is in direct continuity. However, because these are rarely done in practice, they were not included as a relevant comparator. Intestinal transplant can also be done if all other treatments fail. This is done in some children, but not routinely. Surgery was not considered a comparator in this appraisal, but avoiding the need for a transplant, which has lifelong consequences, could be a benefit of teduglutide. The committee concluded that parenteral support with best supportive care was the only appropriate comparator for teduglutide.\n\n# Clinical evidence\n\n## The clinical trial evidence used in the company model is appropriate, but the patient support programme data is less certain\n\nThe key clinical evidence for teduglutide came from 1 clinical trial and its long-term open-label extension study, and 1 non-interventional real-world study in adults with SBS:\n\nSTEPS: a phase\xa03, multinational, randomised, double-blind, placebo-controlled 24‑week study and STEPS‑2: a 2‑year, open-label, multinational extension study for people who had screening or treatment in STEPS.\n\nPSP: a non-interventional patient support programme (PSP) in Australia.The company submitted clinical evidence for adults from an extension to STEPS‑2 and 1 further clinical trial and its extension that were not included in the economic model:\n\n\n\nSTEPS‑3: an up to 1-year, open-label extension study for people in STEPS‑2 at 5 US sites.\n\n: a phase\xa03, multinational, randomised, double-blind, placebo-controlled, 24‑week study and 005: a 28‑week, open-label, multinational, extension study for people who had treatment with teduglutide or placebo in 004.The company decided not to include STEPS‑3 data in its model because the relevant cohort of patients only contained 5\xa0people. 004 and 005 were not included because the results have weak external validity due to the restrictive parenteral support weaning algorithm used as part of the study protocol. The company also submitted evidence from 8 non-interventional real-world studies in adults which were not included in the model. The company submitted clinical evidence for children from 2 open-label studies and their extensions, but did not include this evidence in the economic model:\n\n\n\nC13: a phase\xa03, open-label, non-randomised, 12‑week study in the UK and US and SHP633‑303: its open-label, long-term extension.\n\nC14: a phase\xa03, multinational, open-label, non-randomised, 24‑week study and SHP633‑304: its open-label, multinational, long-term extension. No clinical data from studies in children was used in the modelling. The company's justification for this was that the trials in children had small sample sizes and non-continuous treatment across follow-on studies. The ERG was satisfied with the company's choice of clinical evidence used in the model. It agreed that STEPS was of good methodological quality. It highlighted the small sample size of STEPS‑3 and accepted that the weaning algorithm used in 004 and 005 was not closely matched to clinical practice. It also recognised the small sample numbers in C13, C14 and their extensions. The committee concluded that the clinical trial evidence chosen by the company for use in the model was appropriate.\n\n## Results from trials in children show that teduglutide reduces parenteral support needs, but there are limitations in the trial design, which justifies the use of adult data for children\n\nThe company provided efficacy data for children from 2 clinical trials and their long-term extensions. This data was provided to show that the efficacy of teduglutide in children is similar to and may even exceed its efficacy in adults. In C14, the primary outcome was the percentage of people who had a 20% to 100% reduction in parenteral volume from baseline at week\xa024. This was defined as a 'clinical response'. Reduction in days of parenteral support per week was measured as a secondary outcome. C14 found that more children with SBS had a clinical response on teduglutide compared with the standard care group (69% compared with 11%). Children having teduglutide also had a reduction in days of parenteral support per week from baseline, while those on standard care did not (1.3\xa0days reduction compared with 0\xa0days). The primary outcome for C13 was the reduction in days of parenteral support per week. The results of this are confidential and cannot be disclosed here. Reduction in parenteral support volume was measured as a secondary outcome. Results from C13 also showed reductions in parenteral volume from baseline at 12\xa0weeks. Results from the extension studies are confidential and cannot be disclosed here. C13, C14 and their extensions were not included in the model because they had small sample sizes and the extensions had non-continuous treatment with teduglutide (see section\xa03.5). Instead, the company used adult data to inform both the adult and child base cases. The committee concluded that the results in children did indicate that teduglutide has clinical benefits for children, but they were not suitable for use in the model because of their limitations in study design.\n\n## Clinical evidence from adult trials shows that teduglutide reduces parenteral support needs\n\nIn STEPS, the primary outcome was the percentage of people with SBS who had a 20% to 100% reduction of parenteral volume from baseline at week\xa020 maintained to week\xa024. This was defined by the company as a 'clinical response'. A key outcome in both STEPS and STEPS-2 was the change in days per week of parenteral support from baseline. Both STEPS and STEPS‑2 assessed the safety of teduglutide. Outcomes considered from PSP were a 20% to 100% reduction in parenteral support volume from baseline ('clinical response') and change in days per week of parenteral support from baseline. The ERG noted the definition of 'clinical response' differed slightly between STEPS and PSP, but did not consider that it would affect the trial results. Both clinical and patient experts agreed that a reduction in days on parenteral support per week is more valuable to patients than reducing parenteral volume alone. People in the STEPS trial had an average number of days on parenteral support of 5.6 and 5.9\xa0days (teduglutide and placebo arms respectively) before treatment. After treatment, significantly more people with SBS had a 1‑day or more reduction in weekly parenteral support on teduglutide over placebo (53.8% compared with 23.1%). The results from PSP are confidential and cannot be disclosed here. The committee concluded that the clinical evidence indicates that teduglutide reduces parenteral support needs in adults with SBS.\n\n## The weaning algorithm in STEPS may have affected generalisability of the results in both arms\n\nPeople with SBS taking teduglutide can potentially reduce parenteral support and increase their oral diet through a process known as weaning. The STEPS trial used a weaning algorithm to decide if people with SBS should have their parenteral support reduced. A feature of the STEPS results is the apparent efficacy of placebo, with 23.1% of the placebo arm reducing their days of parenteral support by 1\xa0day or more. The company commented that this is unrealistic, and that any reduction in days of parenteral support per week in the placebo arm were unlikely to be because of improved intestinal function. It emphasised that people entering STEPS had undergone parenteral support optimisation and stabilisation before starting teduglutide or placebo, so any differences in parenteral support over time in the placebo arm could not be explained by further optimisation of care. It suggested that the observed placebo effect is instead a result of the strict weaning algorithm used in the trial that was solely based on urine output. The ERG noted that the company's argument was plausible, and that changes in parenteral support do not rely on urine output alone in clinical practice. The company also stated that people in the placebo arm lost weight over the course of the trial and this indicates that they were not having adequate parenteral support. The committee queried whether this placebo effect reflected clinical practice. The clinical experts explained that in clinical practice clinicians do not know urine output on a day-to-day basis, and so weaning is less precise than in STEPS. They added that the weaning algorithm relying entirely on urine output was unrealistic and that maintaining weight should also be part of the weaning criteria. They clarified that while it may be possible for adults with SBS temporarily to reduce their parenteral support while having current standard care, this would not be sustainable if medical advice was followed correctly. This means that the placebo effect seen in STEPS did not reflect clinical practice. Conversely, the company also commented that the weaning algorithm used in STEPS in the teduglutide arm underestimated the extent to which parenteral support could be reduced, thereby underestimating the effect of teduglutide. The company's view was that the strict nature of this algorithm was therefore likely to underestimate the relative treatment effect of teduglutide compared with placebo. Also, the weaning algorithm constrained how quickly people were able to wean off parenteral support if they improved on teduglutide. The ERG highlighted that while the weaning algorithm is restrictive and may not reflect clinical practice, it was applied to both arms of the STEPS trial. Therefore, the internal validity of the results could be considered robust, but the absolute effects of teduglutide and placebo may not be valid. The ERG also received clinical feedback that adults on standard care were unlikely to reduce their parenteral support. The committee then explored whether teduglutide might allow some people with SBS to stop parenteral support altogether. Clinical experts commented that they would expect some people taking teduglutide to come off parenteral support entirely, and they have seen such cases in clinical practice. They stated that while some children may be able to wean off parenteral support naturally as their bowel matures and they grow, teduglutide allows them to improve faster and avoid both the clinical and social challenges associated with parenteral support. The committee considered whether it was more important to consider benefits relating to the clinical effectiveness of teduglutide independently, or in comparison with other treatments. The ERG agreed with the company's arguments relating to the impact of the weaning algorithm on the results. Clinical experts confirmed that people on standard care were unlikely to reduce their parenteral support. The committee was unable to come to a clear conclusion on the impact of the weaning algorithm on the trial results, but noted that placebo-controlled trials are usually appropriately designed to determine the true treatment effect of a new drug. It concluded that the weaning algorithm may have affected generalisability of the results from both arms of STEPS, which made the true relative treatment effect of teduglutide compared with placebo uncertain.\n\n## The frequency of adverse events is broadly similar between teduglutide and placebo for adults\n\nThe company provided safety evidence for adults, pooled from STEPS, STEPS‑2, 004 and 005. The ERG found that the pooling of safety data from these trials was appropriate. In the 24-week randomised trials, adults on teduglutide most commonly reported abdominal pain (38.5% compared with 27.1%), gastrointestinal stoma complications (37.8% compared with 13.6%), upper respiratory tract infections (27.5% compared with 13.6%) and abdominal distension (16.5% compared with 1.7%). The frequency and severity of these adverse events were broadly similar between the people having teduglutide and placebo, except for abdominal distension. The company commented that the observed adverse events were likely to be because of pro-absorptive and intestinotrophic effects of teduglutide, insufficient parenteral support weaning or the underlying nature of SBS. The ERG accepted this reasoning following advice from clinical experts. The committee concluded that the overall frequency and severity of adverse events resemble those of the placebo group.\n\n## The safety profile of teduglutide in children is similar to adults\n\nThe company also provided safety data for children, pooled from C13, SHP633‑303, C14 and SHP633‑304. The most common adverse events were vomiting (51.7%), pyrexia (43.8%), upper respiratory tract infection (41.6%), cough (33.7%) and device-related (central venous catheter) infection (29.2%). The ERG commented that the overall rates of adverse events were similar to adults, but respiratory infections, pyrexia, vomiting and catheter complications (including infections) were more common in children than in adults. The company stated that these adverse events would be expected to be more frequent in children. The committee commented that children are often admitted to hospital with catheter complications, because frequent diarrhoea can mean it is difficult for carers to always keep the catheter completely clean. The committee concluded that the safety profile of teduglutide is similar for adults and children.\n\n# Economic model\n\n## The estimation of health-state transition probabilities within the model is a source of uncertainty, but is appropriate for decision making\n\nThe economic model was developed using a Markov structure, comprising 9 health states defined by the days of parenteral support per week (from 7\xa0days to parental support independence or to death). The company included a treatment stopping rule so that modelled teduglutide use would reflect its use in clinical practice as closely as possible. The summary of product characteristics recommends that treatment should be stopped if there is no overall improvement in the condition. It recommends that adults should have an evaluation after 6\xa0months, with treatment continuation being reconsidered if there is no treatment benefit by 12\xa0months. The model reflected this by assuming that those who had not had a reduction of at least 1\xa0day of parenteral support per week at 12\xa0months, compared with baseline, stop teduglutide. Once treatment is stopped, they immediately reverted to their baseline parenteral support state before teduglutide. Teduglutide is modelled to affect both cost and quality-adjusted life years (QALYs):\n\nCosts:\n\n\n\nDrug treatment (teduglutide) costs are increased.\n\nCosts associated with parenteral support, concomitant drugs, and complications linked to parenteral support are reduced.\n\nIncidence of adverse events are changed compared with standard care.\n\n\n\nQALYs:\n\n\n\nThe number of days that people need parenteral support per week is reduced. This is modelled to improve the health-related quality of life of people with SBS and their carers.\n\nThe incidence of complications associated with parenteral support are reduced.\n\nThere are carer benefits.To calculate transition probabilities for teduglutide, the company pooled clinical data from the teduglutide arms of STEPS and STEPS‑2 and data from the PSP when estimating the reductions in parenteral support for the teduglutide group. It explained that it took this approach rather than using the relative treatment effect from the trial because the weaning algorithm in STEPS and STEPS‑2 underestimates parenteral support reductions for teduglutide (see section\xa03.8). The company supported this claim by doing an analysis comparing the percentage of people stopping parenteral support entirely while taking teduglutide between STEPS, PSP, and a combination of other real-world studies. The company also assumed that there is no change in parenteral support in the standard care arm and applied the STEPS baseline parenteral support requirement over the time horizon in the standard care arm of the model. The reasoning for this was that people need to have a stable parenteral support requirement before teduglutide, and reductions in parenteral support would not be expected in clinical practice without teduglutide (see section\xa03.3). The ERG confirmed that the model structure is appropriate. It advised that the company's explanation for underestimation of teduglutide effectiveness in the STEPS and STEPS‑2 trials was plausible, but that any comparison of effects between observational studies and randomised controlled trials should be interpreted with caution. The committee expressed some concern around the company's methodology for estimating transition probabilities. This was specifically related to breaking randomisation when pooling the real-world and teduglutide arm trial data while disregarding the relative treatment effect and placebo data from STEPS. The ERG stated that it had done a scenario analysis exploring the relative treatment effect of teduglutide from the STEPS data alone. This had a substantial upwards impact on the incremental cost-effectiveness ratio (ICER). But because it received clinical expert feedback that people having standard care would not be expected to reduce their parenteral support needs, the ERG considered this scenario to be conservative and did not incorporate it into its base case. At its first meeting, the committee concluded that the company's approach to modelling health-state transitions in both arms was a source of uncertainty and requested further scenario analyses. In response to these concerns, the company provided 2 scenarios:\n\n\n\nUsing STEPS placebo arm data to calculate the first 6\xa0months of transitions within the standard of care arm of the adult base case (only 6\xa0months was considered by the company because it did not consider the placebo effect in STEPS to be sustainable long term).\n\nUsing only data from STEPS or STEPS‑2 in the teduglutide arm of the adult base case, rather than pooling data from STEPS, STEPS‑2 and PSP.Both these scenarios had a modest upwards impact on the ICER. The ERG combined the 2 scenarios but stated that this was pessimistic and probably underestimated the benefit of teduglutide. The committee agreed that these scenarios resolved some uncertainty around the calculation of transition probabilities in the model. It concluded that the transition probabilities were a source of uncertainty but were appropriate for decision making.\n\n## The assumptions and data sources are very similar between the models for adults and children\n\nNo clinical study data from studies in children was used in the modelling (see section\xa03.5). The company considered that children would gain more benefit from teduglutide and so using adult data would give a conservative cost-effectiveness estimate for children. Clinical experts confirmed that children have more possibility for intestinal development and their SBS may be more responsive to treatment. The committee noted that offering teduglutide to children would reduce the likelihood of repeated line infections, because it is more difficult to avoid contamination of the catheter in children. The company decided to model the 2 populations separately. When modelling for children, treatment is allowed to continue beyond the age of 18. After the age of 18, adult model assumptions are applied to this population. The ERG agreed that the 2 populations should be considered separately. The assumptions and data sources are very similar between the models for adults and children. The differences in model assumptions to reflect children included:\n\nchanging the starting age from 50\xa0years to 6\xa0years\n\nextending the time horizon from 50\xa0years to 94\xa0years\n\nusing an alternative source of survival data (Pironi et al. 2011)\n\nlonger hospital stays and more frequent hospitalisations (line fracture occlusion only)\n\nspecialist visits a year, with additional testing (haematology, inflammatory markers, clinical biochemistry)\n\nreducing the vial used for delivery from 5\xa0mg teduglutide to 1.25\xa0mg teduglutide for children under 8 years old\n\nincreasing the number of carers from 1 to 2.The cost-effectiveness results for children are much more favourable than for adults. The ERG clarified that this is because of the younger starting age and longer time horizon in the model for children. Teduglutide also reduces the costs associated with parenteral support (see section\xa03.11), and these 2 contributing factors mean that QALYs and cost benefits accrue for longer in the model. The committee concluded that the difference seen between the ICERs for adults and children are plausible.\n\n## The choice of starting age is appropriate for use in the adult base case\n\nThe company modelled adults and children separately. To do this, it used different starting ages for the 2 populations. The starting age for the adult base case was 50\xa0years. The company's justification for using this age was that it was the average age of the STEPS trial population. The committee commented that it was unsure how much this age reflected the average age of adults with SBS in the clinical practice. As a result, the committee requested further justification for the company's choice of starting age and a set of scenarios with different plausible starting ages. The company responded that the mean age of adults with SBS from real-world studies ranged from 46 to 54. So, it did not change its base-case age of 50, but provided scenario analyses in which the starting age was reduced to 40 and 45 years. These scenario analyses resulted in lower ICERs. The ERG agreed with the company's choice of starting age and considered it appropriate to use in the adult base case. The committee concluded that the starting age of 50 was appropriate to use in the adult base case.\n\n## The company's choice of the log-normal distribution to extrapolate overall survival in adults is acceptable\n\nThere were very few deaths during the STEPS trial, so the company explained that it was not able to extrapolate overall survival for adults from this data. Instead, overall survival in the adult model is based on extrapolation of published Kaplan–Meier data for people with SBS on long-term parenteral support (Salazar et al. 2021). An alternative source of survival data is used for modelling overall survival in children (see section\xa03.12). The company chose to use the log-normal curve in its adult base case, based on both statistical fit and predicted hazard functions compared with Salazar et al. 2021. The survival probabilities were adjusted using life tables for England from the Office for National Statistics, to ensure extrapolations did not cause the mortality rate to fall below that of the general population. The ERG questioned if it was plausible for a proportion of people with SBS on long-term parenteral support to have the same mortality as the general population. The ERG explored this using an exponential curve because this retains mortality at a higher level than the general population for longer. However, it used the log-normal curve in its base case after accepting that it provides a better fit to the data than the exponential curve. Clinical experts commented that people with SBS have a near normal life expectancy once weaned off parenteral support. The committee therefore considered the company's assumptions around life expectancy for people on parenteral support to be acceptable. The committee concluded that the log-normal distribution was acceptable for extrapolating overall survival.\n\n## The company's approach to modelling complications associated with parenteral support is acceptable for decision making\n\nParenteral support can cause complications including intestinal failure associated liver disease (IFALD) and chronic kidney disease (CKD). In the company model, the risk of developing IFALD and CKD increases with days of parenteral support per week. The company explained that teduglutide reduces the incidence of these complications by reducing the number of days of parenteral support needed per week. Clinical experts agreed that teduglutide should reduce the risk of IFALD and CKD by reducing days of parenteral support and improving intestinal fluid absorption. The company did not model a mortality risk for IFALD and CKD. This was because clinical feedback stated that deaths because of these conditions in SBS are very rare, and the real-world data used to inform mortality already includes death from complications. The ERG highlighted that a lack of structural link in the model between the proportion of people with SBS living with complications and risk of death may lead to overestimation of IFALD and CKD over time. It stated that this could cause bias in both directions by overestimating costs and utility losses related to living with IFALD or CKD, and failing to capture the small, expected survival benefit for teduglutide. The committee concluded that the company's approach to modelling these complications was acceptable for decision making.\n\n## The company's approach to modelling adverse events is appropriate for decision making\n\nThe company considered 2 time periods when modelling adverse events, based on STEPS (first 6\xa0months) and STEPS‑2 (after 6\xa0months). When modelling adverse events in the teduglutide arm, observed adverse events in the teduglutide arm of STEPS were used to estimate a rate per person for the length of STEPS (6\xa0months). This was then divided by 6 to get a per-cycle rate of individual adverse events. A similar method was used when modelling adverse events in the teduglutide arm from 6\xa0months onwards, except the rate per person for the length of STEPS‑2 (24\xa0months) was divided by 24 to obtain a per-cycle rate of individual adverse events. When modelling adverse events in the standard care arm, observed adverse events in the placebo arm of STEPS were used. These analyses showed that adverse event rates decreased substantially from 6\xa0months onwards in people taking teduglutide (0.98 adverse events per cycle per person to 0.43 adverse events per cycle per person). The company stated that this was because people became more tolerant to teduglutide as treatment progressed. People on teduglutide also needed less parenteral support so any adverse events relating to this would be reduced in the teduglutide arm compared with the standard care arm. The ERG highlighted that there was no standard care safety data available beyond 6\xa0months to validate these results. However, it was satisfied with the company's explanations of reduced adverse events in the teduglutide arm. Clinical experts agreed that they would expect the rate of adverse events to decrease over time with teduglutide, but only in people who had reductions in days of parenteral support per week. The committee concluded that the company's approach to modelling adverse events was appropriate for decision making.\n\n## The company's approach to modelling the incidence and costs of line sepsis is appropriate for decision making\n\nAnother complication of parenteral support is line sepsis. The company model assumes that health-state costs related to line sepsis increase with the number of days of parenteral support per week. The company explained that time spent on a catheter is recognised as being linked to sepsis incidence. Days of parenteral support per week is equivalent to days when the catheter will need to be manipulated to administer the treatment, and so it is appropriate to vary rates of line sepsis according to this in the model. The ERG commented that its understanding of catheter days is the number of days a catheter is inserted for access, not the number of days it is used for delivering parenteral support. However, it supported the plausibility of a relationship between the number of days of parenteral support per week and risk of line sepsis. Clinical experts agreed that they would expect the risk of line sepsis to be greater when parenteral support is administered more frequently. Also, they would expect some people on teduglutide to not need a central venous catheter at all, meaning related complications would be reduced. The committee concluded that the company's approach to modelling the incidence and costs of line sepsis is appropriate for decision making.\n\n# Utilities\n\n## The health-state utilities from STEPS do not reflect the quality of life of people with SBS\n\nWhen considering impact on quality of life, patients and clinical experts both agreed that a reduction in days of parenteral support per week is the most relevant outcome of teduglutide treatment. STEPS used the SBS-quality-of-life scale, a disease-specific tool to measure quality of life in adults with SBS. People with SBS were asked to rate the influence of SBS on 17 items, including general wellbeing, leisure activities, work life and social life. The company stated that the health-related quality-of-life data collected in STEPS did not show statistically significant quality-of-life differences between teduglutide and standard care after 24\xa0weeks of treatment. The company also argued that the STEPS health-related quality-of-life data showed an inconsistent relationship between days of parenteral support and health-state utilities. When the quality-of-life data was stratified and mapped to utility values, the highest utility values were seen for 4\xa0days of parenteral support per week. The company explained that this lacked face validity because there was no gain in quality of life for fewer days per week of parenteral support. As a result, the company used values used in health-state vignettes (Ballinger et al. 2018) instead of the quality-of-life data from STEPS in its base case. It also assumed that carer utilities are related to days of parenteral support per week. The ERG accepted the company's use of the vignette utilities but explored uncertainty through various scenario analyses. It stated that the company's approach may exaggerate the quality-of-life benefits from reduction in days of parenteral support per week. However, clinical and patient experts agreed that a reduction of even 1\xa0day of parenteral support per week can have a huge impact for people with SBS. This is because it allows for respite and gives time for normal activities for the person and their family and carers. The committee noted that using vignettes instead of trial data does not meet the NICE reference case. However, it agreed with the company and ERG that the use of vignette utilities was justified in this case.\n\n## The company's approach to estimating carer disutility is appropriate for decision making\n\nBoth adults and children with SBS commonly need caregivers for help with day-to-day tasks, complex medical procedures and emotional support. Carer utilities are linked to days of parenteral support per week in the modelling. The company's adult base case assumes that adults will have 1\xa0carer, while its base case for children assumes 2\xa0carers, based on the assumption that the child's parents would act as carers. Patient experts emphasised the challenging experience of being a carer for a person with SBS. They highlighted the amount of time taken to provide caregiving duties as well as the impact of the high responsibility and emotional burden of keeping people with SBS alive and well. They confirmed that the carer role for somebody with SBS had a huge impact on the carer's quality of life. Clinical experts confirmed that the expectation of carers was high, and they were often formally trained to be able to undertake care that was usually only done in hospitals. The ERG accepted the company's approach to modelling carer disutility. But it did specify that the carers' utilities derived from the UK caregiver survey do not provide support for an association between days of parenteral support per week and carer health-related quality of life. Clinical and patient experts highlighted that a reduction in days of parenteral support per week can have a huge impact on carers of people with SBS. The committee raised concerns that the company may have overestimated carer disutility by assuming children would have 2 carers rather than 1, which would favour teduglutide. It also questioned whether it was appropriate for all adults to have a caregiver. The company clarified that they had calculated adult caregiver requirements using results from a multinational survey that included the UK. In this survey, 21% of adults with SBS did not have a carer, 62% had 1\xa0carer and 17% had 2\xa0carers. From this, a weighted average of 0.96 carers per adult was calculated. The company also provided a scenario analysis in which the carer requirement was reduced from 1 as in the base case to 0.8 carers per adult. This had a small upward impact on the ICER. The ERG agreed with the assumption of 1 caregiver per adult but provided a scenario analysis in which carer disutility and home nurse costs were removed from the model entirely. The committee noted that it would be unrealistic to expect carer requirements to be removed entirely and acknowledged that both clinicians and patient groups supported the assumption that adults need a caregiver. It concluded that the company's approach to estimating carer disutility was appropriate for decision making.\n\n# Resource use and costs in the economic model\n\n## Using the mean price of home parenteral nutrition available on the NHS is appropriate for decision making\n\nParenteral support is provided by the NHS through the home parenteral nutrition (HPN) framework. The company estimated the resource use of HPN (consisting of parenteral support bags, catheter lock solution [Taurolock] and costs for delivery and nursing) in its original submission based on resource use studies for both adults and children. It obtained prices using publicly available sources and expert input. There are several HPN providers in the HPN framework, each with different prices for the various components of HPN. These prices are confidential so cannot be disclosed here and were not available to the company at the start of the appraisal. According to the NICE methods guide, the price used should be transparent to the NHS and nationally available. When commercial discounts are to be considered, the lowest nationally available tender price should be used. Feedback from NHS England was that choosing the lowest cost HPN provider was unlikely to reflect the price paid across the NHS. The ERG provided ICERs using the lowest cost HPN provider, highest cost HPN provider and the mean price of all HPN providers to explore uncertainties around the true price of HPN in the NHS. When doing this, the ICERs ranged from cost-saving to cost-ineffective. The committee would have preferred for a weighted average of the different provider costs to have been used based on market share data but noted that this was not available. A patient expert highlighted that parenteral support provision and delivery is a very complex area and will differ according to individual needs. They also noted that supply issues add to the complexity. During the consultation period, multiple stakeholders also highlighted current issues with the HPN service, stating that the demand for parenteral support outweighs available supply. They highlighted that teduglutide could ease the parenteral support supply burden, addressing the current inequality and unfairness in the existing distribution of parenteral support. The committee considered the cost of parenteral support to be highly uncertain and noted the large impact on the cost-effectiveness results. After the first committee meeting, the top-level average cost of HPN in the NHS was provided to the company. The company updated its adult base-case analyses with this overall mean price of HPN and provided scenario analyses that varied the cost of parenteral support by plus or minus 20%. The ERG agreed that the mean price was the most appropriate price to use, but highlighted that the company's pricing for individual components of parenteral support were different to its own because the company was only provided with a top-level average. This meant that the company overestimated the price of some parts of the service, while underestimating others. The committee concluded that using the mean price of HPN was likely to be most appropriate for decision making, because it is unlikely that the lowest HPN price would be accessed by the entire population with SBS.\n\n## Concomitant medication resource use and costs reflect NHS practice in both the company's and ERG's base cases\n\nWhen on parenteral support, people with SBS often take numerous concomitant medications, including proton pump inhibitors, antimotility agents (such as loperamide and codeine), fragmin and ondansetron. The company estimated the resource use of these concomitant medications following expert discussion and took their costs from the BNF. The ERG also provided scenario analyses exploring different dosing regimens and formulations for the concomitant medications in response to feedback from clinical experts before the committee meeting. During the committee meeting, clinical experts provided clarification around the resource use of concomitant medications for people on parenteral support in clinical practice:\n\nFor adults and children:\n\n\n\nThe company assumed proton pump inhibitors are given intravenously. Experts clarified that they are generally oral treatments, with only around 20% of adults and children with SBS having them intravenously.\n\nThe company assumed that everyone gets daily fragmin, while experts confirmed that fragmin is only used in around 5% of adults and children with SBS.\n\nThe company assumed that everyone gets daily Taurolock, while experts confirmed Taurolock is only used in about 50% of adults and children with SBS.\n\n\n\nFor adults:\n\n\n\nThe company assumed that codeine (an antimotility agent) is an intramuscular injection for SBS, whereas clinical experts confirmed it is always an oral treatment.\n\nThe company assumed that all adults have ondansetron as a solution for injection. Clinical experts confirmed that it is used in a small proportion of adults (5%) and is usually an oral treatment. It is often offered to people with nausea and vomiting.\n\n\n\nFor children:\n\n\n\nThe company assumed that children have antimotility agents daily and assumed that loperamide and codeine were used equally in practice. Clinical experts confirmed that children need fewer antimotility agents when on teduglutide compared with standard care, and codeine is not generally used in children.\n\nThe company assumed that all children have ondansetron as a solution for injection. Clinical experts confirmed that ondansetron is not generally used in children.\n\nWhen children become adults they may have different concomitant medication needs compared with people who develop SBS in adulthood.The clinical experts also confirmed that most concomitant medications are prescribed in primary care. Only intravenous proton pump inhibitors, ondansetron and Taurolock are available as secondary care prescriptions. The committee noted that there will be cost implications of this because of the different prices available to primary and secondary care providers. The company's original base case used higher dosing frequencies and different drug formulations than used in established clinical practice. The ERG's original base case differed from the company's in terms of assumptions surrounding associated medications. However, while the ERG's scenario analyses explored uncertainties around concomitant medication resource use, it also overestimated the use of concomitant medicines in clinical practice, and therefore the costs (which in the model offsets some of the costs of teduglutide). The ERG confirmed that ondansetron, intravenous proton pump inhibitors, codeine by injection and fragmin were major drivers of the cost-effectiveness results. The committee considered that neither the company's nor the ERG's base case accurately reflected the use of concomitant medications in the NHS. Addressing these overestimates would substantially increase the ICER. In response to this, the company amended its adult base-case analyses to reflect the feedback given by the clinical experts. The ERG agreed with the company's amendments to the concomitant medication assumptions, but also applied eMIT pricing to intravenous proton pump inhibitors and ondansetron because these are initially prescribed in a secondary care setting. The company highlighted that while these are prescribed in secondary care, the long-term use may be through a primary care service. The committee concluded that the concomitant medication assumptions used in the updated company and ERG adult base cases reflected NHS practice, giving a more realistic ICER for teduglutide.\n\n\n\n# Cost-effectiveness estimate\n\n## Uncertainties associated with the cost-effectiveness estimates for adults were addressed by the company\n\nNICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICERs. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. At its first meeting, the committee recommended teduglutide for children despite uncertainties in the evidence, because the cost-effectiveness estimates were well below what NICE normally considers an acceptable use of NHS resources. However, the committee requested further clarification and analyses from the company for adults because the ICER was likely to be above an acceptable use of NHS resources when its preferences were incorporated. After changes made in response to consultation, the company's updated analyses for adults reflected the committee's preferences as follows:\n\nan updated base case for adults that aligns dosing and administration assumptions for concomitant medications with NHS practice\n\nscenario analyses considering different starting ages in the adult model, alongside justification for the starting age used\n\nscenario analyses applying the placebo arm data from STEPS rather than assuming a steady state for those not on teduglutide.The company also provided further justification for its adult carer requirement assumptions and increased its patient access scheme discount. The committee noted some uncertainties with the model inputs remained after its second meeting, namely:\n\nthe generalisability of clinical-effectiveness results of both the teduglutide and placebo arms of STEPS (see section\xa03.8)\n\nthe company's approach to estimating health-state transition probabilities for both the teduglutide and standard care arms (see section\xa03.11).The committee considered that the uncertainty about the generalisability of clinical-effectiveness results from both the teduglutide and placebo arms of STEPS, and other areas of uncertainty in the modelling, would mean that the ICER would have to be comfortably within the acceptable range of cost effectiveness before recommending teduglutide. The committee concluded that while uncertainty remained within the clinical evidence, the company had provided a sufficient response to resolve some of the uncertainties.\n\n## Teduglutide is likely to be cost effective in both children and adults with SBS\n\nAt its first meeting, the committee concluded that the company's and ERG's cost-effectiveness estimates for teduglutide in children with SBS were well below what NICE normally considers an acceptable use of NHS resources. Because of confidential commercial arrangements for teduglutide and comparator treatments, the cost-effectiveness results cannot be reported here. However, the committee needed further evidence and analysis relating to adults, and at its first meeting was unable to recommend teduglutide for adults. It considered that the ICER was highly dependent on the costs related to the concomitant medications given alongside parenteral support, and the original ICERs did not reflect concomitant medications given in NHS practice. When the company updated its base case in response to consultation to reflect the committee's preferred assumptions, and increased its patient access scheme discount, the ICER for adults was below an acceptable use of NHS resources (see section\xa03.21). Scenario analyses exploring the other areas of uncertainty (see section\xa03.22) did not increase the ICER above an acceptable use of NHS resources. Therefore, teduglutide is considered cost effective for children and adults with the current analyses.\n\n# Other factors\n\nThere were no equality issues identified for teduglutide.\n\n## There may be additional benefits of teduglutide that are not captured in the cost-effectiveness analysis\n\nThe company considers teduglutide to be innovative because it represents a step change in the treatment of SBS, and existing treatment (parenteral support) only manages the symptoms of the disease. The ERG commented that the economic base case for teduglutide hinges on an evidence base with many uncertainties that cannot easily be resolved given the rarity and heterogeneity of SBS. The committee highlighted that there may be an uncaptured benefit to teduglutide in that it may prevent the need for intestinal transplant when parenteral support has not worked. The ERG noted that this was an important point to consider, but it was not possible to model this because of a lack of data on teduglutide's ability to reduce the need for intestinal transplant. The company stated that its base case for children is conservative because children may benefit more from teduglutide (see section\xa03.6). But the extent of this benefit is uncertain and may be countered by the fact that some children on standard care also have the potential to reduce their parenteral support needs (see section\xa03.8). The company also stated that their model only considers people with SBS to have improved quality of life when they reduce their parenteral support needs by 1\xa0day or more. Because of this, people with SBS who reduce their weekly parenteral support volume, but not the number of days they have it across, are assumed to have no benefit. They highlighted that this is unlikely to be the case, because people with SBS will have a better quality of life when having parenteral support for fewer hours per day. Reduced hours of parenteral support per day means more flexibility and people can use the extra time to sleep or enjoy their usual activities. The company stated that these changes in lifestyle are not currently captured in the model. The committee concluded that there may be additional benefits of teduglutide that are not captured in the cost-effectiveness analysis. But the extent of these benefits is unclear because of uncertainties in the evidence.\n\n# Conclusion\n\n## Teduglutide is recommended for treating short bowel syndrome in people aged 1\xa0year or above\n\nTeduglutide is recommended for use in the NHS for treating SBS in people aged 1\xa0year or above. The cost-effectiveness estimates for people with SBS were uncertain because of uncertainties within the clinical evidence. But they were highly likely to remain below what is considered an acceptable use of NHS resources, even when accounting for uncertainties."}	https://www.nice.org.uk/guidance/ta804	Evidence-based recommendations on teduglutide (Resvestive) for treating short bowel syndrome in people 1 year and above.
ca1a31b75c519469569f8c7c9b48705eab60167f	nice	Faricimab for treating diabetic macular oedema	Faricimab for treating diabetic macular oedema Evidence-based recommendations on faricimab (Vabysmo) for diabetic macular oedema in adults. # Recommendations Faricimab is recommended as an option for treating visual impairment due to diabetic macular oedema in adults, only if: the eye has a central retinal thickness of 400 micrometres or more at the start of treatment the company provides faricimab according to the commercial arrangement. If patients and their clinicians consider faricimab to be 1 of a range of suitable treatments (including aflibercept and ranibizumab), choose the least expensive treatment. Take account of administration costs, dosage, price per dose and commercial arrangements. These recommendations are not intended to affect treatment with faricimab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Diabetic macular oedema is usually treated first with aflibercept or ranibizumab, which are already recommended by NICE for treating diabetic macular oedema if the eye has a central retinal thickness of 400 micrometres or more when treatment starts. Faricimab is another treatment option that works in a similar way. Evidence from clinical trials shows that faricimab is as effective as aflibercept. An indirect comparison of faricimab with ranibizumab also suggests similar clinical effectiveness. A cost comparison suggests faricimab has similar costs and overall health benefits to aflibercept or ranibizumab. So, faricimab is recommended for treating diabetic macular oedema if it is used in the same population as aflibercept and ranibizumab.# Information about faricimab # Marketing authorisation indication Faricimab (Vabysmo, Roche) is indicated for 'the treatment of adults with visual impairment due to diabetic macular oedema'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for faricimab. # Price Faricimab costs £857 for 1 vial of 120 mg per 1 ml solution for injection (excluding VAT; company submission, accessed April 2022). The company has a commercial arrangement. This makes faricimab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Comparators ## Aflibercept and ranibizumab are appropriate comparators Aflibercept and ranibizumab are anti-vascular endothelial growth factor (anti-VEGF) injections recommended by NICE for treating diabetic macular oedema. Faricimab is another anti-VEGF injection that works in a similar way to aflibercept and ranibizumab, but it also targets the Ang‑2 pathway. The company proposes that faricimab will extend the time needed between injections compared with aflibercept and ranibizumab. The ERG suggested aflibercept and ranibizumab were both appropriate comparators for faricimab. Clinical experts said that the 2 treatments are both used. But they said aflibercept may be used more and it may be more effective than ranibizumab. The ERG's clinical experts suggested that 80% to 90% of people have aflibercept. The committee was aware that anti-VEGF treatments are used as a first treatment for diabetic macular oedema. It was aware that NICE's technology appraisal guidance 301 recommends fluocinolone acetonide implant if the diabetic macular oedema is insufficiently responsive to available therapies. It was also aware that NICE's technology appraisal guidance 349 recommends dexamethasone intravitreal implant if the diabetic macular oedema does not respond to non-corticosteroid treatment, or such treatment is unsuitable. The committee concluded that aflibercept and ranibizumab were the appropriate NICE-recommended comparators. # Clinical evidence ## Evidence from 2 clinical trials, YOSEMITE and RHINE, shows similar clinical effectiveness of faricimab and aflibercept Clinical evidence for faricimab compared with aflibercept came from 2 clinical trials. These were YOSEMITE and RHINE. Both were phase 3 randomised controlled trials that compared faricimab (using the dosing regimen in the marketing authorisation) with aflibercept in 1,259 adults. After the initial loading doses specified in the summary of product characteristics, aflibercept was given every 8 weeks and faricimab was administered as needed, with a maximum gap of 16 weeks between injections (a personalised treatment interval). The primary outcome measure was the mean change in best corrected visual acuity from baseline to 1 year. The evidence suggested that both treatments were similarly effective and had similar adverse events. The company had to break trial randomisation to provide subgroup results in people with central retinal thickness of 400 micrometres, which added uncertainty compared with results for the whole populations (these results are considered confidential by the company so cannot be presented here). Also, because there is only data up to 100 weeks, there is some uncertainty about how many faricimab injections are needed beyond the first 2 years. Despite these uncertainties, the committee considered that faricimab is likely to be similarly clinically effective as aflibercept. ## Faricimab is likely to have similar clinical effectiveness as ranibizumab The company did a network meta-analysis comparing faricimab with ranibizumab and aflibercept. Similar to the clinical trial subgroup evidence, for the network meta-analysis the company had to break randomisation to get subgroup results for people with central retinal thickness of 400 micrometres. This made the subgroup results of the network meta-analysis uncertain (these results are academic in confidence so cannot be presented here). The ERG considered that the network meta-analysis results were potentially unreliable due to the use of inappropriate statistical methods and incorrect dosing. The committee noted that the width of the confidence intervals made it difficult to say if the treatments have similar clinical effectiveness. But clinical opinion suggests that the treatments are similarly effective. Also, the network meta-analysis results show that faricimab has comparable ocular adverse events to ranibizumab and aflibercept. The committee concluded that there was sufficient evidence of similar clinical efficacy for faricimab compared with ranibizumab. # Cost comparison ## Faricimab is likely to be cost saving or have similar costs compared with aflibercept or ranibizumab The company base case assumed there would be fewer injections and monitoring visits needed for faricimab compared with the comparators. But clinical experts explained that in NHS clinical practice faricimab may have a similar dosing regimen as aflibercept and ranibizumab. They explained that this is to reduce the inconsistencies in clinical practice and chance of error in busy clinical settings. Because of this, along with the lack of long-term data, the committee considered scenarios in which the number of injections and monitoring visits was the same for faricimab, aflibercept and ranibizumab after the initial loading doses. The committee acknowledged that if the time needed between injections is lengthened, then the cost of faricimab would reduce. When taking account of the commercial arrangements for all treatments, the committee was satisfied that the total cost associated with faricimab was similar or lower than aflibercept or ranibizumab (the exact results are confidential and cannot be reported here). The committee agreed that choosing the least expensive option from the available treatment options at the same point in the pathway was appropriate. The committee therefore recommended faricimab for treating diabetic macular oedema in line with the previous recommendations for aflibercept and ranibizumab. # Other factors ## There are no equality issues relevant to the recommendations The committee did not identify any equality issues.	{'Recommendations': 'Faricimab is recommended as an option for treating visual impairment due to diabetic macular oedema in adults, only if:\n\nthe eye has a central retinal thickness of 400\xa0micrometres or more at the start of treatment\n\nthe company provides faricimab according to the commercial arrangement.\n\nIf patients and their clinicians consider faricimab to be 1 of a range of suitable treatments (including aflibercept and ranibizumab), choose the least expensive treatment. Take account of administration costs, dosage, price per dose and commercial arrangements.\n\nThese recommendations are not intended to affect treatment with faricimab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nDiabetic macular oedema is usually treated first with aflibercept or ranibizumab, which are already recommended by NICE for treating diabetic macular oedema if the eye has a central retinal thickness of 400\xa0micrometres or more when treatment starts. Faricimab is another treatment option that works in a similar way.\n\nEvidence from clinical trials shows that faricimab is as effective as aflibercept. An indirect comparison of faricimab with ranibizumab also suggests similar clinical effectiveness.\n\nA cost comparison suggests faricimab has similar costs and overall health benefits to aflibercept or ranibizumab. So, faricimab is recommended for treating diabetic macular oedema if it is used in the same population as aflibercept and ranibizumab.', 'Information about faricimab': "# Marketing authorisation indication\n\nFaricimab (Vabysmo, Roche) is indicated for 'the treatment of adults with visual impairment due to diabetic macular oedema'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for faricimab.\n\n# Price\n\nFaricimab costs £857 for 1\xa0vial of 120\xa0mg per 1\xa0ml solution for injection (excluding VAT; company submission, accessed April 2022).\n\nThe company has a commercial arrangement. This makes faricimab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Comparators\n\n## Aflibercept and ranibizumab are appropriate comparators\n\nAflibercept and ranibizumab are anti-vascular endothelial growth factor (anti-VEGF) injections recommended by NICE for treating diabetic macular oedema. Faricimab is another anti-VEGF injection that works in a similar way to aflibercept and ranibizumab, but it also targets the Ang‑2 pathway. The company proposes that faricimab will extend the time needed between injections compared with aflibercept and ranibizumab. The ERG suggested aflibercept and ranibizumab were both appropriate comparators for faricimab. Clinical experts said that the 2 treatments are both used. But they said aflibercept may be used more and it may be more effective than ranibizumab. The ERG's clinical experts suggested that 80% to 90% of people have aflibercept. The committee was aware that anti-VEGF treatments are used as a first treatment for diabetic macular oedema. It was aware that NICE's technology appraisal guidance 301 recommends fluocinolone acetonide implant if the diabetic macular oedema is insufficiently responsive to available therapies. It was also aware that NICE's technology appraisal guidance 349 recommends dexamethasone intravitreal implant if the diabetic macular oedema does not respond to non-corticosteroid treatment, or such treatment is unsuitable. The committee concluded that aflibercept and ranibizumab were the appropriate NICE-recommended comparators.\n\n# Clinical evidence\n\n## Evidence from 2 clinical trials, YOSEMITE and RHINE, shows similar clinical effectiveness of faricimab and aflibercept\n\nClinical evidence for faricimab compared with aflibercept came from 2\xa0clinical trials. These were YOSEMITE and RHINE. Both were phase 3\xa0randomised controlled trials that compared faricimab (using the dosing regimen in the marketing authorisation) with aflibercept in 1,259\xa0adults. After the initial loading doses specified in the summary of product characteristics, aflibercept was given every 8\xa0weeks and faricimab was administered as needed, with a maximum gap of 16\xa0weeks between injections (a personalised treatment interval). The primary outcome measure was the mean change in best corrected visual acuity from baseline to 1\xa0year. The evidence suggested that both treatments were similarly effective and had similar adverse events. The company had to break trial randomisation to provide subgroup results in people with central retinal thickness of 400\xa0micrometres, which added uncertainty compared with results for the whole populations (these results are considered confidential by the company so cannot be presented here). Also, because there is only data up to 100\xa0weeks, there is some uncertainty about how many faricimab injections are needed beyond the first 2\xa0years. Despite these uncertainties, the committee considered that faricimab is likely to be similarly clinically effective as aflibercept.\n\n## Faricimab is likely to have similar clinical effectiveness as ranibizumab\n\nThe company did a network meta-analysis comparing faricimab with ranibizumab and aflibercept. Similar to the clinical trial subgroup evidence, for the network meta-analysis the company had to break randomisation to get subgroup results for people with central retinal thickness of 400\xa0micrometres. This made the subgroup results of the network meta-analysis uncertain (these results are academic in confidence so cannot be presented here). The ERG considered that the network meta-analysis results were potentially unreliable due to the use of inappropriate statistical methods and incorrect dosing. The committee noted that the width of the confidence intervals made it difficult to say if the treatments have similar clinical effectiveness. But clinical opinion suggests that the treatments are similarly effective. Also, the network meta-analysis results show that faricimab has comparable ocular adverse events to ranibizumab and aflibercept. The committee concluded that there was sufficient evidence of similar clinical efficacy for faricimab compared with ranibizumab.\n\n# Cost comparison\n\n## Faricimab is likely to be cost saving or have similar costs compared with aflibercept or ranibizumab\n\nThe company base case assumed there would be fewer injections and monitoring visits needed for faricimab compared with the comparators. But clinical experts explained that in NHS clinical practice faricimab may have a similar dosing regimen as aflibercept and ranibizumab. They explained that this is to reduce the inconsistencies in clinical practice and chance of error in busy clinical settings. Because of this, along with the lack of long-term data, the committee considered scenarios in which the number of injections and monitoring visits was the same for faricimab, aflibercept and ranibizumab after the initial loading doses. The committee acknowledged that if the time needed between injections is lengthened, then the cost of faricimab would reduce. When taking account of the commercial arrangements for all treatments, the committee was satisfied that the total cost associated with faricimab was similar or lower than aflibercept or ranibizumab (the exact results are confidential and cannot be reported here). The committee agreed that choosing the least expensive option from the available treatment options at the same point in the pathway was appropriate. The committee therefore recommended faricimab for treating diabetic macular oedema in line with the previous recommendations for aflibercept and ranibizumab.\n\n# Other factors\n\n## There are no equality issues relevant to the recommendations\n\nThe committee did not identify any equality issues."}	https://www.nice.org.uk/guidance/ta799	Evidence-based recommendations on faricimab (Vabysmo) for diabetic macular oedema in adults.
381e3da23c4c86a8a7eafa4f024dc7ad4547c6cd	nice	Faricimab for treating wet age-related macular degeneration	Faricimab for treating wet age-related macular degeneration Evidence-based recommendations on faricimab (Vabysmo) for wet age-related macular degeneration in adults. # Recommendations Faricimab is recommended as an option for treating wet age-related macular degeneration in adults, only if: the eye has a best-corrected visual acuity between 6/12 and 6/96 there is no permanent structural damage to the central fovea the lesion size is 12 disc areas or less in greatest linear dimension there are signs of recent disease progression (for example, blood vessel growth as shown by fluorescein angiography, or recent visual acuity changes) the company provides faricimab according to the commercial arrangement. If patients and their clinicians consider faricimab to be 1 of a range of suitable treatments (including aflibercept and ranibizumab), choose the least expensive treatment. Take account of administration costs, dosage, price per dose and commercial arrangements. Only continue faricimab if an adequate response to treatment is maintained. Criteria for stopping should include persistent deterioration in visual acuity and anatomical changes in the retina. These recommendations are not intended to affect treatment with faricimab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Wet age-related macular degeneration is usually treated with aflibercept or ranibizumab, which are already recommended by NICE for treating wet age-related macular degeneration. Faricimab is another treatment option that works in a similar way. Evidence from clinical trials shows that faricimab is as effective as aflibercept. An indirect comparison of faricimab with ranibizumab also suggests similar clinical effectiveness. A cost comparison suggests faricimab has similar costs and overall health benefits to aflibercept or ranibizumab. So, faricimab is recommended for treating wet age-related macular degeneration if it is used in the same population as aflibercept and ranibizumab.# Information about faricimab # Marketing authorisation indication Faricimab (Vabysmo, Roche) is indicated for 'the treatment of adults with neovascular (wet) age-related macular degeneration'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for faricimab. # Price Faricimab costs £857 for 1 vial of 120 mg per 1 ml solution for injection (excluding VAT; company submission, accessed April 2022). The company has a commercial arrangement. This makes faricimab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Comparators ## Aflibercept and ranibizumab are appropriate comparators Aflibercept and ranibizumab are anti-vascular endothelial growth factor (anti-VEGF) injections recommended by NICE for treating wet age-related macular degeneration. Faricimab is another anti-VEGF injection that works in a similar way to aflibercept and ranibizumab, but it also targets the Ang‑2 pathway. The company proposes that faricimab will extend the time needed between injections compared with aflibercept and ranibizumab. The ERG suggested aflibercept was the most appropriate comparator for faricimab. Clinical experts said that the 2 treatments are both used. But they said aflibercept may be used more than ranibizumab. The ERG's clinical experts suggested that 65% of people have aflibercept. The committee concluded that aflibercept and ranibizumab were both appropriate NICE-recommended comparators. # Clinical evidence ## Evidence from 2 clinical trials, TENAYA and LUCERNE, shows similar clinical effectiveness of faricimab and aflibercept Clinical evidence for faricimab compared with aflibercept came from 2 clinical trials. These were TENAYA and LUCERNE. Both were phase 3 randomised controlled trials that compared faricimab with aflibercept in 1,329 adults. After the initial loading doses specified in the summary of product characteristics, aflibercept was given every 8 weeks and faricimab was administered every 8, 12 or 16 weeks based on an assessment of disease activity at weeks 20 and 24. The assessment was based on objective prespecified criteria (best corrected visual acuity and optical coherence tomography) and physician's clinical assessment. People stayed on the fixed dosing intervals until week 60 without having any other treatment. The primary outcome measure was the mean change in best corrected visual acuity from baseline averaged over 40, 44 and 48 weeks. The difference in adjusted mean best corrected visual acuity from baseline at weeks 40, 44 and 48 was 0.4 letters, 95% confidence interval -0.9 to 1.6. The results were also reported averaged over 52, 56 and 60 weeks (these are considered confidential by the company and cannot be reported here). The evidence suggested that both treatments were similarly effective and had similar adverse events. Because there is only data up to 112 weeks, there is some uncertainty about how many faricimab injections are needed beyond the first 2 years. Despite the uncertainty, the committee considered that faricimab is likely to be similarly clinically effective as aflibercept. ## Faricimab is likely to have similar clinical effectiveness as ranibizumab The company did a network meta-analysis comparing faricimab with ranibizumab and aflibercept. The ERG considered that the network meta-analysis showed that faricimab has similar clinical effectiveness and had similar adverse events to aflibercept and ranibizumab. Also, clinical opinion suggests that the treatments are similar. The committee concluded that there was sufficient evidence of similar clinical efficacy for faricimab compared with ranibizumab. # Cost comparison ## Faricimab is likely to be cost saving or have similar costs compared with aflibercept or ranibizumab The company base case assumed there would be fewer injections and monitoring visits needed for faricimab compared with the comparators. But the committee was aware that in NHS clinical practice faricimab may have a similar dosing regimen as aflibercept and ranibizumab. This is to reduce inconsistencies in clinical practice and chance of error in busy clinical settings. Because of this, along with the lack of long-term data, the committee considered scenarios in which the number of injections and monitoring visits was the same for faricimab, aflibercept and ranibizumab after the initial loading doses. The committee acknowledged that if the time needed between injections is lengthened, then the cost of faricimab would reduce. When taking account of the commercial arrangements for all treatments, the committee was satisfied that the total cost associated with faricimab was similar or lower than aflibercept or ranibizumab (the exact results are confidential and cannot be reported here). The committee therefore recommended faricimab for treating wet age-related macular degeneration in line with the previous recommendations for aflibercept and ranibizumab. # Other factors ## There are no equality issues relevant to the recommendations The committee did not identify any equality issues.	{'Recommendations': 'Faricimab is recommended as an option for treating wet age-related macular degeneration in adults, only if:\n\nthe eye has a best-corrected visual acuity between 6/12 and 6/96\n\nthere is no permanent structural damage to the central fovea\n\nthe lesion size is 12\xa0disc areas or less in greatest linear dimension\n\nthere are signs of recent disease progression (for example, blood vessel growth as shown by fluorescein angiography, or recent visual acuity changes)\n\nthe company provides faricimab according to the commercial arrangement.\n\nIf patients and their clinicians consider faricimab to be 1 of a range of suitable treatments (including aflibercept and ranibizumab), choose the least expensive treatment. Take account of administration costs, dosage, price per dose and commercial arrangements.\n\nOnly continue faricimab if an adequate response to treatment is maintained. Criteria for stopping should include persistent deterioration in visual acuity and anatomical changes in the retina.\n\nThese recommendations are not intended to affect treatment with faricimab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nWet age-related macular degeneration is usually treated with aflibercept or ranibizumab, which are already recommended by NICE for treating wet age-related macular degeneration. Faricimab is another treatment option that works in a similar way.\n\nEvidence from clinical trials shows that faricimab is as effective as aflibercept. An indirect comparison of faricimab with ranibizumab also suggests similar clinical effectiveness.\n\nA cost comparison suggests faricimab has similar costs and overall health benefits to aflibercept or ranibizumab. So, faricimab is recommended for treating wet age-related macular degeneration if it is used in the same population as aflibercept and ranibizumab.', 'Information about faricimab': "# Marketing authorisation indication\n\nFaricimab (Vabysmo, Roche) is indicated for 'the treatment of adults with neovascular (wet) age-related macular degeneration'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for faricimab.\n\n# Price\n\nFaricimab costs £857 for 1\xa0vial of 120\xa0mg per 1\xa0ml solution for injection (excluding VAT; company submission, accessed April 2022).\n\nThe company has a commercial arrangement. This makes faricimab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Comparators\n\n## Aflibercept and ranibizumab are appropriate comparators\n\nAflibercept and ranibizumab are anti-vascular endothelial growth factor (anti-VEGF) injections recommended by NICE for treating wet age-related macular degeneration. Faricimab is another anti-VEGF injection that works in a similar way to aflibercept and ranibizumab, but it also targets the Ang‑2 pathway. The company proposes that faricimab will extend the time needed between injections compared with aflibercept and ranibizumab. The ERG suggested aflibercept was the most appropriate comparator for faricimab. Clinical experts said that the 2\xa0treatments are both used. But they said aflibercept may be used more than ranibizumab. The ERG's clinical experts suggested that 65% of people have aflibercept. The committee concluded that aflibercept and ranibizumab were both appropriate NICE-recommended comparators.\n\n# Clinical evidence\n\n## Evidence from 2 clinical trials, TENAYA and LUCERNE, shows similar clinical effectiveness of faricimab and aflibercept\n\nClinical evidence for faricimab compared with aflibercept came from 2\xa0clinical trials. These were TENAYA and LUCERNE. Both were phase 3 randomised controlled trials that compared faricimab with aflibercept in 1,329\xa0adults. After the initial loading doses specified in the summary of product characteristics, aflibercept was given every 8\xa0weeks and faricimab was administered every 8, 12 or 16\xa0weeks based on an assessment of disease activity at weeks\xa020 and 24. The assessment was based on objective prespecified criteria (best corrected visual acuity and optical coherence tomography) and physician's clinical assessment. People stayed on the fixed dosing intervals until week\xa060 without having any other treatment. The primary outcome measure was the mean change in best corrected visual acuity from baseline averaged over 40, 44 and 48\xa0weeks. The difference in adjusted mean best corrected visual acuity from baseline at weeks\xa040, 44 and 48 was 0.4 letters, 95% confidence interval -0.9 to 1.6. The results were also reported averaged over 52, 56 and 60\xa0weeks (these are considered confidential by the company and cannot be reported here). The evidence suggested that both treatments were similarly effective and had similar adverse events. Because there is only data up to 112\xa0weeks, there is some uncertainty about how many faricimab injections are needed beyond the first 2\xa0years. Despite the uncertainty, the committee considered that faricimab is likely to be similarly clinically effective as aflibercept.\n\n## Faricimab is likely to have similar clinical effectiveness as ranibizumab\n\nThe company did a network meta-analysis comparing faricimab with ranibizumab and aflibercept. The ERG considered that the network meta-analysis showed that faricimab has similar clinical effectiveness and had similar adverse events to aflibercept and ranibizumab. Also, clinical opinion suggests that the treatments are similar. The committee concluded that there was sufficient evidence of similar clinical efficacy for faricimab compared with ranibizumab.\n\n# Cost comparison\n\n## Faricimab is likely to be cost saving or have similar costs compared with aflibercept or ranibizumab\n\nThe company base case assumed there would be fewer injections and monitoring visits needed for faricimab compared with the comparators. But the committee was aware that in NHS clinical practice faricimab may have a similar dosing regimen as aflibercept and ranibizumab. This is to reduce inconsistencies in clinical practice and chance of error in busy clinical settings. Because of this, along with the lack of long-term data, the committee considered scenarios in which the number of injections and monitoring visits was the same for faricimab, aflibercept and ranibizumab after the initial loading doses. The committee acknowledged that if the time needed between injections is lengthened, then the cost of faricimab would reduce. When taking account of the commercial arrangements for all treatments, the committee was satisfied that the total cost associated with faricimab was similar or lower than aflibercept or ranibizumab (the exact results are confidential and cannot be reported here). The committee therefore recommended faricimab for treating wet age-related macular degeneration in line with the previous recommendations for aflibercept and ranibizumab.\n\n# Other factors\n\n## There are no equality issues relevant to the recommendations\n\nThe committee did not identify any equality issues."}	https://www.nice.org.uk/guidance/ta800	Evidence-based recommendations on faricimab (Vabysmo) for wet age-related macular degeneration in adults.
6603424a6299b18757c0579b17a445fa40960b8d	nice	Pembrolizumab plus chemotherapy for untreated, triple-negative, locally recurrent unresectable or metastatic breast cancer	Pembrolizumab plus chemotherapy for untreated, triple-negative, locally recurrent unresectable or metastatic breast cancer Evidence-based recommendations on pembrolizumab (Keytruda) with paclitaxel or nab‑paclitaxel for triple-negative, locally recurrent unresectable or metastatic breast cancer in adults who have not had chemotherapy for metastatic disease. # Recommendations Pembrolizumab plus chemotherapy (paclitaxel or nab‑paclitaxel) is recommended as an option for treating triple‑negative, locally recurrent unresectable or metastatic breast cancer in adults who have not had chemotherapy for metastatic disease. It is recommended only if: the tumours express PD‑L1 with a combined positive score (CPS) of 10 or more and an immune cell staining (IC) of less than 1%, and the company provides pembrolizumab according to the commercial arrangement. This recommendation is not intended to affect treatment with pembrolizumab plus chemotherapy that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Treatment for untreated, triple‑negative, locally recurrent unresectable or metastatic breast cancer includes chemotherapy such as docetaxel or paclitaxel, or atezolizumab plus nab‑paclitaxel immunotherapy (from now, atezolizumab combination). There is an unmet need for alternative treatments for people who cannot have atezolizumab combination. Pembrolizumab plus paclitaxel or nab‑paclitaxel (from now, pembrolizumab combination) is another immunotherapy that could be used. The company proposed pembrolizumab combination for people whose tumours express PD‑L1 with a CPS of 10 or more and an IC of less than 1%. This is narrower than the marketing authorisation and makes pembrolizumab combination an alternative treatment for people who cannot have atezolizumab combination. Clinical trial evidence shows that, compared with paclitaxel, pembrolizumab combination increases how long people have before their cancer gets worse and how long they live. The cost‑effectiveness estimates for pembrolizumab combination compared with both paclitaxel and docetaxel are within what NICE usually considers an acceptable use of NHS resources. Therefore, it is recommended.# Information about pembrolizumab # Marketing authorisation indication Pembrolizumab (Keytruda, Merck Sharp and Dohme) has a marketing authorisation for use in combination with chemotherapy 'for the treatment of locally recurrent unresectable or metastatic triple‑negative breast cancer in adults whose tumours express PD‑L1 with a CPS more than or equal to 10 and who have not received prior chemotherapy for metastatic disease'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for pembrolizumab. # Price The company's list price is £2,630 per 100‑mg solution for infusion vial (excluding VAT, BNF online accessed January 2022). The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Merck Sharp and Dohme, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need and treatment pathway ## Triple‑negative breast cancer has a high disease burden Some breast cancers test negative for oestrogen and progesterone receptors (hormone receptor‑negative) and human epidermal growth factor receptor 2 (HER2‑negative). They are called triple‑negative and account for about 15% of all breast cancers. The patient expert explained that being diagnosed with locally recurrent unresectable or metastatic breast cancer is extremely difficult for people, and their family and friends. It can cause considerable anxiety and fear, and it can be very difficult to cope with the uncertainty of the outcome. People with locally recurrent unresectable and metastatic breast cancer must also organise their lives around hospital appointments, which restricts their everyday activities. There is no cure for metastatic breast cancer. Treatment aims to stop progression of the disease, extend life, and maintain or improve quality of life for as long as possible. The committee concluded that there is a high disease burden for people with triple‑negative breast cancer (TNBC). ## There is a need for first‑line TNBC treatments, particularly for people who cannot have atezolizumab combination Until recently, there were limited first‑line treatment options for people with triple‑negative, locally recurrent unresectable or metastatic breast cancer, especially compared with other types of breast cancer. Atezolizumab plus nab‑paclitaxel (from now, atezolizumab combination) is the only immunotherapy recommended by NICE for this condition (see NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel for untreated PD-L1-positive, locally advanced or metastatic, triple-negative breast cancer). Other first‑line treatment options for triple‑negative, locally recurrent unresectable or metastatic breast cancer are paclitaxel, docetaxel, nab‑paclitaxel, anthracycline‑based chemotherapy, or gemcitabine with or without carboplatin (see NICE's guideline on advanced breast cancer: diagnosis and treatment). The clinical expert explained that atezolizumab combination is an option for some people whose tumours express PD‑L1. However, they explained that some people would not be able to have atezolizumab combination but could have pembrolizumab plus paclitaxel or nab‑paclitaxel (from now, pembrolizumab combination). This is because the marketing authorisation for each treatment option includes a different measurement of PD‑L1 expression. The PD‑L1 expression for pembrolizumab combination is measured using combined positive score (CPS). However, in NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel, it is based on immune cell staining (IC). Both measurements use slightly different methods for measuring and calculating PD‑L1 expression. The company estimated that the overall percentage agreement between the 2 measures is 75%. However, it also stated that there are some instances in which only 1 of the measurements would show PD‑L1 positivity. The clinical expert and Cancer Drugs Fund clinical lead explained that the measurement used would vary between hospital trusts. They explained that trusts are likely to adopt one measurement in the first instance and only use the other if the first did not show PD‑L1 positivity. The patient expert highlighted that, because of the differences in PD‑L1 measurements, there is an unmet need for immunotherapy for people who cannot have atezolizumab combination. They explained that pembrolizumab combination could be a critical option for these people. The committee concluded that there is an unmet need for immunotherapy for untreated, triple‑negative, locally recurrent unresectable or metastatic breast cancer, especially for people who cannot have atezolizumab combination. ## Atezolizumab combination is not included as a comparator in the company's updated cost-effectiveness analyses, but additional testing costs need to be accounted for in the economic model In its initial submission, the company included atezolizumab combination as a comparator. At the first committee meeting, the committee agreed atezolizumab combination was a relevant comparator for tumours that express PD‑L1 with an IC more than 1% and CPS of 10 or more. In its response to consultation, the company did not include a comparison with atezolizumab combination. Instead, the company submitted updated cost‑effectiveness results only for people whose tumours have an IC less than 1% and CPS of 10 or more. This is the group of people for whom atezolizumab combination is not indicated. The company explained that they chose to focus on this population because they recognised its high unmet need. It estimated this population would comprise approximately 17% of people with metastatic TNBC. The ERG highlighted that the removal of atezolizumab combination resulted in an underestimation of CPS and IC testing costs in the company model, because both tests would have to be done for some people. The Cancer Drugs Fund clinical lead explained that it will be difficult for pathology departments to do both tests and that the cost of both should be included in the economic model. The committee acknowledged the challenge for pathology departments with backlogs following the COVID‑19 pandemic but noted that NHS implementation is beyond its remit. The ERG also cautioned that the company assumed the efficacy data from the trial using a CPS of 10 or more is generalisable to the more limited population. It explained that this added additional uncertainty. The Cancer Drugs Fund clinical lead explained that it is unknown if the trial data from the population with a CPS of 10 or more is generalisable to the proposed population. Therefore, they agreed with the ERG that it would have to be treated as an uncertainty. The committee agreed that the population the company had focused on had the greatest unmet need, but that increased testing costs would need to be accounted for in the economic model. ## The relevant comparators are paclitaxel and docetaxel In its initial submission, the company used paclitaxel as its base‑case comparator, docetaxel as a secondary comparator, and did not include gemcitabine with or without carboplatin or nab-paclitaxel. The clinical expert agreed that gemcitabine with or without carboplatin and nab‑paclitaxel were not relevant comparators. Gemcitabine with or without carboplatin is not widely used in the NHS, especially as a first‑line treatment for metastatic disease. This is because it is difficult to administer and has a high toxicity. The clinical expert and Cancer Drugs Fund clinical lead also explained that nab‑paclitaxel is rarely used in the NHS because of its cost. However, there is currently some use of nab‑paclitaxel because access has been given during COVID‑19. Also, because of recent resource pressures in the NHS, docetaxel is being used more often. This is because docetaxel and nab‑paclitaxel are given at 3‑weekly intervals, compared with paclitaxel, which is usually given weekly. The company explained that docetaxel is not relevant as a primary comparator because it is used at earlier stages of breast cancer and has a less favourable safety profile than paclitaxel. The committee recalled that docetaxel was not considered a relevant comparator in NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel. However, the Cancer Drugs Fund clinical lead explained the recent resource pressures that have resulted in the move to docetaxel use are likely to remain in chemotherapy units post‑COVID‑19 pressures. The clinical expert also noted that docetaxel would not be used if someone had had it before, but that a substantial and increasing number of people would be able to have it. In its response to consultation, the company explained that pembrolizumab combination is disadvantaged by using docetaxel as a comparator. This is because the company assumed docetaxel has the same efficacy as paclitaxel despite docetaxel having a worse safety profile and potentially a shorter treatment response. As an alternative, the company presented a blended comparator cost-effectiveness estimate where it assumed 70% of people are treated with paclitaxel and 30% of people are treated with docetaxel. This was estimated using clinical opinion and KEYNOTE-355 data. The Cancer Drugs Fund clinical lead explained that the ratio of paclitaxel to docetaxel use is continually changing because chemotherapy units are trying to minimise the number of visits people make. He estimated approximately 50% of people would be treated with paclitaxel and 50% of people would be treated with docetaxel. The ERG explained it preferred a fully incremental analysis where the 3 treatments were ranked individually rather than a blend of 2 comparators because it can improve the efficient allocation of resources. It also noted that it would have preferred the toxicity and potentially shorter treatment duration of docetaxel to have been included in the economic model, instead of a blend of 2 comparators assumed to be the same apart from cost. The committee acknowledged the blended comparator estimates but noted that a fully incremental analysis against paclitaxel and docetaxel was more methodologically robust. The committee concluded the blended comparator cost‑effectiveness estimate was not appropriate. It also concluded that the relevant comparators are paclitaxel and docetaxel but that the cost‑effectiveness estimates compared with docetaxel are potentially unfavourable to pembrolizumab combination. This was because of the company assumption that paclitaxel and docetaxel have the same efficacy. # Clinical evidence ## KEYNOTE‑355 trial data excluding gemcitabine is appropriate for decision making The clinical evidence was based on KEYNOTE‑355, a randomised double‑blind placebo‑controlled active‑comparator trial in people with untreated, triple‑negative, locally recurrent unresectable or metastatic breast cancer. The trial protocol was updated to only include TNBC with a CPS of 10 or more, which is in line with the marketing authorisation. Chemotherapies included in the trial, either with pembrolizumab or placebo, were nab‑paclitaxel, paclitaxel or gemcitabine plus carboplatin. Most (57%) people had gemcitabine plus carboplatin in KEYNOTE‑355, but the company excluded this clinical trial data in the clinical and economic analysis. It only included the population who had a taxane (that is, paclitaxel or nab‑paclitaxel). The company excluded the gemcitabine plus carboplatin data because this treatment would not be expected to be used in the UK. The committee recalled its conclusion that gemcitabine was not a relevant comparator (see section 3.4). The ERG noted that the baseline characteristics were stratified by chemotherapy combinations, so randomisation was not broken when the gemcitabine data was removed for the economic analysis. The committee recalled that the company assumed the trial data for CPS of 10 or more was generalisable to the proposed population (see section 3.3). The committee concluded the trial data, excluding gemcitabine with or without carboplatin, was appropriate for decision making. ## Pembrolizumab combination is more effective than paclitaxel or nab‑paclitaxel The trial results showed a consistent clinically meaningful and statistically significant benefit for pembrolizumab combination compared with taxanes alone for both progression‑free survival (exact progression‑free survival results are considered confidential by the company and cannot be reported here) and overall survival. The hazard ratio for overall survival was 0.54 (95% confidence interval 0.36 to 0.82). The committee noted the long‑term benefit of pembrolizumab combination was uncertain. In response to consultation, the company provided additional explanations and clinical opinion to demonstrate the long‑term benefit of pembrolizumab combination. The company clinical experts estimated 20% survival at year 5 and 10% survival at year 10 for those having pembrolizumab combination. By contrast, they estimated survival of 10% at year 5 and 0% at year 10 for those having paclitaxel or docetaxel. The committee concluded that pembrolizumab combination is more effective than taxanes. # Indirect treatment comparison ## The comparison with atezolizumab combination using a network meta‑analysis is no longer needed for decision making In the company's initial submission, atezolizumab combination was a secondary comparator. There is no head‑to‑head evidence comparing pembrolizumab combination with atezolizumab combination. Therefore, the company did a network meta‑analysis to allow for an indirect treatment comparison. The company presented the results of the fixed‑effect network meta‑analysis because of the small number of studies in the network, which meant the between study heterogeneity could not be estimated. The point estimates favoured pembrolizumab combination but had wide credible intervals that crossed 1, meaning that the results were not statistically significant. The ERG considered that the network meta‑analysis had limitations because of heterogeneity between trials and would have preferred a random‑effects model. In response to consultation, the company removed atezolizumab combination as a comparator because it proposed that pembrolizumab should be used in a population for which atezolizumab was not indicated (IC less than 1% and CPS of 10 or more). The committee concluded the network meta‑analysis results were no longer needed for decision making in this population. # Cost‑effectiveness evidence ## The company's economic model uses a standard approach The company submitted a partitioned survival model to estimate the cost effectiveness of pembrolizumab combination compared with paclitaxel, docetaxel and atezolizumab combination. It had 3 health states: progression‑free survival, post‑progression survival and death. The committee considered that the partitioned survival model is a standard approach to estimate the cost effectiveness of cancer drugs. ## Exponential distribution for extrapolating overall survival better fitted the smoothed hazard plot for the pembrolizumab arm The company chose a log‑normal model for pembrolizumab combination and a log‑logistic model for paclitaxel to extrapolate overall survival. It chose these curves based on goodness‑of‑fit statistics, clinical plausibility of long‑term extrapolations and validity of long‑term projections. The ERG agreed with the company's choice of log‑logistic extrapolation for paclitaxel but preferred an exponential model for pembrolizumab combination. It explained that the goodness‑of‑fit statistics between the exponential and log‑normal models both corresponded with the observed data. It noted that the log‑normal distribution showed a turning point within the first year, but the smoothed hazard plot of the observed data did not show a turning point in the underlying hazard. The exponential distribution did not have a turning point. Using the exponential distribution resulted in a substantial increase in the incremental cost‑effectiveness ratio (ICER). The company disagreed with the choice of an exponential distribution. It stated that this was overly simple and assumed a constant hazard that was not seen in the trial. In response to consultation, the company further cautioned against over‑interpreting smoothed hazard plots. The company explained that the lack of turning point could be because of the method used to generate the 'smoothed' hazard plot or the small sample size. It highlighted that NICE Decision Support Unit technical support document 14 states goodness‑of‑fit should not be measured by hazard plots but instead by using the survival curves. The ERG maintained its view that the exponential is the most appropriate extrapolation. It explained the constant hazard is in keeping with the observed hazards from KEYNOTE‑355 and that the lack of observed turning point could be because there is no turning in the true distribution. The committee concluded that both extrapolations broadly fitted the data, but that the exponential distribution better fitted the smoothed hazard plot. ## The duration of benefit for pembrolizumab combination should include an assumption that the treatment effect wanes after stopping treatment In KEYNOTE‑355, treatment was stopped after about 2 years. A stopping rule was not included in the marketing authorisation, but the company assumed a stopping rule would apply in line with the trial. The company assumed that, despite stopping treatment after a maximum of 2 years, the treatment benefit would be maintained for a lifetime horizon. It explained that this was because the unique mode of action of pembrolizumab results in an extended period of benefit after treatment has stopped. Also, KEYNOTE‑355 showed no evidence of treatment benefit decreasing over the median follow-up duration (the exact follow-up period is considered confidential by the company and cannot be reported here). The company highlighted that, in NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel, a treatment waning effect was considered inappropriate. The committee recalled that, in this appraisal, there was no stopping rule and people could continue to have atezolizumab combination beyond 2 years. The ERG explained a lifetime treatment benefit created the possibility that 2 people alive at year 7 on third-line treatment would have different chances of death depending on their first course of treatment. The committee considered that this was implausible and noted that, in some people who had pembrolizumab combination in the trial, their cancer still progressed after 2 years. The ERG also noted that subsequent treatment use from KEYNOTE‑355 showed that many people moved on to second-line treatment. Also, some people moved on to third- and fourth-line treatment during the trial follow-up period. The ERG preferred a total treatment benefit duration of 5 years (3 years after treatment is stopped). It explained that KEYNOTE‑355 did not provide long-term data to support a lifetime treatment benefit. This increased the ICER of pembrolizumab combination compared with all comparators. The committee noted a 5-year treatment effect had been used in previous appraisals of immuno-oncology drugs when a stopping rule applied. In response to consultation, the company explained that an abrupt treatment-effect stop at a specific timepoint, as suggested by the ERG, was not clinically plausible. The company therefore presented an alternative scenario using the Surveillance, Epidemiology and End Results (SEER) program. This assumed a constant hazard rate for 4 years across both pembrolizumab combination and taxanes, which results in gradual treatment waning adjustments being made from 4 years onwards using the SEER data. The ERG explained that the SEER program is a US database that is unlikely to include a large proportion of patients treated with pembrolizumab combination. It also explained that this method of waning lacks face validity because the cost-effectiveness estimates decreased compared with no treatment waning. The committee concluded that there is a lack of clear evidence to predict a precise waning of effect. But a waning effect had been assumed in previous appraisals and was more plausible than a continuing effect long after treatment was stopped, even if the disease had progressed. It concluded that a 5‑year treatment effect combined with the 2‑year stopping rule was appropriate for pembrolizumab combination. ## Vial sharing should be included in the analysis The company included vial sharing for intravenous drugs but not pembrolizumab in its base case. Pembrolizumab is given in fixed doses, so vial sharing does not apply. It understood that vial sharing would be routine practice to minimise drug wastage of intravenous drugs. The ERG did not include vial sharing in its model, which had a small upward effect on the ICER. The clinical expert and Cancer Drugs Fund clinical lead explained that vial sharing does happen in clinical practice and is particularly encouraged for expensive chemotherapies. The committee concluded that vial sharing should be included in the analysis. ## Using the time-to-death approach to estimate utilities is appropriate The company used 2 methods to estimate utility in the economic model: the time-to-death approach and the health-state approach. The time-to-death approach categorises utility based on the length of time before death. The health-state approach categorises utilities based on the health states in the model (progression-free survival, post-progression and death). The company's base case used the time-to-death approach, but the company stated that it did not have a preference for which approach should be used. It explained that it chose the time-to-death approach because it is most appropriate based on the aggressiveness of TNBC and had been used in other NICE appraisals. The ERG noted both methods have their limitations. It explained that neither approach overcomes the main limitation that the data collected has been heavily censored, either at the point of progression, or at treatment discontinuation. The ERG also stated that it had no preference for which approach was used. However, it noted that the health-state approach consistently had slightly higher ICERs than the time-to-death approach. The committee concluded that both approaches were acceptable, but that it would consider the time-to-death approach in its decision making, based on the aggressiveness of TNBC. ## The economic model is suitable for decision making When considering the end of life criteria, the committee recalled that the life expectancy in NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel was around half that projected in the pembrolizumab model for a similar population (see section 3.14). The committee therefore questioned the validity of the company's pembrolizumab model results and whether they were suitable for decision making. In its response to consultation, the company explained that these differences could be due to differences in trial design, population characteristics and alternative survival extrapolation assumptions. The company also used published studies and clinical opinion to validate survival predictions in the economic model. Median overall survival in the published studies ranged from 14.3 months to 21.3 months. The percentage of survivors at 2 years in the real-world evidence ranged from 12.1% to 36.58%. Overall survival and percentage survivorship from KEYNOTE-355 and the economic model are considered confidential by the company so cannot be reported here. It concluded that the model accurately predicts short- to medium-term taxane overall-survival projections and longer-term overall survival based on a 12-year study. The committee concluded that the economic model was suitable for decision making. # End of life ## Pembrolizumab combination meets end of life criteria The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The ERG agreed with the company that the extension-to-life criterion was met for pembrolizumab combination compared with taxanes. The ERG disagreed with the company that the short life-expectancy criterion was met. The company's base-case model estimated that the mean life expectancy was longer than 24.0 months for taxanes at 27.7 months, atezolizumab combination at 30.4 months and pembrolizumab combination at 54.5 months. The committee also considered overall survival at 24.0 months in KEYNOTE‑355 to assess whether the short life-expectancy criterion was met. It appreciated that a large proportion of people in the placebo arm had an overall survival of less than 24.0 months. The exact overall-survival numbers are considered confidential by the company and cannot be reported here. The clinical expert explained that, in some people, there is a prolonged response to standard therapies. The committee appreciated that, when the whole population was modelled over a lifetime horizon (not just over the trial follow up), having people who survived a long time would make the mean estimates higher than the median in the trial. The committee noted that this effect would apply to all survival estimates, including the treatment arm. This meant that the mean modelled overall survival in the treatment arm would also be longer than might be predicted based on the Kaplan–Meier curves, in this case 54.5 months. The committee was aware that all sources of evidence should be considered. It also recalled that the short life-expectancy criterion was met in NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel. The life-expectancy estimates in the modelling in that appraisal were 13.8 months for paclitaxel and 14.3 months for docetaxel. This was around half that projected in the pembrolizumab model for a similar population. In response to consultation, the company explored the mean, median and 2-year survivorship in this submission and NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel. It explained that median survival demonstrated a high level of consistency in modelled short-term predictions. The exact numbers are considered academic in confidence by the company and cannot be reported here. The company explained that the end of life estimate for taxanes produced by the model should be considered an upper estimate of the mean survival for this very aggressive type of cancer. The ERG cautioned that the longer life expectancy shown in KEYNOTE-355 may be due to the study recruiting healthier patients. The committee considered that as the trial population is mainly younger people this could skew the estimates because they would have fewer co-morbidities, and possibly therefore live longer with their cancer. The committee considered the appeal outcome of NICE's technology appraisal guidance on avelumab, which stated that 'normally less than 24 months' allowed a committee discretion to apply end of life criteria even if it felt some measures of life expectancy may be over 24 months. Based on the percentage survival at 24 months in KEYNOTE-355, the real-world evidence and the observed and modelled medians, the committee concluded that survival is normally less than 24 months for the population treated with taxanes. Therefore, the committee accepted that the end of life criteria had been met. # Cost-effectiveness results ## Pembrolizumab combination is a cost-effective use of NHS resources As there are confidential commercial arrangements for pembrolizumab, nab-paclitaxel and post-progression therapies, the ICERs are confidential and cannot be reported here. The company addressed several of the committee's concerns in its response to consultation, including model validation and survival estimates. However, the committee noted the company's updated base case was not fully aligned with its preferences and instead considered the following ERG scenarios in its decision making: -verall-survival extrapolations based on the exponential function (see section 3.9) a 5‑year treatment benefit duration for pembrolizumab combination (see section 3.10) the inclusion of vial sharing (see section 3.11) utilities based on the time-to-death approach (see section 3.12).Taking into account all confidential discounts, the committee concluded that the cost-effectiveness estimates for pembrolizumab combination compared with paclitaxel and docetaxel were within the range NICE considers a cost-effective use of NHS resources. # Innovation ## Pembrolizumab combination improves the treatment options for TNBC Until recently, there have been limited treatment options for TNBC compared with other types of breast cancer. Pembrolizumab combination provides benefit for people with TNBC whose tumours express PD‑L1 with an IC of less than 1% and a CPS of 10 or more. The committee concluded that pembrolizumab combination has potential benefits for people with TNBC who cannot have atezolizumab combination, and that the health-related quality-of-life gains had been captured in the quality-adjusted life year calculations. # Conclusion Having concluded that pembrolizumab combination is a cost-effective use of NHS resources for tumours that express PD‑L1 with a CPS of 10 or more and an IC less than 1%, the committee recommended it for routine use in the NHS.	{'Recommendations': 'Pembrolizumab plus chemotherapy (paclitaxel or nab‑paclitaxel) is recommended as an option for treating triple‑negative, locally recurrent unresectable or metastatic breast cancer in adults who have not had chemotherapy for metastatic disease. It is recommended only if:\n\nthe tumours express PD‑L1 with a combined positive score (CPS) of\xa010 or more and an immune cell staining (IC) of less than 1%, and\n\nthe company provides pembrolizumab according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with pembrolizumab plus chemotherapy that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment for untreated, triple‑negative, locally recurrent unresectable or metastatic breast cancer includes chemotherapy such as docetaxel or paclitaxel, or atezolizumab plus nab‑paclitaxel immunotherapy (from now, atezolizumab combination). There is an unmet need for alternative treatments for people who cannot have atezolizumab combination. Pembrolizumab plus paclitaxel or nab‑paclitaxel (from now, pembrolizumab combination) is another immunotherapy that could be used. The company proposed pembrolizumab combination for people whose tumours express PD‑L1 with a CPS of\xa010 or more and an IC of less than 1%. This is narrower than the marketing authorisation and makes pembrolizumab combination an alternative treatment for people who cannot have atezolizumab combination.\n\nClinical trial evidence shows that, compared with paclitaxel, pembrolizumab combination increases how long people have before their cancer gets worse and how long they live.\n\nThe cost‑effectiveness estimates for pembrolizumab combination compared with both paclitaxel and docetaxel are within what NICE usually considers an acceptable use of NHS resources. Therefore, it is recommended.', 'Information about pembrolizumab': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, Merck Sharp and Dohme) has a marketing authorisation for use in combination with chemotherapy 'for the treatment of locally recurrent unresectable or metastatic triple‑negative breast cancer in adults whose tumours express PD‑L1 with a CPS more than or equal to 10 and who have not received prior chemotherapy for metastatic disease'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for pembrolizumab.\n\n# Price\n\nThe company's list price is £2,630 per 100‑mg solution for infusion vial (excluding VAT, BNF online accessed January 2022).\n\nThe company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Merck Sharp and Dohme, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need and treatment pathway\n\n## Triple‑negative breast cancer has a high disease burden\n\nSome breast cancers test negative for oestrogen and progesterone receptors (hormone receptor‑negative) and human epidermal growth factor receptor\xa02 (HER2‑negative). They are called triple‑negative and account for about 15% of all breast cancers. The patient expert explained that being diagnosed with locally recurrent unresectable or metastatic breast cancer is extremely difficult for people, and their family and friends. It can cause considerable anxiety and fear, and it can be very difficult to cope with the uncertainty of the outcome. People with locally recurrent unresectable and metastatic breast cancer must also organise their lives around hospital appointments, which restricts their everyday activities. There is no cure for metastatic breast cancer. Treatment aims to stop progression of the disease, extend life, and maintain or improve quality of life for as long as possible. The committee concluded that there is a high disease burden for people with triple‑negative breast cancer (TNBC).\n\n## There is a need for first‑line TNBC treatments, particularly for people who cannot have atezolizumab combination\n\nUntil recently, there were limited first‑line treatment options for people with triple‑negative, locally recurrent unresectable or metastatic breast cancer, especially compared with other types of breast cancer. Atezolizumab plus nab‑paclitaxel (from now, atezolizumab combination) is the only immunotherapy recommended by NICE for this condition (see NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel for untreated PD-L1-positive, locally advanced or metastatic, triple-negative breast cancer). Other first‑line treatment options for triple‑negative, locally recurrent unresectable or metastatic breast cancer are paclitaxel, docetaxel, nab‑paclitaxel, anthracycline‑based chemotherapy, or gemcitabine with or without carboplatin (see NICE's guideline on advanced breast cancer: diagnosis and treatment). The clinical expert explained that atezolizumab combination is an option for some people whose tumours express PD‑L1. However, they explained that some people would not be able to have atezolizumab combination but could have pembrolizumab plus paclitaxel or nab‑paclitaxel (from now, pembrolizumab combination). This is because the marketing authorisation for each treatment option includes a different measurement of PD‑L1 expression. The PD‑L1 expression for pembrolizumab combination is measured using combined positive score (CPS). However, in NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel, it is based on immune cell staining (IC). Both measurements use slightly different methods for measuring and calculating PD‑L1 expression. The company estimated that the overall percentage agreement between the 2\xa0measures is 75%. However, it also stated that there are some instances in which only 1 of the measurements would show PD‑L1 positivity. The clinical expert and Cancer Drugs Fund clinical lead explained that the measurement used would vary between hospital trusts. They explained that trusts are likely to adopt one measurement in the first instance and only use the other if the first did not show PD‑L1 positivity. The patient expert highlighted that, because of the differences in PD‑L1 measurements, there is an unmet need for immunotherapy for people who cannot have atezolizumab combination. They explained that pembrolizumab combination could be a critical option for these people. The committee concluded that there is an unmet need for immunotherapy for untreated, triple‑negative, locally recurrent unresectable or metastatic breast cancer, especially for people who cannot have atezolizumab combination.\n\n## Atezolizumab combination is not included as a comparator in the company's updated cost-effectiveness analyses, but additional testing costs need to be accounted for in the economic model\n\nIn its initial submission, the company included atezolizumab combination as a comparator. At the first committee meeting, the committee agreed atezolizumab combination was a relevant comparator for tumours that express PD‑L1 with an IC more than 1% and CPS of 10 or more. In its response to consultation, the company did not include a comparison with atezolizumab combination. Instead, the company submitted updated cost‑effectiveness results only for people whose tumours have an IC less than 1% and CPS of 10 or more. This is the group of people for whom atezolizumab combination is not indicated. The company explained that they chose to focus on this population because they recognised its high unmet need. It estimated this population would comprise approximately 17% of people with metastatic TNBC. The ERG highlighted that the removal of atezolizumab combination resulted in an underestimation of CPS and IC testing costs in the company model, because both tests would have to be done for some people. The Cancer Drugs Fund clinical lead explained that it will be difficult for pathology departments to do both tests and that the cost of both should be included in the economic model. The committee acknowledged the challenge for pathology departments with backlogs following the COVID‑19 pandemic but noted that NHS implementation is beyond its remit. The ERG also cautioned that the company assumed the efficacy data from the trial using a CPS of 10 or more is generalisable to the more limited population. It explained that this added additional uncertainty. The Cancer Drugs Fund clinical lead explained that it is unknown if the trial data from the population with a CPS of 10 or more is generalisable to the proposed population. Therefore, they agreed with the ERG that it would have to be treated as an uncertainty. The committee agreed that the population the company had focused on had the greatest unmet need, but that increased testing costs would need to be accounted for in the economic model.\n\n## The relevant comparators are paclitaxel and docetaxel\n\nIn its initial submission, the company used paclitaxel as its base‑case comparator, docetaxel as a secondary comparator, and did not include gemcitabine with or without carboplatin or nab-paclitaxel. The clinical expert agreed that gemcitabine with or without carboplatin and nab‑paclitaxel were not relevant comparators. Gemcitabine with or without carboplatin is not widely used in the NHS, especially as a first‑line treatment for metastatic disease. This is because it is difficult to administer and has a high toxicity. The clinical expert and Cancer Drugs Fund clinical lead also explained that nab‑paclitaxel is rarely used in the NHS because of its cost. However, there is currently some use of nab‑paclitaxel because access has been given during COVID‑19. Also, because of recent resource pressures in the NHS, docetaxel is being used more often. This is because docetaxel and nab‑paclitaxel are given at 3‑weekly intervals, compared with paclitaxel, which is usually given weekly. The company explained that docetaxel is not relevant as a primary comparator because it is used at earlier stages of breast cancer and has a less favourable safety profile than paclitaxel. The committee recalled that docetaxel was not considered a relevant comparator in NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel. However, the Cancer Drugs Fund clinical lead explained the recent resource pressures that have resulted in the move to docetaxel use are likely to remain in chemotherapy units post‑COVID‑19 pressures. The clinical expert also noted that docetaxel would not be used if someone had had it before, but that a substantial and increasing number of people would be able to have it. In its response to consultation, the company explained that pembrolizumab combination is disadvantaged by using docetaxel as a comparator. This is because the company assumed docetaxel has the same efficacy as paclitaxel despite docetaxel having a worse safety profile and potentially a shorter treatment response. As an alternative, the company presented a blended comparator cost-effectiveness estimate where it assumed 70% of people are treated with paclitaxel and 30% of people are treated with docetaxel. This was estimated using clinical opinion and KEYNOTE-355 data. The Cancer Drugs Fund clinical lead explained that the ratio of paclitaxel to docetaxel use is continually changing because chemotherapy units are trying to minimise the number of visits people make. He estimated approximately 50% of people would be treated with paclitaxel and 50% of people would be treated with docetaxel. The ERG explained it preferred a fully incremental analysis where the 3 treatments were ranked individually rather than a blend of 2 comparators because it can improve the efficient allocation of resources. It also noted that it would have preferred the toxicity and potentially shorter treatment duration of docetaxel to have been included in the economic model, instead of a blend of 2 comparators assumed to be the same apart from cost. The committee acknowledged the blended comparator estimates but noted that a fully incremental analysis against paclitaxel and docetaxel was more methodologically robust. The committee concluded the blended comparator cost‑effectiveness estimate was not appropriate. It also concluded that the relevant comparators are paclitaxel and docetaxel but that the cost‑effectiveness estimates compared with docetaxel are potentially unfavourable to pembrolizumab combination. This was because of the company assumption that paclitaxel and docetaxel have the same efficacy.\n\n# Clinical evidence\n\n## KEYNOTE‑355 trial data excluding gemcitabine is appropriate for decision making\n\nThe clinical evidence was based on KEYNOTE‑355, a randomised double‑blind placebo‑controlled active‑comparator trial in people with untreated, triple‑negative, locally recurrent unresectable or metastatic breast cancer. The trial protocol was updated to only include TNBC with a CPS of\xa010 or more, which is in line with the marketing authorisation. Chemotherapies included in the trial, either with pembrolizumab or placebo, were nab‑paclitaxel, paclitaxel or gemcitabine plus carboplatin. Most (57%) people had gemcitabine plus carboplatin in KEYNOTE‑355, but the company excluded this clinical trial data in the clinical and economic analysis. It only included the population who had a taxane (that is, paclitaxel or nab‑paclitaxel). The company excluded the gemcitabine plus carboplatin data because this treatment would not be expected to be used in the UK. The committee recalled its conclusion that gemcitabine was not a relevant comparator (see section\xa03.4). The ERG noted that the baseline characteristics were stratified by chemotherapy combinations, so randomisation was not broken when the gemcitabine data was removed for the economic analysis. The committee recalled that the company assumed the trial data for CPS of 10 or more was generalisable to the proposed population (see section 3.3). The committee concluded the trial data, excluding gemcitabine with or without carboplatin, was appropriate for decision making.\n\n## Pembrolizumab combination is more effective than paclitaxel or nab‑paclitaxel\n\nThe trial results showed a consistent clinically meaningful and statistically significant benefit for pembrolizumab combination compared with taxanes alone for both progression‑free survival (exact progression‑free survival results are considered confidential by the company and cannot be reported here) and overall survival. The hazard ratio for overall survival was 0.54 (95% confidence interval 0.36 to 0.82). The committee noted the long‑term benefit of pembrolizumab combination was uncertain. In response to consultation, the company provided additional explanations and clinical opinion to demonstrate the long‑term benefit of pembrolizumab combination. The company clinical experts estimated 20% survival at year\xa05 and 10% survival at year\xa010 for those having pembrolizumab combination. By contrast, they estimated survival of 10% at year\xa05 and 0% at year\xa010 for those having paclitaxel or docetaxel. The committee concluded that pembrolizumab combination is more effective than taxanes.\n\n# Indirect treatment comparison\n\n## The comparison with atezolizumab combination using a network meta‑analysis is no longer needed for decision making\n\nIn the company's initial submission, atezolizumab combination was a secondary comparator. There is no head‑to‑head evidence comparing pembrolizumab combination with atezolizumab combination. Therefore, the company did a network meta‑analysis to allow for an indirect treatment comparison. The company presented the results of the fixed‑effect network meta‑analysis because of the small number of studies in the network, which meant the between study heterogeneity could not be estimated. The point estimates favoured pembrolizumab combination but had wide credible intervals that crossed 1, meaning that the results were not statistically significant. The ERG considered that the network meta‑analysis had limitations because of heterogeneity between trials and would have preferred a random‑effects model. In response to consultation, the company removed atezolizumab combination as a comparator because it proposed that pembrolizumab should be used in a population for which atezolizumab was not indicated (IC less than 1% and CPS of 10 or more). The committee concluded the network meta‑analysis results were no longer needed for decision making in this population.\n\n# Cost‑effectiveness evidence\n\n## The company's economic model uses a standard approach\n\nThe company submitted a partitioned survival model to estimate the cost effectiveness of pembrolizumab combination compared with paclitaxel, docetaxel and atezolizumab combination. It had 3\xa0health states: progression‑free survival, post‑progression survival and death. The committee considered that the partitioned survival model is a standard approach to estimate the cost effectiveness of cancer drugs.\n\n## Exponential distribution for extrapolating overall survival better fitted the smoothed hazard plot for the pembrolizumab arm\n\nThe company chose a log‑normal model for pembrolizumab combination and a log‑logistic model for paclitaxel to extrapolate overall survival. It chose these curves based on goodness‑of‑fit statistics, clinical plausibility of long‑term extrapolations and validity of long‑term projections. The ERG agreed with the company's choice of log‑logistic extrapolation for paclitaxel but preferred an exponential model for pembrolizumab combination. It explained that the goodness‑of‑fit statistics between the exponential and log‑normal models both corresponded with the observed data. It noted that the log‑normal distribution showed a turning point within the first year, but the smoothed hazard plot of the observed data did not show a turning point in the underlying hazard. The exponential distribution did not have a turning point. Using the exponential distribution resulted in a substantial increase in the incremental cost‑effectiveness ratio (ICER). The company disagreed with the choice of an exponential distribution. It stated that this was overly simple and assumed a constant hazard that was not seen in the trial. In response to consultation, the company further cautioned against over‑interpreting smoothed hazard plots. The company explained that the lack of turning point could be because of the method used to generate the 'smoothed' hazard plot or the small sample size. It highlighted that NICE Decision Support Unit technical support document 14 states goodness‑of‑fit should not be measured by hazard plots but instead by using the survival curves. The ERG maintained its view that the exponential is the most appropriate extrapolation. It explained the constant hazard is in keeping with the observed hazards from KEYNOTE‑355 and that the lack of observed turning point could be because there is no turning in the true distribution. The committee concluded that both extrapolations broadly fitted the data, but that the exponential distribution better fitted the smoothed hazard plot.\n\n## The duration of benefit for pembrolizumab combination should include an assumption that the treatment effect wanes after stopping treatment\n\nIn KEYNOTE‑355, treatment was stopped after about 2\xa0years. A stopping rule was not included in the marketing authorisation, but the company assumed a stopping rule would apply in line with the trial. The company assumed that, despite stopping treatment after a maximum of 2\xa0years, the treatment benefit would be maintained for a lifetime horizon. It explained that this was because the unique mode of action of pembrolizumab results in an extended period of benefit after treatment has stopped. Also, KEYNOTE‑355 showed no evidence of treatment benefit decreasing over the median follow-up duration (the exact follow-up period is considered confidential by the company and cannot be reported here). The company highlighted that, in NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel, a treatment waning effect was considered inappropriate. The committee recalled that, in this appraisal, there was no stopping rule and people could continue to have atezolizumab combination beyond 2\xa0years. The ERG explained a lifetime treatment benefit created the possibility that 2\xa0people alive at year\xa07 on third-line treatment would have different chances of death depending on their first course of treatment. The committee considered that this was implausible and noted that, in some people who had pembrolizumab combination in the trial, their cancer still progressed after 2\xa0years. The ERG also noted that subsequent treatment use from KEYNOTE‑355 showed that many people moved on to second-line treatment. Also, some people moved on to third- and fourth-line treatment during the trial follow-up period. The ERG preferred a total treatment benefit duration of 5\xa0years (3\xa0years after treatment is stopped). It explained that KEYNOTE‑355 did not provide long-term data to support a lifetime treatment benefit. This increased the ICER of pembrolizumab combination compared with all comparators. The committee noted a 5-year treatment effect had been used in previous appraisals of immuno-oncology drugs when a stopping rule applied. In response to consultation, the company explained that an abrupt treatment-effect stop at a specific timepoint, as suggested by the ERG, was not clinically plausible. The company therefore presented an alternative scenario using the Surveillance, Epidemiology and End Results (SEER) program. This assumed a constant hazard rate for 4\xa0years across both pembrolizumab combination and taxanes, which results in gradual treatment waning adjustments being made from 4\xa0years onwards using the SEER data. The ERG explained that the SEER program is a US database that is unlikely to include a large proportion of patients treated with pembrolizumab combination. It also explained that this method of waning lacks face validity because the cost-effectiveness estimates decreased compared with no treatment waning. The committee concluded that there is a lack of clear evidence to predict a precise waning of effect. But a waning effect had been assumed in previous appraisals and was more plausible than a continuing effect long after treatment was stopped, even if the disease had progressed. It concluded that a 5‑year treatment effect combined with the 2‑year stopping rule was appropriate for pembrolizumab combination.\n\n## Vial sharing should be included in the analysis\n\nThe company included vial sharing for intravenous drugs but not pembrolizumab in its base case. Pembrolizumab is given in fixed doses, so vial sharing does not apply. It understood that vial sharing would be routine practice to minimise drug wastage of intravenous drugs. The ERG did not include vial sharing in its model, which had a small upward effect on the ICER. The clinical expert and Cancer Drugs Fund clinical lead explained that vial sharing does happen in clinical practice and is particularly encouraged for expensive chemotherapies. The committee concluded that vial sharing should be included in the analysis.\n\n## Using the time-to-death approach to estimate utilities is appropriate\n\nThe company used 2\xa0methods to estimate utility in the economic model: the time-to-death approach and the health-state approach. The time-to-death approach categorises utility based on the length of time before death. The health-state approach categorises utilities based on the health states in the model (progression-free survival, post-progression and death). The company's base case used the time-to-death approach, but the company stated that it did not have a preference for which approach should be used. It explained that it chose the time-to-death approach because it is most appropriate based on the aggressiveness of TNBC and had been used in other NICE appraisals. The ERG noted both methods have their limitations. It explained that neither approach overcomes the main limitation that the data collected has been heavily censored, either at the point of progression, or at treatment discontinuation. The ERG also stated that it had no preference for which approach was used. However, it noted that the health-state approach consistently had slightly higher ICERs than the time-to-death approach. The committee concluded that both approaches were acceptable, but that it would consider the time-to-death approach in its decision making, based on the aggressiveness of TNBC.\n\n## The economic model is suitable for decision making\n\nWhen considering the end of life criteria, the committee recalled that the life expectancy in NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel was around half that projected in the pembrolizumab model for a similar population (see section 3.14). The committee therefore questioned the validity of the company's pembrolizumab model results and whether they were suitable for decision making. In its response to consultation, the company explained that these differences could be due to differences in trial design, population characteristics and alternative survival extrapolation assumptions. The company also used published studies and clinical opinion to validate survival predictions in the economic model. Median overall survival in the published studies ranged from 14.3\xa0months to 21.3\xa0months. The percentage of survivors at 2\xa0years in the real-world evidence ranged from 12.1% to 36.58%. Overall survival and percentage survivorship from KEYNOTE-355 and the economic model are considered confidential by the company so cannot be reported here. It concluded that the model accurately predicts short- to medium-term taxane overall-survival projections and longer-term overall survival based on a 12-year study. The committee concluded that the economic model was suitable for decision making.\n\n# End of life\n\n## Pembrolizumab combination meets end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The ERG agreed with the company that the extension-to-life criterion was met for pembrolizumab combination compared with taxanes. The ERG disagreed with the company that the short life-expectancy criterion was met. The company's base-case model estimated that the mean life expectancy was longer than 24.0\xa0months for taxanes at 27.7\xa0months, atezolizumab combination at 30.4\xa0months and pembrolizumab combination at 54.5\xa0months. The committee also considered overall survival at 24.0\xa0months in KEYNOTE‑355 to assess whether the short life-expectancy criterion was met. It appreciated that a large proportion of people in the placebo arm had an overall survival of less than 24.0\xa0months. The exact overall-survival numbers are considered confidential by the company and cannot be reported here. The clinical expert explained that, in some people, there is a prolonged response to standard therapies. The committee appreciated that, when the whole population was modelled over a lifetime horizon (not just over the trial follow up), having people who survived a long time would make the mean estimates higher than the median in the trial. The committee noted that this effect would apply to all survival estimates, including the treatment arm. This meant that the mean modelled overall survival in the treatment arm would also be longer than might be predicted based on the Kaplan–Meier curves, in this case 54.5\xa0months. The committee was aware that all sources of evidence should be considered. It also recalled that the short life-expectancy criterion was met in NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel. The life-expectancy estimates in the modelling in that appraisal were 13.8\xa0months for paclitaxel and 14.3\xa0months for docetaxel. This was around half that projected in the pembrolizumab model for a similar population. In response to consultation, the company explored the mean, median and 2-year survivorship in this submission and NICE's technology appraisal guidance on atezolizumab with nab-paclitaxel. It explained that median survival demonstrated a high level of consistency in modelled short-term predictions. The exact numbers are considered academic in confidence by the company and cannot be reported here. The company explained that the end of life estimate for taxanes produced by the model should be considered an upper estimate of the mean survival for this very aggressive type of cancer. The ERG cautioned that the longer life expectancy shown in KEYNOTE-355 may be due to the study recruiting healthier patients. The committee considered that as the trial population is mainly younger people this could skew the estimates because they would have fewer co-morbidities, and possibly therefore live longer with their cancer. The committee considered the appeal outcome of NICE's technology appraisal guidance on avelumab, which stated that 'normally less than 24\xa0months' allowed a committee discretion to apply end of life criteria even if it felt some measures of life expectancy may be over 24\xa0months. Based on the percentage survival at 24\xa0months in KEYNOTE-355, the real-world evidence and the observed and modelled medians, the committee concluded that survival is normally less than 24\xa0months for the population treated with taxanes. Therefore, the committee accepted that the end of life criteria had been met.\n\n# Cost-effectiveness results\n\n## Pembrolizumab combination is a cost-effective use of NHS resources\n\nAs there are confidential commercial arrangements for pembrolizumab, nab-paclitaxel and post-progression therapies, the ICERs are confidential and cannot be reported here. The company addressed several of the committee's concerns in its response to consultation, including model validation and survival estimates. However, the committee noted the company's updated base case was not fully aligned with its preferences and instead considered the following ERG scenarios in its decision making:\n\noverall-survival extrapolations based on the exponential function (see section\xa03.9)\n\na 5‑year treatment benefit duration for pembrolizumab combination (see section\xa03.10)\n\nthe inclusion of vial sharing (see section\xa03.11)\n\nutilities based on the time-to-death approach (see section\xa03.12).Taking into account all confidential discounts, the committee concluded that the cost-effectiveness estimates for pembrolizumab combination compared with paclitaxel and docetaxel were within the range NICE considers a cost-effective use of NHS resources.\n\n# Innovation\n\n## Pembrolizumab combination improves the treatment options for TNBC\n\nUntil recently, there have been limited treatment options for TNBC compared with other types of breast cancer. Pembrolizumab combination provides benefit for people with TNBC whose tumours express PD‑L1 with an IC of less than 1% and a CPS of\xa010 or more. The committee concluded that pembrolizumab combination has potential benefits for people with TNBC who cannot have atezolizumab combination, and that the health-related quality-of-life gains had been captured in the quality-adjusted life year calculations.\n\n# Conclusion\n\nHaving concluded that pembrolizumab combination is a cost-effective use of NHS resources for tumours that express PD‑L1 with a CPS of 10 or more and an IC less than 1%, the committee recommended it for routine use in the NHS."}	https://www.nice.org.uk/guidance/ta801	Evidence-based recommendations on pembrolizumab (Keytruda) with paclitaxel or nab‑paclitaxel for triple-negative, locally recurrent unresectable or metastatic breast cancer in adults who have not had chemotherapy for metastatic disease.
86956d81afc9599dc89013197972120dd7965e6d	nice	Cemiplimab for treating advanced cutaneous squamous cell carcinoma	Cemiplimab for treating advanced cutaneous squamous cell carcinoma Evidence-based recommendations on cemiplimab (Libtayo) for metastatic or locally advanced cutaneous squamous cell carcinoma in adults. # Recommendations Cemiplimab is recommended as an option for treating metastatic or locally advanced cutaneous squamous cell carcinoma in adults when curative surgery or curative radiotherapy is not suitable, only if: it is stopped at 24 months, or earlier if their disease progresses, and the company provides cemiplimab according to the commercial arrangement. Why the committee made these recommendations This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund for cemiplimab for treating metastatic or locally advanced cutaneous squamous cell carcinoma (NICE technology appraisal guidance TA592). Standard care for people with advanced cutaneous squamous cell carcinoma is best supportive care so there is a need for effective and well-tolerated treatment options. The new clinical evidence includes additional data from a clinical trial and from people having cemiplimab in the NHS while it was available in the Cancer Drugs Fund. People in the clinical trial and Cancer Drugs Fund followed a stopping rule which meant they stopped treatment at 22 months and 24 months respectively, or earlier if their disease progressed. There are no trials directly comparing cemiplimab with best supportive care. But an indirect comparison suggests that people taking cemiplimab are likely to live longer than people having best supportive care. There is still not enough data from the Cancer Drugs Fund and the trial to be certain by how much cemiplimab increases the length of time people live. Because of the uncertainty with the clinical data, the cost-effectiveness estimates are also uncertain. The life expectancy of people with advanced cutaneous squamous cell carcinoma receiving best supportive care, and the evidence for how long life might be extended with cemiplimab, meet the end of life criteria. Therefore, the most likely cost-effectiveness estimates fall within what NICE considers an acceptable use of NHS resources. So, cemiplimab is recommended for routine use.# Information about cemiplimab # Conditional marketing authorisation indication Cemiplimab (Libtayo, Sanofi) 'as monotherapy is indicated for the treatment of adult patients with metastatic or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for cemiplimab. # Price The list price for cemiplimab is £4,650 per 350 mg vial (excluding VAT; BNF online accessed April 2022). The cost per course of treatment is £4,650. The cost for 1 year of treatment with cemiplimab based on the list price is £80,877. The company has a commercial arrangement. This makes cemiplimab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by the company, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. This review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. Data was collected on the use of cemiplimab in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset. As a condition of the Cancer Drugs Fund's managed access agreement, the company was required to collect updated efficacy data from the EMPOWER-CSCC 1 study for people with metastatic or locally advanced cutaneous squamous cell carcinoma. The company also collected data on the effectiveness of treatment with platinum-based chemotherapy and with best supportive care in the UK through a retrospective chart review. # Clinical need and current management ## Living with advanced unresectable cutaneous squamous cell carcinoma is physically and emotionally challenging Cutaneous squamous cell carcinoma (CSCC) is a distinct disease that differs from malignant melanoma and other squamous cell carcinomas such as primary head and neck or lung squamous cell carcinoma. Risk factors include exposure to ultraviolet radiation, increasing age, and immunosuppression. Early CSCC can be cured in most people, but in a small proportion of people the disease reaches an advanced state (metastatic or locally advanced) that cannot be removed with surgery (unresectable) or cured with radiotherapy. Often, people with advanced disease are older, have other comorbidities, and have a poor prognosis. The skin lesions can grow to be quite large and the disease can spread to different parts of the body. Because of the link with ultraviolet exposure, the lesions often develop on parts of the body that are visible, such as the face. The patient expert described how advanced CSCC can be extremely debilitating because it can result in unpleasant foul-smelling wounds. Living with advanced unresectable CSCC is challenging and, because of the visibility of the disease, it often results in people avoiding social interaction. Caring for a person with CSCC can be physically and emotionally draining. The committee concluded that living with advanced unresectable CSCC is physically and emotionally challenging for both people with the disease and their carers. ## Best supportive care is the most appropriate comparator The company presented clinical and cost-effectiveness evidence for cemiplimab compared with platinum-based chemotherapy and best supportive care. The clinical experts stated that very few people aged over 70 would be offered platinum-based chemotherapy in the NHS, because of its side effects and lack of clinical benefit. People with advanced CSCC are typically older, and therefore are less likely to be able to tolerate platinum-based chemotherapy. The committee heard from the NHS England expert that in the SACT dataset 75% of people were aged 70 and above and 36% were aged 80 and above. The clinical experts stated that in their experience, the number of people who receive chemotherapy is less than 5%, and probably less than 2%. The patient expert stated that there are limited treatment options for this patient group, very few patients are offered radiotherapy and this rarely works. Therefore, treatment for most people with advanced unresectable CSCC is limited to best supportive care. The committee agreed that platinum-based chemotherapy is not routinely used for treating advanced unresectable CSCC in the NHS and therefore concluded that best supportive care is the most appropriate comparator for this appraisal. ## Cemiplimab is a highly valued and well tolerated treatment option for people with advanced unresectable CSCC The clinical and patient experts described the substantial burden of advanced unresectable CSCC on quality of life and the lack of current treatment options. One clinical expert emphasised that because local disease can result in large, fungating tumours, it is particularly important to also consider progression-free survival when assessing the benefits of cemiplimab. The committee also heard that people who respond to cemiplimab can experience substantial benefits, that tumours shrink, and some people remain disease free for 2 years. In addition, the committee heard that single agent immunotherapies are generally well tolerated, including in older people. One of the clinical experts stated that the most common side effects of cemiplimab are fatigue and rashes, which can be easily resolved. Some people can experience more serious autoimmune side effects. These are generally manageable and can be resolved with high-dose steroids or by having a treatment break. The committee noted cemiplimab's benefits for those who respond and concluded that cemiplimab is a highly valued treatment option for people with advanced unresectable CSCC. # Clinical evidence ## Trial data for cemiplimab is promising but it has not been directly compared with other treatments Data on response and survival outcomes for cemiplimab was reported in 2 single-arm trials: a phase 1 trial and an ongoing phase 2 trial known as EMPOWER-CSCC 1. The phase 1 trial included 26 people with metastatic and locally advanced CSCC who had a cemiplimab dose of 3 mg per kg every 2 weeks for up to 48 weeks. In EMPOWER-CSCC 1, two groups of people had a cemiplimab dose of 3 mg per kg every 2 weeks with a stopping rule which stopped treatment at 96 weeks (22 months), or sooner if disease progressed. One of the groups had metastatic CSCC (59 people) and the other had locally advanced CSCC (78 people). A third group of 56 people with metastatic CSCC had the licensed cemiplimab dose of 350 mg every 3 weeks, with a stopping rule of up to 54 weeks, or sooner if disease progressed. The results were consistent between groups and the company presented this data pooled together in a base-case integrated analysis population. Across the 219 people included in the pooled company trials, 40% had locally advanced disease and 60% had metastatic disease. The median age was 72 years and 83% of people were male. All the people in the company trials had an Eastern Cooperative Group (ECOG) performance status of 0 (44% of people) or 1 (56% of people). At the October 2019 data cut-off for EMPOWER-CSCC 1, the objective response rate was 46.1% (95% confidence interval 38.9% to 53.4%) and median overall survival had not been reached after a median follow up of 15.7 months. The company submitted the results from the most recent data cut in July 2021, however these are academic in confidence and cannot be presented in full here. Median overall survival had not been reached at the July 2021 data cut-off. The committee concluded that the trial data for cemiplimab is promising because of the response rate seen in the trial population, but it has not been compared with other treatments, and the long-term overall survival benefit is uncertain. ## There are differences between the cemiplimab trial data and SACT dataset, so there is uncertainty about whether the cemiplimab trial results are generalisable to UK clinical practice Through the Cancer Drugs Fund, SACT data was collected from people having a cemiplimab dose of 350 mg every 3 weeks for metastatic or locally advanced CSCC in UK clinical practice. Between 2 July 2019 and 1 March 2021, 352 people had cemiplimab with a stopping rule of up to 24 months, or sooner if disease progressed, with a median follow up of 10.2 months. People in the SACT dataset had a median age of 77 years, 81% had an ECOG performance status score of 0 or 1, and 49% of people had locally advanced disease. Median overall survival in the SACT population was 21 months. The ERG noted that people in the SACT dataset were older than in the company trials and that overall survival was lower. Therefore the ERG expressed concerns about the generalisability of the company trials to UK clinical practice. The company stated that the SACT data shows that older and sicker patients could be treated with cemiplimab. The company also highlighted that there are limitations with the SACT dataset, including the unknown impact of the COVID-19 pandemic, limited information on patient characteristics and the shorter follow up compared with the company trials. The company stated that this makes it difficult to determine the generalisability of the company trials to UK practice using the SACT dataset. The clinical experts explained that clinical trials typically include a more selected population in terms of age and fitness, therefore results are expected to be more favourable than in clinical practice. In addition, it is likely that the COVID-19 pandemic impacted treatment with cemiplimab in the SACT dataset, for example, through missed doses, people presenting later in the disease course and mortality because of COVID-19. However, the extent of the impact of the COVID-19 pandemic is unknown, resulting in additional uncertainty. The clinical experts also stated that the SACT dataset is immature and included people treated by clinicians with little or no experience of using cemiplimab. The clinical experts expected that clinical outcomes with cemiplimab would improve as clinicians become more experienced and learn who should be treated with cemiplimab and when to start treatment. The committee discussed whether the lower overall survival in the SACT dataset than in the trial population may be because of the reduced life expectancy of the older population in the SACT dataset. It discussed the possibility of more deaths from non-cancer causes, but noted that this was uncertain because the SACT data does not include cause of death, and neither the SACT data nor the company clinical trials included comparator arms. The committee agreed that there were differences in the patient characteristics and the outcomes between the clinical trials and the SACT dataset and concluded that it was uncertain whether the cemiplimab clinical trial results are generalisable to UK clinical practice. ## The overall survival estimates with best supportive care are very uncertain Comparator data in advanced CSCC is extremely limited. Because chemotherapy is not considered to be a relevant comparator for this appraisal (see section 3.2), only the evidence for best supportive care is discussed here. The company conducted a retrospective chart review to address the lack of comparative evidence that was highlighted during the original appraisal. The chart review was done between 1 January 2011 and 31 December 2015 and included 106 people with metastatic or locally advanced CSCC in the UK. However, both the company and the ERG agreed that the chart review lacks face validity, because of concerns about the comparability of the chart review population and the EMPOWER-CSCC 1 population. Also, the population characteristics and results were highly uncertain. In addition, very few people included in the chart review had CSCC that was eligible for best supportive care. Therefore, the analysis was limited to people receiving chemotherapy, which was not considered to be a relevant comparator by the committee. In the company's base-case analysis, the estimates for the clinical effectiveness of best supportive care were based on evidence from a non-UK retrospective chart review (Sun et al. 2019). Data was used from a subset of 20 non-immunocompromised people with unresectable head and neck CSCC. Patient characteristics were not reported for this specific subset, however patient characteristics of the wider study population were generally similar to the cemiplimab trials. The median overall survival in the subset of non-immunocompromised people receiving best supportive care was 5 months. A committee member suggested that these reviews may reflect clinical practice better than a clinical trial. However, the company explained that the estimates of survival for best supportive care from the Sun et al. chart review are likely to be more favourable than in clinical practice. This is because the Sun et al. study included a highly selected population who were treated in academic treatment centres. The ERG agreed that the study population was highly selected and noted that the results are very uncertain because of the small study population. The clinical expert explained that there is a lack of survival data for people with advanced CSCC, partly because the lack of treatment options means that people are usually discharged back to primary care and are not followed up in the hospital setting. The committee concluded that the estimates of survival with best supportive care are very uncertain. # Indirect comparisons ## None of the indirect comparisons provide a reliable estimate of cemiplimab's effectiveness There are no available studies directly comparing cemiplimab with best supportive care, so the company did an indirect treatment comparison (ITC). For the comparison of cemiplimab with best supportive care the company explored 2 ITC methods: a simulated treatment comparison (STC) and a matching-adjusted indirect comparison (MAIC). The company also presented the results of a naive comparison, which fitted survival extrapolations directly to the observed data. The results from all 3 methods suggest that people who had cemiplimab had a longer overall survival than people who had best supportive care. The ERG noted that the company's approach to the ITC was systematic and in line with the recommendations in the technical support document published by the Decision Support Unit. The committee noted that the ITC is based on comparator data that is considered highly uncertain and concluded that none of the indirect comparisons provide a reliable estimate of relative effectiveness. However, the committee agreed that it was likely that cemiplimab extended survival compared with best supportive care. # The company's economic model ## The company model is suitable for decision-making As in the original appraisal, the company modelled cost effectiveness using a partitioned survival model with 3 health states (pre-progression, post-progression and death). The model had a 30‑year time horizon and a monthly cycle length with a half-cycle correction. A 2‑year stopping rule was applied for cemiplimab which is similar to the 22‑month stopping rule applied for 2 of the groups in the EMPOWER-CSCC 1 study (see section 3.4) and was agreed in TA592. The company extended the assumed duration of effectiveness of cemiplimab from the original appraisal to align with the longer duration of follow up from EMPOWER-CSCC 1 and updated the quality-of-life data with the most recent data cut. The company model used the baseline characteristics from the company trials in its base case. However, after technical engagement, the company updated the baseline characteristics to those from the SACT dataset. This aligned with the ERG's preference, as this reflects the population who had cemiplimab in NHS practice. The company presented cost-effectiveness estimates for cemiplimab compared with chemotherapy and best supportive care. However, because best supportive care was agreed as the most appropriate comparator in this appraisal (see section 3.2), the cost-effectiveness results for cemiplimab compared with chemotherapy were not discussed further. The committee concluded that the company model is suitable for decision-making. ## Survival extrapolations for cemiplimab and best supportive care are highly uncertain, but cemiplimab is likely to extend survival The ERG noted that there is a high degree of uncertainty in the survival extrapolations for cemiplimab and best supportive care, because of limitations in the data (see sections 3.4 to 3.6). The committee noted that the ERG used the same survival extrapolations as the company in its base case, and explored a range of alternative extrapolations in scenario analyses. The committee was not presented with the SACT overall survival Kaplan–Meier data for comparison against the results from the company's trials and the modelled extrapolations. The committee noted that overall survival data from the SACT dataset has been used in economic modelling in other appraisals. The committee agreed that a scenario analysis using the overall survival estimates from the SACT Kaplan–Meier curve would have been helpful to quantify the uncertainty of the survival estimates for cemiplimab, given the lower overall survival in the SACT dataset than in the clinical trials. The committee concluded that the survival extrapolations for cemiplimab and best supportive care are highly uncertain. However, despite the uncertainties, the committee agreed that it was likely that cemiplimab did extend survival, although the extent to which is uncertain. # End of life ## Cemiplimab for advanced unresectable CSCC meets the end of life criteria The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the company's and ERG's base-case analysis, the mean life expectancy for people receiving best supportive care was 1.42 life years. The committee also noted that the median life expectancy of people receiving best supportive care in the Sun et al. (2019) study was 5 months. The committee was satisfied that the life expectancy in this population was less than 24 months, despite the uncertainty in the evidence base for best supportive care. It was also satisfied that cemiplimab offers at least a 3‑month life extension, based on the evidence from the SACT dataset and the clinical trials, despite the uncertainties. Therefore, the committee concluded that cemiplimab for advanced CSCC that cannot be removed with surgery (unresectable) or cured with radiotherapy meets the end of life criteria. # Cost-effectiveness estimates ## The cost-effectiveness estimates for cemiplimab are uncertain but are likely to fall within what NICE considers an acceptable use of NHS resources At technical engagement, the company accepted the ERG's preferred assumptions in its base case. Both the company's and the ERG's base-case incremental cost-effectiveness ratio (ICER) for cemiplimab compared with best supportive care was £30,952 per quality-adjusted life year (QALY) gained. All the ICERs from the company and ERG scenario analyses were lower than £50,000 per QALY gained. The committee noted the significant uncertainty around the clinical effectiveness of cemiplimab in the NHS (see section 3.5) and that overall survival from the SACT dataset had not been used in the economic modelling (see section 3.9). The committee was also aware of the substantial uncertainty surrounding the comparator data for best supportive care and the indirect comparison (see sections 3.6 and 3.7). The committee considered its conclusion that the end of life criteria were met for cemiplimab. Because of the high level of uncertainty in the clinical evidence, the committee agreed that an acceptable ICER should be towards the lower end of the range normally considered a cost-effective use of NHS resources. Taking all of this into account, the committee concluded that cemiplimab was an acceptable use of NHS resources. # Other issues ## Innovation Cemiplimab is considered innovative because it potentially provides a new treatment option for people who currently have limited access to any life-extending treatment. Cemiplimab is therefore considered a step-change in the treatment of advanced CSCC that cannot be removed with surgery or cured with radiotherapy. ## Equalities No equality issues were identified. # Conclusion ## Cemiplimab is recommended for routine use The committee concluded that, while there is significant uncertainty in the survival estimates for cemiplimab and best supportive care, the most likely cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. Therefore, cemiplimab is recommend as an option for treating metastatic or locally advanced cutaneous squamous cell carcinoma in adults when curative surgery or curative radiotherapy is not appropriate, if it is stopped at 24 months, or earlier if disease progresses.	{'Recommendations': 'Cemiplimab is recommended as an option for treating metastatic or locally advanced cutaneous squamous cell carcinoma in adults when curative surgery or curative radiotherapy is not suitable, only if:\n\nit is stopped at 24\xa0months, or earlier if their disease progresses, and\n\nthe company provides cemiplimab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund for cemiplimab for treating metastatic or locally advanced cutaneous squamous cell carcinoma (NICE technology appraisal guidance TA592).\n\nStandard care for people with advanced cutaneous squamous cell carcinoma is best supportive care so there is a need for effective and well-tolerated treatment options.\n\nThe new clinical evidence includes additional data from a clinical trial and from people having cemiplimab in the NHS while it was available in the Cancer Drugs Fund. People in the clinical trial and Cancer Drugs Fund followed a stopping rule which meant they stopped treatment at 22\xa0months and 24\xa0months respectively, or earlier if their disease progressed. There are no trials directly comparing cemiplimab with best supportive care. But an indirect comparison suggests that people taking cemiplimab are likely to live longer than people having best supportive care. There is still not enough data from the Cancer Drugs Fund and the trial to be certain by how much cemiplimab increases the length of time people live.\n\nBecause of the uncertainty with the clinical data, the cost-effectiveness estimates are also uncertain. The life expectancy of people with advanced cutaneous squamous cell carcinoma receiving best supportive care, and the evidence for how long life might be extended with cemiplimab, meet the end of life criteria. Therefore, the most likely cost-effectiveness estimates fall within what NICE considers an acceptable use of NHS resources. So, cemiplimab is recommended for routine use.', 'Information about cemiplimab': "# Conditional marketing authorisation indication\n\nCemiplimab (Libtayo, Sanofi) 'as monotherapy is indicated for the treatment of adult patients with metastatic or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for cemiplimab.\n\n# Price\n\nThe list price for cemiplimab is £4,650 per 350\xa0mg vial (excluding VAT; BNF online accessed April 2022). The cost per course of treatment is £4,650. The cost for 1 year of treatment with cemiplimab based on the list price is £80,877.\n\nThe company has a commercial arrangement. This makes cemiplimab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by the company, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThis review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. Data was collected on the use of cemiplimab in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset. As a condition of the Cancer Drugs Fund's managed access agreement, the company was required to collect updated efficacy data from the EMPOWER-CSCC\xa01 study for people with metastatic or locally advanced cutaneous squamous cell carcinoma. The company also collected data on the effectiveness of treatment with platinum-based chemotherapy and with best supportive care in the UK through a retrospective chart review.\n\n# Clinical need and current management\n\n## Living with advanced unresectable cutaneous squamous cell carcinoma is physically and emotionally challenging\n\nCutaneous squamous cell carcinoma (CSCC) is a distinct disease that differs from malignant melanoma and other squamous cell carcinomas such as primary head and neck or lung squamous cell carcinoma. Risk factors include exposure to ultraviolet radiation, increasing age, and immunosuppression. Early CSCC can be cured in most people, but in a small proportion of people the disease reaches an advanced state (metastatic or locally advanced) that cannot be removed with surgery (unresectable) or cured with radiotherapy. Often, people with advanced disease are older, have other comorbidities, and have a poor prognosis. The skin lesions can grow to be quite large and the disease can spread to different parts of the body. Because of the link with ultraviolet exposure, the lesions often develop on parts of the body that are visible, such as the face. The patient expert described how advanced CSCC can be extremely debilitating because it can result in unpleasant foul-smelling wounds. Living with advanced unresectable CSCC is challenging and, because of the visibility of the disease, it often results in people avoiding social interaction. Caring for a person with CSCC can be physically and emotionally draining. The committee concluded that living with advanced unresectable CSCC is physically and emotionally challenging for both people with the disease and their carers.\n\n## Best supportive care is the most appropriate comparator\n\nThe company presented clinical and cost-effectiveness evidence for cemiplimab compared with platinum-based chemotherapy and best supportive care. The clinical experts stated that very few people aged over 70 would be offered platinum-based chemotherapy in the NHS, because of its side effects and lack of clinical benefit. People with advanced CSCC are typically older, and therefore are less likely to be able to tolerate platinum-based chemotherapy. The committee heard from the NHS England expert that in the SACT dataset 75% of people were aged 70 and above and 36% were aged 80 and above. The clinical experts stated that in their experience, the number of people who receive chemotherapy is less than 5%, and probably less than 2%. The patient expert stated that there are limited treatment options for this patient group, very few patients are offered radiotherapy and this rarely works. Therefore, treatment for most people with advanced unresectable CSCC is limited to best supportive care. The committee agreed that platinum-based chemotherapy is not routinely used for treating advanced unresectable CSCC in the NHS and therefore concluded that best supportive care is the most appropriate comparator for this appraisal.\n\n## Cemiplimab is a highly valued and well tolerated treatment option for people with advanced unresectable CSCC\n\nThe clinical and patient experts described the substantial burden of advanced unresectable CSCC on quality of life and the lack of current treatment options. One clinical expert emphasised that because local disease can result in large, fungating tumours, it is particularly important to also consider progression-free survival when assessing the benefits of cemiplimab. The committee also heard that people who respond to cemiplimab can experience substantial benefits, that tumours shrink, and some people remain disease free for 2\xa0years. In addition, the committee heard that single agent immunotherapies are generally well tolerated, including in older people. One of the clinical experts stated that the most common side effects of cemiplimab are fatigue and rashes, which can be easily resolved. Some people can experience more serious autoimmune side effects. These are generally manageable and can be resolved with high-dose steroids or by having a treatment break. The committee noted cemiplimab's benefits for those who respond and concluded that cemiplimab is a highly valued treatment option for people with advanced unresectable CSCC.\n\n# Clinical evidence\n\n## Trial data for cemiplimab is promising but it has not been directly compared with other treatments\n\nData on response and survival outcomes for cemiplimab was reported in 2 single-arm trials: a phase 1\xa0trial and an ongoing phase 2\xa0trial known as EMPOWER-CSCC\xa01. The phase 1\xa0trial included 26\xa0people with metastatic and locally advanced CSCC who had a cemiplimab dose of 3\xa0mg\xa0per\xa0kg every 2\xa0weeks for up to 48\xa0weeks. In EMPOWER-CSCC\xa01, two groups of people had a cemiplimab dose of 3\xa0mg\xa0per\xa0kg every 2\xa0weeks with a stopping rule which stopped treatment at 96\xa0weeks (22\xa0months), or sooner if disease progressed. One of the groups had metastatic CSCC (59\xa0people) and the other had locally advanced CSCC (78\xa0people). A third group of 56\xa0people with metastatic CSCC had the licensed cemiplimab dose of 350\xa0mg\xa0every\xa03\xa0weeks, with a stopping rule of up to 54\xa0weeks, or sooner if disease progressed. The results were consistent between groups and the company presented this data pooled together in a base-case integrated analysis population. Across the 219\xa0people included in the pooled company trials, 40% had locally advanced disease and 60% had metastatic disease. The median age was 72\xa0years and 83% of people were male. All the people in the company trials had an Eastern Cooperative Group (ECOG) performance status of 0 (44% of people) or 1 (56% of people). At the October\xa02019 data cut-off for EMPOWER-CSCC\xa01, the objective response rate was 46.1% (95% confidence interval 38.9% to 53.4%) and median overall survival had not been reached after a median follow up of 15.7\xa0months. The company submitted the results from the most recent data cut in July\xa02021, however these are academic in confidence and cannot be presented in full here. Median overall survival had not been reached at the July\xa02021 data cut-off. The committee concluded that the trial data for cemiplimab is promising because of the response rate seen in the trial population, but it has not been compared with other treatments, and the long-term overall survival benefit is uncertain.\n\n## There are differences between the cemiplimab trial data and SACT dataset, so there is uncertainty about whether the cemiplimab trial results are generalisable to UK clinical practice\n\nThrough the Cancer Drugs Fund, SACT data was collected from people having a cemiplimab dose of 350 mg every 3 weeks for metastatic or locally advanced CSCC in UK clinical practice. Between 2\xa0July\xa02019 and 1\xa0March\xa02021, 352\xa0people had cemiplimab with a stopping rule of up to 24 months, or sooner if disease progressed, with a median follow up of 10.2\xa0months. People in the SACT dataset had a median age of 77\xa0years, 81% had an ECOG performance status score of 0\xa0or\xa01, and 49% of people had locally advanced disease. Median overall survival in the SACT population was 21\xa0months. The ERG noted that people in the SACT dataset were older than in the company trials and that overall survival was lower. Therefore the ERG expressed concerns about the generalisability of the company trials to UK clinical practice. The company stated that the SACT data shows that older and sicker patients could be treated with cemiplimab. The company also highlighted that there are limitations with the SACT dataset, including the unknown impact of the COVID-19 pandemic, limited information on patient characteristics and the shorter follow up compared with the company trials. The company stated that this makes it difficult to determine the generalisability of the company trials to UK practice using the SACT dataset. The clinical experts explained that clinical trials typically include a more selected population in terms of age and fitness, therefore results are expected to be more favourable than in clinical practice. In addition, it is likely that the COVID-19 pandemic impacted treatment with cemiplimab in the SACT dataset, for example, through missed doses, people presenting later in the disease course and mortality because of COVID-19. However, the extent of the impact of the COVID-19 pandemic is unknown, resulting in additional uncertainty. The clinical experts also stated that the SACT dataset is immature and included people treated by clinicians with little or no experience of using cemiplimab. The clinical experts expected that clinical outcomes with cemiplimab would improve as clinicians become more experienced and learn who should be treated with cemiplimab and when to start treatment. The committee discussed whether the lower overall survival in the SACT dataset than in the trial population may be because of the reduced life expectancy of the older population in the SACT dataset. It discussed the possibility of more deaths from non-cancer causes, but noted that this was uncertain because the SACT data does not include cause of death, and neither the SACT data nor the company clinical trials included comparator arms. The committee agreed that there were differences in the patient characteristics and the outcomes between the clinical trials and the SACT dataset and concluded that it was uncertain whether the cemiplimab clinical trial results are generalisable to UK clinical practice.\n\n## The overall survival estimates with best supportive care are very uncertain\n\nComparator data in advanced CSCC is extremely limited. Because chemotherapy is not considered to be a relevant comparator for this appraisal (see section 3.2), only the evidence for best supportive care is discussed here. The company conducted a retrospective chart review to address the lack of comparative evidence that was highlighted during the original appraisal. The chart review was done between 1\xa0January\xa02011 and 31\xa0December\xa02015 and included 106\xa0people with metastatic or locally advanced CSCC in the UK. However, both the company and the ERG agreed that the chart review lacks face validity, because of concerns about the comparability of the chart review population and the EMPOWER-CSCC\xa01 population. Also, the population characteristics and results were highly uncertain. In addition, very few people included in the chart review had CSCC that was eligible for best supportive care. Therefore, the analysis was limited to people receiving chemotherapy, which was not considered to be a relevant comparator by the committee. In the company's base-case analysis, the estimates for the clinical effectiveness of best supportive care were based on evidence from a non-UK retrospective chart review (Sun et al. 2019). Data was used from a subset of 20\xa0non-immunocompromised people with unresectable head and neck CSCC. Patient characteristics were not reported for this specific subset, however patient characteristics of the wider study population were generally similar to the cemiplimab trials. The median overall survival in the subset of non-immunocompromised people receiving best supportive care was 5\xa0months. A committee member suggested that these reviews may reflect clinical practice better than a clinical trial. However, the company explained that the estimates of survival for best supportive care from the Sun et al. chart review are likely to be more favourable than in clinical practice. This is because the Sun et al. study included a highly selected population who were treated in academic treatment centres. The ERG agreed that the study population was highly selected and noted that the results are very uncertain because of the small study population. The clinical expert explained that there is a lack of survival data for people with advanced CSCC, partly because the lack of treatment options means that people are usually discharged back to primary care and are not followed up in the hospital setting. The committee concluded that the estimates of survival with best supportive care are very uncertain.\n\n# Indirect comparisons\n\n## None of the indirect comparisons provide a reliable estimate of cemiplimab's effectiveness\n\nThere are no available studies directly comparing cemiplimab with best supportive care, so the company did an indirect treatment comparison (ITC). For the comparison of cemiplimab with best supportive care the company explored 2 ITC methods: a simulated treatment comparison (STC) and a matching-adjusted indirect comparison (MAIC). The company also presented the results of a naive comparison, which fitted survival extrapolations directly to the observed data. The results from all 3 methods suggest that people who had cemiplimab had a longer overall survival than people who had best supportive care. The ERG noted that the company's approach to the ITC was systematic and in line with the recommendations in the technical support document published by the Decision Support Unit. The committee noted that the ITC is based on comparator data that is considered highly uncertain and concluded that none of the indirect comparisons provide a reliable estimate of relative effectiveness. However, the committee agreed that it was likely that cemiplimab extended survival compared with best supportive care.\n\n# The company's economic model\n\n## The company model is suitable for decision-making\n\nAs in the original appraisal, the company modelled cost effectiveness using a partitioned survival model with 3\xa0health states (pre-progression, post-progression and death). The model had a 30‑year time horizon and a monthly cycle length with a half-cycle correction. A 2‑year stopping rule was applied for cemiplimab which is similar to the 22‑month stopping rule applied for 2 of the groups in the EMPOWER-CSCC\xa01 study (see section 3.4) and was agreed in TA592. The company extended the assumed duration of effectiveness of cemiplimab from the original appraisal to align with the longer duration of follow up from EMPOWER-CSCC\xa01 and updated the quality-of-life data with the most recent data cut. The company model used the baseline characteristics from the company trials in its base case. However, after technical engagement, the company updated the baseline characteristics to those from the SACT dataset. This aligned with the ERG's preference, as this reflects the population who had cemiplimab in NHS practice. The company presented cost-effectiveness estimates for cemiplimab compared with chemotherapy and best supportive care. However, because best supportive care was agreed as the most appropriate comparator in this appraisal (see section 3.2), the cost-effectiveness results for cemiplimab compared with chemotherapy were not discussed further. The committee concluded that the company model is suitable for decision-making.\n\n## Survival extrapolations for cemiplimab and best supportive care are highly uncertain, but cemiplimab is likely to extend survival\n\nThe ERG noted that there is a high degree of uncertainty in the survival extrapolations for cemiplimab and best supportive care, because of limitations in the data (see sections 3.4 to 3.6). The committee noted that the ERG used the same survival extrapolations as the company in its base case, and explored a range of alternative extrapolations in scenario analyses. The committee was not presented with the SACT overall survival Kaplan–Meier data for comparison against the results from the company's trials and the modelled extrapolations. The committee noted that overall survival data from the SACT dataset has been used in economic modelling in other appraisals. The committee agreed that a scenario analysis using the overall survival estimates from the SACT Kaplan–Meier curve would have been helpful to quantify the uncertainty of the survival estimates for cemiplimab, given the lower overall survival in the SACT dataset than in the clinical trials. The committee concluded that the survival extrapolations for cemiplimab and best supportive care are highly uncertain. However, despite the uncertainties, the committee agreed that it was likely that cemiplimab did extend survival, although the extent to which is uncertain.\n\n# End of life\n\n## Cemiplimab for advanced unresectable CSCC meets the end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the company's and ERG's base-case analysis, the mean life expectancy for people receiving best supportive care was 1.42\xa0life years. The committee also noted that the median life expectancy of people receiving best supportive care in the Sun et al. (2019) study was 5\xa0months. The committee was satisfied that the life expectancy in this population was less than 24\xa0months, despite the uncertainty in the evidence base for best supportive care. It was also satisfied that cemiplimab offers at least a 3‑month life extension, based on the evidence from the SACT dataset and the clinical trials, despite the uncertainties. Therefore, the committee concluded that cemiplimab for advanced CSCC that cannot be removed with surgery (unresectable) or cured with radiotherapy meets the end of life criteria.\n\n# Cost-effectiveness estimates\n\n## The cost-effectiveness estimates for cemiplimab are uncertain but are likely to fall within what NICE considers an acceptable use of NHS resources\n\nAt technical engagement, the company accepted the ERG's preferred assumptions in its base case. Both the company's and the ERG's base-case incremental cost-effectiveness ratio (ICER) for cemiplimab compared with best supportive care was £30,952 per quality-adjusted life year (QALY) gained. All the ICERs from the company and ERG scenario analyses were lower than £50,000 per QALY gained. The committee noted the significant uncertainty around the clinical effectiveness of cemiplimab in the NHS (see section 3.5) and that overall survival from the SACT dataset had not been used in the economic modelling (see section 3.9). The committee was also aware of the substantial uncertainty surrounding the comparator data for best supportive care and the indirect comparison (see sections 3.6 and 3.7). The committee considered its conclusion that the end of life criteria were met for cemiplimab. Because of the high level of uncertainty in the clinical evidence, the committee agreed that an acceptable ICER should be towards the lower end of the range normally considered a cost-effective use of NHS resources. Taking all of this into account, the committee concluded that cemiplimab was an acceptable use of NHS resources.\n\n# Other issues\n\n## Innovation\n\nCemiplimab is considered innovative because it potentially provides a new treatment option for people who currently have limited access to any life-extending treatment. Cemiplimab is therefore considered a step-change in the treatment of advanced CSCC that cannot be removed with surgery or cured with radiotherapy.\n\n## Equalities\n\nNo equality issues were identified.\n\n# Conclusion\n\n## Cemiplimab is recommended for routine use\n\nThe committee concluded that, while there is significant uncertainty in the survival estimates for cemiplimab and best supportive care, the most likely cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. Therefore, cemiplimab is recommend as an option for treating metastatic or locally advanced cutaneous squamous cell carcinoma in adults when curative surgery or curative radiotherapy is not appropriate, if it is stopped at 24\xa0months, or earlier if disease progresses."}	https://www.nice.org.uk/guidance/ta802	Evidence-based recommendations on cemiplimab (Libtayo) for metastatic or locally advanced cutaneous squamous cell carcinoma in adults.
7a6b3f43e99f875bc7e701f79193f0ae993ba72c	nice	Depression in adults: treatment and management	Depression in adults: treatment and management This guideline covers identifying, treating and managing depression in people aged 18 and over. It recommends treatments for first episodes of depression and further-line treatments, and provides advice on preventing relapse, and managing chronic depression, psychotic depression and depression with a coexisting diagnosis of personality disorder. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. Definitions of depression and severity Depression refers to a wide range of mental health problems characterised by the absence of a positive affect (a loss of interest and enjoyment in ordinary things and experiences), low mood and a range of associated emotional, cognitive, physical and behavioural symptoms. For more detail, see the International Classification of Diseases-11 (ICD-11) or the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for depression. Depression severity exists along a continuum and is essentially composed of 3 elements: symptoms (which may vary in frequency and intensity) duration of the disorder the impact on personal and social functioning. Severity of depression is therefore a consequence of the contribution of all of these elements. Traditionally, depression severity has been grouped under 4 categories (subthreshold, mild, moderate and severe) but in the development of this guideline the committee wanted to develop a way of representing the severity of depression which best represents the available evidence on the classification and would help the uptake of the recommendations in routine clinical practice. This guideline has therefore defined new episodes of depression as less severe or more severe depression. Less severe depression encompasses subthreshold and mild depression, and more severe depression encompasses moderate and severe depression. Thresholds on validated scales were used in this guideline as an indicator of severity. For example, a score 16 on the PHQ-9 scale was used, with scores less than 16 defined as less severe depression, and scores of 16 or more defined as more severe depression. # Principles of care When working with people with depression and their families or carers: build a trusting relationship and work in an open, engaging and non‑judgemental manner explore treatment choices (see the recommendations on choice of treatments) in an atmosphere of hope and optimism, explaining the different courses of depression and that recovery is possible be aware that stigma and discrimination can be associated with a diagnosis of depression be aware that the symptoms of depression itself, and the impact of stigma and discrimination, can make it difficult for people to access mental health services or take up offers of treatment ensure steps are taken to reduce stigma, discrimination and barriers for individuals seeking help for depression (for example, reducing judgemental attitudes, showing compassion, parity of esteem between mental illness and physical illness, treating people as individuals) ensure that discussions take place in settings in which confidentiality, privacy and dignity are respected. ## Providing information and support Make sure people with depression are aware of self-help groups, peer support groups and other local and national resources. Follow the guidance on providing information in the NICE guideline on service user experience in adult mental health. Provide people with depression with up-to-date and evidence-based verbal and written information about depression and its treatment, appropriate to their language, cultural and communication needs. Follow the sections on communication and information in the NICE guideline on patient experience in adult NHS services. ## Advance decisions and statements Consider developing advance decisions about treatment choices (including declining treatment) and advance statements collaboratively with people who have recurrent severe depression or depression with psychotic symptoms, and for those who had treatment under the Mental Health Act 2007, in line with the Mental Capacity Act 2005, and review them regularly. Record the decisions and statements and include copies in the person's care plan in primary and secondary care, and give copies to the person and to their family or carer, if the person agrees. Advise people with depression that they can set up a Health and Welfare Lasting Power of Attorney, and support them to do so if appropriate, so that a trusted person can represent their interests and make decisions on their behalf if they do not have the capacity to make decisions themselves at any point. ## Supporting families and carers When families or carers are involved in supporting a person with severe or chronic depression, see the recommendations in the NICE guideline on supporting adult carers on identifying, assessing and meeting the caring, physical and mental health needs of families and carers. # Recognition and assessment Be alert to possible depression (particularly in people with a past history of depression or a chronic physical health problem with associated functional impairment) and consider asking people who may have depression if: During the last month, have they often been bothered by feeling down, depressed or hopeless? During the last month, have they often been bothered by having little interest or pleasure in doing things?See also the NICE guideline on depression in adults with a chronic physical health problem. If a person answers 'yes' to either of the depression identification questions (see recommendation 1.2.1) but the practitioner is not competent to perform a mental health assessment, refer the person to an appropriate professional who can. If this professional is not the person's GP, inform the person's GP about the referral. If a person answers 'yes' to either of the depression identification questions (see recommendation 1.2.1) and the practitioner is competent to perform a mental health assessment, review the person's mental state and associated functional, interpersonal and social difficulties. Consider using a validated measure (for example, for symptoms, functions and/or disability) when assessing a person with suspected depression to inform and evaluate treatment. If a person has language or communication difficulties (for example, sensory or cognitive impairments or autism), to help identify possible depression consider: asking the person about their symptoms directly, using an appropriate method of communication depending on the person's needs (for example, using a British Sign Language interpreter, English interpreter, or augmentative and alternative communication) asking a family member or carer about the person's symptoms.See also the NICE guideline on mental health problems in people with learning disabilities and the NICE guideline on autism spectrum disorder. ## Initial assessment Conduct a comprehensive assessment that does not rely simply on a symptom count when assessing a person who may have depression, but also takes into account severity of symptoms, previous history, duration and course of illness. Also, take into account both the degree of functional impairment and/or disability associated with the possible depression and the length of the episode. Discuss with the person how the factors below may have affected the development, course and severity of their depression in addition to assessing symptoms and associated functional impairment: any history of depression and coexisting mental health or physical disorders any history of mood elevation (to determine if the depression may be part of bipolar disorder); see the NICE guideline on bipolar disorder any past experience of, and response to, previous treatments personal strengths and resources, including supportive relationships difficulties with previous and current interpersonal relationships current lifestyle (for example, diet, physical activity, sleep) any recent or past experience of stressful or traumatic life events, such as redundancy, divorce, bereavement, trauma (also see the NICE guideline on post-traumatic stress disorder) living conditions, drug (prescribed or illicit) and alcohol use, debt, employment situation, loneliness and social isolation. ## Risk assessment and management Always ask people with depression directly about suicidal ideation and intent. If there is a risk of self-harm or suicide: assess whether the person has adequate social support and is aware of sources of help arrange help appropriate to the level of need advise the person to seek further help if the situation deteriorates. If a person with depression presents considerable immediate risk to themselves or others, refer them urgently to specialist mental health services. Advise people with depression of the potential for increased agitation, anxiety and suicidal ideation in the initial stages of treatment. Check if they have any of these symptoms and: ensure that the person knows how to seek help promptly review the person's treatment if they develop marked and/or prolonged agitation. Advise a person with depression and their family or carer to be vigilant for mood changes, agitation, negativity and hopelessness, and suicidal ideation, and to contact their practitioner if concerned. This is particularly important during high-risk periods, such as starting or changing treatment and at times of increased personal stress. If a person with depression is assessed to be at risk of suicide: do not withhold treatment for depression on the basis of their suicide risk take into account toxicity in overdose if an antidepressant is prescribed, or the person is taking other medication, and if necessary limit the amount of medicine available consider increasing the level of support provided, such as more frequent in-person, video call or telephone contact consider referral to specialist mental health services.For further advice on risk assessment, see the NICE guideline on self-harm. For further advice on medication, see the recommendations on antidepressant medication for people at risk of suicide. ## Depression with anxiety When depression is accompanied by symptoms of anxiety, which is particularly common in older people, the first priority should usually be to treat the depression. When the person has an anxiety disorder and comorbid depression or depressive symptoms, consult NICE guidance for the relevant anxiety disorder if available and consider treating the anxiety disorder first. ## Depression in people with acquired cognitive impairments When assessing a person with suspected depression: be aware of any acquired cognitive impairments if needed, consult with a relevant specialist when developing treatment plans and strategies. When providing interventions for people with an acquired cognitive impairment who have a diagnosis of depression: if possible, provide the same interventions as for other people with depression if needed, adjust the method of delivery or length of the intervention to take account of the person's ability to communicate, disability or impairment.For people with depression who also have dementia, see the section on depression and anxiety in the NICE guideline on dementia. # Choice of treatments Discuss with people with depression: what, if anything, they think might be contributing to the development of their depression (see recommendation 1.2.7) whether they have ideas or preferences about starting treatment, and what treatment options they have previously found helpful or might prefer their experience of any prior episodes of depression, or treatments for depression what they hope to gain from treatment. Allow adequate time for the initial discussion about treatment options, and involve family members, carers or other supporters if agreed by the person with depression. Help build a trusting relationship with the person with depression and facilitate continuity of care by: ensuring they can see the same healthcare professional wherever possible recording their views and preferences so that other practitioners are aware of these details. Discuss with people with depression their preferences for treatments (including declining an offer of treatment, or changing their mind once a treatment has started) by providing: information on what treatments are NICE-recommended, their potential benefits and harms, any waiting times for treatments, and the expected outcomes (see table 1 and table 2 on the recommended treatments for a new episode of less severe and more severe depression) a choice of: the treatments recommended in this guideline how they will be delivered (for example individual or group, in person or remotely) and where they will be delivered the option to attend with a family member or friend when possible, for some or all of their treatment the option to express a preference for the gender of the healthcare professional, to see a professional they already have a good relationship with, or to change professional if the relationship is not working. Make a shared decision with the person about their treatment. See the NICE guideline on shared decision making. Commissioners and service managers should ensure that people can express a preference for NICE-recommended treatments, that those treatments are available in a timely manner, particularly in severe depression, and that they are monitored to ensure equality of access, provision, outcomes and experience. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on choice of treatments . Full details of the evidence and the committee's discussion are in evidence review I: patient choice. Loading. Please wait. # Delivery of treatments ## All treatments When considering treatments for people with depression: carry out an assessment of need develop a treatment plan take into account any physical health problems take into account any coexisting mental health problems discuss what factors would make the person most likely to engage with treatment (including reviewing positive and negative experiences of previous treatment) take into account previous treatment history address any barriers to the delivery of treatments because of any disabilities, language or communication difficulties ensure regular liaison between healthcare professionals in specialist and non-specialist settings, if the person is receiving specialist support or treatment.For people with depression who also have learning disabilities, see the NICE guideline on mental health problems in people with learning disabilities. For people with depression who also have autism, see the NICE guideline on autism spectrum disorder. For people with depression who also have dementia, see the NICE guideline on dementia. For people with depression in pregnancy or the postnatal period, or who are breastfeeding, see the NICE guideline on antenatal and postnatal mental health. For people with depression who are menopausal, see the NICE guideline on menopause. For people with depression and physical health problems, see the NICE guideline on depression in adults with a chronic physical health problem and also see the recommendations on collaborative care. Match the choice of treatment to meet the needs and preferences of the person with depression. Use the least intrusive and most resource efficient treatment that is appropriate for their clinical needs, or one that has worked for them in the past. For all people with depression having treatment: review how well the treatment is working with the person between 2 and 4 weeks after starting treatment monitor and evaluate treatment concordance monitor for side effects and harms of treatment monitor suicidal ideation, particularly in the early weeks of treatment (see also the recommendations on antidepressant medication for people at risk of suicide and recommendations on risk assessment) consider routine outcome monitoring (using appropriate validated sessional outcome measures, for example PHQ-9) and follow up. ## Psychological and psychosocial interventions Inform people if there are waiting lists for a course of treatment and how long the wait is likely to be (for example, the NHS constitution advises that treatment should be started within 18 weeks). Keep in touch with people at regular intervals, ensure they are aware of how to access help if their condition worsens, ensure they are made aware of who they can contact about their progress on the waiting list. Consider providing self-help materials and addressing social support issues in the interim. Use psychological and psychosocial treatment manuals to guide the form, duration and ending of interventions. Consider using competence frameworks developed from treatment manual(s) for psychological and psychosocial interventions to support the effective training, delivery and supervision of interventions. All healthcare professionals delivering interventions for people with depression should: receive regular clinical supervision have their competence monitored and evaluated; this could include their supervisor reviewing video and audio recordings of their work (with patient consent). When delivering psychological treatments for people with neurodevelopmental or learning disabilities, consider adapting the intervention as advised in the NICE guideline on mental health problems in people with learning disabilities. When people are nearing the end of a course of psychological treatment, discuss ways in which they can maintain the benefits of treatment and ensure their ongoing wellness. ## Pharmacological treatments When offering a person medication for the treatment of depression, discuss and agree a management plan with the person. Include: the reasons for offering medication the choices of medication (if a number of different antidepressants are suitable) the dose, and how the dose may need to be adjusted the benefits, covering what improvements the person would like to see in their life and how the medication may help the harms, covering both the possible side effects and withdrawal effects, including any side effects they would particularly like to avoid (for example, weight gain, sedation, effects on sexual function) any concerns they have about taking or stopping the medication (also see the recommendations on stopping medication).Make sure they have written information to take away and to review that is appropriate for their needs. When prescribing antidepressant medication, ensure people have information about: how they may be affected when they first start taking antidepressant medication, and what these effects might be how long it takes to see an effect (usually, if the antidepressant medication is going to work, within 4 weeks) when their first review will be; this will usually be within 2 weeks to check their symptoms are improving and for side effects, or 1 week after starting antidepressant medication if a new prescription is for a person aged 18 to 25 years or if there is a particular concern for risk of suicide (see recommendations on antidepressant medication for people at risk of suicide) the importance of following instructions on how to take antidepressant medication (for example, time of day, interactions with other medicines and alcohol) why regular monitoring is needed, and how often they will need to attend for review how they can self-monitor their symptoms, and how this may help them feel involved in their own recovery that treatment might need to be taken for at least 6 months after the remission of symptoms, but should be reviewed regularly how some side effects may persist throughout treatment withdrawal symptoms and how these withdrawal effects can be minimised (see also the recommendations on stopping antidepressant medication). For further advice on safe prescribing of antidepressants, see the NICE guideline on medicines associated with dependence or withdrawal symptoms: safe prescribing and withdrawal management for adults. For further advice on the safe and effective use of medicines for people taking 1 or more medicines, see the NICE guideline on medicines optimisation. Advise people taking antidepressant medication to talk with the person who prescribed their medication (for example, their primary healthcare or mental health professional) if they want to stop taking it. Explain that it is usually necessary to reduce the dose in stages over time (called 'tapering') but that most people stop antidepressants successfully. Advise people taking antidepressant medication that if they stop taking it abruptly, miss doses or do not take a full dose, they may have withdrawal symptoms. Also advise them that withdrawal symptoms do not affect everyone, and can vary in type and severity between individuals. Symptoms may include: unsteadiness, vertigo or dizziness altered sensations (for example, electric shock sensations) altered feelings (for example, irritability, anxiety, low mood tearfulness, panic attacks, irrational fears, confusion, or very rarely suicidal thoughts) restlessness or agitation problems sleeping sweating abdominal symptoms (for example, nausea) palpitations, tiredness, headaches, and aches in joints and muscles. Explain to people taking antidepressant medication that: withdrawal symptoms can be mild, may appear within a few days of reducing or stopping antidepressant medication, and usually go away within 1 to 2 weeks withdrawal can sometimes be more difficult, with symptoms lasting longer (in some cases several weeks, and occasionally several months) withdrawal symptoms can sometimes be severe, particularly if the antidepressant medication is stopped suddenly. Recognise that people may have fears and concerns about stopping their antidepressant medication (for example, the withdrawal effects they may experience, or that their depression will return) and may need support to withdraw successfully, particularly if previous attempts have led to withdrawal symptoms or have not been successful. This could include: details of online or written resources that may be helpful increased support from a clinician or therapist (for example, regular check-in phone calls, seeing them more frequently, providing advice about sleep hygiene). When stopping a person's antidepressant medication: take into account the pharmacokinetic profile (for example, the half-life of the medication as antidepressants with a short half-life will need to be tapered more slowly) and the duration of treatment slowly reduce the dose to zero in a step-wise fashion, at each step prescribing a proportion of the previous dose (for example, 50% of previous dose) consider using smaller reductions (for example, 25%) as the dose becomes lower if, once very small doses have been reached, slow tapering cannot be achieved using tablets or capsules, consider using liquid preparations if available ensure the speed and duration of withdrawal is led by and agreed with the person taking the prescribed medication, ensuring that any withdrawal symptoms have resolved or are tolerable before making the next dose reduction take into account the broader clinical context such as the potential benefit of more rapid withdrawal if there are serious or intolerable side effects (for example, hyponatraemia or upper gastrointestinal tract bleeding) take into account that more rapid withdrawal may be appropriate when switching antidepressants recognise that withdrawal may take weeks or months to complete successfully. Monitor and review people taking antidepressant medication while their dose is being reduced, both for withdrawal symptoms and the return of symptoms of depression. Base the frequency of monitoring on the person's clinical and support needs. When reducing a person's dose of antidepressant medication, be aware that: withdrawal symptoms can be experienced with a wide range of antidepressant medication (including tricyclic antidepressants , selective serotonin reuptake inhibitors , serotonin–norepinephrine reuptake inhibitors , and monoamine oxidase inhibitors ) some commonly used antidepressants such as paroxetine and venlafaxine, are more likely to be associated with withdrawal symptoms, so particular care is needed with them fluoxetine's prolonged duration of action means that it can sometimes be safely stopped in the following way: in people taking 20 mg fluoxetine a day, a period of alternate day dosing can provide a suitable dose reduction in people taking higher doses (40 mg to 60 mg fluoxetine a day), use a gradual withdrawal schedule. allow 1 to 2 weeks to evaluate the effects of dose reduction before considering further dose reductions. If a person has withdrawal symptoms when they stop taking antidepressant medication or reduce their dose, reassure them that they are not having a relapse of their depression. Explain that: these symptoms are common relapse does not usually happen as soon as you stop taking an antidepressant medication or lower the dose even if they start taking an antidepressant medication again or increase their dose, the withdrawal symptoms may take a few days to disappear. If a person has mild withdrawal symptoms when they stop taking antidepressant medication: monitor their symptoms reassure them that such symptoms are common and usually time‑limited advise them to contact the person who prescribed their medication (for example, their primary healthcare or mental health professional) if the symptoms do not improve, or if they get worse. If a person has more severe withdrawal symptoms, consider restarting the original antidepressant medication at the previous dose, and then attempt dose reduction at a slower rate with smaller decrements after symptoms have resolved. For further advice on stopping antidepressants, see also the NICE guideline on safe prescribing. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on starting and stopping antidepressants . For full details of the evidence and the committee's discussion, see the evidence reviews for the NICE guideline on safe prescribing (evidence review A: patient information; evidence review B: prescribing strategies; evidence review C: safe withdrawal; evidence review D: withdrawal symptoms; evidence review F: monitoring. Loading. Please wait. When prescribing antidepressant medication for people with depression who are aged 18 to 25 years or are thought to be at increased risk of suicide: assess their mental state and mood before starting the prescription, ideally in person (or by video call or by telephone call if in-person assessment is not possible, or not preferred) be aware of the possible increased prevalence of suicidal thoughts, self-harm and suicide in the early stages of antidepressant treatment, and ensure that a risk management strategy is in place (see the section on risk assessment and management) review them 1 week after starting the antidepressant medication or increasing the dose for suicidality (ideally in person, or by video call, or by telephone if these options are not possible or not preferred) review them again after this as often as needed, but no later than 4 weeks after the appointment at which the antidepressant was started base the frequency and method of ongoing review on their circumstances (for example, the availability of support, unstable housing, new life events such as bereavement, break-up of a relationship, loss of employment), and any changes in suicidal ideation or assessed risk of suicide. Take into account toxicity in overdose when prescribing an antidepressant medication for people at significant risk of suicide. Do not routinely start treatment with TCAs, except lofepramine, as they are associated with the greatest risk in overdose. When prescribing antidepressant medication for older people: take into account the person's general physical health, comorbidities and possible interactions with any other medicines they may be taking carefully monitor the person for side effects be alert to an increased risk of falls and fractures be alert to the risks of hyponatraemia (particularly in those with other risk factors for hyponatraemia, such as concomitant use of diuretics).See also the NICE guideline on dementia: assessment, management and support for people living with dementia and their carers. For people with depression taking lithium, assess weight, renal and thyroid function and calcium levels before treatment and then monitor at least every 6 months during treatment, or more often if there is evidence of significant renal impairment. For women of reproductive age, in particular if they are planning a pregnancy, discuss the risks and benefits of lithium, preconception planning and the need for additional monitoring. Monitor serum lithium levels 12 hours post dose, 1 week after starting treatment and 1 week after each dose change, and then weekly until levels are stable. Adjust the dose according to serum levels until the target level is reached. when the dose is stable, monitor every 3 months for the first year after the first year, measure plasma lithium levels every 6 months, or every 3 months for people in any of the following groups: -lder people people taking medicines that interact with lithium people who are at risk of impaired renal or thyroid function, raised calcium levels or other complications people who have poor symptom control people with poor adherence people whose last plasma lithium level was 0.8 mmol per litre or higher. Determine the dose of lithium according to response and tolerability: plasma lithium levels should not exceed 1.0 mmol/L (therapeutic levels for augmentation of antidepressant medication are usually at or above 0.4 mmol/L; consider levels 0.4 to 0.6 mmol/L for older people aged 65 or above) do not start repeat prescriptions until lithium levels and renal function are stable take into account a person's overall physical health when reviewing test results (including possible dehydration or infection) take into account any changes to concomitant medication (for example, angiotensin-converting enzyme inhibitors, angiotensin 2 receptor blockers, diuretics and non-steroidal anti-inflammatory drugs , or over-the-counter preparations) which may affect lithium levels, and seek specialist advice if necessary monitor at each review for signs of lithium toxicity, including diarrhoea, vomiting, coarse tremor, ataxia, confusion and convulsions seek specialist advice if there is uncertainty about the interpretation of any test results. Manage lithium prescribing under shared care arrangements. If there are concerns about toxicity or side effects (for example, in older people or people with renal impairment), manage their lithium prescribing in conjunction with specialist secondary care services. Consider electrocardiogram (ECG) monitoring in people taking lithium who have a high risk of, or existing, cardiovascular disease. Provide people taking lithium with information on how to do so safely, including the NHS lithium treatment pack. Only stop lithium in specialist mental health services, or with their advice. When stopping lithium, whenever possible reduce doses gradually over 1 to 3 months. For a short explanation of why the committee made these consensus recommendations and how they might affect practice, see the rationale and impact section on use of lithium as augmentation . Loading. Please wait. In June 2022, use of antipsychotics for the treatment of depression was an off-label use for some antipsychotics. See NICE's information on prescribing medicines. Before starting an antipsychotic, check the person's baseline pulse and blood pressure, weight, nutritional status, diet, level of physical activity, fasting blood glucose or HbA1c and fasting lipids. Carry out monitoring as indicated in the summary of product characteristics for individual medicines, for people who take an antipsychotic for the treatment of their depression. This may include: monitoring full blood count, urea and electrolytes, liver function tests and prolactin monitoring their weight weekly for the first 6 weeks, then at 12 weeks, 1 year and annually monitoring their fasting blood glucose or HbA1c and fasting lipids at 12 weeks, 1 year, and then annually ECG monitoring (at baseline and when final dose is reached) for people with established cardiovascular disease or a specific cardiovascular risk (such as diagnosis of high blood pressure) and for those taking other medicines known to prolong the cardiac QT interval (for example, citalopram or escitalopram) at each review, monitoring for adverse effects, including extrapyramidal effects (for example, tremor, parkinsonism) and prolactin-related side effects (for example, sexual or menstrual disturbances) and reducing the dose if necessary being aware of any possible drug interactions which may increase the levels of some antipsychotics, and monitoring and adjusting doses if necessary if there is rapid or excessive weight gain, or abnormal lipid or blood glucose levels, investigating and managing as needed. Manage antipsychotic prescribing under shared care arrangements. For people with depression who are taking an antipsychotic, consider at each review whether to continue the antipsychotic based on their current physical and mental health risks. Only stop antipsychotics in specialist mental health services, or with their advice. When stopping antipsychotics, reduce doses gradually over at least 4 weeks and in proportion to the length of treatment. For a short explanation of why the committee made these consensus recommendations and how they might affect practice, see the rationale and impact section on use of oral antipsychotics as augmentation . Loading. Please wait. Although there is evidence that St John's Wort may be of benefit in less severe depression, healthcare professionals should: advise people with depression of the different potencies of the preparations available and of the potential serious interactions of St John's Wort with other drugs not prescribe or advise its use by people with depression because of uncertainty about appropriate doses, persistence of effect, variation in the nature of preparations and potential serious interactions with other drugs (including hormonal contraceptives, anticoagulants and anticonvulsants). ## Physical treatments and activities Advise people with winter depression that follows a seasonal pattern and who wish to try light therapy in preference to antidepressant medication or psychological treatment that the evidence for the efficacy of light therapy is uncertain. Advise people that doing any form of physical activity on a regular basis (for example, walking, jogging, swimming, dance, gardening) could help enhance their sense of wellbeing. The benefits can be greater if this activity is outdoors. Advise people that maintaining a healthy lifestyle (for example, eating a healthy diet, not over-using alcohol, getting enough sleep) may help improve their sense of wellbeing. See the also the NHS advice on mental wellbeing. For a short explanation of why the committee made these consensus recommendations and how they might affect practice, see the rationale and impact section on activities to help wellbeing . Loading. Please wait. # Treatment for a new episode of less severe depression In this guideline, the term less severe depression includes the traditional categories of subthreshold symptoms and mild depression. ## Active monitoring in people who do not want treatment For people with less severe depression who do not want treatment, or people who feel that their depressive symptoms are improving: discuss the presenting problem(s) and any underlying vulnerabilities and risk factors, as well as any concerns that the person may have make sure the person knows they can change their mind and how to seek help provide information about the nature and course of depression arrange a further assessment, normally within 2 to 4 weeks make contact (with repeated attempts if necessary), if the person does not attend follow-up appointments. ## Treatment options Discuss treatment options with people with a new episode of less severe depression, and match their choice of treatment to their clinical needs and preferences: use table 1 and the visual summary to guide and inform the conversation take into account that all treatments in table 1 can be used as first-line treatments, but consider the least intrusive and least resource intensive treatment first (guided self-help) reach a shared decision on a treatment choice appropriate to the person's clinical needs, taking into account their preferences (see also the recommendations on choice of treatments) recognise that people have a right to decline treatment. Do not routinely offer antidepressant medication as first-line treatment for less severe depression, unless that is the person's preference. Treatment How is this delivered? Key features Other things to think about Guided self-help Printed or digital materials that follow the principles of guided self-help including structured cognitive behavioural therapy (CBT), structured behavioural activation (BA), problem-solving or psychoeducation materials. These can be delivered in person, by telephone, or online. Support from a trained practitioner who facilitates the self-help intervention, encourages completion and reviews progress and outcomes. Usually consists of 6 to 8 structured regular sessions. Focuses on how thoughts, beliefs, attitudes, feelings and behaviour interact, and teaches coping skills to deal with things in life differently. Goal-oriented and structured. Focuses on resolving current issues. May suit people who do not like talking about their depression in a group. Needs self-motivation and willingness to work alone (although regular support is provided). Allows flexibility in terms of fitting sessions in around other commitments. Need to consider access, and ability to engage with computer programme for digital formats. Less capacity for individual adaptations than individual psychological treatments. Avoids potential side effects of medication. Group cognitive behavioural therapy (CBT) A group intervention delivered by 2 practitioners, at least 1 of whom has therapy-specific training and competence. Usually consists of 8 regular sessions. Usually 8 participants in the group. Delivered in line with current treatment manuals. Focuses on how thoughts, beliefs, attitudes, feelings and behaviour interact, and teaches coping skills to deal with things in life differently. Goal-oriented and structured. Focuses on resolving current issues. May be helpful for people who can recognise negative thoughts or unhelpful patterns of behaviour they wish to change. May allow peer support from others who may be having similar experiences. Avoids potential side effects of medication. The person will need to be willing to complete homework assignments. Group behavioural activation (BA) A group intervention delivered by 2 practitioners, at least 1 of whom has therapy-specific training and competence. Usually consists of 8 regular sessions. Usually 8 participants in the group. Delivered in line with current treatment manuals. Focuses on identifying the link between an individual's activities and their mood. Helps the person to recognise patterns and plan practical changes that reduce avoidance and focus on behaviours that are linked to improved mood. Goal-oriented and structured. Focuses on resolving current issues. Does not directly target thoughts and feelings. May be helpful for people whose depression has led to social withdrawal, doing fewer things, inactivity, or has followed a change of circumstances or routine. May allow peer support from others who may be having similar experiences. Avoids potential side effects of medication. The person will need to be willing to complete homework assignments. Individual CBT Individual intervention delivered by a practitioner with therapy-specific training and competence. Usually consists of 8 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms. Delivered in line with current treatment manuals. Focuses on how thoughts, beliefs, attitudes, feelings and behaviour interact, and teaches coping skills to deal with things in life differently. Goal-oriented and structured. Focuses on resolving current issues. May be helpful for people who can recognise negative thoughts or unhelpful patterns of behaviour they wish to change. May suit people who do not like talking about their depression in a group. No opportunity to receive peer support from others who may be having similar experiences. Avoids potential side effects of medication. The person will need to be willing to complete homework assignments. Individual BA Individual intervention delivered by a practitioner with therapy-specific training and competence. Usually consists of 8 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms. Delivered in line with current treatment manuals. Focuses on identifying the link between an individual's activities and their mood. Helps the person to recognise patterns and plan practical changes that reduce avoidance and focus on behaviours that are linked to improved mood. Goal-oriented and structured. Focuses on resolving current issues. Does not directly target thoughts and feelings. May be helpful for people whose depression has led to social withdrawal, doing fewer things, inactivity, or has followed a change of circumstances or routine. May suit people who do not like talking about their depression in a group. No opportunity to receive peer support from others who may be having similar experiences. Avoids potential side effects of medication. The person will need to be willing to complete homework assignments. Group exercise A group physical activity intervention provided by a trained practitioner. Uses a physical activity programme specifically designed for people with depression. Usually consists of more than 1 session per week for 10 weeks. Usually 8 participants in the group. Includes moderate intensity aerobic exercise. Does not directly target thoughts and feelings. May allow peer support from others who may be having similar experiences. May need to be adapted if the person has physical health problems that make it difficult to exercise. May need to be adapted to accommodate psychological aspects, for example anxiety or shame which may act as barriers to engagement. Needs a considerable time commitment. Can help with physical health too. Avoids potential side effects of medication. Group mindfulness and meditation A group intervention provided preferably by 2 practitioners, at least 1 of whom has therapy-specific training and competence. Uses a programme such as mindfulness-based cognitive therapy specifically designed for people with depression. Usually consists of 8 regular sessions. Usually, 8 to 15 participants in the group. Focus is on concentrating on the present, observing and sitting with thoughts and feelings and bodily sensations, and breathing exercises. Involves increasing awareness and recognition of thoughts and feelings, rather than on changing them. Does not directly help with relationship, employment or other stressors that may contribute to depression. May be helpful for people who want to develop a different perspective on negative thoughts, feelings or bodily sensations. May be difficult for people experiencing intense or highly distressing thoughts, or who find focusing on the body difficult. May allow peer support from others who may be having similar experiences. Avoids potential side effects of medication. The person will need to be willing to complete homework assignments, including using mindfulness recordings at home in between sessions. Interpersonal psychotherapy (IPT) Individual intervention delivered by a practitioner with therapy-specific training and competence. Usually consists of 8 to 16 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms. Delivered in line with current treatment manuals. Focus is on identifying how interpersonal relationships or circumstances are related to feelings of depression, exploring emotions and changing interpersonal responses. Structured approach. Focuses on resolving current issues. The goal is to change relationship patterns rather than directly targeting associated depressive thoughts. May be helpful for people with depression associated with interpersonal difficulties, especially adjusting to transitions in relationships, loss, or changing interpersonal roles. May suit people who do not like talking about their depression in a group. Needs a willingness to examine interpersonal relationships. Avoids potential side effects of medication. Selective serotonin reuptake inhibitors (SSRIs) A course of antidepressant medication. Usually taken for at least 6 months (including after symptoms remit). See the recommendations on starting and stopping antidepressant medication for more details. Modify neuronal transmission in the brain. Minimal time commitment although regular reviews needed (especially when starting and stopping treatment). Benefits should be felt within 4 weeks. There may be side effects from the medication, and some people may find it difficult to later stop antidepressant medication. Counselling Individual intervention delivered by a practitioner with therapy-specific training and competence. Usually consists of 8 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms. Uses an empirically validated protocol developed specifically for depression. Focus is on emotional processing and finding emotional meaning, to help people find their own solutions and develop coping mechanisms. Provides empathic listening, facilitated emotional exploration and encouragement. Collaborative use of emotion focused activities to increase self-awareness, to help people gain greater understanding of themselves, their relationships, and their responses to others, but not specific advice to change behaviour. May be useful for people with psychosocial, relationship or employment problems contributing to their depression. May suit people who do not like talking about their depression in a group. Avoids potential side effects of medication. Short-term psychodynamic psychotherapy (STPP) Individual sessions delivered by a practitioner with therapy-specific training and competence. Usually consists of 8 to 16 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms. Uses an empirically validated protocol developed specifically for depression. Focus is on recognising difficult feelings in significant relationships and stressful situations, and identifying how patterns can be repeated. Both insight-oriented and affect focused. Relationship between therapist and person with depression is included as a focus to help support working through key current conflicts. May be useful for people with emotional and developmental difficulties in relationships contributing to their depression. May be less suitable for people who do not want to focus on their own feelings, or who do not wish or feel ready to discuss any close and/or family relationships. May suit people who do not like talking about their depression in a group. Focusing on painful experiences in close and/or family relationships could initially be distressing. Avoids potential side effects of medication. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatment for a new episode of less severe depression . Full details of the evidence and the committee's discussion are in evidence review B: treatment of a new episode of depression. Loading. Please wait. # Treatment for a new episode of more severe depression In this guideline the term more severe depression includes the traditional categories of moderate and severe depression. ## Treatment options Discuss treatment options with people who have a new episode of more severe depression, and match their choice of treatment to their clinical needs and preferences: use table 2 and the visual summary to guide and inform the conversation take into account that all treatments in table 2 can be used as first-line treatments reach a shared decision on a treatment choice appropriate to the person's clinical needs, taking into account their preferences (see also the recommendations on choice of treatments) recognise that people have a right to decline treatment. Treatment How is this delivered? Key features Other things to think about Combination of individual cognitive behavioural therapy (CBT) and an antidepressant A combination of individual CBT and a course of antidepressant medication (see details below). Combines the benefits of regular CBT sessions with a therapist and medication. Sessions with a therapist provide immediate support while the medication takes time to work or medication can be started immediately, and then CBT started as soon as possible afterwards to obtain combined effects. There may be side effects from the medication, and some people may find it difficult to later stop antidepressant medication. Individual CBT Individual intervention delivered by a practitioner with therapy-specific training and competence. Usually consists of 16 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms. Delivered in line with current treatment manuals. Focuses on how thoughts, beliefs, attitudes, feelings and behaviour interact, and teaches coping skills to deal with things in life differently. Goal-oriented and structured. Focuses on resolving current issues. May be helpful for people who can recognise negative thoughts or unhelpful patterns of behaviour they wish to change. Avoids potential side effects of medication. The person will need to be willing to complete homework assignments. Individual behavioural activation (BA) Individual intervention delivered by a practitioner with therapy-specific training and competence. Usually consists of 12 to 16 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms. Delivered in line with current treatment manuals. Focuses on identifying the link between an individual's activities and their mood. Helps the person to recognise patterns and plan practical changes that reduce avoidance and focus on behaviours that are linked to improved mood. Goal-oriented and structured. Focuses on resolving current issues. Does not directly target thoughts and feelings. May be helpful for people whose depression has led to social withdrawal, doing fewer things, inactivity, or has followed a change of circumstances or routine. May suit people who do not like talking about their depression in a group. No opportunity to receive peer support from others who may be having similar experiences. Avoids potential side effects of medication. The person will need to be willing to complete homework assignments. Antidepressant medication Usually taken for at least 6 months (and for some time after symptoms remit). Can be a selective serotonin reuptake inhibitor (SSRI), serotonin–norepinephrine reuptake inhibitor (SNRI), or other antidepressant if indicated based on previous clinical and treatment history. See the recommendations on starting and stopping antidepressant medication for more details. SSRIs are generally well tolerated, have a good safety profile and should be considered as the first choice for most people. Tricyclic antidepressant (TCAs) are dangerous in overdose, although lofepramine has the best safety profile. Choice of treatment will depend on preference for specific medication effects such as sedation, concomitant illnesses or medications, suicide risk and previous history of response to antidepressant medicines. Minimal time commitment, although regular reviews needed (especially when starting and stopping treatment). Benefits should be felt within 4 weeks. There may be side effects from the medication, and some people may find it difficult to later stop antidepressant medication. Individual problem-solving Individual sessions delivered by a practitioner with therapy-specific training and competence. Usually consists of 6 to 12 regular sessions. Delivered in line with current treatment manuals. Focus is on identifying problems, generating alternative solutions, selecting the best option, developing a plan and evaluating whether it has helped solve the problem. Goal-oriented and structured. Focuses on resolving current issues. May be helpful for people who want to tackle current difficulties and improve future experiences. Avoids potential side effects of medication. The person will need to be willing to complete homework assignments. Counselling Individual sessions delivered by a practitioner with therapy-specific training and competence. Usually consists of 12 to 16 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms. Uses an empirically validated protocol developed specifically for depression. Focus is on emotional processing and finding emotional meaning, to help people find their own solutions and develop coping mechanisms. Provides empathic listening, facilitated emotional exploration and encouragement. Collaborative use of emotion focused activities to increase self-awareness, to help people gain greater understanding of themselves, their relationships, and their responses to others, but not specific advice to change behaviour. May be useful for people with psychosocial, relationship or employment problems contributing to their depression. May suit people who do not like talking about their depression in a group. Avoids potential side effects of medication. Short-term psychodynamic psychotherapy (STPP) Individual sessions delivered by a practitioner with therapy-specific training and competence. Usually consists of 16 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms. Uses an empirically validated protocol developed specifically for depression. Focus is on recognising difficult feelings in significant relationships and stressful situations, and identifying how patterns can be repeated. Both insight-oriented and affect focused. Relationship between therapist and person with depression is included as a focus to help support working through key current conflicts. May be useful for people with emotional and developmental difficulties in relationships contributing to their depression. May be less suitable for people who do not want to focus on their own feelings, or who do not wish or feel ready to discuss any close and/or family relationships. May suit people who do not like talking about their depression in a group. Focusing on painful experiences in close and/or family relationships could initially be distressing. Avoids potential side effects of medication. Interpersonal psychotherapy (IPT) Individual sessions delivered by a practitioner with therapy-specific training and competence. Usually consists of 16 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms. Delivered in line with current treatment manuals. Focus is on identifying how interpersonal relationships or circumstances are related to feelings of depression, exploring emotions and changing interpersonal responses. Structured approach. Focuses on resolving current issues. The goal is to change relationship patterns rather than directly targeting associated depressive thoughts. May be helpful for people with depression associated with interpersonal difficulties, especially adjusting to transitions in relationships, loss, or changing interpersonal roles. May suit people who do not like talking about their depression in a group. Needs a willingness to examine interpersonal relationships. Avoids potential side effects of medication. Guided self-help Printed or digital materials that follow the principles of guided self-help including structured CBT, structured BA, problem-solving or psychoeducation materials. These can be delivered in person, by telephone, or online. Support from a trained practitioner who facilitates the self-help intervention, encourages completion and reviews progress and outcome. Support usually consists of 6 to 8 structured, regular sessions. Focuses on how thoughts, beliefs, attitudes, feelings and behaviour interact, and teaches coping skills to deal with things in life differently. Goal-oriented and structured. Focuses on resolving current issues. In more severe depression, the potential advantages of providing other treatment choices with more therapist contact should be carefully considered first. Needs self-motivation and willingness to work alone (although regular support is provided). Allows flexibility in terms of fitting sessions in around other commitments. Need to consider access, and ability to engage with computer programme for digital formats. Less capacity for individual adaptations than individual psychological treatments. Avoids potential side effects of medication. Group exercise A group physical activity intervention provided by a trained practitioner. Uses a physical activity programme specifically designed for people with depression. Usually consists of more than 1 session per week for 10 weeks. Usually 8 participants in the group. Includes moderate intensity aerobic exercise. Does not directly target thoughts and feelings. In more severe depression, the potential advantages of providing other treatment choices with more therapist contact should be carefully considered first. May allow peer support from others who are may be having similar experiences. May need to be adapted if the person has physical health problems that prevent exercise. May need to be adapted to accommodate psychological aspects, for example anxiety or shame which may act as barriers to engagement. Needs a considerable time commitment. Can help with physical health too. Avoids potential side effects of medication. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on treatment for a new episode of more severe depression . Full details of the evidence and the committee's discussion are in evidence review B: treatment of a new episode of depression. Loading. Please wait. # Behavioural couples therapy for depression Consider behavioural couples therapy for people with either less severe or more severe depression who have problems in the relationship with their partner if: the relationship problem(s) could be contributing to their depression, or involving their partner may help in the treatment of their depression. Deliver behavioural couples therapy for people with depression that: follows the behavioural principles for couples therapy provides 15 to 20 sessions over 5 to 6 months. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on behavioural couples therapy . Full details of the evidence and the committee's discussion are in evidence review B: treatment of a new episode of depression. Loading. Please wait. # Preventing relapse Discuss with people that continuation of treatment (antidepressants or psychological therapies) after full or partial remission may reduce their risk of relapse and may help them stay well. Reach a shared decision on whether or not to continue a treatment for depression based on their clinical needs and preferences. See the visual summary on preventing relapse. Discuss with people that the likelihood of having a relapse may be increased if they have: a history of recurrent episodes of depression, particularly if these have occurred frequently or within the last 2 years a history of incomplete response to previous treatment, including residual symptoms unhelpful coping styles (for example, avoidance and rumination) a history of severe depression (including people with severe functional impairment) -ther chronic physical health or mental health problems personal, social and environmental factors that contributed to their depression (see recommendation 1.2.7) and that are still present (for example, relationship problems, ongoing stress, poverty, isolation, unemployment). Discuss with people the potential risks of continuing with antidepressants long term, and how these balance against the risks of depression relapse. These include: possible side effects, such as an increased bleeding risk or long-term effects on sexual function difficulty stopping antidepressants. If a person chooses not to continue antidepressant medication for relapse prevention, advise them: how to stop their antidepressant medication (see the recommendations on stopping antidepressant medication) and to seek help as soon as possible if the symptoms of depression return or residual symptoms worsen. For people who have remitted from depression when treated with antidepressant medication alone, but who have been assessed as being at higher risk of relapse, consider: continuing with their antidepressant medication to prevent relapse, maintaining the dose that led to full or partial remission, unless there is good reason to reduce it (such as side effects) or a course of psychological therapy (group CBT or mindfulness-based cognitive therapy ) for people who do not wish to continue on antidepressants (follow the recommendations on stopping antidepressants) or continuing with their antidepressant medication and a course of psychological therapy (group CBT or MBCT). For people starting group CBT or MBCT for relapse prevention, offer a course of therapy with an explicit focus on the development of relapse prevention skills and what is needed to stay well. This usually consists of 8 sessions over 2 to 3 months with the option of additional sessions in the next 12 months. Relapse prevention components of psychological interventions may include: reviewing what lessons and insights were learnt in therapy and what was helpful in therapy making concrete plans to maintain progress beyond the end of therapy including plans to consolidate any changes made to stay well and to continue to practice useful strategies identifying stressful circumstances, triggering events, warning signs (such as anxiety or poor sleep), or unhelpful behaviours (such as avoidance or rumination) that have preceded worsening of symptoms and personal or social functioning, and making detailed contingency plans of what to do if each of these re-occur making plans for any anticipated challenging events over the next 12 months, including life changes and anniversaries of difficult events. Discuss with people who have remitted from depression when treated with a psychological therapy alone, but who have been assessed as being at higher risk of relapse, whether they wish to continue with their psychological therapy for relapse prevention. Reach a shared decision on further treatment. Discuss with people who have remitted from depression when treated with a combination of an antidepressant medication and psychological therapy, but who have been assessed as being at higher risk of relapse, whether they wish to continue 1 or both treatments. Reach a shared decision on further treatment. Continue the same therapy for people who wish to stay on a psychological therapy for relapse prevention (either alone or in combination with an antidepressant), adapted by the therapist for relapse prevention. This should include at least 4 more sessions of the same treatment with a focus on a relapse prevention component (see recommendation 1.8.7) and what is needed to stay well. Review treatment for people continuing with antidepressant medication to prevent relapse at least every 6 months. At each review: monitor their mood using a validated rating scale (see the recommendations on delivery of treatments) review any side effects review any medical, personal, social or environmental factors that may affect their risk of relapse, and encourage them to access help from other agencies discuss with them if they wish to continue treatment; if they wish to stop antidepressant treatment, see the recommendations on stopping antidepressant medication. Reassess the risk of relapse for people who continue with psychological therapy to prevent relapse, when they are finishing the relapse prevention treatment, and assess the need for any further follow up. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preventing relapse . Full details of the evidence and the committee's discussion are in evidence review C: preventing relapse. Loading. Please wait. # Further-line treatment If a person's depression has not responded at all after 4 weeks of antidepressant medication at a recognised therapeutic dose, or after 4 to 6 weeks for psychological therapy or combined medication and psychological therapy, discuss with them: whether there are any personal, social or environmental factors or physical or other mental health conditions that might explain why the treatment is not working whether they have had problems adhering to the treatment plan (for example, stopping or reducing medication because of side effects, or missing sessions with their therapist).If any of these are the case, make a shared decision with the person about the best way to try and address any problems raised, including how other agencies may be able to help with these factors. See the visual summary on further-line treatment. If a person's depression has not responded to treatment after addressing any problems raised (see recommendation 1.9.1), and allowing an adequate time for treatment changes to work, review the diagnosis and consider the possibility of alternative or comorbid conditions that may limit response to depression treatments. Reassure the person that although treatment has not worked, other treatments can be tried, and may be effective. If a person's depression has had no or a limited response to treatment with psychological therapy alone, and no obvious cause can be found and resolved, discuss further treatment options with the person (including what other treatments they have found helpful in the past) and make a shared decision on how to proceed based on their clinical need and preferences. Options include: switching to an alternative psychological treatment adding an SSRI to the psychological therapy switching to an SSRI alone. If a person's depression has had no or a limited response to treatment with antidepressant medication alone, and no obvious cause can be found and resolved, discuss further treatment options with the person and make a shared decision on how to proceed based on their clinical need and preferences. Options include: adding a group exercise intervention switching to a psychological therapy (see the suggested treatment options for more severe depression) continuing antidepressant therapy by either increasing the dose or changing the drug. For example, by: increasing the dose of the current medication (within the licensed dose range) if the medication is well tolerated; be aware that higher doses of antidepressants may not be more effective and can increase the frequency and severity of side effects; ensure follow-up and frequent monitoring of symptoms and side effects after dose increases. switching to another medication in the same class (for example, another SSRI) switching to a medication of a different class (for example, an SSRI, SNRI, or in secondary care a TCA or MAOI); take into account that: switching medication may mean cross-tapering is needed; see the NICE clinical knowledge summary on switching antidepressants switching to or from an MAOI, or from one MAOI to another, will need to take place in, or with advice from, secondary care TCAs are dangerous in overdose, although lofepramine has the best safety profile changing to a combination of psychological therapy (for example, CBT, interpersonal psychotherapy or STPP) and medication.Consider whether some of these decisions and treatments need other services to be involved (for example, specialist mental health services for advice on switching antidepressants). If a person's depression has had no or a limited response to treatment with a combination of antidepressant medication and psychological therapy, discuss further treatment options with the person and make a shared decision on how to proceed based on their clinical need and preferences. Options include: switching to another psychological therapy increasing the dose or switching to another antidepressant (see recommendation 1.9.5) adding in another medication (see recommendation 1.9.9). Only consider vortioxetine when there has been no or limited response to at least 2 previous antidepressants. See the NICE technology appraisal guidance on the use of vortioxetine. If a person whose depression has had no response or a limited response to antidepressant medication does not want to try a psychological therapy, and instead wants to try a combination of medications, explain the possible increase in their side-effect burden. If a person with depression wants to try a combination treatment and is willing to accept the possibility of an increased side-effect burden (see recommendation 1.9.8), consider referral to a specialist mental health setting or consulting a specialist. Treatment options include: adding an additional antidepressant medication from a different class (for example, adding mirtazapine or trazodone to an SSRI) combining an antidepressant medication with a second-generation antipsychotic (for example, aripiprazole, olanzapine, quetiapine or risperidone) or lithium augmenting antidepressants with electroconvulsive therapy (see the recommendations on electroconvulsive therapy for depression), lamotrigine, or triiodothyronine (liothyronine).Be aware that some combinations of classes of antidepressants are potentially dangerous and should be avoided (for example, a SSRI, SNRI or TCA with a MAOI), and that when using an antipsychotic the effects of this on depression, including loss of interest and motivation, should be carefully reviewed.In June 2022, this was an off-label use for some antipsychotics, lamotrigine, and triiodothyronine (liothyronine). See NICE's information on prescribing medicines. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on further-line treatment . Full details of the evidence and the committee's discussion are in evidence review D: further-line treatment. Loading. Please wait. # Chronic depressive symptoms Be aware that people presenting with chronic depressive symptoms may not have sought treatment for depression previously and may be unaware that they have depression. Discussions about their mood and symptoms initiated by a healthcare practitioner may help them access treatment and services. See the visual summary on treatment for chronic depression. For people who present with chronic depressive symptoms that significantly impair personal and social functioning and who have not received previous treatment for depression, treatment options include: CBT or SSRIs or SNRIs or TCAs (be aware that TCAs are dangerous in overdose, although lofepramine has the best safety profile) or combination therapy with CBT and either an SSRI or a TCA.Discuss the options with the person and reach a shared decision on treatment choice, based on their clinical needs and preferences (see also the recommendations on choice of treatments). For people with chronic depressive symptoms, offer cognitive behavioural treatment that: has a focus on chronic depressive symptoms covers related maintaining processes, including avoidance, rumination and interpersonal difficulties. For people who have had, or are still receiving, treatment for depression and who present with chronic depressive symptoms, see the recommendations on further-line treatment. If a person with chronic depressive symptoms that significantly impair personal and social functioning cannot tolerate a particular SSRI, consider treatment with an alternative SSRI. For people with chronic depressive symptoms that significantly impair personal and social functioning, who have not responded to SSRIs or SNRIs, consider alternative medication in specialist settings, or after consulting a specialist. Take into account that switching medication may mean that an adequate wash-out period is needed, particularly when switching to or from irreversible MAOIs or moclobemide. See the NICE clinical knowledge summary on switching antidepressants. Alternatives include: TCAs moclobemide irreversible MAOIs such as phenlezine low-dose amisulpride (maximum dose of 50 mg daily, as higher doses may worsen depression and lead to side effects such as hyperprolactinaemia and QT interval prolongation).In June 2022, this was an off-label use for amisulpride. See NICE's information on prescribing medicines. For people with chronic depressive symptoms that significantly impair personal and social functioning, who have been assessed as likely to benefit from extra social or vocational support, consider: befriending in combination with existing antidepressant medication or psychological therapy; this should be done by trained volunteers, typically with at least weekly contact for between 2 to 6 months a rehabilitation programme, if their depression has led to loss of work or their withdrawing from social activities over the longer term. For people with no or limited response to treatment for chronic depressive symptoms that significantly impair personal and social functioning who have not responded to the treatments recommended in the sections on further-line treatment and chronic depressive symptoms, offer a referral to specialist mental health services for advice and further treatment. See also the recommendations on collaborative care. For people with chronic depressive symptoms that have not responded to the treatments recommended in the sections on further-line treatment and chronic depressive symptoms, and who are on long-term antidepressant medication: review the benefits of treatment with the person consider stopping the medication (see the recommendations on stopping antidepressants) discuss with the person possible reasons for non-response and what other treatments and support (including from other agencies) may be helpful. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on chronic depressive symptoms . Full details of the evidence and the committee's discussion are in evidence review E: chronic depression. Loading. Please wait. # Depression in people with a diagnosis of personality disorder Do not withhold treatment for depression because of a coexisting personality disorder. See the visual summary on treatment of depression with personality disorder. For people with depression and a diagnosis of personality disorder consider a combination of antidepressant medication and a psychological treatment (for example, BA, CBT, IPT or STPP). To help people choose between these psychological treatments, see the information on them provided in table 1 and table 2. When delivering antidepressant medication in combination with psychological treatment for people with depression and a diagnosis of personality disorder: give the person support and encourage them to carry on with the treatment provide the treatment in a structured, multidisciplinary setting use a validated measure of prospective mood monitoring or a symptom checklist or chart to assess response, or any exacerbation of emotional instability extend the duration of treatment if needed, up to a year. For people with depression and a diagnosis of personality disorder, consider referral to a specialist personality disorder treatment programme. See the NICE guideline on borderline personality disorder for recommendations on treatment for borderline personality disorder with coexisting depression. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on depression in people with a diagnosis of personality disorder . Full details of the evidence and the committee's discussion are in evidence review F: depression with coexisting personality disorder. Loading. Please wait. # Psychotic depression In June 2022, use of antipsychotics for the treatment of depression was an off-label use for some antipsychotics. See NICE's information on prescribing medicines. Offer referral to specialist mental health services for people with depression with psychotic symptoms, where the treatment should include: a risk assessment an assessment of needs a programme of coordinated multidisciplinary care access to psychological treatments, after improvement of acute psychotic symptoms.Discuss treatment options and, for those people who have capacity, reach a shared decision based on their clinical needs and preferences. See the visual summary on treatment of psychotic depression. Consider combination treatment for people with depression with psychotic symptoms with antidepressant medication and antipsychotic medication (for example, olanzapine or quetiapine). If a person with depression with psychotic symptoms does not wish to take antipsychotic medication in addition to an antidepressant, then treat with an antidepressant alone. Monitor people with depression with psychotic symptoms for treatment response (in particular for unusual thought content and hallucinations). Consider continuing antipsychotic medication for people with depression with psychotic symptoms for a number of months after remission, if tolerated. The decision about if and when to stop antipsychotic medication should be made by, or in consultation with, specialist services. For more advice on prescribing and monitoring antipsychotics see the recommendations on use of oral antipsychotics as augmentation and the NICE guideline on psychosis and schizophrenia in adults. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychotic depression . Full details of the evidence and the committee's discussion are in evidence review G: psychotic depression. Loading. Please wait. # Electroconvulsive therapy for depression Consider electroconvulsive therapy (ECT) for the treatment of severe depression if: the person chooses ECT in preference to other treatments based on their past experience of ECT and what has previously worked for them or a rapid response is needed (for example, if the depression is life‑threatening because the person is not eating or drinking) or -ther treatments have been unsuccessful (see the recommendations on further-line treatment). Make sure people with depression who are going to have ECT are fully informed of the risks, and of the risks and benefits specific to them. Take into account: the risks associated with a general anaesthetic any medical comorbidities potential adverse events, in particular cognitive impairment if the person is older, the possible increased risk associated with ECT treatment for this age group the risks associated with not having ECT.Document the assessment and discussion. Discuss the use of ECT as a treatment option with the person with depression, and reach a shared decision on its use based on their clinical needs and preferences, if they have capacity to give consent. Take into account the capacity of the person and the requirements of the Mental Health Act 2007 (if applicable), and make sure: informed consent is given without pressure or coercion from the circumstances or clinical setting the person is aware of their right to change their mind and withdraw consent at any time there is strict adherence to recognised guidelines on consent, and advocates or carers are involved to help informed discussions. If a person with depression cannot give informed consent, only give ECT if it does not conflict with a valid advance treatment decision the person made. For people whose depression has not responded well to ECT previously, only consider a repeat trial of ECT after: reviewing the adequacy of the previous treatment course considering all other options discussing the risks and benefits with the person or, if appropriate, their advocate or carer. Clinics should only provide ECT if they: are Electroconvulsive Therapy Accreditation Service (ECTAS) accredited provide ECT services in accordance with ECTAS standards submit data, including outcomes, on each course of acute and maintenance ECT they deliver as needed for the ECTAS minimum dataset.Follow the ECT Accreditation Service Standards for Administering ECT. Trusts which provide ECT services should ensure compliance with the ECTAS standards for administering ECT through board-level performance management. Stop ECT treatment for a person with depression: immediately, if the side effects outweigh the potential benefits, or when stable remission has been achieved. If a person's depression has responded to a course of ECT: start (or continue) antidepressant medication or a psychological intervention to prevent relapse and to provide ongoing care for their depression (see the recommendations on preventing relapse) consider lithium augmentation of antidepressant medication (see the recommendations on further-line treatment). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on further-line treatment . Full details of the evidence and the committee's discussion are in evidence review D: further-line treatment. Loading. Please wait. # Transcranial magnetic stimulation for depression See the NICE interventional procedures guidance on repetitive transcranial magnetic stimulation for depression. # Implanted vagus nerve stimulation for treatment-resistant depression See the NICE interventional procedures guidance on implanted vagus nerve stimulation for treatment-resistant depression. # Access, coordination and delivery of care ## Access to services Commissioners and providers of mental health services should consider using models such as stepped care or matched care for organising the delivery of care and treatment of people with depression. See the matched care model visual summary.Pathways should: promote easy access to, and uptake of, the treatments covered allow for prompt assessment of adults with depression, including assessment of severity and risk ensure coordination and continuity of care, with agreed protocols for sharing information support the integrated delivery of services across primary and secondary care, to ensure individuals do not fall into gaps in service provision have clear criteria for entry to all levels of a stepped care service have multiple entry points and ways to access the service, including self-referral have routine collection of data on access to, uptake of and outcomes of the specific treatments in the pathway. Commissioners and providers of mental health services for people with depression should ensure the effective delivery of treatments. This should build on the key functions of a catchment area-based community mental health service and be provided in the context of a coordinated primary and secondary care mental health service, as well as community services (for example social care, education, housing, statutory services and the voluntary and social enterprise sector). This should include: assessment procedures shared decision making collaboration between professionals delivery of pharmacological, psychological and physical (for example exercise, ECT) interventions delivery of interventions for personal, social and environmental factors (for example, housing problems, isolation and unemployment) care coordination involvement of service users in design, monitoring and evaluation of services the effective monitoring and evaluation of services. Commissioners and providers of primary and secondary care mental health services should ensure support is in place so integrated services can be delivered by: individual practitioners (including primary care healthcare professionals), providing treatments, support or supervision mental health staff, for team-based treatments in primary care for the majority of people with depression mental health specialists, providing advice, consultation and support for primary care mental health staff specialist-based mental health teams, for people with severe and complex needs. Commissioners and providers of mental health services should ensure that accessible, inclusive and culturally adapted information about the pathways into treatment and different explanatory models of depression is available, for example in different languages and formats and in line with NHS England's Accessible Information Standard. Commissioners and providers of mental health services should ensure pathways have the following in place for people with depression to promote access, and increased uptake and retention: services delivered in culturally appropriate or culturally adapted language and formats services available outside normal working hours a range of different methods to engage with and deliver treatments in addition to in-person meetings, such as text messages, email, telephone and online or remote consultations (where clinically appropriate, and for people who wish to access and are able to access services in this way) services provided in community-based settings, for example in a person's home, community centres, leisure centres, care homes, social centres and integrated clinics within primary care (particularly for older people) services delivered jointly with charities or the voluntary sector bilingual therapists or independent translators procedures to support active involvement of families, partners and carers, if agreed by the person with depression. When promoting access and uptake of services, identify and address the needs of groups who may have difficulty in accessing, or face stigma or discrimination when using some or all mental health services. This may include: men -lder people lesbian, gay, bisexual and trans people people from black, Asian and minority ethnic communities people with learning disabilities or acquired cognitive impairments (see the NICE guideline on mental health problems in people with learning disabilities) people with physical or sensory disabilities, who may need reasonable adjustments to services as defined by legislation to enable this access; see the Equality Act 2010 people who have conditions which compromise their ability to communicate people who are homeless, refugees and asylum seekers. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on access to services . Full details of the evidence and the committee's discussion are in evidence review H: access to services. Loading. Please wait. ## Collaborative care Consider collaborative care for people with depression, particularly older people, those with significant physical health problems or social isolation, or those with more chronic depression not responding to usual specialist care. Collaborative care for people with depression should comprise: patient-centred assessment and engagement symptom measurement and monitoring medication management (a plan for starting, reviewing and discontinuing medication) active care planning and follow up by a designated case manager delivery of psychological and psychosocial treatments within a structured protocol integrated care of both physical health and mental health joint working with primary and secondary care colleagues involvement of other agencies that provide support supervision of practitioners by an experienced mental health professional. ## Specialist care Refer people with more severe depression or chronic depressive symptoms, to specialist mental health services for coordinated multidisciplinary care if: their depression significantly impairs personal and social functioning and they have not benefitted from previous treatments, and either have multiple complicating problems, for example unemployment, poor housing or financial problems or have significant coexisting mental and physical health conditions. Deliver multidisciplinary care plans for people with more severe depression or chronic depressive symptoms (either of which significantly impairs personal and social functioning) and multiple complicating problems, or significant coexisting conditions that: are developed together with the person, their GP and other relevant people involved in their care (with the person's agreement), and that a copy in an appropriate format is offered to the person set out the roles and responsibilities of all health and social care professionals involved in delivering the care include information about 24-hour support services, and how to contact them include a crisis plan that identifies potential crisis triggers, and strategies to manage those triggers and their consequences are updated if there are any significant changes in the person's needs or condition are reviewed at agreed regular intervals include medication management (a plan for starting, reviewing and discontinuing medication). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on collaborative care and specialist care . Full details of the evidence and the committee's discussion are in evidence review A: service delivery. Loading. Please wait. ## Crisis care, home treatment and inpatient care Consider crisis resolution and home treatment (CRHT) for people with more severe depression who are at significant risk of: suicide, in particular for those who live alone self-harm harm to others self-neglect complications in response to their treatment, for example older people with medical comorbidities. Ensure teams providing CRHT interventions to support people with depression: monitor and manage risk as a high-priority routine activity establish and implement a treatment programme ensure continuity of any treatment programme while the person is in contact with the CRHT team, and on discharge or transfer to other services when this is needed put a crisis management plan in place before the person is discharged from the team's care. Consider inpatient treatment for people with more severe depression who cannot be adequately supported by a CRHT team. See also the NICE guideline on mental health problems in people with learning disabilities. Make psychological therapies recommended for the treatment of more severe depression, relapse prevention, chronic depressive symptoms and depression with a diagnosis of personality disorder available for people with depression in secondary care settings (including community and inpatient). When providing psychological therapies for people with depression in inpatient settings: increase the intensity and duration of the interventions ensure that they continue to be provided effectively and promptly on discharge. Consider using CRHT teams for people with depression having a period of inpatient care who might benefit from early discharge from hospital. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on crisis care, home treatment and inpatient care . Full details of the evidence and the committee's discussion are in evidence review A: service delivery. Loading. Please wait. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster. ## Acquired cognitive impairments Cognitive impairments are neurological disorders that affect cognitive abilities (for example, learning, memory, communication and problem-solving). Acquired disorders may be because of medical conditions that affect mental function (for example, dementia, Parkinson's disease or traumatic brain injury). ## Avoidance An unhelpful form of coping behaviour in which a person changes their behaviour to avoid thinking about, feeling or doing difficult things. This includes putting things off, reducing activities, not tackling problems, not speaking up for oneself, distraction and using alcohol or substances to numb feelings. ## Chronic depressive symptoms People with chronic depressive symptoms includes those who continually meet criteria for the diagnosis of a major depressive episode for at least 2 years, or have persistent subthreshold symptoms for at least 2 years, or who have persistent low mood with or without concurrent episodes of major depression for at least 2 years. People with depressive symptoms may also have a number of social and personal difficulties that contribute to the maintenance of their chronic depressive symptoms. ## Collaborative care Collaborative care requires that the service user and healthcare professional jointly identify problems and agree goals for treatments, and normally comprises: case management which is supervised and supported by a senior mental health professional close collaboration between primary and secondary physical health services and specialist mental health services in the delivery of services the provision of a range of evidence-based treatments the long-term coordination of care and follow up. ## Depression In ICD-11, depression is defined as the presence of depressed mood or diminished interest in activities occurring most of the day, nearly every day, for at least 2 weeks, accompanied by other symptoms such as: reduced ability to concentrate and sustain attention or marked indecisiveness beliefs of low self-worth or excessive or inappropriate guilt hopelessness about the future recurrent thoughts of death or suicidal ideation or evidence of attempted suicide significantly disrupted sleep or excessive sleep significant changes in appetite or weight psychomotor agitation or retardation reduced energy or fatigue In DSM-5 depression is defined as the presence of 5 or more symptoms from a list of 9 symptoms, during the same 2-week period and where at least 1 of the symptoms is depressed mood or loss of interest or pleasure, most of the day, nearly every day. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The 9 symptoms are: depressed mood – indicated by subjective report or observation by others loss of interest or pleasure in almost all activities – indicated by subjective report or observation by others significant (more than 5% in a month) unintentional weight loss or gain or decrease or increase in appetite sleep disturbance (insomnia or hypersomnia) psychomotor changes (agitation or retardation) severe enough to be observable by others tiredness, fatigue, or low energy, or decreased efficiency with which routine tasks are completed a sense of worthlessness or excessive, inappropriate, or delusional guilt (not merely self-reproach or guilt about being sick) impaired ability to think, concentrate, or make decisions – indicated by subjective report or observation by others recurrent thoughts of death (not just fear of dying), suicidal ideation, or suicide attempts. In this guideline the term 'people with depression' is used. This includes people with a clinical diagnosis of depression and those who feel themselves to be experiencing depression or depressive symptoms, and recognises that people experience, describe and label their experiences of depression in very individual ways. ## Less severe depression Less severe depression encompasses subthreshold and mild depression, and in this guideline was defined as depression scoring less than 16 on the PHQ-9 scale. ## Medication management Medication management is giving a person advice on how to keep to a regimen for the use of medication (for example, how to take it, when to take it and how often). The focus in such programmes is only on the management of medication and not on other aspects of depression. ## More severe depression More severe depression encompasses moderate and severe depression, and in this guideline was defined as depression scoring 16 or more on the PHQ-9 scale. ## Personal and social functioning Personal functioning represents the ability of an individual to effectively engage in the normal activities of everyday living and react to experiences. Social functioning is the ability to interact with other people, develop relationships and to gain from and develop these interactions. ## Routine (sessional) outcome monitoring This is a system for the monitoring of the outcomes of treatments which involves regular assessment (usually at each contact; referred to as sessional) of symptoms or personal and social functioning using a valid scale. It can inform both service user and practitioner of progress in treatment. It is often supported by computerised delivery and scoring of the measures which ensures better completion of the questionnaires and service level audit and evaluation. Alternative terms such as 'sessional outcome monitoring' or 'sessional outcomes' may also be used which emphasise that outcomes should be recorded at each contact. ## Rumination Repetitive and prolonged negative thinking about the depression, feelings and symptoms, the self, problems or difficult life events and about their causes, consequences, meanings and implications (for example 'Why did this happen to me?', 'Why can I not get better?'). ## Stepped care or matched care This is a system of delivering and monitoring treatments, so that the most effective, least intrusive and least resource intensive treatments are delivered first. Stepped care has a built in 'self-correcting' mechanism so that people who do not benefit from initial treatments can be 'stepped up' to more intensive treatments as needed. Matched care follows the principles of stepped care, but also takes into account other factors such as patient presentation, previous experience of treatment, patient choice and preferences. See the matched care model visual summary. ## Treatment manuals Treatment manuals are based on those that were used in the trials that provided the evidence for the efficacy of treatments recommended in this guideline.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Stopping antidepressants What is the incidence and severity of withdrawal symptoms for antidepressant medication? For a short explanation of why the committee made the recommendation for research, see the rationale section on starting and stopping antidepressants . For full details of the evidence and the committee's discussion, see the evidence reviews for the NICE guideline on safe prescribing (evidence review A: patient information and support; evidence review B: prescribing strategies; evidence review C: safe withdrawal; evidence review D: withdrawal interventions; evidence review E: monitoring). Full details of the research recommendation have been added to evidence review B: treatment of a new episode of depression. Loading. Please wait. ## Relapse prevention What is the effectiveness and cost effectiveness of brief courses of psychological treatment in preventing relapse for people who have had a successful course of treatment with antidepressants or psychological therapies but remain at high risk of relapse? For a short explanation of why the committee made the recommendation for research, see the rationale section on preventing relapse . Full details of the evidence and the committee's discussion are in evidence review C: preventing relapse. Loading. Please wait. ## Further-line treatment What are the relative benefits and harms of further-line psychological, psychosocial, pharmacological and physical treatments (alone or in combination), for adults with depression showing an inadequate response to an initial psychological treatment for the current episode? For a short explanation of why the committee made the recommendation for research, see the rationale section on further-line treatment . Full details of the evidence and the committee's discussion are in evidence review D: further-line treatment. Loading. Please wait. ## Chronic depression Are psychological, pharmacological or a combination of these treatments effective and cost effective for the treatment of older adults with chronic depressive symptoms? For a short explanation of why the committee made the recommendation for research, see the rationale section on chronic depressive symptoms . Full details of the evidence and the committee's discussion are in evidence review E: chronic depression. Loading. Please wait. ## Access What are the most effective and cost-effective methods to promote increased access to, and uptake of, treatments for people with depression who are under-served and under-represented in current services? For a short explanation of why the committee made the recommendation for research, see the rationale section on access to services . Full details of the evidence and the committee's discussion are in evidence review H: access to services. Loading. Please wait. # Other recommendations for research ## First-line treatment of less severe depression Is peer support an effective and cost-effective treatment in improving outcomes, including symptoms, personal and social functioning and quality of life in adults as a stand-alone treatment in people with less severe depression and as an adjunct to other evidence-based treatments in more severe depression? What are the mechanisms of action of effective psychological treatments for acute episodes of depression in adults? (This question is applicable to less severe and more severe depression.) For a short explanation of why the committee made these recommendations for research, see the rationale section on treatment for a new episode of less severe depression . Full details of the evidence and the committee's discussion are in evidence review B: treatment of a new episode of depression. Loading. Please wait. ## First-line treatment of more severe depression What is the effectiveness and cost effectiveness of combination treatment with acupuncture and antidepressants in people with more severe depression in the UK? For a short explanation of why the committee made these recommendations for research, see the rationale section on treatment for a new episode of more severe depression . Full details of the evidence and the committee's discussion are in evidence review B: treatment of a new episode of depression. Loading. Please wait. ## Chronic depression What is the effectiveness, acceptability and safety of monoamine oxidase inhibitors (MAOIs; for example, phenelzine) compared to alternative SSRI or SNRI options in treatment-resistant chronic depression with anhedonia? How can identifying and focusing on the social determinants of chronic depression, and on the outcomes that matter to people with depression, enable greater precision for targeting the relevant causal factors and mechanisms that contribute to sustained recovery? For a short explanation of why the committee made these recommendations for research, see the rationale section on chronic depressive symptoms . Full details of the evidence and the committee's discussion are in evidence review E: chronic depression. Loading. Please wait. ## Psychotic depression What are the most effective and cost-effective interventions for the treatment and management of psychotic depression (including consideration of pharmacological, psychological, psychosocial interventions and electroconvulsive therapy )? For a short explanation of why the committee made the recommendation for research, see the rationale section on psychotic depression . Full details of the evidence and the committee's discussion are in evidence review G: psychotic depression. Loading. Please wait. ## Electroconvulsive therapy Is maintenance electroconvulsive therapy (ECT) effective and safe for relapse prevention in people with severe and recurring depression whose depression has remitted on ECT? For a short explanation of why the committee made the recommendation for research, see the rationale section on preventing relapse . Full details of the evidence and the committee's discussion are in evidence review C: preventing relapse. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice or services. # Choice of treatments Recommendations 1.3.1 to 1.3.6 ## Why the committee made the recommendations The evidence showed that both people with depression and healthcare professionals want time to engage in meaningful discussions and to build trusting relationships with healthcare professionals who they feel comfortable with, so that people with depression can be actively involved in decision making about treatment options and choices. There was evidence that people's involvement in making choices about their treatment may be impacted by preconceptions about different treatment options, the depression symptoms themselves, and the resources available. ## How the recommendations might affect practice Offering people choice of treatments and discussing treatment options may mean longer consultation times are needed, and this may have a resource impact for the NHS. However, providing information about choices is likely to lead to improved adherence with therapy and better outcomes for people with depression, offsetting any costs associated with longer consultations. Return to recommendations # Starting and stopping antidepressants Recommendations 1.4.10 to 1.4.23 ## Why the committee made the recommendations The committee reviewed the evidence on antidepressants identified as part of the development of the NICE guideline on safe prescribing, and used this together with their knowledge and experience to develop recommendations. There was some limited evidence that people with depression wanted information about how and when they would be monitored when prescribed antidepressants, and that they appreciated being able to self-monitor their symptoms as this was empowering. There was also some limited evidence that, when planning to stop medication, tapering antidepressants may reduce withdrawal effects. The committee used their knowledge to add more detail to the recommendations on techniques for tapering, drugs that may be associated with more withdrawal symptoms, and those which could be tapered more quickly such as fluoxetine. There was evidence on the range of adverse effects that people experienced when withdrawing from antidepressants, but the committee agreed that more detailed information on incidence and severity for specific interventions would be useful to inform patient choice and so they made a research recommendation on stopping antidepressants. There was evidence on the information needs and support needs of people with depression, that showed that people would like to receive realistic information about the potential benefits and harms of antidepressants, how long they will take to work, the length of treatment and the process of withdrawal. The evidence also showed they value support from healthcare professionals when withdrawing from medication, including a recognition of their fears and concerns about the withdrawal process. ## How the recommendations might affect practice The recommendations reflect current practice, but may reduce variation in practice across the NHS. Return to recommendations # Use of lithium as augmentation Recommendations 1.4.28 to 1.4.31, 1.4.33 and 1.4.34 ## Why the committee made the recommendations The committee made the recommendations on the use of lithium by informal consensus and based on their knowledge and experience and in line with the monitoring requirements specified in the BNF. ## How the recommendations might affect practice The recommendations reflect current practice, but may reduce variation in practice across the NHS. Return to recommendations # Use of oral antipsychotics as augmentation Recommendations 1.4.35 to 1.4.39 ## Why the committee made the recommendations The committee made the recommendations on the use of antipsychotics by informal consensus and based on their knowledge and experience and in line with the monitoring requirements for antipsychotics specified in the BNF and the NICE guideline on psychosis and schizophrenia. ## How the recommendations might affect practice The recommendations reflect current practice, but may reduce variation in practice across the NHS. Return to recommendations # Activities to help wellbeing Recommendations 1.4.42 and 1.4.43 ## Why the committee made the recommendations The committee were aware, based on their knowledge and experience, that informal exercise, and particularly exercise outdoors, may lead to an improved sense of wellbeing. They were also aware that a healthy lifestyle may improve a sense of wellbeing. These views were confirmed by stakeholder comments ## How the recommendations might affect practice The recommendations may encourage conversations about the value of informal exercise and a healthy lifestyle, but as this is self-directed exercise and lifestyle changes there will not be resource implications for the NHS. Return to recommendations # Treatment for a new episode of less severe depression Recommendations 1.5.2 and 1.5.3 ## Why the committee made the recommendations There was good evidence for the effectiveness of group cognitive behavioural therapy (CBT) and group behavioural activation (BA) and these treatments were found to likely be the most cost effective, on average, for adults with less severe depression. There was also good evidence for the effectiveness of individual BA, individual CBT and some evidence for the effectiveness of guided self-help, and these interventions were also likely to be cost effective. Therefore, these options were provided as alternatives for people who did not wish to participate in group therapy. The committee discussed that, in practice, it was logical to offer the least intrusive and least resource intensive treatments first, and then step up to other treatments if necessary. For this reason, the committee agreed that guided self-help should be considered first for most people with less severe depression. There was some evidence for the effectiveness of group mindfulness and meditation, group exercise, interpersonal psychotherapy (IPT) and antidepressants and they were also cost effective so these were recommended as alternative treatments for people who did not wish to receive CBT or BA (in a group, individual or self-help format). The committee advised that selective serotonin reuptake inhibitors (SSRIs) would be the preferred antidepressants to use in people with less severe depression because of their safety and tolerability. The committee discussed that as the evidence suggested that some psychological therapies were more effective than antidepressants and due to the potential for side effects, medication should not be the default treatment for people with less severe depression, unless it was the person's preference to take antidepressants rather than engage in a psychological intervention. There was some evidence that counselling and short-term psychodynamic psychotherapy (STPP) may be effective, but these treatments did not appear to be as cost effective, on average, at improving the symptoms of less severe depression. However, the committee recognised that these treatments may be helpful for some people and so included them as options as well. The committee provided details of the treatments in a table to allow a discussion between healthcare professionals and people with depression about treatment options. Apart from the advice to use guided self-help first for pragmatic reasons, this table is arranged in order of the committee's consensus on the average effectiveness and cost effectiveness of the treatments in adults with less severe depression, with the most effective and cost effective listed at the top of the table, but to also take into account factors which may promote implementation, such as the use of least intrusive treatments first. However, the committee agreed that choice of therapy should be a personalised decision and that some people may prefer to use a treatment further down the table and that this is a valid choice. As there was a lack of evidence on the effectiveness of peer support, the committee made a research recommendation on peer support. As there was considerable uncertainty in the evidence for the effectiveness and cost effectiveness of psychological interventions, the committee made a further research recommendation to find out if identifying the mode of action of psychological interventions would allow greater differentiation between the interventions and aid patient choice. ## How the recommendations might affect practice The recommendations reflect current practice, but may reduce variation in practice across the NHS. Commissioners and services will need to ensure that a meaningful choice of all NHS-recommended therapies is available, and depending on current availability, this may need an increase in resource use. Initial consultations and assessment may need longer because of the need for detailed discussions to support informed choice, but a positive choice may improve engagement and outcomes. Return to recommendations # Treatment for a new episode of more severe depression Recommendation 1.6.1 ## Why the committee made the recommendation There was good evidence for the effectiveness of combination of CBT with antidepressants, individual CBT and individual behavioural therapies and these treatments also appeared to be cost effective, on average, for adults with more severe depression. There was good evidence for the effectiveness and cost effectiveness of antidepressants (SSRIs, SNRIs, tricyclic antidepressants and mirtazapine) and the committee agreed that SSRIs and SNRIs should be recommended as first line because of their tolerability, but for people whose symptoms had responded well to a TCA in the past and who had no contraindications, a TCA might be preferred. The committee agreed that mirtazapine should not be included as a first-line option, but the committee decided to reserve it for use for further-line treatment. There was some evidence for the effectiveness of counselling and individual problem-solving therapy, both of which also appeared to be cost effective. There was some evidence for the effectiveness of IPT and STPP but these treatments did not appear to be as cost effective, on average, at improving the symptoms of depression. However, the committee recognised that these treatments may be helpful for some people and so included them as options as well. There was some evidence of effectiveness and cost effectiveness for the combination of acupuncture and antidepressants but the committee were aware this evidence was based on Chinese acupuncture which is different to Western acupuncture and so these results may not be applicable to the UK population, so the committee made a research recommendation on acupuncture and antidepressants. Both guided self-help and group exercise were, on average, shown to be effective and appeared to be cost effective, but the committee were concerned that in clinical practice these interventions may be offered to people with severe depression in whom regular contact with a healthcare professional may be of benefit, and so advised that the potential advantages of providing other treatment choices with more therapist contact should be carefully considered first. In addition to the evidence reviewed, the committee were aware of large-scale and pragmatic trials that were excluded from the network meta-analysis (because they involved patient populations that did not meet specific search criteria). However, the results of these studies were largely consistent with the evidence reviewed and supported the recommendations. The committee provided details of the treatments in a table to allow a discussion between healthcare professionals and people with depression about treatment options. This table is arranged in order of the committee's consensus on the average effectiveness and cost effectiveness of the treatments (as well as consideration of implementation factors) with the most effective and cost effective listed at the top of the table, but the committee agreed that choice of therapy should be a personalised decision and that some people may prefer to use a treatment further down the table and that this is a valid choice. ## How the recommendation might affect practice The recommendation reflects current practice, but may reduce variation in practice across the NHS. Commissioners and services will need to ensure that a meaningful choice of all recommended therapies is available, and depending on current availability, this may need an increase in resource use. Initial consultations and assessment may need longer because of the need for detailed discussions to support informed choice, but a positive choice may improve engagement and outcomes. Return to recommendations # Behavioural couples therapy Recommendation 1.7.1 ## Why the committee made the recommendation There was some very limited evidence for the effectiveness of behavioural couples therapy for people with depression and who had problems in their relationship, but the committee agreed this was a treatment that was available through the Improving Access to Psychological Therapy (IAPT) services and should be included as an option in the guideline. ## How the recommendation might affect practice The recommendation reflects current practice, but may reduce variation in practice across the NHS. Return to recommendation # Preventing relapse Recommendations 1.8.1 to 1.8.12 ## Why the committee made the recommendations The committee highlighted a number of risk factors, based on their knowledge of the wider literature and experience, which increase the likelihood of relapse. They agreed that people with a higher risk of relapse should be considered for continuation of treatment, but recognised that not all people would wish to take relapse prevention treatment. They also agreed those who wished to continue on antidepressant medication should be warned about the possible long-term effects. There was good evidence that SSRIs, SNRIs and TCAs, group CBT and mindfulness-based cognitive therapy (MBCT) were effective for relapse prevention and were, on average, cost-effective treatments for people at a high risk of relapse, with data for treatment periods up to 2 years. The committee therefore recommended continuation antidepressant treatment or group CBT or MBCT, with their advice framed to take into account the therapy the person had already received. The committee agreed that psychological therapies used for relapse prevention should explicitly focus on relapse prevention skills. The committee used their knowledge and experience to recommend follow-up arrangements for people on relapse prevention therapy, to ensure that people did not remain on therapy indefinitely. As there was little evidence for the use of brief courses of psychotherapy or maintenance electroconvulsive therapy (ECT) in preventing relapse, the committee made a research recommendation on the effectiveness and cost effectiveness of brief courses of psychological treatment and a research recommendation on maintenance ECT. ## How the recommendations might affect practice The recommendations reflect current practice, but may reduce variation in practice across the NHS. Commissioners and services will need to provide therapies with an explicit relapse prevention component. Return to recommendations # Further-line treatment Recommendations 1.9.1 to 1.9.9 and 1.13.1 to 1.13.9 ## Why the committee made the recommendations The committee made recommendations based on their knowledge and experience that people's symptoms may not respond to treatment for depression for a number of reasons, and that these reasons should be explored and addressed before considering further-line treatment. No evidence was identified for people whose depression had not responded to the use of psychological therapies as first-line treatment, but the committee used their experience to recommend further-line treatment options for people whose depression had initially been treated with psychological therapies. As there was no evidence for people whose symptoms did not respond to initial psychological treatments, the committee made a research recommendation on further-line treatment. For people whose depression had not responded to antidepressants, there was some evidence that augmenting antidepressant regimens with group exercise was effective. There was also some very limited evidence that switching to a different antidepressant or increasing the dose of the antidepressant may be effective. There was also some evidence that a combination of psychological therapy and antidepressants was effective so the committee also recommended the use of combination treatment. Based on the evidence from the review of first-line treatment for more severe depression, the committee agreed that the psychological interventions that had been effective and cost effective for first-line treatment of more severe depression could be used for people whose symptoms had not responded to antidepressants and wished to try a psychological therapy instead. There was evidence that combinations of antidepressants, or combinations of an antidepressant with other treatments (ECT, antipsychotics, lithium, lamotrigine and triiodothyronine), were effective, but the committee agreed these combinations would need specialist advice. There was some limited evidence for the use of ECT as further-line treatment, alone or in combination with exercise, so the committee agreed ECT should remain available as an option for the further-line treatment of depression in certain situations when there has been no or inadequate response to other treatment. Based on their knowledge, experience and awareness of the wider evidence base for ECT, the committee were aware that ECT leads to rapid effects and so they advised that it should also be considered in other circumstances (not just as further-line treatment), when a rapid response was needed, and provided some examples of situations where this might be appropriate. The committee were also aware that there may be people with depression who have had ECT in the past, know it is effective, and express a preference for it. Based on their knowledge and experience, and to ensure better patient experience, the committee reinforced the recommendations about taking into account patient preferences when considering ECT as a treatment option, in line with their recommendations for other treatment options. The committee discussed the existing recommendations on the delivery of ECT and agreed these were still correct and so retained them. However, the committee agreed that there were now recognised up-to-date standards produced by the Royal College of Psychiatrists which covered the standards of service provision needed for a safe and effective ECT service, and a recognised ECT accreditation service (ECTAS), and so the committee recommended that clinics and trusts delivering ECT should be accredited and should adhere to these standards. ## How the recommendations might affect practice The recommendations for further-line treatment reflect current practice, but may reduce variation in practice across the NHS. The recommendations for ECT should ensure the availability of ECT for people if it is an appropriate treatment option for them, but reinforce that it is only a treatment option in certain circumstances. Return to recommendations 1.9.1 to 1.9.9 and 1.13.1 to 1.13.9 # Chronic depressive symptoms Recommendations 1.10.1 to 1.10.6, 1.10.8 and 1.10.9 ## Why the committee made the recommendations There was some evidence for CBT, SSRIs, SNRIs and TCAs for the treatment of chronic depressive symptoms and some very limited evidence that combinations of psychological therapies and antidepressants may be more effective, on average, than either alone. As there was such limited evidence, particularly for older people who may be more susceptible to chronic depression, and for those whose chronic depression may be because of the impact of social determinants, the committee made a research recommendation on the effectiveness and cost effectiveness of psychological, pharmacological or a combination of these treatments. There was some evidence for the effectiveness of other medications, including TCAs, phenelzine, amisulpride and moclobemide for people with chronic depression, so the committee considered these could be used as alternatives with specialist advice in people whose symptoms did not respond to SSRIs or SNRIs. However, this was an extrapolation of the evidence which was for the first-line treatment of chronic depression (not further-line). As there was no evidence for the use of monoamine oxidase inhibitors (MAOIs) for further-line treatment of chronic depression, the committee made a research recommendation on the effectiveness, acceptability and safety of MAOIs. ## How the recommendations might affect practice The recommendations reflect current practice, but may reduce variation in practice across the NHS. Return to recommendations # Depression in people with a diagnosis of personality disorder Recommendations 1.11.1 to 1.11.4 ## Why the committee made the recommendations There was some limited evidence for the effectiveness of psychological therapies in combination with antidepressants for the treatment of depression in people with a personality disorder, and the committee were aware that extended duration of use and multidisciplinary support may be beneficial to improve uptake and adherence. However, the evidence base was very limited, with small studies of low to very low quality. As a result, the committee were not able to recommend a specific antidepressant or psychological therapy, but agreed that the choice should be guided by the person's preference. The committee were also limited by the available data when making recommendations for different types of personality disorders, as the evidence was for mixed or non-specified types of personality disorder. Based on their knowledge and experience, and in accordance with existing NICE guidelines, the committee were aware that in people with depression and personality disorder, treatment of the personality disorder by specialist services may lead to an improvement in depression. ## How the recommendations might affect practice The recommendations may reduce variation in the treatment offered to people presenting with depression and personality disorder, and will reinforce current practice to treat people with personality disorder in a specialist programme. Return to recommendations # Psychotic depression Recommendations 1.12.1 to 1.12.6 ## Why the committee made the recommendations There was some limited evidence that the combination of an antidepressant and an antipsychotic may provide some benefits in the treatment of psychotic depression. There was some evidence for olanzapine and quetiapine, and the committee knew that quetiapine has antidepressant actions as well as antipsychotic actions and is therefore widely used for psychotic depression. The committee discussed that combination therapy would not usually be started in primary care and therefore people who wished to start an antipsychotic, would need a referral to specialist mental health services. Based on their experience, the committee agreed the effectiveness of this combination should be monitored and that people should be reviewed regularly, not left on the combination longer than necessary, and that specialist advice would be needed to determine when the antipsychotic medication could be stopped. As there was limited evidence, the committee made a research recommendation on the most effective and cost-effective interventions for the treatment and management of psychotic depression. ## How the recommendations might affect practice The recommendations reflect current practice, but may reduce variation in practice across the NHS. Return to recommendations # Access to services Recommendations 1.16.1 to 1.16.6 ## Why the committee made the recommendations For recommendations on access to services for all people with depression, the committee used their knowledge and experience of how access to services could be improved using a stepped care or matched care approach by, good integration between primary and secondary care, ensuring information on services was available and using a variety of different methods to deliver services. There was some evidence that modifying the way interventions to treat depression were delivered, such as the co-location of physical and mental health services, use of telephone or online video interventions, collaborative care, and culturally adapted services, led to increased uptake and engagement with services for some men, older people and those from black, Asian and minority ethnic groups with depression. However, as there was limited evidence, the committee made a research recommendation on the most effective and cost-effective methods to promote increased access to, and uptake of, treatments for people with depression who are under-served and under-represented in current services. ## How the recommendations might affect practice Modifying the way treatments are delivered to improve access for certain groups may mean modifications to services are needed, and may have resource implications. However, prompt and effective treatment of depression may lead to reduced health and social care costs in the longer term. Return to recommendations # Collaborative care and specialist care Recommendations 1.16.7 to 1.16.10 ## Why the committee made the recommendations There was good evidence that simple collaborative care improved outcomes in people with depression, and that overall, it was cost effective in people with depression, including older people with depression. There was some evidence that certain components of collaborative care led to benefits, and this was supplemented by the committee's expertise. The committee did not specifically review evidence for specialist care for people with severe depression with multiple complicating problems or significant coexisting conditions. However, based on their in-depth understanding of the evidence base, the committee were aware of studies suggesting benefits for this group of people, and together with their knowledge and expertise, the committee recommended specialist care. ## How the recommendations might affect practice The recommendations on collaborative care may increase resource use but there is evidence that this is cost effective. Specialist care is likely to increase resource use, but will only be necessary for a small number of people, and may offset future costs for long-term care and treatment. Return to recommendations # Crisis care, home treatment and inpatient care Recommendations 1.16.11 to 1.16.14 ## Why the committee made the recommendations There was some evidence that crisis resolution and home treatment (CHRT) teams improved symptoms in people with severe non-psychotic mental illness, and that this was a cost-effective option compared to standard inpatient care. However, based on their experience, the committee recognised that people with more severe depression may need inpatient care. Based on their knowledge and experience, the committee agreed that psychological therapies should be available for people with depression in inpatient settings. ## How the recommendations might affect practice There may be some reduction in costs as CRHT is less costly than inpatient care, and it may prevent longer and more costly inpatient admissions. If used effectively it may also prevent readmission after inpatient stays. Return to recommendations# Context Each year, 6% of adults in England will experience an episode of depression and more than 15% of people will experience an episode of depression over the course of their lifetime. For many people the episode will not be severe, but for more than 20% the depression will be more severe and have a significant impact on their daily lives. Recurrence rates are high: there is a 50% chance of recurrence after a first episode, rising to 70% and 90% after a second or third episode, respectively. Women are between 1.5 and 2.5 times more likely to be diagnosed with depression than men. However, although men are less likely to be diagnosed with depression, they are more likely to die by suicide, have higher levels of substance misuse and are less likely to seek help than women. The symptoms of depression can be disabling and the effects of the illness pervasive. Depression can have a major detrimental effect on a person's personal, social and work life. This places a heavy burden on the person and their carers and dependents, as well as placing considerable demands on the healthcare system. Depression is the leading cause of suicide, accounting for two-thirds of all deaths by suicide. Under-treatment of depression is widespread, because many people are unwilling to seek help for depression and detection of depression by professionals is variable. For example, of the 130 people with depression per 1,000 population, only 80 will consult their GP. Of these 80 people, 49 are not recognised as having depression. This is mainly because they have contacted their GP because of a somatic symptom and do not consider themselves as having a mental health problem (despite the presence of symptoms of depression).	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nDefinitions of depression and severity\n\nDepression refers to a wide range of mental health problems characterised by the absence of a positive affect (a loss of interest and enjoyment in ordinary things and experiences), low mood and a range of associated emotional, cognitive, physical and behavioural symptoms. For more detail, see the International Classification of Diseases-11 (ICD-11) or the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for depression.\n\nDepression severity exists along a continuum and is essentially composed of 3 elements:\n\nsymptoms (which may vary in frequency and intensity)\n\nduration of the disorder\n\nthe impact on personal and social functioning.\n\nSeverity of depression is therefore a consequence of the contribution of all of these elements.\n\nTraditionally, depression severity has been grouped under 4 categories (subthreshold, mild, moderate and severe) but in the development of this guideline the committee wanted to develop a way of representing the severity of depression which best represents the available evidence on the classification and would help the uptake of the recommendations in routine clinical practice. This guideline has therefore defined new episodes of depression as less severe or more severe depression.\n\nLess severe depression encompasses subthreshold and mild depression, and more severe depression encompasses moderate and severe depression. Thresholds on validated scales were used in this guideline as an indicator of severity. For example, a score 16 on the PHQ-9 scale was used, with scores less than 16 defined as less severe depression, and scores of 16 or more defined as more severe depression.\n\n# Principles of care\n\nWhen working with people with depression and their families or carers:\n\nbuild a trusting relationship and work in an open, engaging and non‑judgemental manner\n\nexplore treatment choices (see the recommendations on choice of treatments) in an atmosphere of hope and optimism, explaining the different courses of depression and that recovery is possible\n\nbe aware that stigma and discrimination can be associated with a diagnosis of depression\n\nbe aware that the symptoms of depression itself, and the impact of stigma and discrimination, can make it difficult for people to access mental health services or take up offers of treatment\n\nensure steps are taken to reduce stigma, discrimination and barriers for individuals seeking help for depression (for example, reducing judgemental attitudes, showing compassion, parity of esteem between mental illness and physical illness, treating people as individuals)\n\nensure that discussions take place in settings in which confidentiality, privacy and dignity are respected. [2009, amended 2022]\n\n## Providing information and support\n\nMake sure people with depression are aware of self-help groups, peer support groups and other local and national resources. Follow the guidance on providing information in the NICE guideline on service user experience in adult mental health. [2009, amended 2022]\n\nProvide people with depression with up-to-date and evidence-based verbal and written information about depression and its treatment, appropriate to their language, cultural and communication needs. Follow the sections on communication and information in the NICE guideline on patient experience in adult NHS services. \n\n## Advance decisions and statements\n\nConsider developing advance decisions about treatment choices (including declining treatment) and advance statements collaboratively with people who have recurrent severe depression or depression with psychotic symptoms, and for those who had treatment under the Mental Health Act 2007, in line with the Mental Capacity Act 2005, and review them regularly. Record the decisions and statements and include copies in the person's care plan in primary and secondary care, and give copies to the person and to their family or carer, if the person agrees. [2009, amended 2022]\n\nAdvise people with depression that they can set up a Health and Welfare Lasting Power of Attorney, and support them to do so if appropriate, so that a trusted person can represent their interests and make decisions on their behalf if they do not have the capacity to make decisions themselves at any point. \n\n## Supporting families and carers\n\nWhen families or carers are involved in supporting a person with severe or chronic depression, see the recommendations in the NICE guideline on supporting adult carers on identifying, assessing and meeting the caring, physical and mental health needs of families and carers. [2009, amended 2022]\n\n# Recognition and assessment\n\nBe alert to possible depression (particularly in people with a past history of depression or a chronic physical health problem with associated functional impairment) and consider asking people who may have depression if:\n\nDuring the last month, have they often been bothered by feeling down, depressed or hopeless?\n\nDuring the last month, have they often been bothered by having little interest or pleasure in doing things?See also the NICE guideline on depression in adults with a chronic physical health problem. [2009, amended 2022]\n\nIf a person answers 'yes' to either of the depression identification questions (see recommendation 1.2.1) but the practitioner is not competent to perform a mental health assessment, refer the person to an appropriate professional who can. If this professional is not the person's GP, inform the person's GP about the referral. \n\nIf a person answers 'yes' to either of the depression identification questions (see recommendation 1.2.1) and the practitioner is competent to perform a mental health assessment, review the person's mental state and associated functional, interpersonal and social difficulties. \n\nConsider using a validated measure (for example, for symptoms, functions and/or disability) when assessing a person with suspected depression to inform and evaluate treatment. \n\nIf a person has language or communication difficulties (for example, sensory or cognitive impairments or autism), to help identify possible depression consider:\n\nasking the person about their symptoms directly, using an appropriate method of communication depending on the person's needs (for example, using a British Sign Language interpreter, English interpreter, or augmentative and alternative communication)\n\nasking a family member or carer about the person's symptoms.See also the NICE guideline on mental health problems in people with learning disabilities and the NICE guideline on autism spectrum disorder. [2009, amended 2022]\n\n## Initial assessment\n\nConduct a comprehensive assessment that does not rely simply on a symptom count when assessing a person who may have depression, but also takes into account severity of symptoms, previous history, duration and course of illness. Also, take into account both the degree of functional impairment and/or disability associated with the possible depression and the length of the episode. [2009, amended 2022]\n\nDiscuss with the person how the factors below may have affected the development, course and severity of their depression in addition to assessing symptoms and associated functional impairment:\n\nany history of depression and coexisting mental health or physical disorders\n\nany history of mood elevation (to determine if the depression may be part of bipolar disorder); see the NICE guideline on bipolar disorder\n\nany past experience of, and response to, previous treatments\n\npersonal strengths and resources, including supportive relationships\n\ndifficulties with previous and current interpersonal relationships\n\ncurrent lifestyle (for example, diet, physical activity, sleep)\n\nany recent or past experience of stressful or traumatic life events, such as redundancy, divorce, bereavement, trauma (also see the NICE guideline on post-traumatic stress disorder)\n\nliving conditions, drug (prescribed or illicit) and alcohol use, debt, employment situation, loneliness and social isolation. [2009, amended 2022]\n\n## Risk assessment and management\n\nAlways ask people with depression directly about suicidal ideation and intent. If there is a risk of self-harm or suicide:\n\nassess whether the person has adequate social support and is aware of sources of help\n\narrange help appropriate to the level of need\n\nadvise the person to seek further help if the situation deteriorates. \n\nIf a person with depression presents considerable immediate risk to themselves or others, refer them urgently to specialist mental health services. \n\nAdvise people with depression of the potential for increased agitation, anxiety and suicidal ideation in the initial stages of treatment. Check if they have any of these symptoms and:\n\nensure that the person knows how to seek help promptly\n\nreview the person's treatment if they develop marked and/or prolonged agitation. \n\nAdvise a person with depression and their family or carer to be vigilant for mood changes, agitation, negativity and hopelessness, and suicidal ideation, and to contact their practitioner if concerned. This is particularly important during high-risk periods, such as starting or changing treatment and at times of increased personal stress. [2009, amended 2022]\n\nIf a person with depression is assessed to be at risk of suicide:\n\ndo not withhold treatment for depression on the basis of their suicide risk\n\ntake into account toxicity in overdose if an antidepressant is prescribed, or the person is taking other medication, and if necessary limit the amount of medicine available\n\nconsider increasing the level of support provided, such as more frequent in-person, video call or telephone contact\n\nconsider referral to specialist mental health services.For further advice on risk assessment, see the NICE guideline on self-harm. For further advice on medication, see the recommendations on antidepressant medication for people at risk of suicide. [2009, amended 2022]\n\n## Depression with anxiety\n\nWhen depression is accompanied by symptoms of anxiety, which is particularly common in older people, the first priority should usually be to treat the depression. When the person has an anxiety disorder and comorbid depression or depressive symptoms, consult NICE guidance for the relevant anxiety disorder if available and consider treating the anxiety disorder first. [2009, amended 2022]\n\n## Depression in people with acquired cognitive impairments\n\nWhen assessing a person with suspected depression:\n\nbe aware of any acquired cognitive impairments\n\nif needed, consult with a relevant specialist when developing treatment plans and strategies. \n\nWhen providing interventions for people with an acquired cognitive impairment who have a diagnosis of depression:\n\nif possible, provide the same interventions as for other people with depression\n\nif needed, adjust the method of delivery or length of the intervention to take account of the person's ability to communicate, disability or impairment.For people with depression who also have dementia, see the section on depression and anxiety in the NICE guideline on dementia. [2009, amended 2022]\n\n# Choice of treatments\n\nDiscuss with people with depression:\n\nwhat, if anything, they think might be contributing to the development of their depression (see recommendation 1.2.7)\n\nwhether they have ideas or preferences about starting treatment, and what treatment options they have previously found helpful or might prefer\n\ntheir experience of any prior episodes of depression, or treatments for depression\n\nwhat they hope to gain from treatment. \n\nAllow adequate time for the initial discussion about treatment options, and involve family members, carers or other supporters if agreed by the person with depression. \n\nHelp build a trusting relationship with the person with depression and facilitate continuity of care by:\n\nensuring they can see the same healthcare professional wherever possible\n\nrecording their views and preferences so that other practitioners are aware of these details. \n\nDiscuss with people with depression their preferences for treatments (including declining an offer of treatment, or changing their mind once a treatment has started) by providing:\n\ninformation on what treatments are NICE-recommended, their potential benefits and harms, any waiting times for treatments, and the expected outcomes (see table\xa01 and table\xa02 on the recommended treatments for a new episode of less severe and more severe depression)\n\na choice of:\n\n\n\nthe treatments recommended in this guideline\n\nhow they will be delivered (for example individual or group, in person or remotely) and\n\nwhere they will be delivered\n\n\n\nthe option to attend with a family member or friend when possible, for some or all of their treatment\n\nthe option to express a preference for the gender of the healthcare professional, to see a professional they already have a good relationship with, or to change professional if the relationship is not working. \n\nMake a shared decision with the person about their treatment. See the NICE guideline on shared decision making. \n\nCommissioners and service managers should ensure that people can express a preference for NICE-recommended treatments, that those treatments are available in a timely manner, particularly in severe depression, and that they are monitored to ensure equality of access, provision, outcomes and experience. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on choice of treatments\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: patient choice.\n\nLoading. Please wait.\n\n# Delivery of treatments\n\n## All treatments\n\nWhen considering treatments for people with depression:\n\ncarry out an assessment of need\n\ndevelop a treatment plan\n\ntake into account any physical health problems\n\ntake into account any coexisting mental health problems\n\ndiscuss what factors would make the person most likely to engage with treatment (including reviewing positive and negative experiences of previous treatment)\n\ntake into account previous treatment history\n\naddress any barriers to the delivery of treatments because of any disabilities, language or communication difficulties\n\nensure regular liaison between healthcare professionals in specialist and non-specialist settings, if the person is receiving specialist support or treatment.For people with depression who also have learning disabilities, see the NICE guideline on mental health problems in people with learning disabilities. For people with depression who also have autism, see the NICE guideline on autism spectrum disorder. For people with depression who also have dementia, see the NICE guideline on dementia. For people with depression in pregnancy or the postnatal period, or who are breastfeeding, see the NICE guideline on antenatal and postnatal mental health. For people with depression who are menopausal, see the NICE guideline on menopause. For people with depression and physical health problems, see the NICE guideline on depression in adults with a chronic physical health problem and also see the recommendations on collaborative care. \n\nMatch the choice of treatment to meet the needs and preferences of the person with depression. Use the least intrusive and most resource efficient treatment that is appropriate for their clinical needs, or one that has worked for them in the past. \n\nFor all people with depression having treatment:\n\nreview how well the treatment is working with the person between 2\xa0and 4\xa0weeks after starting treatment\n\nmonitor and evaluate treatment concordance\n\nmonitor for side effects and harms of treatment\n\nmonitor suicidal ideation, particularly in the early weeks of treatment (see also the recommendations on antidepressant medication for people at risk of suicide and recommendations on risk assessment)\n\nconsider routine outcome monitoring (using appropriate validated sessional outcome measures, for example PHQ-9) and follow up. [2009, amended 2022]\n\n## Psychological and psychosocial interventions\n\nInform people if there are waiting lists for a course of treatment and how long the wait is likely to be (for example, the NHS constitution advises that treatment should be started within 18\xa0weeks). Keep in touch with people at regular intervals, ensure they are aware of how to access help if their condition worsens, ensure they are made aware of who they can contact about their progress on the waiting list. Consider providing self-help materials and addressing social support issues in the interim. \n\nUse psychological and psychosocial treatment manuals to guide the form, duration and ending of interventions. [2009, amended 2022]\n\nConsider using competence frameworks developed from treatment manual(s) for psychological and psychosocial interventions to support the effective training, delivery and supervision of interventions. \n\nAll healthcare professionals delivering interventions for people with depression should:\n\nreceive regular clinical supervision\n\nhave their competence monitored and evaluated; this could include their supervisor reviewing video and audio recordings of their work (with patient consent). [2009, amended 2022]\n\nWhen delivering psychological treatments for people with neurodevelopmental or learning disabilities, consider adapting the intervention as advised in the NICE guideline on mental health problems in people with learning disabilities. \n\nWhen people are nearing the end of a course of psychological treatment, discuss ways in which they can maintain the benefits of treatment and ensure their ongoing wellness. \n\n## Pharmacological treatments\n\nWhen offering a person medication for the treatment of depression, discuss and agree a management plan with the person. Include:\n\nthe reasons for offering medication\n\nthe choices of medication (if a number of different antidepressants are suitable)\n\nthe dose, and how the dose may need to be adjusted\n\nthe benefits, covering what improvements the person would like to see in their life and how the medication may help\n\nthe harms, covering both the possible side effects and withdrawal effects, including any side effects they would particularly like to avoid (for example, weight gain, sedation, effects on sexual function)\n\nany concerns they have about taking or stopping the medication (also see the recommendations on stopping medication).Make sure they have written information to take away and to review that is appropriate for their needs. \n\nWhen prescribing antidepressant medication, ensure people have information about:\n\nhow they may be affected when they first start taking antidepressant medication, and what these effects might be\n\nhow long it takes to see an effect (usually, if the antidepressant medication is going to work, within 4\xa0weeks)\n\nwhen their first review will be; this will usually be within 2\xa0weeks to check their symptoms are improving and for side effects, or 1\xa0week after starting antidepressant medication if a new prescription is for a person aged 18\xa0to 25\xa0years or if there is a particular concern for risk of suicide (see recommendations on antidepressant medication for people at risk of suicide)\n\nthe importance of following instructions on how to take antidepressant medication (for example, time of day, interactions with other medicines and alcohol)\n\nwhy regular monitoring is needed, and how often they will need to attend for review\n\nhow they can self-monitor their symptoms, and how this may help them feel involved in their own recovery\n\nthat treatment might need to be taken for at least 6\xa0months after the remission of symptoms, but should be reviewed regularly\n\nhow some side effects may persist throughout treatment\n\nwithdrawal symptoms and how these withdrawal effects can be minimised (see also the recommendations on stopping antidepressant medication). \n\nFor further advice on safe prescribing of antidepressants, see the NICE guideline on medicines associated with dependence or withdrawal symptoms: safe prescribing and withdrawal management for adults. For further advice on the safe and effective use of medicines for people taking 1 or more medicines, see the NICE guideline on medicines optimisation. \n\nAdvise people taking antidepressant medication to talk with the person who prescribed their medication (for example, their primary healthcare or mental health professional) if they want to stop taking it. Explain that it is usually necessary to reduce the dose in stages over time (called 'tapering') but that most people stop antidepressants successfully. \n\nAdvise people taking antidepressant medication that if they stop taking it abruptly, miss doses or do not take a full dose, they may have withdrawal symptoms. Also advise them that withdrawal symptoms do not affect everyone, and can vary in type and severity between individuals. Symptoms may include:\n\nunsteadiness, vertigo or dizziness\n\naltered sensations (for example, electric shock sensations)\n\naltered feelings (for example, irritability, anxiety, low mood tearfulness, panic attacks, irrational fears, confusion, or very rarely suicidal thoughts)\n\nrestlessness or agitation\n\nproblems sleeping\n\nsweating\n\nabdominal symptoms (for example, nausea)\n\npalpitations, tiredness, headaches, and aches in joints and muscles. \n\nExplain to people taking antidepressant medication that:\n\nwithdrawal symptoms can be mild, may appear within a few days of reducing or stopping antidepressant medication, and usually go away within 1\xa0to 2\xa0weeks\n\nwithdrawal can sometimes be more difficult, with symptoms lasting longer (in some cases several weeks, and occasionally several months)\n\nwithdrawal symptoms can sometimes be severe, particularly if the antidepressant medication is stopped suddenly. \n\nRecognise that people may have fears and concerns about stopping their antidepressant medication (for example, the withdrawal effects they may experience, or that their depression will return) and may need support to withdraw successfully, particularly if previous attempts have led to withdrawal symptoms or have not been successful. This could include:\n\ndetails of online or written resources that may be helpful\n\nincreased support from a clinician or therapist (for example, regular check-in phone calls, seeing them more frequently, providing advice about sleep hygiene). \n\nWhen stopping a person's antidepressant medication:\n\ntake into account the pharmacokinetic profile (for example, the half-life of the medication as antidepressants with a short half-life will need to be tapered more slowly) and the duration of treatment\n\nslowly reduce the dose to zero in a step-wise fashion, at each step prescribing a proportion of the previous dose (for example, 50% of previous dose)\n\nconsider using smaller reductions (for example, 25%) as the dose becomes lower\n\nif, once very small doses have been reached, slow tapering cannot be achieved using tablets or capsules, consider using liquid preparations if available\n\nensure the speed and duration of withdrawal is led by and agreed with the person taking the prescribed medication, ensuring that any withdrawal symptoms have resolved or are tolerable before making the next dose reduction\n\ntake into account the broader clinical context such as the potential benefit of more rapid withdrawal if there are serious or intolerable side effects (for example, hyponatraemia or upper gastrointestinal tract bleeding)\n\ntake into account that more rapid withdrawal may be appropriate when switching antidepressants\n\nrecognise that withdrawal may take weeks or months to complete successfully. \n\nMonitor and review people taking antidepressant medication while their dose is being reduced, both for withdrawal symptoms and the return of symptoms of depression. Base the frequency of monitoring on the person's clinical and support needs. \n\nWhen reducing a person's dose of antidepressant medication, be aware that:\n\nwithdrawal symptoms can be experienced with a wide range of antidepressant medication (including tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs], serotonin–norepinephrine reuptake inhibitors [SNRIs], and monoamine oxidase inhibitors [MAOIs])\n\nsome commonly used antidepressants such as paroxetine and venlafaxine, are more likely to be associated with withdrawal symptoms, so particular care is needed with them\n\nfluoxetine's prolonged duration of action means that it can sometimes be safely stopped in the following way:\n\n\n\nin people taking 20\xa0mg fluoxetine a day, a period of alternate day dosing can provide a suitable dose reduction\n\nin people taking higher doses (40\xa0mg to 60\xa0mg fluoxetine a day), use a gradual withdrawal schedule.\n\nallow 1\xa0to 2\xa0weeks to evaluate the effects of dose reduction before considering further dose reductions. \n\n\n\nIf a person has withdrawal symptoms when they stop taking antidepressant medication or reduce their dose, reassure them that they are not having a relapse of their depression. Explain that:\n\nthese symptoms are common\n\nrelapse does not usually happen as soon as you stop taking an antidepressant medication or lower the dose\n\neven if they start taking an antidepressant medication again or increase their dose, the withdrawal symptoms may take a few days to disappear. \n\nIf a person has mild withdrawal symptoms when they stop taking antidepressant medication:\n\nmonitor their symptoms\n\nreassure them that such symptoms are common and usually time‑limited\n\nadvise them to contact the person who prescribed their medication (for example, their primary healthcare or mental health professional) if the symptoms do not improve, or if they get worse. \n\nIf a person has more severe withdrawal symptoms, consider restarting the original antidepressant medication at the previous dose, and then attempt dose reduction at a slower rate with smaller decrements after symptoms have resolved. \n\nFor further advice on stopping antidepressants, see also the NICE guideline on safe prescribing.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on starting and stopping antidepressants\xa0.\n\nFor full details of the evidence and the committee's discussion, see the evidence reviews for the NICE guideline on safe prescribing (evidence review\xa0A: patient information; evidence review\xa0B: prescribing strategies; evidence review\xa0C: safe withdrawal; evidence review\xa0D: withdrawal symptoms; evidence review\xa0F: monitoring.\n\nLoading. Please wait.\n\nWhen prescribing antidepressant medication for people with depression who are aged 18\xa0to 25\xa0years or are thought to be at increased risk of suicide:\n\nassess their mental state and mood before starting the prescription, ideally in person (or by video call or by telephone call if in-person assessment is not possible, or not preferred)\n\nbe aware of the possible increased prevalence of suicidal thoughts, self-harm and suicide in the early stages of antidepressant treatment, and ensure that a risk management strategy is in place (see the section on risk assessment and management)\n\nreview them 1\xa0week after starting the antidepressant medication or increasing the dose for suicidality (ideally in person, or by video call, or by telephone if these options are not possible or not preferred)\n\nreview them again after this as often as needed, but no later than 4\xa0weeks after the appointment at which the antidepressant was started\n\nbase the frequency and method of ongoing review on their circumstances (for example, the availability of support, unstable housing, new life events such as bereavement, break-up of a relationship, loss of employment), and any changes in suicidal ideation or assessed risk of suicide. [2009, amended 2022]\n\nTake into account toxicity in overdose when prescribing an antidepressant medication for people at significant risk of suicide. Do not routinely start treatment with TCAs, except lofepramine, as they are associated with the greatest risk in overdose. [2009, amended 2022]\n\nWhen prescribing antidepressant medication for older people:\n\ntake into account the person's general physical health, comorbidities and possible interactions with any other medicines they may be taking\n\ncarefully monitor the person for side effects\n\nbe alert to an increased risk of falls and fractures\n\nbe alert to the risks of hyponatraemia (particularly in those with other risk factors for hyponatraemia, such as concomitant use of diuretics).See also the NICE guideline on dementia: assessment, management and support for people living with dementia and their carers. [2009, amended 2022]\n\nFor people with depression taking lithium, assess weight, renal and thyroid function and calcium levels before treatment and then monitor at least every 6\xa0months during treatment, or more often if there is evidence of significant renal impairment. [2009, amended 2022]\n\nFor women of reproductive age, in particular if they are planning a pregnancy, discuss the risks and benefits of lithium, preconception planning and the need for additional monitoring. \n\nMonitor serum lithium levels 12\xa0hours post dose, 1\xa0week after starting treatment and 1\xa0week after each dose change, and then weekly until levels are stable. Adjust the dose according to serum levels until the target level is reached.\n\nwhen the dose is stable, monitor every 3\xa0months for the first year\n\nafter the first year, measure plasma lithium levels every 6\xa0months, or every 3\xa0months for people in any of the following groups:\n\n\n\nolder people\n\npeople taking medicines that interact with lithium\n\npeople who are at risk of impaired renal or thyroid function, raised calcium levels or other complications\n\npeople who have poor symptom control\n\npeople with poor adherence\n\npeople whose last plasma lithium level was 0.8\xa0mmol per litre or higher. \n\n\n\nDetermine the dose of lithium according to response and tolerability:\n\nplasma lithium levels should not exceed 1.0\xa0mmol/L (therapeutic levels for augmentation of antidepressant medication are usually at or above 0.4\xa0mmol/L; consider levels 0.4 to 0.6\xa0mmol/L for older people aged\xa065 or above)\n\ndo not start repeat prescriptions until lithium levels and renal function are stable\n\ntake into account a person's overall physical health when reviewing test results (including possible dehydration or infection)\n\ntake into account any changes to concomitant medication (for example, angiotensin-converting enzyme inhibitors, angiotensin 2 receptor blockers, diuretics and non-steroidal anti-inflammatory drugs [NSAIDs], or over-the-counter preparations) which may affect lithium levels, and seek specialist advice if necessary\n\nmonitor at each review for signs of lithium toxicity, including diarrhoea, vomiting, coarse tremor, ataxia, confusion and convulsions\n\nseek specialist advice if there is uncertainty about the interpretation of any test results. \n\nManage lithium prescribing under shared care arrangements. If there are concerns about toxicity or side effects (for example, in older people or people with renal impairment), manage their lithium prescribing in conjunction with specialist secondary care services. \n\nConsider electrocardiogram (ECG) monitoring in people taking lithium who have a high risk of, or existing, cardiovascular disease. \n\nProvide people taking lithium with information on how to do so safely, including the NHS lithium treatment pack. \n\nOnly stop lithium in specialist mental health services, or with their advice. When stopping lithium, whenever possible reduce doses gradually over 1\xa0to 3\xa0months. \n\nFor a short explanation of why the committee made these consensus recommendations and how they might affect practice, see the rationale and impact section on use of lithium as augmentation\xa0.\n\nLoading. Please wait.\n\nIn June\xa02022, use of antipsychotics for the treatment of depression was an off-label use for some antipsychotics. See NICE's information on prescribing medicines.\n\nBefore starting an antipsychotic, check the person's baseline pulse and blood pressure, weight, nutritional status, diet, level of physical activity, fasting blood glucose or HbA1c and fasting lipids. \n\nCarry out monitoring as indicated in the summary of product characteristics for individual medicines, for people who take an antipsychotic for the treatment of their depression. This may include:\n\nmonitoring full blood count, urea and electrolytes, liver function tests and prolactin\n\nmonitoring their weight weekly for the first 6\xa0weeks, then at 12\xa0weeks, 1\xa0year and annually\n\nmonitoring their fasting blood glucose or HbA1c and fasting lipids at 12\xa0weeks, 1\xa0year, and then annually\n\nECG monitoring (at baseline and when final dose is reached) for people with established cardiovascular disease or a specific cardiovascular risk (such as diagnosis of high blood pressure) and for those taking other medicines known to prolong the cardiac QT interval (for example, citalopram or escitalopram)\n\nat each review, monitoring for adverse effects, including extrapyramidal effects (for example, tremor, parkinsonism) and prolactin-related side effects (for example, sexual or menstrual disturbances) and reducing the dose if necessary\n\nbeing aware of any possible drug interactions which may increase the levels of some antipsychotics, and monitoring and adjusting doses if necessary\n\nif there is rapid or excessive weight gain, or abnormal lipid or blood glucose levels, investigating and managing as needed. \n\nManage antipsychotic prescribing under shared care arrangements. \n\nFor people with depression who are taking an antipsychotic, consider at each review whether to continue the antipsychotic based on their current physical and mental health risks. \n\nOnly stop antipsychotics in specialist mental health services, or with their advice. When stopping antipsychotics, reduce doses gradually over at least 4\xa0weeks and in proportion to the length of treatment. \n\nFor a short explanation of why the committee made these consensus recommendations and how they might affect practice, see the rationale and impact section on use of oral antipsychotics as augmentation\xa0.\n\nLoading. Please wait.\n\nAlthough there is evidence that St John's Wort may be of benefit in less severe depression, healthcare professionals should:\n\nadvise people with depression of the different potencies of the preparations available and of the potential serious interactions of St John's Wort with other drugs\n\nnot prescribe or advise its use by people with depression because of uncertainty about appropriate doses, persistence of effect, variation in the nature of preparations and potential serious interactions with other drugs (including hormonal contraceptives, anticoagulants and anticonvulsants). \n\n## Physical treatments and activities\n\nAdvise people with winter depression that follows a seasonal pattern and who wish to try light therapy in preference to antidepressant medication or psychological treatment that the evidence for the efficacy of light therapy is uncertain. \n\nAdvise people that doing any form of physical activity on a regular basis (for example, walking, jogging, swimming, dance, gardening) could help enhance their sense of wellbeing. The benefits can be greater if this activity is outdoors. \n\nAdvise people that maintaining a healthy lifestyle (for example, eating a healthy diet, not over-using alcohol, getting enough sleep) may help improve their sense of wellbeing. See the also the NHS advice on mental wellbeing. \n\nFor a short explanation of why the committee made these consensus recommendations and how they might affect practice, see the rationale and impact section on activities to help wellbeing\xa0.\n\nLoading. Please wait.\n\n# Treatment for a new episode of less severe depression\n\nIn this guideline, the term less severe depression includes the traditional categories of subthreshold symptoms and mild depression.\n\n## Active monitoring in people who do not want treatment\n\nFor people with less severe depression who do not want treatment, or people who feel that their depressive symptoms are improving:\n\ndiscuss the presenting problem(s) and any underlying vulnerabilities and risk factors, as well as any concerns that the person may have\n\nmake sure the person knows they can change their mind and how to seek help\n\nprovide information about the nature and course of depression\n\narrange a further assessment, normally within 2\xa0to 4\xa0weeks\n\nmake contact (with repeated attempts if necessary), if the person does not attend follow-up appointments. [2009, amended 2022]\n\n## Treatment options\n\nDiscuss treatment options with people with a new episode of less severe depression, and match their choice of treatment to their clinical needs and preferences:\n\nuse table\xa01 and the visual summary to guide and inform the conversation\n\ntake into account that all treatments in table\xa01 can be used as first-line treatments, but consider the least intrusive and least resource intensive treatment first (guided self-help)\n\nreach a shared decision on a treatment choice appropriate to the person's clinical needs, taking into account their preferences (see also the recommendations on choice of treatments)\n\nrecognise that people have a right to decline treatment. \n\nDo not routinely offer antidepressant medication as first-line treatment for less severe depression, unless that is the person's preference. \n\nTreatment\n\nHow is this delivered?\n\nKey features\n\nOther things to think about\n\nGuided self-help\n\nPrinted or digital materials that follow the principles of guided self-help including structured cognitive behavioural therapy (CBT), structured behavioural activation (BA), problem-solving or psychoeducation materials. These can be delivered in person, by telephone, or online.\n\nSupport from a trained practitioner who facilitates the self-help intervention, encourages completion and reviews progress and outcomes.\n\nUsually consists of 6 to 8 structured regular sessions.\n\nFocuses on how thoughts, beliefs, attitudes, feelings and behaviour interact, and teaches coping skills to deal with things in life differently.\n\nGoal-oriented and structured.\n\nFocuses on resolving current issues.\n\nMay suit people who do not like talking about their depression in a group.\n\nNeeds self-motivation and willingness to work alone (although regular support is provided).\n\nAllows flexibility in terms of fitting sessions in around other commitments.\n\nNeed to consider access, and ability to engage with computer programme for digital formats.\n\nLess capacity for individual adaptations than individual psychological treatments.\n\nAvoids potential side effects of medication.\n\nGroup cognitive behavioural therapy (CBT)\n\nA group intervention delivered by 2\xa0practitioners, at least 1 of whom has therapy-specific training and competence.\n\nUsually consists of 8 regular sessions.\n\nUsually 8\xa0participants in the group.\n\nDelivered in line with current treatment manuals.\n\nFocuses on how thoughts, beliefs, attitudes, feelings and behaviour interact, and teaches coping skills to deal with things in life differently.\n\nGoal-oriented and structured.\n\nFocuses on resolving current issues.\n\nMay be helpful for people who can recognise negative thoughts or unhelpful patterns of behaviour they wish to change.\n\nMay allow peer support from others who may be having similar experiences.\n\nAvoids potential side effects of medication.\n\nThe person will need to be willing to complete homework assignments.\n\n\n\nGroup behavioural activation (BA)\n\nA group intervention delivered by 2\xa0practitioners, at least 1 of whom has therapy-specific training and competence.\n\nUsually consists of 8 regular sessions.\n\nUsually 8\xa0participants in the group.\n\nDelivered in line with current treatment manuals.\n\nFocuses on identifying the link between an individual's activities and their mood. Helps the person to recognise patterns and plan practical changes that reduce avoidance and focus on behaviours that are linked to improved mood.\n\nGoal-oriented and structured.\n\nFocuses on resolving current issues.\n\nDoes not directly target thoughts and feelings.\n\nMay be helpful for people whose depression has led to social withdrawal, doing fewer things, inactivity, or has followed a change of circumstances or routine.\n\nMay allow peer support from others who may be having similar experiences.\n\nAvoids potential side effects of medication.\n\nThe person will need to be willing to complete homework assignments.\n\nIndividual CBT\n\nIndividual intervention delivered by a practitioner with therapy-specific training and competence.\n\nUsually consists of 8 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms.\n\nDelivered in line with current treatment manuals.\n\nFocuses on how thoughts, beliefs, attitudes, feelings and behaviour interact, and teaches coping skills to deal with things in life differently.\n\nGoal-oriented and structured.\n\nFocuses on resolving current issues.\n\nMay be helpful for people who can recognise negative thoughts or unhelpful patterns of behaviour they wish to change.\n\nMay suit people who do not like talking about their depression in a group.\n\nNo opportunity to receive peer support from others who may be having similar experiences.\n\nAvoids potential side effects of medication.\n\nThe person will need to be willing to complete homework assignments.\n\n\n\nIndividual BA\n\nIndividual intervention delivered by a practitioner with therapy-specific training and competence.\n\nUsually consists of 8 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms.\n\nDelivered in line with current treatment manuals.\n\nFocuses on identifying the link between an individual's activities and their mood. Helps the person to recognise patterns and plan practical changes that reduce avoidance and focus on behaviours that are linked to improved mood.\n\nGoal-oriented and structured.\n\nFocuses on resolving current issues.\n\nDoes not directly target thoughts and feelings.\n\nMay be helpful for people whose depression has led to social withdrawal, doing fewer things, inactivity, or has followed a change of circumstances or routine.\n\nMay suit people who do not like talking about their depression in a group.\n\nNo opportunity to receive peer support from others who may be having similar experiences.\n\nAvoids potential side effects of medication.\n\nThe person will need to be willing to complete homework assignments.\n\nGroup exercise\n\nA group physical activity intervention provided by a trained practitioner.\n\nUses a physical activity programme specifically designed for people with depression.\n\nUsually consists of more than 1\xa0session per week for 10\xa0weeks.\n\nUsually 8\xa0participants in the group.\n\nIncludes moderate intensity aerobic exercise.\n\nDoes not directly target thoughts and feelings.\n\nMay allow peer support from others who may be having similar experiences.\n\nMay need to be adapted if the person has physical health problems that make it difficult to exercise.\n\nMay need to be adapted to accommodate psychological aspects, for example anxiety or shame which may act as barriers to engagement.\n\nNeeds a considerable time commitment.\n\nCan help with physical health too.\n\nAvoids potential side effects of medication.\n\nGroup mindfulness and meditation\n\nA group intervention provided preferably by 2\xa0practitioners, at least 1 of whom has therapy-specific training and competence.\n\nUses a programme such as mindfulness-based cognitive therapy specifically designed for people with depression.\n\nUsually consists of 8 regular sessions.\n\nUsually, 8\xa0to\xa015\xa0participants in the group.\n\n\n\nFocus is on concentrating on the present, observing and sitting with thoughts and feelings and bodily sensations, and breathing exercises.\n\nInvolves increasing awareness and recognition of thoughts and feelings, rather than on changing them.\n\nDoes not directly help with relationship, employment or other stressors that may contribute to depression.\n\nMay be helpful for people who want to develop a different perspective on negative thoughts, feelings or bodily sensations.\n\nMay be difficult for people experiencing intense or highly distressing thoughts, or who find focusing on the body difficult.\n\nMay allow peer support from others who may be having similar experiences.\n\nAvoids potential side effects of medication.\n\nThe person will need to be willing to complete homework assignments, including using mindfulness recordings at home in between sessions.\n\nInterpersonal psychotherapy (IPT)\n\nIndividual intervention delivered by a practitioner with therapy-specific training and competence.\n\nUsually consists of 8 to 16 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms.\n\nDelivered in line with current treatment manuals.\n\nFocus is on identifying how interpersonal relationships or circumstances are related to feelings of depression, exploring emotions and changing interpersonal responses.\n\nStructured approach.\n\nFocuses on resolving current issues.\n\nThe goal is to change relationship patterns rather than directly targeting associated depressive thoughts.\n\nMay be helpful for people with depression associated with interpersonal difficulties, especially adjusting to transitions in relationships, loss, or changing interpersonal roles.\n\nMay suit people who do not like talking about their depression in a group.\n\nNeeds a willingness to examine interpersonal relationships.\n\nAvoids potential side effects of medication.\n\nSelective serotonin reuptake inhibitors (SSRIs)\n\nA course of antidepressant medication.\n\nUsually taken for at least 6\xa0months (including after symptoms remit).\n\nSee the recommendations on starting and stopping antidepressant medication for more details.\n\nModify neuronal transmission in the brain.\n\n\n\nMinimal time commitment although regular reviews needed (especially when starting and stopping treatment).\n\nBenefits should be felt within 4\xa0weeks.\n\nThere may be side effects from the medication, and some people may find it difficult to later stop antidepressant medication.\n\nCounselling\n\nIndividual intervention delivered by a practitioner with therapy-specific training and competence.\n\nUsually consists of 8 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms.\n\nUses an empirically validated protocol developed specifically for depression.\n\nFocus is on emotional processing and finding emotional meaning, to help people find their own solutions and develop coping mechanisms.\n\nProvides empathic listening, facilitated emotional exploration and encouragement.\n\nCollaborative use of emotion focused activities to increase self-awareness, to help people gain greater understanding of themselves, their relationships, and their responses to others, but not specific advice to change behaviour.\n\nMay be useful for people with psychosocial, relationship or employment problems contributing to their depression.\n\nMay suit people who do not like talking about their depression in a group.\n\nAvoids potential side effects of medication.\n\nShort-term psychodynamic psychotherapy (STPP)\n\nIndividual sessions delivered by a practitioner with therapy-specific training and competence.\n\nUsually consists of 8 to 16 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms.\n\nUses an empirically validated protocol developed specifically for depression.\n\nFocus is on recognising difficult feelings in significant relationships and stressful situations, and identifying how patterns can be repeated.\n\nBoth insight-oriented and affect focused.\n\nRelationship between therapist and person with depression is included as a focus to help support working through key current conflicts.\n\nMay be useful for people with emotional and developmental difficulties in relationships contributing to their depression.\n\nMay be less suitable for people who do not want to focus on their own feelings, or who do not wish or feel ready to discuss any close and/or family relationships.\n\nMay suit people who do not like talking about their depression in a group.\n\nFocusing on painful experiences in close and/or family relationships could initially be distressing.\n\nAvoids potential side effects of medication.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatment for a new episode of less severe depression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: treatment of a new episode of depression.\n\nLoading. Please wait.\n\n# Treatment for a new episode of more severe depression\n\nIn this guideline the term more severe depression includes the traditional categories of moderate and severe depression.\n\n## Treatment options\n\nDiscuss treatment options with people who have a new episode of more severe depression, and match their choice of treatment to their clinical needs and preferences:\n\nuse table\xa02 and the visual summary to guide and inform the conversation\n\ntake into account that all treatments in table\xa02 can be used as first-line treatments\n\nreach a shared decision on a treatment choice appropriate to the person's clinical needs, taking into account their preferences (see also the recommendations on choice of treatments)\n\nrecognise that people have a right to decline treatment. \n\nTreatment\n\nHow is this delivered?\n\nKey features\n\nOther things to think about\n\nCombination of individual cognitive behavioural therapy (CBT) and an antidepressant\n\nA combination of individual CBT and a course of antidepressant medication (see details below).\n\nCombines the benefits of regular CBT sessions with a therapist and medication.\n\nSessions with a therapist provide immediate support while the medication takes time to work or medication can be started immediately, and then CBT started as soon as possible afterwards to obtain combined effects.\n\nThere may be side effects from the medication, and some people may find it difficult to later stop antidepressant medication.\n\nIndividual CBT\n\nIndividual intervention delivered by a practitioner with therapy-specific training and competence.\n\nUsually consists of 16 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms.\n\nDelivered in line with current treatment manuals.\n\nFocuses on how thoughts, beliefs, attitudes, feelings and behaviour interact, and teaches coping skills to deal with things in life differently.\n\nGoal-oriented and structured.\n\nFocuses on resolving current issues.\n\nMay be helpful for people who can recognise negative thoughts or unhelpful patterns of behaviour they wish to change.\n\nAvoids potential side effects of medication.\n\nThe person will need to be willing to complete homework assignments.\n\n\n\nIndividual behavioural activation (BA)\n\nIndividual intervention delivered by a practitioner with therapy-specific training and competence.\n\nUsually consists of 12 to 16 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms.\n\nDelivered in line with current treatment manuals.\n\nFocuses on identifying the link between an individual's activities and their mood. Helps the person to recognise patterns and plan practical changes that reduce avoidance and focus on behaviours that are linked to improved mood.\n\nGoal-oriented and structured.\n\nFocuses on resolving current issues.\n\nDoes not directly target thoughts and feelings.\n\nMay be helpful for people whose depression has led to social withdrawal, doing fewer things, inactivity, or has followed a change of circumstances or routine.\n\nMay suit people who do not like talking about their depression in a group.\n\nNo opportunity to receive peer support from others who may be having similar experiences.\n\nAvoids potential side effects of medication.\n\nThe person will need to be willing to complete homework assignments.\n\nAntidepressant medication\n\nUsually taken for at least 6\xa0months (and for some time after symptoms remit).\n\nCan be a selective serotonin reuptake inhibitor (SSRI), serotonin–norepinephrine reuptake inhibitor (SNRI), or other antidepressant if indicated based on previous clinical and treatment history.\n\nSee the recommendations on starting and stopping antidepressant medication for more details.\n\nSSRIs are generally well tolerated, have a good safety profile and should be considered as the first choice for most people.\n\nTricyclic antidepressant (TCAs) are dangerous in overdose, although lofepramine has the best safety profile.\n\nChoice of treatment will depend on preference for specific medication effects such as sedation, concomitant illnesses or medications, suicide risk and previous history of response to antidepressant medicines.\n\nMinimal time commitment, although regular reviews needed (especially when starting and stopping treatment).\n\nBenefits should be felt within 4\xa0weeks.\n\nThere may be side effects from the medication, and some people may find it difficult to later stop antidepressant medication.\n\nIndividual problem-solving\n\nIndividual sessions delivered by a practitioner with therapy-specific training and competence.\n\nUsually consists of 6 to 12 regular sessions.\n\nDelivered in line with current treatment manuals.\n\nFocus is on identifying problems, generating alternative solutions, selecting the best option, developing a plan and evaluating whether it has helped solve the problem.\n\nGoal-oriented and structured.\n\nFocuses on resolving current issues.\n\nMay be helpful for people who want to tackle current difficulties and improve future experiences.\n\nAvoids potential side effects of medication.\n\nThe person will need to be willing to complete homework assignments.\n\nCounselling\n\nIndividual sessions delivered by a practitioner with therapy-specific training and competence.\n\nUsually consists of 12 to 16 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms.\n\nUses an empirically validated protocol developed specifically for depression.\n\nFocus is on emotional processing and finding emotional meaning, to help people find their own solutions and develop coping mechanisms.\n\nProvides empathic listening, facilitated emotional exploration and encouragement.\n\nCollaborative use of emotion focused activities to increase self-awareness, to help people gain greater understanding of themselves, their relationships, and their responses to others, but not specific advice to change behaviour.\n\nMay be useful for people with psychosocial, relationship or employment problems contributing to their depression.\n\nMay suit people who do not like talking about their depression in a group.\n\nAvoids potential side effects of medication.\n\nShort-term psychodynamic psychotherapy (STPP)\n\nIndividual sessions delivered by a practitioner with therapy-specific training and competence.\n\nUsually consists of 16 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms.\n\nUses an empirically validated protocol developed specifically for depression.\n\nFocus is on recognising difficult feelings in significant relationships and stressful situations, and identifying how patterns can be repeated.\n\nBoth insight-oriented and affect focused.\n\nRelationship between therapist and person with depression is included as a focus to help support working through key current conflicts.\n\n\n\nMay be useful for people with emotional and developmental difficulties in relationships contributing to their depression.\n\nMay be less suitable for people who do not want to focus on their own feelings, or who do not wish or feel ready to discuss any close and/or family relationships.\n\nMay suit people who do not like talking about their depression in a group.\n\nFocusing on painful experiences in close and/or family relationships could initially be distressing.\n\nAvoids potential side effects of medication.\n\nInterpersonal psychotherapy (IPT)\n\nIndividual sessions delivered by a practitioner with therapy-specific training and competence.\n\nUsually consists of 16 regular sessions, although additional sessions may be needed for people with comorbid mental or physical health problems or complex social needs, or to address residual symptoms.\n\nDelivered in line with current treatment manuals.\n\nFocus is on identifying how interpersonal relationships or circumstances are related to feelings of depression, exploring emotions and changing interpersonal responses.\n\nStructured approach.\n\nFocuses on resolving current issues.\n\nThe goal is to change relationship patterns rather than directly targeting associated depressive thoughts.\n\nMay be helpful for people with depression associated with interpersonal difficulties, especially adjusting to transitions in relationships, loss, or changing interpersonal roles.\n\nMay suit people who do not like talking about their depression in a group.\n\nNeeds a willingness to examine interpersonal relationships.\n\nAvoids potential side effects of medication.\n\nGuided self-help\n\nPrinted or digital materials that follow the principles of guided self-help including structured CBT, structured BA, problem-solving or psychoeducation materials. These can be delivered in person, by telephone, or online.\n\nSupport from a trained practitioner who facilitates the self-help intervention, encourages completion and reviews progress and outcome.\n\nSupport usually consists of 6 to 8 structured, regular sessions.\n\nFocuses on how thoughts, beliefs, attitudes, feelings and behaviour interact, and teaches coping skills to deal with things in life differently.\n\nGoal-oriented and structured.\n\nFocuses on resolving current issues.\n\nIn more severe depression, the potential advantages of providing other treatment choices with more therapist contact should be carefully considered first.\n\nNeeds self-motivation and willingness to work alone (although regular support is provided).\n\nAllows flexibility in terms of fitting sessions in around other commitments.\n\nNeed to consider access, and ability to engage with computer programme for digital formats.\n\nLess capacity for individual adaptations than individual psychological treatments.\n\nAvoids potential side effects of medication.\n\nGroup exercise\n\nA group physical activity intervention provided by a trained practitioner.\n\nUses a physical activity programme specifically designed for people with depression.\n\nUsually consists of more than 1\xa0session per week for 10\xa0weeks.\n\nUsually 8\xa0participants in the group.\n\nIncludes moderate intensity aerobic exercise.\n\nDoes not directly target thoughts and feelings.\n\nIn more severe depression, the potential advantages of providing other treatment choices with more therapist contact should be carefully considered first.\n\nMay allow peer support from others who are may be having similar experiences.\n\nMay need to be adapted if the person has physical health problems that prevent exercise.\n\nMay need to be adapted to accommodate psychological aspects, for example anxiety or shame which may act as barriers to engagement.\n\nNeeds a considerable time commitment.\n\nCan help with physical health too.\n\nAvoids potential side effects of medication.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on treatment for a new episode of more severe depression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: treatment of a new episode of depression.\n\nLoading. Please wait.\n\n# Behavioural couples therapy for depression\n\nConsider behavioural couples therapy for people with either less severe or more severe depression who have problems in the relationship with their partner if:\n\nthe relationship problem(s) could be contributing to their depression, or\n\ninvolving their partner may help in the treatment of their depression. \n\nDeliver behavioural couples therapy for people with depression that:\n\nfollows the behavioural principles for couples therapy\n\nprovides 15 to 20\xa0sessions over 5\xa0to 6\xa0months. \n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on behavioural couples therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: treatment of a new episode of depression.\n\nLoading. Please wait.\n\n# Preventing relapse\n\nDiscuss with people that continuation of treatment (antidepressants or psychological therapies) after full or partial remission may reduce their risk of relapse and may help them stay well. Reach a shared decision on whether or not to continue a treatment for depression based on their clinical needs and preferences. See the visual summary on preventing relapse. \n\nDiscuss with people that the likelihood of having a relapse may be increased if they have:\n\na history of recurrent episodes of depression, particularly if these have occurred frequently or within the last 2\xa0years\n\na history of incomplete response to previous treatment, including residual symptoms\n\nunhelpful coping styles (for example, avoidance and rumination)\n\na history of severe depression (including people with severe functional impairment)\n\nother chronic physical health or mental health problems\n\npersonal, social and environmental factors that contributed to their depression (see recommendation 1.2.7) and that are still present (for example, relationship problems, ongoing stress, poverty, isolation, unemployment). \n\nDiscuss with people the potential risks of continuing with antidepressants long term, and how these balance against the risks of depression relapse. These include:\n\npossible side effects, such as an increased bleeding risk or long-term effects on sexual function\n\ndifficulty stopping antidepressants. \n\nIf a person chooses not to continue antidepressant medication for relapse prevention, advise them:\n\nhow to stop their antidepressant medication (see the recommendations on stopping antidepressant medication) and\n\nto seek help as soon as possible if the symptoms of depression return or residual symptoms worsen. \n\nFor people who have remitted from depression when treated with antidepressant medication alone, but who have been assessed as being at higher risk of relapse, consider:\n\ncontinuing with their antidepressant medication to prevent relapse, maintaining the dose that led to full or partial remission, unless there is good reason to reduce it (such as side effects) or\n\na course of psychological therapy (group CBT or mindfulness-based cognitive therapy [MBCT]) for people who do not wish to continue on antidepressants (follow the recommendations on stopping antidepressants) or\n\ncontinuing with their antidepressant medication and a course of psychological therapy (group CBT or MBCT). \n\nFor people starting group CBT or MBCT for relapse prevention, offer a course of therapy with an explicit focus on the development of relapse prevention skills and what is needed to stay well. This usually consists of 8\xa0sessions over 2\xa0to 3\xa0months with the option of additional sessions in the next 12\xa0months. \n\nRelapse prevention components of psychological interventions may include:\n\nreviewing what lessons and insights were learnt in therapy and what was helpful in therapy\n\nmaking concrete plans to maintain progress beyond the end of therapy including plans to consolidate any changes made to stay well and to continue to practice useful strategies\n\nidentifying stressful circumstances, triggering events, warning signs (such as anxiety or poor sleep), or unhelpful behaviours (such as avoidance or rumination) that have preceded worsening of symptoms and personal or social functioning, and making detailed contingency plans of what to do if each of these re-occur\n\nmaking plans for any anticipated challenging events over the next 12\xa0months, including life changes and anniversaries of difficult events. \n\nDiscuss with people who have remitted from depression when treated with a psychological therapy alone, but who have been assessed as being at higher risk of relapse, whether they wish to continue with their psychological therapy for relapse prevention. Reach a shared decision on further treatment. \n\nDiscuss with people who have remitted from depression when treated with a combination of an antidepressant medication and psychological therapy, but who have been assessed as being at higher risk of relapse, whether they wish to continue 1 or both treatments. Reach a shared decision on further treatment. \n\nContinue the same therapy for people who wish to stay on a psychological therapy for relapse prevention (either alone or in combination with an antidepressant), adapted by the therapist for relapse prevention. This should include at least 4 more sessions of the same treatment with a focus on a relapse prevention component (see recommendation 1.8.7) and what is needed to stay well. \n\nReview treatment for people continuing with antidepressant medication to prevent relapse at least every 6\xa0months. At each review:\n\nmonitor their mood using a validated rating scale (see the recommendations on delivery of treatments)\n\nreview any side effects\n\nreview any medical, personal, social or environmental factors that may affect their risk of relapse, and encourage them to access help from other agencies\n\ndiscuss with them if they wish to continue treatment; if they wish to stop antidepressant treatment, see the recommendations on stopping antidepressant medication. \n\nReassess the risk of relapse for people who continue with psychological therapy to prevent relapse, when they are finishing the relapse prevention treatment, and assess the need for any further follow up. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preventing relapse\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: preventing relapse.\n\nLoading. Please wait.\n\n# Further-line treatment\n\nIf a person's depression has not responded at all after 4\xa0weeks of antidepressant medication at a recognised therapeutic dose, or after 4\xa0to\xa06\xa0weeks for psychological therapy or combined medication and psychological therapy, discuss with them:\n\nwhether there are any personal, social or environmental factors or physical or other mental health conditions that might explain why the treatment is not working\n\nwhether they have had problems adhering to the treatment plan (for example, stopping or reducing medication because of side effects, or missing sessions with their therapist).If any of these are the case, make a shared decision with the person about the best way to try and address any problems raised, including how other agencies may be able to help with these factors. See the visual summary on further-line treatment. \n\nIf a person's depression has not responded to treatment after addressing any problems raised (see recommendation 1.9.1), and allowing an adequate time for treatment changes to work, review the diagnosis and consider the possibility of alternative or comorbid conditions that may limit response to depression treatments. \n\nReassure the person that although treatment has not worked, other treatments can be tried, and may be effective. \n\nIf a person's depression has had no or a limited response to treatment with psychological therapy alone, and no obvious cause can be found and resolved, discuss further treatment options with the person (including what other treatments they have found helpful in the past) and make a shared decision on how to proceed based on their clinical need and preferences. Options include:\n\nswitching to an alternative psychological treatment\n\nadding an SSRI to the psychological therapy\n\nswitching to an SSRI alone. \n\nIf a person's depression has had no or a limited response to treatment with antidepressant medication alone, and no obvious cause can be found and resolved, discuss further treatment options with the person and make a shared decision on how to proceed based on their clinical need and preferences. Options include:\n\nadding a group exercise intervention\n\nswitching to a psychological therapy (see the suggested treatment options for more severe depression)\n\ncontinuing antidepressant therapy by either increasing the dose or changing the drug. For example, by:\n\n\n\nincreasing the dose of the current medication (within the licensed dose range) if the medication is well tolerated; be aware that higher doses of antidepressants may not be more effective and can increase the frequency and severity of side effects; ensure follow-up and frequent monitoring of symptoms and side effects after dose increases.\n\nswitching to another medication in the same class (for example, another SSRI)\n\nswitching to a medication of a different class (for example, an SSRI, SNRI, or in secondary care a TCA or MAOI); take into account that:\n\n\n\nswitching medication may mean cross-tapering is needed; see the NICE clinical knowledge summary on switching antidepressants\n\nswitching to or from an MAOI, or from one MAOI to another, will need to take place in, or with advice from, secondary care\n\nTCAs are dangerous in overdose, although lofepramine has the best safety profile\n\n\n\n\n\nchanging to a combination of psychological therapy (for example, CBT, interpersonal psychotherapy [IPT] or STPP) and medication.Consider whether some of these decisions and treatments need other services to be involved (for example, specialist mental health services for advice on switching antidepressants). \n\nIf a person's depression has had no or a limited response to treatment with a combination of antidepressant medication and psychological therapy, discuss further treatment options with the person and make a shared decision on how to proceed based on their clinical need and preferences. Options include:\n\nswitching to another psychological therapy\n\nincreasing the dose or switching to another antidepressant (see recommendation 1.9.5)\n\nadding in another medication (see recommendation 1.9.9). \n\nOnly consider vortioxetine when there has been no or limited response to at least 2 previous antidepressants. See the NICE technology appraisal guidance on the use of vortioxetine. \n\nIf a person whose depression has had no response or a limited response to antidepressant medication does not want to try a psychological therapy, and instead wants to try a combination of medications, explain the possible increase in their side-effect burden. \n\nIf a person with depression wants to try a combination treatment and is willing to accept the possibility of an increased side-effect burden (see recommendation 1.9.8), consider referral to a specialist mental health setting or consulting a specialist. Treatment options include:\n\nadding an additional antidepressant medication from a different class (for example, adding mirtazapine or trazodone to an SSRI)\n\ncombining an antidepressant medication with a second-generation antipsychotic (for example, aripiprazole, olanzapine, quetiapine or risperidone) or lithium\n\naugmenting antidepressants with electroconvulsive therapy (see the recommendations on electroconvulsive therapy for depression), lamotrigine, or triiodothyronine (liothyronine).Be aware that some combinations of classes of antidepressants are potentially dangerous and should be avoided (for example, a SSRI, SNRI or TCA with a MAOI), and that when using an antipsychotic the effects of this on depression, including loss of interest and motivation, should be carefully reviewed.In June\xa02022, this was an off-label use for some antipsychotics, lamotrigine, and triiodothyronine (liothyronine). See NICE's information on prescribing medicines. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on further-line treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: further-line treatment.\n\nLoading. Please wait.\n\n# Chronic depressive symptoms\n\nBe aware that people presenting with chronic depressive symptoms may not have sought treatment for depression previously and may be unaware that they have depression. Discussions about their mood and symptoms initiated by a healthcare practitioner may help them access treatment and services. See the visual summary on treatment for chronic depression. \n\nFor people who present with chronic depressive symptoms that significantly impair personal and social functioning and who have not received previous treatment for depression, treatment options include:\n\nCBT or\n\nSSRIs or\n\nSNRIs or\n\nTCAs (be aware that TCAs are dangerous in overdose, although lofepramine has the best safety profile) or\n\ncombination therapy with CBT and either an SSRI or a TCA.Discuss the options with the person and reach a shared decision on treatment choice, based on their clinical needs and preferences (see also the recommendations on choice of treatments). \n\nFor people with chronic depressive symptoms, offer cognitive behavioural treatment that:\n\nhas a focus on chronic depressive symptoms\n\ncovers related maintaining processes, including avoidance, rumination and interpersonal difficulties. \n\nFor people who have had, or are still receiving, treatment for depression and who present with chronic depressive symptoms, see the recommendations on further-line treatment. \n\nIf a person with chronic depressive symptoms that significantly impair personal and social functioning cannot tolerate a particular SSRI, consider treatment with an alternative SSRI. \n\nFor people with chronic depressive symptoms that significantly impair personal and social functioning, who have not responded to SSRIs or SNRIs, consider alternative medication in specialist settings, or after consulting a specialist. Take into account that switching medication may mean that an adequate wash-out period is needed, particularly when switching to or from irreversible MAOIs or moclobemide. See the NICE clinical knowledge summary on switching antidepressants. Alternatives include:\n\nTCAs\n\nmoclobemide\n\nirreversible MAOIs such as phenlezine\n\nlow-dose amisulpride (maximum dose of 50\xa0mg daily, as higher doses may worsen depression and lead to side effects such as hyperprolactinaemia and QT interval prolongation).In June\xa02022, this was an off-label use for amisulpride. See NICE's information on prescribing medicines. \n\nFor people with chronic depressive symptoms that significantly impair personal and social functioning, who have been assessed as likely to benefit from extra social or vocational support, consider:\n\nbefriending in combination with existing antidepressant medication or psychological therapy; this should be done by trained volunteers, typically with at least weekly contact for between 2\xa0to 6\xa0months\n\na rehabilitation programme, if their depression has led to loss of work or their withdrawing from social activities over the longer term. [2009, amended 2022]\n\nFor people with no or limited response to treatment for chronic depressive symptoms that significantly impair personal and social functioning who have not responded to the treatments recommended in the sections on further-line treatment and chronic depressive symptoms, offer a referral to specialist mental health services for advice and further treatment. See also the recommendations on collaborative care. \n\nFor people with chronic depressive symptoms that have not responded to the treatments recommended in the sections on further-line treatment and chronic depressive symptoms, and who are on long-term antidepressant medication:\n\nreview the benefits of treatment with the person\n\nconsider stopping the medication (see the recommendations on stopping antidepressants)\n\ndiscuss with the person possible reasons for non-response and what other treatments and support (including from other agencies) may be helpful. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on chronic depressive symptoms\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: chronic depression.\n\nLoading. Please wait.\n\n# Depression in people with a diagnosis of personality disorder\n\nDo not withhold treatment for depression because of a coexisting personality disorder. See the visual summary on treatment of depression with personality disorder. \n\nFor people with depression and a diagnosis of personality disorder consider a combination of antidepressant medication and a psychological treatment (for example, BA, CBT, IPT or STPP). To help people choose between these psychological treatments, see the information on them provided in table\xa01 and table\xa02. \n\nWhen delivering antidepressant medication in combination with psychological treatment for people with depression and a diagnosis of personality disorder:\n\ngive the person support and encourage them to carry on with the treatment\n\nprovide the treatment in a structured, multidisciplinary setting\n\nuse a validated measure of prospective mood monitoring or a symptom checklist or chart to assess response, or any exacerbation of emotional instability\n\nextend the duration of treatment if needed, up to a year. \n\nFor people with depression and a diagnosis of personality disorder, consider referral to a specialist personality disorder treatment programme. See the NICE guideline on borderline personality disorder for recommendations on treatment for borderline personality disorder with coexisting depression. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on depression in people with a diagnosis of personality disorder\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: depression with coexisting personality disorder.\n\nLoading. Please wait.\n\n# Psychotic depression\n\nIn June\xa02022, use of antipsychotics for the treatment of depression was an off-label use for some antipsychotics. See NICE's information on prescribing medicines.\n\nOffer referral to specialist mental health services for people with depression with psychotic symptoms, where the treatment should include:\n\na risk assessment\n\nan assessment of needs\n\na programme of coordinated multidisciplinary care\n\naccess to psychological treatments, after improvement of acute psychotic symptoms.Discuss treatment options and, for those people who have capacity, reach a shared decision based on their clinical needs and preferences. See the visual summary on treatment of psychotic depression. \n\nConsider combination treatment for people with depression with psychotic symptoms with antidepressant medication and antipsychotic medication (for example, olanzapine or quetiapine). \n\nIf a person with depression with psychotic symptoms does not wish to take antipsychotic medication in addition to an antidepressant, then treat with an antidepressant alone. \n\nMonitor people with depression with psychotic symptoms for treatment response (in particular for unusual thought content and hallucinations). \n\nConsider continuing antipsychotic medication for people with depression with psychotic symptoms for a number of months after remission, if tolerated. The decision about if and when to stop antipsychotic medication should be made by, or in consultation with, specialist services. \n\nFor more advice on prescribing and monitoring antipsychotics see the recommendations on use of oral antipsychotics as augmentation and the NICE guideline on psychosis and schizophrenia in adults. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychotic depression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: psychotic depression.\n\nLoading. Please wait.\n\n# Electroconvulsive therapy for depression\n\nConsider electroconvulsive therapy (ECT) for the treatment of severe depression if:\n\nthe person chooses ECT in preference to other treatments based on their past experience of ECT and what has previously worked for them or\n\na rapid response is needed (for example, if the depression is life‑threatening because the person is not eating or drinking) or\n\nother treatments have been unsuccessful (see the recommendations on further-line treatment). \n\nMake sure people with depression who are going to have ECT are fully informed of the risks, and of the risks and benefits specific to them. Take into account:\n\nthe risks associated with a general anaesthetic\n\nany medical comorbidities\n\npotential adverse events, in particular cognitive impairment\n\nif the person is older, the possible increased risk associated with ECT treatment for this age group\n\nthe risks associated with not having ECT.Document the assessment and discussion. \n\nDiscuss the use of ECT as a treatment option with the person with depression, and reach a shared decision on its use based on their clinical needs and preferences, if they have capacity to give consent. Take into account the capacity of the person and the requirements of the Mental Health Act 2007 (if applicable), and make sure:\n\ninformed consent is given without pressure or coercion from the circumstances or clinical setting\n\nthe person is aware of their right to change their mind and withdraw consent at any time\n\nthere is strict adherence to recognised guidelines on consent, and advocates or carers are involved to help informed discussions. \n\nIf a person with depression cannot give informed consent, only give ECT if it does not conflict with a valid advance treatment decision the person made. \n\nFor people whose depression has not responded well to ECT previously, only consider a repeat trial of ECT after:\n\nreviewing the adequacy of the previous treatment course\n\nconsidering all other options\n\ndiscussing the risks and benefits with the person or, if appropriate, their advocate or carer. \n\nClinics should only provide ECT if they:\n\nare Electroconvulsive Therapy Accreditation Service (ECTAS) accredited\n\nprovide ECT services in accordance with ECTAS standards\n\nsubmit data, including outcomes, on each course of acute and maintenance ECT they deliver as needed for the ECTAS minimum dataset.Follow the ECT Accreditation Service Standards for Administering ECT. \n\nTrusts which provide ECT services should ensure compliance with the ECTAS standards for administering ECT through board-level performance management. \n\nStop ECT treatment for a person with depression:\n\nimmediately, if the side effects outweigh the potential benefits, or\n\nwhen stable remission has been achieved. \n\nIf a person's depression has responded to a course of ECT:\n\nstart (or continue) antidepressant medication or a psychological intervention to prevent relapse and to provide ongoing care for their depression (see the recommendations on preventing relapse)\n\nconsider lithium augmentation of antidepressant medication (see the recommendations on further-line treatment). \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on further-line treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: further-line treatment.\n\nLoading. Please wait.\n\n# Transcranial magnetic stimulation for depression\n\nSee the NICE interventional procedures guidance on repetitive transcranial magnetic stimulation for depression.\n\n# Implanted vagus nerve stimulation for treatment-resistant depression\n\nSee the NICE interventional procedures guidance on implanted vagus nerve stimulation for treatment-resistant depression.\n\n# Access, coordination and delivery of care\n\n## Access to services\n\nCommissioners and providers of mental health services should consider using models such as stepped care or matched care for organising the delivery of care and treatment of people with depression. See the matched care model visual summary.Pathways should:\n\npromote easy access to, and uptake of, the treatments covered\n\nallow for prompt assessment of adults with depression, including assessment of severity and risk\n\nensure coordination and continuity of care, with agreed protocols for sharing information\n\nsupport the integrated delivery of services across primary and secondary care, to ensure individuals do not fall into gaps in service provision\n\nhave clear criteria for entry to all levels of a stepped care service\n\nhave multiple entry points and ways to access the service, including self-referral\n\nhave routine collection of data on access to, uptake of and outcomes of the specific treatments in the pathway. \n\nCommissioners and providers of mental health services for people with depression should ensure the effective delivery of treatments. This should build on the key functions of a catchment area-based community mental health service and be provided in the context of a coordinated primary and secondary care mental health service, as well as community services (for example social care, education, housing, statutory services and the voluntary and social enterprise sector). This should include:\n\nassessment procedures\n\nshared decision making\n\ncollaboration between professionals\n\ndelivery of pharmacological, psychological and physical (for example exercise, ECT) interventions\n\ndelivery of interventions for personal, social and environmental factors (for example, housing problems, isolation and unemployment)\n\ncare coordination\n\ninvolvement of service users in design, monitoring and evaluation of services\n\nthe effective monitoring and evaluation of services. \n\nCommissioners and providers of primary and secondary care mental health services should ensure support is in place so integrated services can be delivered by:\n\nindividual practitioners (including primary care healthcare professionals), providing treatments, support or supervision\n\nmental health staff, for team-based treatments in primary care for the majority of people with depression\n\nmental health specialists, providing advice, consultation and support for primary care mental health staff\n\nspecialist-based mental health teams, for people with severe and complex needs. \n\nCommissioners and providers of mental health services should ensure that accessible, inclusive and culturally adapted information about the pathways into treatment and different explanatory models of depression is available, for example in different languages and formats and in line with NHS England's Accessible Information Standard. \n\nCommissioners and providers of mental health services should ensure pathways have the following in place for people with depression to promote access, and increased uptake and retention:\n\nservices delivered in culturally appropriate or culturally adapted language and formats\n\nservices available outside normal working hours\n\na range of different methods to engage with and deliver treatments in addition to in-person meetings, such as text messages, email, telephone and online or remote consultations (where clinically appropriate, and for people who wish to access and are able to access services in this way)\n\nservices provided in community-based settings, for example in a person's home, community centres, leisure centres, care homes, social centres and integrated clinics within primary care (particularly for older people)\n\nservices delivered jointly with charities or the voluntary sector\n\nbilingual therapists or independent translators\n\nprocedures to support active involvement of families, partners and carers, if agreed by the person with depression. \n\nWhen promoting access and uptake of services, identify and address the needs of groups who may have difficulty in accessing, or face stigma or discrimination when using some or all mental health services. This may include:\n\nmen\n\nolder people\n\nlesbian, gay, bisexual and trans people\n\npeople from black, Asian and minority ethnic communities\n\npeople with learning disabilities or acquired cognitive impairments (see the NICE guideline on mental health problems in people with learning disabilities)\n\npeople with physical or sensory disabilities, who may need reasonable adjustments to services as defined by legislation to enable this access; see the Equality Act 2010\n\npeople who have conditions which compromise their ability to communicate\n\npeople who are homeless, refugees and asylum seekers. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on access to services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: access to services.\n\nLoading. Please wait.\n\n## Collaborative care\n\nConsider collaborative care for people with depression, particularly older people, those with significant physical health problems or social isolation, or those with more chronic depression not responding to usual specialist care. \n\nCollaborative care for people with depression should comprise:\n\npatient-centred assessment and engagement\n\nsymptom measurement and monitoring\n\nmedication management (a plan for starting, reviewing and discontinuing medication)\n\nactive care planning and follow up by a designated case manager\n\ndelivery of psychological and psychosocial treatments within a structured protocol\n\nintegrated care of both physical health and mental health\n\njoint working with primary and secondary care colleagues\n\ninvolvement of other agencies that provide support\n\nsupervision of practitioners by an experienced mental health professional. \n\n## Specialist care\n\nRefer people with more severe depression or chronic depressive symptoms, to specialist mental health services for coordinated multidisciplinary care if:\n\ntheir depression significantly impairs personal and social functioning\xa0and\n\nthey have not benefitted from previous treatments, and either\n\n\n\nhave multiple complicating problems, for example unemployment, poor housing or financial problems or\n\nhave significant coexisting mental and physical health conditions. \n\n\n\nDeliver multidisciplinary care plans for people with more severe depression or chronic depressive symptoms (either of which significantly impairs personal and social functioning) and multiple complicating problems, or significant coexisting conditions that:\n\nare developed together with the person, their GP and other relevant people involved in their care (with the person's agreement), and that a copy in an appropriate format is offered to the person\n\nset out the roles and responsibilities of all health and social care professionals involved in delivering the care\n\ninclude information about 24-hour support services, and how to contact them\n\ninclude a crisis plan that identifies potential crisis triggers, and strategies to manage those triggers and their consequences\n\nare updated if there are any significant changes in the person's needs or condition\n\nare reviewed at agreed regular intervals\n\ninclude medication management (a plan for starting, reviewing and discontinuing medication). \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on collaborative care and specialist care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: service delivery.\n\nLoading. Please wait.\n\n## Crisis care, home treatment and inpatient care\n\nConsider crisis resolution and home treatment (CRHT) for people with more severe depression who are at significant risk of:\n\nsuicide, in particular for those who live alone\n\nself-harm\n\nharm to others\n\nself-neglect\n\ncomplications in response to their treatment, for example older people with medical comorbidities. \n\nEnsure teams providing CRHT interventions to support people with depression:\n\nmonitor and manage risk as a high-priority routine activity\n\nestablish and implement a treatment programme\n\nensure continuity of any treatment programme while the person is in contact with the CRHT team, and on discharge or transfer to other services when this is needed\n\nput a crisis management plan in place before the person is discharged from the team's care. \n\nConsider inpatient treatment for people with more severe depression who cannot be adequately supported by a CRHT team. See also the NICE guideline on mental health problems in people with learning disabilities. \n\nMake psychological therapies recommended for the treatment of more severe depression, relapse prevention, chronic depressive symptoms and depression with a diagnosis of personality disorder available for people with depression in secondary care settings (including community and inpatient). \n\nWhen providing psychological therapies for people with depression in inpatient settings:\n\nincrease the intensity and duration of the interventions\n\nensure that they continue to be provided effectively and promptly on discharge. \n\nConsider using CRHT teams for people with depression having a period of inpatient care who might benefit from early discharge from hospital. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on crisis care, home treatment and inpatient care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: service delivery.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Acquired cognitive impairments\n\nCognitive impairments are neurological disorders that affect cognitive abilities (for example, learning, memory, communication and problem-solving). Acquired disorders may be because of medical conditions that affect mental function (for example, dementia, Parkinson's disease or traumatic brain injury).\n\n## Avoidance\n\nAn unhelpful form of coping behaviour in which a person changes their behaviour to avoid thinking about, feeling or doing difficult things. This includes putting things off, reducing activities, not tackling problems, not speaking up for oneself, distraction and using alcohol or substances to numb feelings.\n\n## Chronic depressive symptoms\n\nPeople with chronic depressive symptoms includes those who continually meet criteria for the diagnosis of a major depressive episode for at least 2\xa0years, or have persistent subthreshold symptoms for at least 2\xa0years, or who have persistent low mood with or without concurrent episodes of major depression for at least 2\xa0years. People with depressive symptoms may also have a number of social and personal difficulties that contribute to the maintenance of their chronic depressive symptoms.\n\n## Collaborative care\n\nCollaborative care requires that the service user and healthcare professional jointly identify problems and agree goals for treatments, and normally comprises:\n\ncase management which is supervised and supported by a senior mental health professional\n\nclose collaboration between primary and secondary physical health services and specialist mental health services in the delivery of services\n\nthe provision of a range of evidence-based treatments\n\nthe long-term coordination of care and follow up.\n\n## Depression\n\nIn ICD-11, depression is defined as the presence of depressed mood or diminished interest in activities occurring most of the day, nearly every day, for at least 2\xa0weeks, accompanied by other symptoms such as:\n\nreduced ability to concentrate and sustain attention or marked indecisiveness\n\nbeliefs of low self-worth or excessive or inappropriate guilt\n\nhopelessness about the future\n\nrecurrent thoughts of death or suicidal ideation or evidence of attempted suicide\n\nsignificantly disrupted sleep or excessive sleep\n\nsignificant changes in appetite or weight\n\npsychomotor agitation or retardation\n\nreduced energy or fatigue\n\nIn DSM-5 depression is defined as the presence of 5 or more symptoms from a list of 9\xa0symptoms, during the same 2-week period and where at least 1 of the symptoms is depressed mood or loss of interest or pleasure, most of the day, nearly every day. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The 9\xa0symptoms are:\n\ndepressed mood – indicated by subjective report or observation by others\n\nloss of interest or pleasure in almost all activities – indicated by subjective report or observation by others\n\nsignificant (more than 5% in a month) unintentional weight loss or gain or decrease or increase in appetite\n\nsleep disturbance (insomnia or hypersomnia)\n\npsychomotor changes (agitation or retardation) severe enough to be observable by others\n\ntiredness, fatigue, or low energy, or decreased efficiency with which routine tasks are completed\n\na sense of worthlessness or excessive, inappropriate, or delusional guilt (not merely self-reproach or guilt about being sick)\n\nimpaired ability to think, concentrate, or make decisions – indicated by subjective report or observation by others\n\nrecurrent thoughts of death (not just fear of dying), suicidal ideation, or suicide attempts.\n\nIn this guideline the term 'people with depression' is used. This includes people with a clinical diagnosis of depression and those who feel themselves to be experiencing depression or depressive symptoms, and recognises that people experience, describe and label their experiences of depression in very individual ways.\n\n## Less severe depression\n\nLess severe depression encompasses subthreshold and mild depression, and in this guideline was defined as depression scoring less than 16 on the PHQ-9 scale.\n\n## Medication management\n\nMedication management is giving a person advice on how to keep to a regimen for the use of medication (for example, how to take it, when to take it and how often). The focus in such programmes is only on the management of medication and not on other aspects of depression.\n\n## More severe depression\n\nMore severe depression encompasses moderate and severe depression, and in this guideline was defined as depression scoring\xa016 or more on the PHQ-9 scale.\n\n## Personal and social functioning\n\nPersonal functioning represents the ability of an individual to effectively engage in the normal activities of everyday living and react to experiences. Social functioning is the ability to interact with other people, develop relationships and to gain from and develop these interactions.\n\n## Routine (sessional) outcome monitoring\n\nThis is a system for the monitoring of the outcomes of treatments which involves regular assessment (usually at each contact; referred to as sessional) of symptoms or personal and social functioning using a valid scale. It can inform both service user and practitioner of progress in treatment. It is often supported by computerised delivery and scoring of the measures which ensures better completion of the questionnaires and service level audit and evaluation. Alternative terms such as 'sessional outcome monitoring' or 'sessional outcomes' may also be used which emphasise that outcomes should be recorded at each contact.\n\n## Rumination\n\nRepetitive and prolonged negative thinking about the depression, feelings and symptoms, the self, problems or difficult life events and about their causes, consequences, meanings and implications (for example 'Why did this happen to me?', 'Why can I not get better?').\n\n## Stepped care or matched care\n\nThis is a system of delivering and monitoring treatments, so that the most effective, least intrusive and least resource intensive treatments are delivered first. Stepped care has a built in 'self-correcting' mechanism so that people who do not benefit from initial treatments can be 'stepped up' to more intensive treatments as needed. Matched care follows the principles of stepped care, but also takes into account other factors such as patient presentation, previous experience of treatment, patient choice and preferences.\n\nSee the matched care model visual summary.\n\n## Treatment manuals\n\nTreatment manuals are based on those that were used in the trials that provided the evidence for the efficacy of treatments recommended in this guideline.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Stopping antidepressants\n\nWhat is the incidence and severity of withdrawal symptoms for antidepressant medication?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on starting and stopping antidepressants\xa0.\n\nFor full details of the evidence and the committee's discussion, see the evidence reviews for the NICE guideline on safe prescribing (evidence review\xa0A: patient information and support; evidence review\xa0B: prescribing strategies; evidence review\xa0C: safe withdrawal; evidence review\xa0D: withdrawal interventions; evidence review\xa0E: monitoring).\n\nFull details of the research recommendation have been added to evidence review\xa0B: treatment of a new episode of depression.\n\nLoading. Please wait.\n\n## Relapse prevention\n\nWhat is the effectiveness and cost effectiveness of brief courses of psychological treatment in preventing relapse for people who have had a successful course of treatment with antidepressants or psychological therapies but remain at high risk of relapse?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on preventing relapse\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: preventing relapse.\n\nLoading. Please wait.\n\n## Further-line treatment\n\nWhat are the relative benefits and harms of further-line psychological, psychosocial, pharmacological and physical treatments (alone or in combination), for adults with depression showing an inadequate response to an initial psychological treatment for the current episode?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on further-line treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: further-line treatment.\n\nLoading. Please wait.\n\n## Chronic depression\n\nAre psychological, pharmacological or a combination of these treatments effective and cost effective for the treatment of older adults with chronic depressive symptoms?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on chronic depressive symptoms\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: chronic depression.\n\nLoading. Please wait.\n\n## Access\n\nWhat are the most effective and cost-effective methods to promote increased access to, and uptake of, treatments for people with depression who are under-served and under-represented in current services?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on access to services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: access to services.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## First-line treatment of less severe depression\n\nIs peer support an effective and cost-effective treatment in improving outcomes, including symptoms, personal and social functioning and quality of life in adults as a stand-alone treatment in people with less severe depression and as an adjunct to other evidence-based treatments in more severe depression?\n\nWhat are the mechanisms of action of effective psychological treatments for acute episodes of depression in adults? (This question is applicable to less severe and more severe depression.)\n\nFor a short explanation of why the committee made these recommendations for research, see the rationale section on treatment for a new episode of less severe depression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: treatment of a new episode of depression.\n\nLoading. Please wait.\n\n## First-line treatment of more severe depression\n\nWhat is the effectiveness and cost effectiveness of combination treatment with acupuncture and antidepressants in people with more severe depression in the UK?\n\nFor a short explanation of why the committee made these recommendations for research, see the rationale section on treatment for a new episode of more severe depression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: treatment of a new episode of depression.\n\nLoading. Please wait.\n\n## Chronic depression\n\nWhat is the effectiveness, acceptability and safety of monoamine oxidase inhibitors (MAOIs; for example, phenelzine) compared to alternative SSRI or SNRI options in treatment-resistant chronic depression with anhedonia?\n\nHow can identifying and focusing on the social determinants of chronic depression, and on the outcomes that matter to people with depression, enable greater precision for targeting the relevant causal factors and mechanisms that contribute to sustained recovery?\n\nFor a short explanation of why the committee made these recommendations for research, see the rationale section on chronic depressive symptoms\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: chronic depression.\n\nLoading. Please wait.\n\n## Psychotic depression\n\nWhat are the most effective and cost-effective interventions for the treatment and management of psychotic depression (including consideration of pharmacological, psychological, psychosocial interventions and electroconvulsive therapy [ECT])?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on psychotic depression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: psychotic depression.\n\nLoading. Please wait.\n\n## Electroconvulsive therapy\n\nIs maintenance electroconvulsive therapy (ECT) effective and safe for relapse prevention in people with severe and recurring depression whose depression has remitted on ECT?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on preventing relapse\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: preventing relapse.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice or services.\n\n# Choice of treatments\n\nRecommendations 1.3.1 to 1.3.6\n\n## Why the committee made the recommendations\n\nThe evidence showed that both people with depression and healthcare professionals want time to engage in meaningful discussions and to build trusting relationships with healthcare professionals who they feel comfortable with, so that people with depression can be actively involved in decision making about treatment options and choices. There was evidence that people's involvement in making choices about their treatment may be impacted by preconceptions about different treatment options, the depression symptoms themselves, and the resources available.\n\n## How the recommendations might affect practice\n\nOffering people choice of treatments and discussing treatment options may mean longer consultation times are needed, and this may have a resource impact for the NHS. However, providing information about choices is likely to lead to improved adherence with therapy and better outcomes for people with depression, offsetting any costs associated with longer consultations.\n\nReturn to recommendations\n\n# Starting and stopping antidepressants\n\nRecommendations 1.4.10 to 1.4.23\n\n## Why the committee made the recommendations\n\nThe committee reviewed the evidence on antidepressants identified as part of the development of the NICE guideline on safe prescribing, and used this together with their knowledge and experience to develop recommendations.\n\nThere was some limited evidence that people with depression wanted information about how and when they would be monitored when prescribed antidepressants, and that they appreciated being able to self-monitor their symptoms as this was empowering. There was also some limited evidence that, when planning to stop medication, tapering antidepressants may reduce withdrawal effects. The committee used their knowledge to add more detail to the recommendations on techniques for tapering, drugs that may be associated with more withdrawal symptoms, and those which could be tapered more quickly such as fluoxetine.\n\nThere was evidence on the range of adverse effects that people experienced when withdrawing from antidepressants, but the committee agreed that more detailed information on incidence and severity for specific interventions would be useful to inform patient choice and so they made a research recommendation on stopping antidepressants. There was evidence on the information needs and support needs of people with depression, that showed that people would like to receive realistic information about the potential benefits and harms of antidepressants, how long they will take to work, the length of treatment and the process of withdrawal. The evidence also showed they value support from healthcare professionals when withdrawing from medication, including a recognition of their fears and concerns about the withdrawal process.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice, but may reduce variation in practice across the NHS.\n\nReturn to recommendations\n\n# Use of lithium as augmentation\n\nRecommendations 1.4.28 to 1.4.31, 1.4.33 and 1.4.34\n\n## Why the committee made the recommendations\n\nThe committee made the recommendations on the use of lithium by informal consensus and based on their knowledge and experience and in line with the monitoring requirements specified in the BNF.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice, but may reduce variation in practice across the NHS.\n\nReturn to recommendations\n\n# Use of oral antipsychotics as augmentation\n\nRecommendations 1.4.35 to 1.4.39\n\n## Why the committee made the recommendations\n\nThe committee made the recommendations on the use of antipsychotics by informal consensus and based on their knowledge and experience and in line with the monitoring requirements for antipsychotics specified in the BNF and the NICE guideline on psychosis and schizophrenia.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice, but may reduce variation in practice across the NHS.\n\nReturn to recommendations\n\n# Activities to help wellbeing\n\nRecommendations 1.4.42 and 1.4.43\n\n## Why the committee made the recommendations\n\nThe committee were aware, based on their knowledge and experience, that informal exercise, and particularly exercise outdoors, may lead to an improved sense of wellbeing. They were also aware that a healthy lifestyle may improve a sense of wellbeing. These views were confirmed by stakeholder comments\n\n## How the recommendations might affect practice\n\nThe recommendations may encourage conversations about the value of informal exercise and a healthy lifestyle, but as this is self-directed exercise and lifestyle changes there will not be resource implications for the NHS.\n\nReturn to recommendations\n\n# Treatment for a new episode of less severe depression\n\nRecommendations 1.5.2 and 1.5.3\n\n## Why the committee made the recommendations\n\nThere was good evidence for the effectiveness of group cognitive behavioural therapy (CBT) and group behavioural activation (BA) and these treatments were found to likely be the most cost effective, on average, for adults with less severe depression. There was also good evidence for the effectiveness of individual BA, individual CBT and some evidence for the effectiveness of guided self-help, and these interventions were also likely to be cost effective. Therefore, these options were provided as alternatives for people who did not wish to participate in group therapy. The committee discussed that, in practice, it was logical to offer the least intrusive and least resource intensive treatments first, and then step up to other treatments if necessary. For this reason, the committee agreed that guided self-help should be considered first for most people with less severe depression.\n\nThere was some evidence for the effectiveness of group mindfulness and meditation, group exercise, interpersonal psychotherapy (IPT) and antidepressants and they were also cost effective so these were recommended as alternative treatments for people who did not wish to receive CBT or BA (in a group, individual or self-help format). The committee advised that selective serotonin reuptake inhibitors (SSRIs) would be the preferred antidepressants to use in people with less severe depression because of their safety and tolerability. The committee discussed that as the evidence suggested that some psychological therapies were more effective than antidepressants and due to the potential for side effects, medication should not be the default treatment for people with less severe depression, unless it was the person's preference to take antidepressants rather than engage in a psychological intervention.\n\nThere was some evidence that counselling and short-term psychodynamic psychotherapy (STPP) may be effective, but these treatments did not appear to be as cost effective, on average, at improving the symptoms of less severe depression. However, the committee recognised that these treatments may be helpful for some people and so included them as options as well.\n\nThe committee provided details of the treatments in a table to allow a discussion between healthcare professionals and people with depression about treatment options. Apart from the advice to use guided self-help first for pragmatic reasons, this table is arranged in order of the committee's consensus on the average effectiveness and cost effectiveness of the treatments in adults with less severe depression, with the most effective and cost effective listed at the top of the table, but to also take into account factors which may promote implementation, such as the use of least intrusive treatments first. However, the committee agreed that choice of therapy should be a personalised decision and that some people may prefer to use a treatment further down the table and that this is a valid choice.\n\nAs there was a lack of evidence on the effectiveness of peer support, the committee made a research recommendation on peer support. As there was considerable uncertainty in the evidence for the effectiveness and cost effectiveness of psychological interventions, the committee made a further research recommendation to find out if identifying the mode of action of psychological interventions would allow greater differentiation between the interventions and aid patient choice.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice, but may reduce variation in practice across the NHS. Commissioners and services will need to ensure that a meaningful choice of all NHS-recommended therapies is available, and depending on current availability, this may need an increase in resource use. Initial consultations and assessment may need longer because of the need for detailed discussions to support informed choice, but a positive choice may improve engagement and outcomes.\n\nReturn to recommendations\n\n# Treatment for a new episode of more severe depression\n\nRecommendation 1.6.1\n\n## Why the committee made the recommendation\n\nThere was good evidence for the effectiveness of combination of CBT with antidepressants, individual CBT and individual behavioural therapies and these treatments also appeared to be cost effective, on average, for adults with more severe depression. There was good evidence for the effectiveness and cost effectiveness of antidepressants (SSRIs, SNRIs, tricyclic antidepressants [TCAs] and mirtazapine) and the committee agreed that SSRIs and SNRIs should be recommended as first line because of their tolerability, but for people whose symptoms had responded well to a TCA in the past and who had no contraindications, a TCA might be preferred. The committee agreed that mirtazapine should not be included as a first-line option, but the committee decided to reserve it for use for further-line treatment.\n\nThere was some evidence for the effectiveness of counselling and individual problem-solving therapy, both of which also appeared to be cost effective.\n\nThere was some evidence for the effectiveness of IPT and STPP but these treatments did not appear to be as cost effective, on average, at improving the symptoms of depression. However, the committee recognised that these treatments may be helpful for some people and so included them as options as well.\n\nThere was some evidence of effectiveness and cost effectiveness for the combination of acupuncture and antidepressants but the committee were aware this evidence was based on Chinese acupuncture which is different to Western acupuncture and so these results may not be applicable to the UK population, so the committee made a research recommendation on acupuncture and antidepressants.\n\nBoth guided self-help and group exercise were, on average, shown to be effective and appeared to be cost effective, but the committee were concerned that in clinical practice these interventions may be offered to people with severe depression in whom regular contact with a healthcare professional may be of benefit, and so advised that the potential advantages of providing other treatment choices with more therapist contact should be carefully considered first.\n\nIn addition to the evidence reviewed, the committee were aware of large-scale and pragmatic trials that were excluded from the network meta-analysis (because they involved patient populations that did not meet specific search criteria). However, the results of these studies were largely consistent with the evidence reviewed and supported the recommendations.\n\nThe committee provided details of the treatments in a table to allow a discussion between healthcare professionals and people with depression about treatment options. This table is arranged in order of the committee's consensus on the average effectiveness and cost effectiveness of the treatments (as well as consideration of implementation factors) with the most effective and cost effective listed at the top of the table, but the committee agreed that choice of therapy should be a personalised decision and that some people may prefer to use a treatment further down the table and that this is a valid choice.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice, but may reduce variation in practice across the NHS. Commissioners and services will need to ensure that a meaningful choice of all recommended therapies is available, and depending on current availability, this may need an increase in resource use. Initial consultations and assessment may need longer because of the need for detailed discussions to support informed choice, but a positive choice may improve engagement and outcomes.\n\nReturn to recommendations\n\n# Behavioural couples therapy\n\nRecommendation 1.7.1\n\n## Why the committee made the recommendation\n\nThere was some very limited evidence for the effectiveness of behavioural couples therapy for people with depression and who had problems in their relationship, but the committee agreed this was a treatment that was available through the Improving Access to Psychological Therapy (IAPT) services and should be included as an option in the guideline.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice, but may reduce variation in practice across the NHS.\n\nReturn to recommendation\n\n# Preventing relapse\n\nRecommendations 1.8.1 to 1.8.12\n\n## Why the committee made the recommendations\n\nThe committee highlighted a number of risk factors, based on their knowledge of the wider literature and experience, which increase the likelihood of relapse. They agreed that people with a higher risk of relapse should be considered for continuation of treatment, but recognised that not all people would wish to take relapse prevention treatment. They also agreed those who wished to continue on antidepressant medication should be warned about the possible long-term effects.\n\nThere was good evidence that SSRIs, SNRIs and TCAs, group CBT and mindfulness-based cognitive therapy (MBCT) were effective for relapse prevention and were, on average, cost-effective treatments for people at a high risk of relapse, with data for treatment periods up to 2\xa0years. The committee therefore recommended continuation antidepressant treatment or group CBT or MBCT, with their advice framed to take into account the therapy the person had already received. The committee agreed that psychological therapies used for relapse prevention should explicitly focus on relapse prevention skills.\n\nThe committee used their knowledge and experience to recommend follow-up arrangements for people on relapse prevention therapy, to ensure that people did not remain on therapy indefinitely.\n\nAs there was little evidence for the use of brief courses of psychotherapy or maintenance electroconvulsive therapy (ECT) in preventing relapse, the committee made a research recommendation on the effectiveness and cost effectiveness of brief courses of psychological treatment and a research recommendation on maintenance ECT.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice, but may reduce variation in practice across the NHS. Commissioners and services will need to provide therapies with an explicit relapse prevention component.\n\nReturn to recommendations\n\n# Further-line treatment\n\nRecommendations 1.9.1 to 1.9.9 and 1.13.1 to 1.13.9\n\n## Why the committee made the recommendations\n\nThe committee made recommendations based on their knowledge and experience that people's symptoms may not respond to treatment for depression for a number of reasons, and that these reasons should be explored and addressed before considering further-line treatment.\n\nNo evidence was identified for people whose depression had not responded to the use of psychological therapies as first-line treatment, but the committee used their experience to recommend further-line treatment options for people whose depression had initially been treated with psychological therapies. As there was no evidence for people whose symptoms did not respond to initial psychological treatments, the committee made a research recommendation on further-line treatment.\n\nFor people whose depression had not responded to antidepressants, there was some evidence that augmenting antidepressant regimens with group exercise was effective. There was also some very limited evidence that switching to a different antidepressant or increasing the dose of the antidepressant may be effective. There was also some evidence that a combination of psychological therapy and antidepressants was effective so the committee also recommended the use of combination treatment. Based on the evidence from the review of first-line treatment for more severe depression, the committee agreed that the psychological interventions that had been effective and cost effective for first-line treatment of more severe depression could be used for people whose symptoms had not responded to antidepressants and wished to try a psychological therapy instead.\n\nThere was evidence that combinations of antidepressants, or combinations of an antidepressant with other treatments (ECT, antipsychotics, lithium, lamotrigine and triiodothyronine), were effective, but the committee agreed these combinations would need specialist advice.\n\nThere was some limited evidence for the use of ECT as further-line treatment, alone or in combination with exercise, so the committee agreed ECT should remain available as an option for the further-line treatment of depression in certain situations when there has been no or inadequate response to other treatment. Based on their knowledge, experience and awareness of the wider evidence base for ECT, the committee were aware that ECT leads to rapid effects and so they advised that it should also be considered in other circumstances (not just as further-line treatment), when a rapid response was needed, and provided some examples of situations where this might be appropriate. The committee were also aware that there may be people with depression who have had ECT in the past, know it is effective, and express a preference for it. Based on their knowledge and experience, and to ensure better patient experience, the committee reinforced the recommendations about taking into account patient preferences when considering ECT as a treatment option, in line with their recommendations for other treatment options.\n\nThe committee discussed the existing recommendations on the delivery of ECT and agreed these were still correct and so retained them. However, the committee agreed that there were now recognised up-to-date standards produced by the Royal College of Psychiatrists which covered the standards of service provision needed for a safe and effective ECT service, and a recognised ECT accreditation service (ECTAS), and so the committee recommended that clinics and trusts delivering ECT should be accredited and should adhere to these standards.\n\n## How the recommendations might affect practice\n\nThe recommendations for further-line treatment reflect current practice, but may reduce variation in practice across the NHS. The recommendations for ECT should ensure the availability of ECT for people if it is an appropriate treatment option for them, but reinforce that it is only a treatment option in certain circumstances.\n\nReturn to recommendations 1.9.1 to 1.9.9 and 1.13.1 to 1.13.9\n\n# Chronic depressive symptoms\n\nRecommendations 1.10.1 to 1.10.6, 1.10.8 and 1.10.9\n\n## Why the committee made the recommendations\n\nThere was some evidence for CBT, SSRIs, SNRIs and TCAs for the treatment of chronic depressive symptoms and some very limited evidence that combinations of psychological therapies and antidepressants may be more effective, on average, than either alone. As there was such limited evidence, particularly for older people who may be more susceptible to chronic depression, and for those whose chronic depression may be because of the impact of social determinants, the committee made a research recommendation on the effectiveness and cost effectiveness of psychological, pharmacological or a combination of these treatments.\n\nThere was some evidence for the effectiveness of other medications, including TCAs, phenelzine, amisulpride and moclobemide for people with chronic depression, so the committee considered these could be used as alternatives with specialist advice in people whose symptoms did not respond to SSRIs or SNRIs. However, this was an extrapolation of the evidence which was for the first-line treatment of chronic depression (not further-line). As there was no evidence for the use of monoamine oxidase inhibitors (MAOIs) for further-line treatment of chronic depression, the committee made a research recommendation on the effectiveness, acceptability and safety of MAOIs.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice, but may reduce variation in practice across the NHS.\n\nReturn to recommendations\n\n# Depression in people with a diagnosis of personality disorder\n\nRecommendations 1.11.1 to 1.11.4\n\n## Why the committee made the recommendations\n\nThere was some limited evidence for the effectiveness of psychological therapies in combination with antidepressants for the treatment of depression in people with a personality disorder, and the committee were aware that extended duration of use and multidisciplinary support may be beneficial to improve uptake and adherence. However, the evidence base was very limited, with small studies of low to very low quality. As a result, the committee were not able to recommend a specific antidepressant or psychological therapy, but agreed that the choice should be guided by the person's preference. The committee were also limited by the available data when making recommendations for different types of personality disorders, as the evidence was for mixed or non-specified types of personality disorder.\n\nBased on their knowledge and experience, and in accordance with existing NICE guidelines, the committee were aware that in people with depression and personality disorder, treatment of the personality disorder by specialist services may lead to an improvement in depression.\n\n## How the recommendations might affect practice\n\nThe recommendations may reduce variation in the treatment offered to people presenting with depression and personality disorder, and will reinforce current practice to treat people with personality disorder in a specialist programme.\n\nReturn to recommendations\n\n# Psychotic depression\n\nRecommendations 1.12.1 to 1.12.6\n\n## Why the committee made the recommendations\n\nThere was some limited evidence that the combination of an antidepressant and an antipsychotic may provide some benefits in the treatment of psychotic depression. There was some evidence for olanzapine and quetiapine, and the committee knew that quetiapine has antidepressant actions as well as antipsychotic actions and is therefore widely used for psychotic depression. The committee discussed that combination therapy would not usually be started in primary care and therefore people who wished to start an antipsychotic, would need a referral to specialist mental health services. Based on their experience, the committee agreed the effectiveness of this combination should be monitored and that people should be reviewed regularly, not left on the combination longer than necessary, and that specialist advice would be needed to determine when the antipsychotic medication could be stopped. As there was limited evidence, the committee made a research recommendation on the most effective and cost-effective interventions for the treatment and management of psychotic depression.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice, but may reduce variation in practice across the NHS.\n\nReturn to recommendations\n\n# Access to services\n\nRecommendations 1.16.1 to 1.16.6\n\n## Why the committee made the recommendations\n\nFor recommendations on access to services for all people with depression, the committee used their knowledge and experience of how access to services could be improved using a stepped care or matched care approach by, good integration between primary and secondary care, ensuring information on services was available and using a variety of different methods to deliver services.\n\nThere was some evidence that modifying the way interventions to treat depression were delivered, such as the co-location of physical and mental health services, use of telephone or online video interventions, collaborative care, and culturally adapted services, led to increased uptake and engagement with services for some men, older people and those from black, Asian and minority ethnic groups with depression. However, as there was limited evidence, the committee made a research recommendation on the most effective and cost-effective methods to promote increased access to, and uptake of, treatments for people with depression who are under-served and under-represented in current services.\n\n## How the recommendations might affect practice\n\nModifying the way treatments are delivered to improve access for certain groups may mean modifications to services are needed, and may have resource implications. However, prompt and effective treatment of depression may lead to reduced health and social care costs in the longer term.\n\nReturn to recommendations\n\n# Collaborative care and specialist care\n\nRecommendations 1.16.7 to 1.16.10\n\n## Why the committee made the recommendations\n\nThere was good evidence that simple collaborative care improved outcomes in people with depression, and that overall, it was cost effective in people with depression, including older people with depression.\n\nThere was some evidence that certain components of collaborative care led to benefits, and this was supplemented by the committee's expertise.\n\nThe committee did not specifically review evidence for specialist care for people with severe depression with multiple complicating problems or significant coexisting conditions. However, based on their in-depth understanding of the evidence base, the committee were aware of studies suggesting benefits for this group of people, and together with their knowledge and expertise, the committee recommended specialist care.\n\n## How the recommendations might affect practice\n\nThe recommendations on collaborative care may increase resource use but there is evidence that this is cost effective. Specialist care is likely to increase resource use, but will only be necessary for a small number of people, and may offset future costs for long-term care and treatment.\n\nReturn to recommendations\n\n# Crisis care, home treatment and inpatient care\n\nRecommendations 1.16.11 to 1.16.14\n\n## Why the committee made the recommendations\n\nThere was some evidence that crisis resolution and home treatment (CHRT) teams improved symptoms in people with severe non-psychotic mental illness, and that this was a cost-effective option compared to standard inpatient care. However, based on their experience, the committee recognised that people with more severe depression may need inpatient care.\n\nBased on their knowledge and experience, the committee agreed that psychological therapies should be available for people with depression in inpatient settings.\n\n## How the recommendations might affect practice\n\nThere may be some reduction in costs as CRHT is less costly than inpatient care, and it may prevent longer and more costly inpatient admissions. If used effectively it may also prevent readmission after inpatient stays.\n\nReturn to recommendations", 'Context': "Each year, 6% of adults in England will experience an episode of depression and more than 15% of people will experience an episode of depression over the course of their lifetime. For many people the episode will not be severe, but for more than 20% the depression will be more severe and have a significant impact on their daily lives. Recurrence rates are high: there is a 50% chance of recurrence after a first episode, rising to 70% and 90% after a second or third episode, respectively.\n\nWomen are between 1.5 and 2.5\xa0times more likely to be diagnosed with depression than men. However, although men are less likely to be diagnosed with depression, they are more likely to die by suicide, have higher levels of substance misuse and are less likely to seek help than women.\n\nThe symptoms of depression can be disabling and the effects of the illness pervasive. Depression can have a major detrimental effect on a person's personal, social and work life. This places a heavy burden on the person and their carers and dependents, as well as placing considerable demands on the healthcare system.\n\nDepression is the leading cause of suicide, accounting for two-thirds of all deaths by suicide.\n\nUnder-treatment of depression is widespread, because many people are unwilling to seek help for depression and detection of depression by professionals is variable. For example, of the 130\xa0people with depression per 1,000\xa0population, only 80 will consult their GP. Of these 80\xa0people, 49 are not recognised as having depression. This is mainly because they have contacted their GP because of a somatic symptom and do not consider themselves as having a mental health problem (despite the presence of symptoms of depression)."}	https://www.nice.org.uk/guidance/ng222	This guideline covers identifying, treating and managing depression in people aged 18 and over. It recommends treatments for first episodes of depression and further-line treatments, and provides advice on preventing relapse, and managing chronic depression, psychotic depression and depression with a coexisting diagnosis of personality disorder.
de4e24bbb35ae48fd02aabaf7282e03c436fe6d6	nice	Vertebral body tethering for idiopathic scoliosis in children and young people	Vertebral body tethering for idiopathic scoliosis in children and young people Evidence-based recommendations on vertebral body tethering for idiopathic scoliosis in children and young people. This involves fixing a cord to screws that have been placed into the vertebral bodies (bone discs in the spine), and pulling it taut to restrict growth on the long side of the spine. # Recommendations Evidence on the safety of vertebral body tethering for idiopathic scoliosis in children and young people is limited but raises concerns of serious complications. Evidence on its efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. Further research should include randomised controlled trials or analysis of registry data. This procedure should only be done in specialist centres by spinal surgeons with specific training in anterior spinal surgery.# The condition, current treatments and procedure # The condition Scoliosis is a 3‑dimensional spinal deformity. It causes the bones of the spine to twist or rotate so that the spine curves sideways. Scoliosis curves most commonly happen in the upper and middle back (thoracic spine). It can also develop in the lower back and, occasionally, happens in both the upper and lower parts of the spine. Idiopathic scoliosis is the most common type of scoliosis. It is a progressive condition, and its exact cause is unknown. There are 3 types of idiopathic scoliosis: infantile idiopathic scoliosis, juvenile idiopathic scoliosis and adolescent idiopathic scoliosis. # Current treatments Treatment of idiopathic scoliosis depends on a number of factors, including age, severity and location of the spinal curve, and the pattern and progression of the curve. In many cases, idiopathic scoliosis is mild and does not need treatment other than close monitoring and physical therapy. For moderate and severe scoliosis, treatment may progress through casting and bracing to spinal surgery. # The procedure Vertebral body tethering is a nonfusion spinal treatment for idiopathic scoliosis. The aim is to preserve the flexibility of the spine and modulate its growth on the concave and convex sides, so slowly correcting the scoliosis. In this procedure, under general anaesthesia, screws are placed into each vertebra on the convex side of the spine. The screws are connected by a flexible cord. Tension is then applied to the cord to partially correct and tether the convex side of the spine and so restrict its growth. Thoracic tethers are usually done through a thoracoscopic or open approach and lumbar tethers need a mini‑open approach. After surgery, the cord continues to restrict growth on the convex side while allowing faster growth on the concave side, so potentially producing further correction of the scoliosis. The technique exploits a known reaction of bone to being stretched or being compressed. This response is known as the Heuter‑Volkmann law and notes that bone growth increases when stretched and decreases when compressed. In scoliosis this response can be used on a curved spine if the bones still have significant growth potential.	{'Recommendations': 'Evidence on the safety of vertebral body tethering for idiopathic scoliosis in children and young people is limited but raises concerns of serious complications. Evidence on its efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should include randomised controlled trials or analysis of registry data.\n\nThis procedure should only be done in specialist centres by spinal surgeons with specific training in anterior spinal surgery.', 'The condition, current treatments and procedure': '# The condition\n\nScoliosis is a 3‑dimensional spinal deformity. It causes the bones of the spine to twist or rotate so that the spine curves sideways. Scoliosis curves most commonly happen in the upper and middle back (thoracic spine). It can also develop in the lower back and, occasionally, happens in both the upper and lower parts of the spine.\n\nIdiopathic scoliosis is the most common type of scoliosis. It is a progressive condition, and its exact cause is unknown. There are 3\xa0types of idiopathic scoliosis: infantile idiopathic scoliosis, juvenile idiopathic scoliosis and adolescent idiopathic scoliosis.\n\n# Current treatments\n\nTreatment of idiopathic scoliosis depends on a number of factors, including age, severity and location of the spinal curve, and the pattern and progression of the curve. In many cases, idiopathic scoliosis is mild and does not need treatment other than close monitoring and physical therapy. For moderate and severe scoliosis, treatment may progress through casting and bracing to spinal surgery.\n\n# The procedure\n\nVertebral body tethering is a nonfusion spinal treatment for idiopathic scoliosis. The aim is to preserve the flexibility of the spine and modulate its growth on the concave and convex sides, so slowly correcting the scoliosis.\n\nIn this procedure, under general anaesthesia, screws are placed into each vertebra on the convex side of the spine. The screws are connected by a flexible cord. Tension is then applied to the cord to partially correct and tether the convex side of the spine and so restrict its growth. Thoracic tethers are usually done through a thoracoscopic or open approach and lumbar tethers need a mini‑open approach. After surgery, the cord continues to restrict growth on the convex side while allowing faster growth on the concave side, so potentially producing further correction of the scoliosis.\n\nThe technique exploits a known reaction of bone to being stretched or being compressed. This response is known as the Heuter‑Volkmann law and notes that bone growth increases when stretched and decreases when compressed. In scoliosis this response can be used on a curved spine if the bones still have significant growth potential.'}	https://www.nice.org.uk/guidance/ipg728	Evidence-based recommendations on vertebral body tethering for idiopathic scoliosis in children and young people. This involves fixing a cord to screws that have been placed into the vertebral bodies (bone discs in the spine), and pulling it taut to restrict growth on the long side of the spine.
cf88ebeca592e56465c066dd2aeb8fc7c5ca769d	nice	Nerve graft for corneal denervation	Nerve graft for corneal denervation Evidence-based recommendations on nerve graft for corneal denervation. This involves attaching a healthy nerve to the damaged cornea to improve healing. # Recommendations Evidence on the safety of nerve graft for corneal denervation is limited but raises no major safety concerns. Evidence on efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do nerve graft for corneal denervation should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers as appropriate) clear information to support shared decision making, including NICE's information for the public. Ensure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Further research should be randomised controlled trials, analysis of registry data or case series. Patient selection should be done by clinicians experienced in managing the condition. The procedure should only be done in specialist centres by surgeons with skills and experience in this procedure.# The condition, current treatments and procedure # The condition The cornea is innervated by the ophthalmic branch of the trigeminal nerve. This innervation maintains the health of the cornea. It does this by providing trophic factors to the corneal cells, activating protective blink reflexes, and stimulating tear production. Damage to the trigeminal nerve can result in a decrease or loss of corneal sensation. The trigeminal nerve can be damaged by various diseases, chemical burns, physical injuries, or by surgery. Loss of innervation to the cornea can result in neurotrophic keratitis (also known as neurotrophic keratopathy). People with neurotrophic keratitis typically have corneal epithelium defects, poor corneal healing, and can develop sight loss. They are also prone to corneal infections. # Current treatments Current treatment for neurotrophic keratitis aims to stop progression to later stages of the disease and promote regeneration of the epithelium. This can include topical lubricants and artificial tears. Antibiotic tear drops may be needed to prevent infections. Options for severe disease include lateral tarsorrhaphy (using sutures to partially or fully close the eyelids), topical nerve growth factor, topical collagenase inhibitors and amniotic membrane grafting. # The procedure Nerve graft to restore corneal sensation is done under general anaesthesia. The nerve graft can be either an autograft, when the graft is taken from the person having the procedure, or an allograft, when the graft is a processed nerve from a deceased donor. Several types of grafts have been described in the literature, including the sural nerve, lateral antebrachial cutaneous nerve, great auricular nerve and a nerve from a deceased donor. The nerve graft is harvested or prepared. At the same time, an incision is made on the contralateral side. This is to access an orbital nerve (the supratrochlear, supraorbital or infraorbital nerve) of the eye that still has normal sensation (the 'donor' nerve). In some people, the ipsilateral supratrochlear, supraorbital or infraorbital nerve, or the ipsilateral great auricular nerve is used as a donor nerve. The nerve graft is attached to the donor nerve and then subcutaneously tunnelled to the perilimbal area of the affected eye. The nerve fascicles can either be placed around the entire limbal circumference and secured to the sclera or are inserted into corneoscleral tunnels. The nerve fascicles are secured with sutures or fibrin glue, or both. The conjunctiva is closed and a temporary lateral tarsorrhaphy may be placed. A patch and topical lubricants may be prescribed after surgery. Over time, new nerve endings grow into the cornea. A corneal transplant may be needed to fully restore sight in people with loss of corneal clarity.	{'Recommendations': "Evidence on the safety of nerve graft for corneal denervation is limited but raises no major safety concerns. Evidence on efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do nerve graft for corneal denervation should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers as appropriate) clear information to support shared decision making, including NICE's information for the public.\n\nEnsure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nFurther research should be randomised controlled trials, analysis of registry data or case series.\n\nPatient selection should be done by clinicians experienced in managing the condition.\n\nThe procedure should only be done in specialist centres by surgeons with skills and experience in this procedure.", 'The condition, current treatments and procedure': "# The condition\n\nThe cornea is innervated by the ophthalmic branch of the trigeminal nerve. This innervation maintains the health of the cornea. It does this by providing trophic factors to the corneal cells, activating protective blink reflexes, and stimulating tear production.\n\nDamage to the trigeminal nerve can result in a decrease or loss of corneal sensation. The trigeminal nerve can be damaged by various diseases, chemical burns, physical injuries, or by surgery. Loss of innervation to the cornea can result in neurotrophic keratitis (also known as neurotrophic keratopathy). People with neurotrophic keratitis typically have corneal epithelium defects, poor corneal healing, and can develop sight loss. They are also prone to corneal infections.\n\n# Current treatments\n\nCurrent treatment for neurotrophic keratitis aims to stop progression to later stages of the disease and promote regeneration of the epithelium. This can include topical lubricants and artificial tears. Antibiotic tear drops may be needed to prevent infections. Options for severe disease include lateral tarsorrhaphy (using sutures to partially or fully close the eyelids), topical nerve growth factor, topical collagenase inhibitors and amniotic membrane grafting.\n\n# The procedure\n\nNerve graft to restore corneal sensation is done under general anaesthesia. The nerve graft can be either an autograft, when the graft is taken from the person having the procedure, or an allograft, when the graft is a processed nerve from a deceased donor. Several types of grafts have been described in the literature, including the sural nerve, lateral antebrachial cutaneous nerve, great auricular nerve and a nerve from a deceased donor.\n\nThe nerve graft is harvested or prepared. At the same time, an incision is made on the contralateral side. This is to access an orbital nerve (the supratrochlear, supraorbital or infraorbital nerve) of the eye that still has normal sensation (the 'donor' nerve). In some people, the ipsilateral supratrochlear, supraorbital or infraorbital nerve, or the ipsilateral great auricular nerve is used as a donor nerve. The nerve graft is attached to the donor nerve and then subcutaneously tunnelled to the perilimbal area of the affected eye. The nerve fascicles can either be placed around the entire limbal circumference and secured to the sclera or are inserted into corneoscleral tunnels. The nerve fascicles are secured with sutures or fibrin glue, or both. The conjunctiva is closed and a temporary lateral tarsorrhaphy may be placed. A patch and topical lubricants may be prescribed after surgery. Over time, new nerve endings grow into the cornea. A corneal transplant may be needed to fully restore sight in people with loss of corneal clarity."}	https://www.nice.org.uk/guidance/ipg729	Evidence-based recommendations on nerve graft for corneal denervation. This involves attaching a healthy nerve to the damaged cornea to improve healing.
4878fd5f2b093bf8a7a9c98a6871bc401259bb31	nice	Type 2 diabetes in adults: management	Type 2 diabetes in adults: management This guideline covers care and management for adults (aged 18 and over) with type 2 diabetes. It focuses on patient education, dietary advice, managing cardiovascular risk, managing blood glucose levels, and identifying and managing long-term complications. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Individualised care Adopt an individualised approach to diabetes care that is tailored to the needs and circumstances of adults with type 2 diabetes, taking into account their personal preferences, comorbidities and risks from polypharmacy, and their likelihood of benefiting from long-term interventions. Such an approach is especially important in the context of multimorbidity. Reassess the person's needs and circumstances at each review and think about whether to stop any medicines that are not effective. Take into account any disabilities, including visual impairment, when planning and delivering care for adults with type 2 diabetes. # Education Offer structured education to adults with type 2 diabetes and their family members or carers (as appropriate) at the time of diagnosis, with annual reinforcement and review. Explain to people that structured education is an integral part of diabetes care. Ensure that any structured education programme for adults with type 2 diabetes: is evidence-based, and suits the needs of the person has specific aims and learning objectives, and supports the person and their family members and carers to develop attitudes, beliefs, knowledge and skills to self-manage diabetes has a structured curriculum that is theory driven, evidence-based and resource-effective, has supporting materials and is written down is delivered by trained educators who: have an understanding of educational theory appropriate to the age and needs of the person are trained and competent to deliver the principles and content of the programme is quality assured, and reviewed by trained, competent, independent assessors who measure it against criteria that ensure consistency has outcomes that are audited regularly. Ensure that education programmes for adults with type 2 diabetes provide the necessary resources to support the educators, and that educators are properly trained and given time to develop and maintain their skills. Offer adults with type 2 diabetes group education programmes as the preferred option. Provide an alternative of equal standard for people who are unable or prefer not to take part in group education. Ensure that education programmes for adults with type 2 diabetes meet the cultural, linguistic, cognitive and literacy needs of people in the local area. Ensure that all members of the diabetes healthcare team are familiar with the education programmes available locally for adults with type 2 diabetes, and that these programmes are integrated with the rest of the care pathway. Ensure that adults with type 2 diabetes and their family members and carers (as appropriate) have the opportunity to contribute to the design and provision of local education programmes for adults with type 2 diabetes. # Dietary advice and bariatric surgery Provide individualised and ongoing nutritional advice from a healthcare professional with specific expertise and competencies in nutrition. Provide dietary advice in a form sensitive to the person's needs, culture and beliefs, being sensitive to their willingness to change and the effects on their quality of life. Encourage adults with type 2 diabetes to follow the same healthy eating advice as the general population, which includes: eating high-fibre, low-glycaemic-index sources of carbohydrate, such as fruit, vegetables, wholegrains and pulses choosing low-fat dairy products eating oily fish controlling their intake of saturated and trans fatty acids. Integrate dietary advice with a personalised diabetes management plan, including other aspects of lifestyle modification such as increasing physical activity and losing weight. For adults with type 2 diabetes who are overweight, discuss and agree an initial body weight loss target of 5% to 10%. Remember that a small amount of weight loss may still be beneficial, and a larger amount will have advantageous metabolic impact in the long term. Individualise recommendations for carbohydrate and alcohol intake, and meal patterns. Make reducing the risk of hypoglycaemia a particular aim for people using insulin or an insulin secretagogue. Advise adults with type 2 diabetes that they can substitute a limited amount of sucrose-containing foods for other carbohydrate in the meal plan but should take care to avoid excess energy intake. Discourage adults with type 2 diabetes from using foods marketed specifically for people with diabetes. When adults with type 2 diabetes are admitted as inpatients to hospital or any other care setting, implement a meal planning system that provides consistency in the carbohydrate content of meals and snacks. For recommendations on lifestyle advice, see the NICE guidelines on preventing excess weight gain, weight management, obesity, physical activity and tobacco. For recommendations on bariatric surgery for people with recent-onset type 2 diabetes, see the section on bariatric surgery for people with recent-onset type 2 diabetes in the NICE guideline on obesity. # Diagnosing and managing hypertension The recommendations on diagnosing and managing hypertension have been removed. For recommendations on hypertension in people with type 2 diabetes, see the NICE guideline on hypertension in adults. Diagnosis, treatment and monitoring of hypertension is broadly the same for people with type 2 diabetes as for other people. When a different approach is needed for people with type 2 diabetes, this is specified in the hypertension guideline. # Antiplatelet therapy Do not offer antiplatelet therapy (aspirin or clopidogrel) to adults with type 2 diabetes without cardiovascular disease. For guidance on the primary and secondary prevention of cardiovascular disease in adults with type 2 diabetes, see the NICE guidelines on cardiovascular disease and acute coronary syndromes. # Blood glucose management ## HbA1c measurement and targets Measure HbA1c levels in adults with type 2 diabetes every: to 6 months (tailored to individual needs) until HbA1c is stable on unchanging therapy months once the HbA1c level and blood glucose lowering therapy are stable. Measure HbA1c using methods calibrated according to International Federation of Clinical Chemistry (IFCC) standardisation. If HbA1c monitoring is invalid because of disturbed erythrocyte turnover or abnormal haemoglobin type, estimate trends in blood glucose control using one of the following: quality-controlled plasma glucose profiles total glycated haemoglobin estimation (if abnormal haemoglobins) fructosamine estimation. Investigate unexplained discrepancies between HbA1c and other glucose measurements. Seek advice from a team with specialist expertise in diabetes or clinical biochemistry. NICE has produced a patient decision aid on agreeing HbA1c targets, which also covers factors to weigh up when discussing HbA1c targets with patients. Discuss and agree an individual HbA1c target with adults with type 2 diabetes (see recommendations 1.6.6 to 1.6.10). Encourage them to reach their target and maintain it, unless any resulting adverse effects (including hypoglycaemia), or their efforts to achieve their target impair their quality of life. Think about using the NICE patient decision aid on weighing up HbA1c targets to support these discussions. Offer lifestyle advice and drug treatment to support adults with type 2 diabetes to reach and maintain their HbA1c target (see the sections on dietary advice and bariatric surgery and choosing drug treatments). For more information about supporting adherence, see the NICE guideline on medicines adherence. For adults whose type 2 diabetes is managed either by lifestyle and diet, or lifestyle and diet combined with a single drug not associated with hypoglycaemia, support them to aim for an HbA1c level of 48 mmol/mol (6.5%). For adults on a drug associated with hypoglycaemia, support them to aim for an HbA1c level of 53 mmol/mol (7.0%). In adults with type 2 diabetes, if HbA1c levels are not adequately controlled by a single drug and rise to 58 mmol/mol (7.5%) or higher: reinforce advice about diet, lifestyle and adherence to drug treatment and support the person to aim for an HbA1c level of 53 mmol/mol (7.0%) and intensify drug treatment. Consider relaxing the target HbA1c level (see recommendations 1.6.7 and 1.6.8 and NICE's patient decision aid) on a case-by-case basis and in discussion with adults with type 2 diabetes, with particular consideration for people who are older or frailer, if: they are unlikely to achieve longer-term risk-reduction benefits, for example, people with a reduced life expectancy tight blood glucose control would put them at high risk if they developed hypoglycaemia, for example, if they are at risk of falling, they have impaired awareness of hypoglycaemia, or they drive or operate machinery as part of their job intensive management would not be appropriate, for example if they have significant comorbidities. If adults with type 2 diabetes reach an HbA1c level that is lower than their target and they are not experiencing hypoglycaemia, encourage them to maintain it. Be aware that there are other possible reasons for a low HbA1c level, for example deteriorating renal function or sudden weight loss. For guidance on HbA1c targets for women with type 2 diabetes who are pregnant or planning to become pregnant, see the NICE guideline on diabetes in pregnancy. ## Self-monitoring of capillary blood glucose These recommendations relate to self-monitoring by capillary blood glucose monitoring. Take the Driver and Vehicle Licensing Agency (DVLA)'s Assessing fitness to drive: a guide for medical professionals into account when offering self‑monitoring of capillary blood glucose levels for adults with type 2 diabetes. Do not routinely offer self-monitoring of capillary blood glucose levels for adults with type 2 diabetes unless: the person is on insulin or there is evidence of hypoglycaemic episodes or the person is on oral medication that may increase their risk of hypoglycaemia while driving or operating machinery or the person is pregnant or is planning to become pregnant (see the NICE guideline on diabetes in pregnancy). Consider short-term self-monitoring of capillary blood glucose levels in adults with type 2 diabetes, reviewing treatment as necessary: when starting treatment with oral or intravenous corticosteroids or to confirm suspected hypoglycaemia. Be aware that adults with type 2 diabetes who have acute intercurrent illness are at risk of worsening hyperglycaemia. Review treatment as necessary. If adults with type 2 diabetes are self-monitoring their capillary blood glucose levels, carry out a structured assessment at least annually. The assessment should include: the person's self-monitoring skills the quality and frequency of testing checking that the person knows how to interpret the blood glucose results and what action to take the impact on the person's quality of life the continued benefit to the person the equipment used. ## Continuous glucose monitoring Offer intermittently scanned continuous glucose monitoring (isCGM, commonly referred to as 'flash') to adults with type 2 diabetes on multiple daily insulin injections if any of the following apply: they have recurrent hypoglycaemia or severe hypoglycaemia they have impaired hypoglycaemia awareness they have a condition or disability (including a learning disability or cognitive impairment) that means they cannot self-monitor their blood glucose by capillary blood glucose monitoring but could use an isCGM device (or have it scanned for them) they would otherwise be advised to self-measure at least 8 times a day. For guidance on continuous glucose monitoring (CGM) for pregnant women, see the NICE guideline on diabetes in pregnancy. Offer isCGM to adults with insulin-treated type 2 diabetes who would otherwise need help from a care worker or healthcare professional to monitor their blood glucose. Consider real-time continuous glucose monitoring (rtCGM) as an alternative to isCGM for adults with insulin-treated type 2 diabetes if it is available for the same or lower cost. CGM should be provided by a team with expertise in its use, as part of supporting people to self-manage their diabetes. Advise adults with type 2 diabetes who are using CGM that they will still need to take capillary blood glucose measurements (although they can do this less often). Explain that is because: they will need to use capillary blood glucose measurements to check the accuracy of their CGM device they will need capillary blood glucose monitoring as a back-up (for example when their blood glucose levels are changing quickly or if the device stops working). Provide them with enough test strips to take capillary blood glucose measurements as needed. If a person is offered rtCGM or isCGM but cannot or does not want to use any of these devices, offer capillary blood glucose monitoring. Ensure CGM is part of the education provided to adults with type 2 diabetes who are using it (see the section on education). Monitor and review the person's use of CGM as part of reviewing their diabetes care plan (see the section on individualised care). If there are concerns about the way a person is using the CGM device: ask if they are having problems using their device look at ways to address any problems and concerns to improve their use of the device, including further education and emotional and psychological support. Commissioners, providers and healthcare professionals should address inequalities in CGM access and uptake by: monitoring who is using CGM identifying groups who are eligible but who have a lower uptake making plans to engage with these groups to encourage them to consider CGM. For a short explanation of why the committee made these recommendations see the rationale and impact section on continuous glucose monitoring . Full details of the evidence and the committee's discussion are in evidence review C: continuous glucose monitoring in adults with type 2 diabetes. Loading. Please wait. # Drug treatment Recommendations in this section that cover dipeptidyl peptidase‑4 (DPP‑4) inhibitors, glucagon‑like peptide‑1 (GLP‑1) mimetics, sulfonylureas and sodium–glucose cotransporter‑2 (SGLT2) inhibitors refer to each of these groups of drugs at class level unless otherwise stated. NICE technology appraisals for SGLT2 inhibitors recommend the use of these medicines only in specific populations and in certain circumstances. The 2022 update of this guideline looked at the clinical- and cost-effectiveness evidence for SGLT2 inhibitors in people with cardiovascular disease or at high risk of developing cardiovascular disease. The guideline recommends SGLT2 inhibitors in a wider population than the technology appraisals that were published before February 2022. ## Choosing drug treatments We have produced a visual summary to provide an overview of the recommendations and additional information to support medicines choice. Discuss with adults with type 2 diabetes the benefits and risks of drug treatment and the options available. Base the choice of drug treatments on: the person's individual clinical circumstances, for example comorbidities, contraindications, weight, and risks from polypharmacy the person's individual preferences and needs the effectiveness of the drug treatments in terms of metabolic response and cardiovascular and renal protection safety and tolerability of the drug treatment monitoring requirements the licensed indications or combinations available cost (if 2 drugs in the same class are appropriate, choose the option with the lowest acquisition cost). See the NICE guideline on shared decision making and the section on safety of medicines for diabetes before and during pregnancy in the NICE guideline on diabetes in pregnancy. ## Rescue therapy at any phase of treatment If an adult with type 2 diabetes is symptomatically hyperglycaemic, consider insulin (see the section on insulin-based treatments) or a sulfonylurea, and review treatment when blood glucose control has been achieved. ## First-line drug treatment Also see the visual summary on first-line drug treatment for an overview of the recommendations and additional information to support medicines choice. For adults with type 2 diabetes and chronic kidney disease, follow recommendations on SGLT2 inhibitors in the section on chronic kidney disease in this guideline. Offer standard-release metformin as first-line drug treatment to adults with type 2 diabetes. Assess the person's cardiovascular status and risk to determine whether they have chronic heart failure or established atherosclerotic cardiovascular disease or are at high risk of developing cardiovascular disease.See the recommendations on using risk scores and QRISK2 to assess cardiovascular disease risk in adults with type 2 diabetes in NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification. Based on the cardiovascular risk assessment for the person with type 2 diabetes: If they have chronic heart failure or established atherosclerotic cardiovascular disease, offer an SGLT2 inhibitor with proven cardiovascular benefit in addition to metformin. If they are at high risk of developing cardiovascular disease, consider an SGLT2 inhibitor with proven cardiovascular benefit in addition to metformin. See the rationale and impact section on first-line drug treatment for an explanation of 'proven cardiovascular benefit' Loading. Please wait. When starting an adult with type 2 diabetes on dual therapy with metformin and an SGLT2 inhibitor as first-line therapy, introduce the drugs sequentially, starting with metformin and checking tolerability. Start the SGLT2 inhibitor as soon as metformin tolerability is confirmed. Gradually increase the dose of standard-release metformin over several weeks to minimise the risk of gastrointestinal side effects in adults with type 2 diabetes. If an adult with type 2 diabetes experiences gastrointestinal side effects with standard‑release metformin, consider a trial of modified‑release metformin. For first-line drug treatment in adults with type 2 diabetes, if metformin is contraindicated or not tolerated: If they have chronic heart failure or established atherosclerotic cardiovascular disease, offer an SGLT2 inhibitor with proven cardiovascular benefit. If they are at high risk of developing cardiovascular disease, consider an SGLT2 inhibitor with proven cardiovascular benefit. For first-line drug treatment in adults with type 2 diabetes, if metformin is contraindicated or not tolerated and if they are not in either of the groups in recommendation 1.7.9, consider: a DPP‑4 inhibitor or pioglitazone or a sulfonylurea or an SGLT2 inhibitor for people who meet the criteria in NICE's technology appraisal guidance on canagliflozin, dapagliflozin and empagliflozin as monotherapies or ertugliflozin as monotherapy or with metformin for treating type 2 diabetes. Before starting an SGLT2 inhibitor, check whether the person may be at increased risk of diabetic ketoacidosis (DKA), for example if: they have had a previous episode of DKA they are unwell with intercurrent illness they are following a very low carbohydrate or ketogenic diet. Address modifiable risks for DKA before starting an SGLT2 inhibitor. For example, for people who are following a very low carbohydrate or ketogenic diet, they may need to delay treatment until they have changed their diet. Advise adults with type 2 diabetes who are taking an SGLT2 inhibitor about the need to minimise their risk of DKA by not starting a very low carbohydrate or ketogenic diet without discussing it with their healthcare professional, because they may need to suspend SGLT2 inhibitor treatment. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on first-line drug treatment . Full details of the evidence and the committee's decision are in evidence review B: pharmacological therapies with cardiovascular and other benefits in people with type 2 diabetes. Loading. Please wait. ## Reviewing drug treatments When reviewing or considering changing treatments for adults with type 2 diabetes, think about and discuss the following with the person: how to optimise their current treatment regimen before thinking about changing treatments, taking into account factors such as: adverse effects adherence to existing medicines the need to revisit advice about diet and lifestyle prescribed doses and formulations stopping medicines that have had no impact on glycaemic control or weight, unless there is an additional clinical benefit, such as cardiovascular or renal protection, from continued treatment (see the note below on off-label use) whether switching rather than adding drugs could be effective the considerations about treatment choice in recommendation 1.7.1. In February 2022, using ertugliflozin to reduce cardiovascular risk when blood glucose is well controlled was off-label. See NICE's information on prescribing medicines.Also see the recommendations on medication review in the NICE guideline on medicines optimisation and on reviewing medicines and supporting adherence in the NICE guideline on medicines adherence. For adults with type 2 diabetes who start taking an SGLT2 inhibitor before they are 40 because they have an elevated lifetime risk of cardiovascular disease, do not stop the SGLT2 inhibitor when they turn 40 even if their QRISK2 score is below 10%. Only stop the SGLT2 inhibitor if the person's circumstances have changed and the SGLT2 inhibitor is no longer appropriate. For adults with type 2 diabetes at any stage after they have started first-line treatment: If they have or develop chronic heart failure or established atherosclerotic cardiovascular disease, offer an SGLT2 inhibitor with proven cardiovascular benefit in addition to current treatment or replace an existing drug with the SGLT2 inhibitor. If they are or become at high risk of developing cardiovascular disease, consider adding an SGLT2 inhibitor with proven cardiovascular benefit to current treatment or replacing an existing drug with the SGLT2 inhibitor.Take into account the person's current treatment regimen and preferences and make a shared decision about switching treatments or adding an SGLT2 inhibitor, as appropriate (also see recommendations 1.7.12 and 1.7.13 on starting an SGLT2 inhibitor). In February 2022, using ertugliflozin to reduce cardiovascular risk when blood glucose is well controlled was off-label. See NICE's information on prescribing medicines. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reviewing drug treatments . Full details of the evidence and the committee's discussion are in evidence review B: pharmacological therapies with cardiovascular and other benefits in people with type 2 diabetes. Loading. Please wait. ## Treatment options if further interventions are needed Also see our visual summary on treatment options if further interventions are needed for an overview of the recommendations and additional information to support medicines choice. Introduce drugs used in combination therapy in a stepwise manner, checking for tolerability and effectiveness of each drug. For adults with type 2 diabetes, if monotherapy has not continued to control HbA1c to below the person's individually agreed threshold for further intervention, consider adding: a DPP‑4 inhibitor or pioglitazone or a sulfonylurea or an SGLT2 inhibitor for people who meet the criteria in NICE's technology appraisal guidance on canagliflozin in combination therapy, ertugliflozin as monotherapy or with metformin, or dapagliflozin or empagliflozin in combination therapy. For adults with type 2 diabetes, if dual therapy with metformin and another oral drug has not continued to control HbA1c to below the person's individually agreed threshold for further intervention consider either: triple therapy by adding a DPP‑4 inhibitor, pioglitazone or a sulfonylurea or an SGLT2 inhibitor for people who meet the criteria in NICE's technology appraisal guidance on canagliflozin in combination therapy, dapagliflozin in triple therapy, empagliflozin in combination therapy, or ertugliflozin with metformin and a dipeptidyl peptidase-4 inhibitor or starting insulin-based treatment (see the section on insulin-based treatments). In adults with type 2 diabetes, if metformin is contraindicated or not tolerated and dual therapy with 2 oral drugs has not continued to control HbA1c to below the person's individually agreed threshold for intervention, consider insulin-based treatment (see the section on insulin-based treatments). If triple therapy with metformin and 2 other oral drugs is not effective, not tolerated or contraindicated, consider triple therapy by switching one drug for a GLP‑1 mimetic for adults with type 2 diabetes who: have a body mass index (BMI) of 35 kg/m2 or higher (adjust accordingly for people from Black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity or have a BMI lower than 35 kg/m2 and: for whom insulin therapy would have significant occupational implications or weight loss would benefit other significant obesity-related comorbidities. Only continue GLP‑1 mimetic therapy if the adult with type 2 diabetes has had a beneficial metabolic response (a reduction of at least 11 mmol/mol in HbA1c and weight loss of at least 3% of initial body weight in 6 months). For adults with type 2 diabetes, only offer combination therapy with a GLP‑1 mimetic and insulin along with specialist care advice and ongoing support from a consultant-led multidisciplinary team. For a short explanation of why the committee did not make any new 2022 recommendations, see the rationale and impact section on treatment options if further interventions are needed . Full details of the evidence and the committee's discussion are in evidence review B: pharmacological therapies with cardiovascular and other benefits in people with type 2 diabetes. Loading. Please wait. ## Insulin-based treatments For adults with type 2 diabetes starting insulin therapy, provide a structured programme using active insulin dose titration that encompasses: injection technique, including rotating injection sites and avoiding repeated injections at the same point within sites continuing telephone support self-monitoring dose titration to target levels dietary advice the DVLA's Assessing fitness to drive: a guide for medical professionals managing hypoglycaemia managing acute changes in plasma glucose control support from an appropriately trained and experienced healthcare professional. For adults with type 2 diabetes starting insulin therapy, continue to offer metformin for people without contraindications or intolerance. Review the continued need for other blood glucose lowering therapies. Start insulin therapy for adults with type 2 diabetes from a choice of the following insulin types and regimens: Offer neutral protamine Hagedorn (NPH) insulin injected once or twice daily according to need. Consider starting both NPH and short‑acting insulin (particularly if the person's HbA1c is 75 mmol/mol or higher), administered either: separately or as a pre-mixed (biphasic) human insulin preparation. Consider, as an alternative to NPH insulin, using insulin detemir or insulin glargine if: the person needs help from a carer or healthcare professional to inject insulin, and use of insulin detemir or insulin glargine would reduce the frequency of injections from twice to once daily or the person's lifestyle is restricted by recurrent symptomatic hypoglycaemic episodes or the person would otherwise need twice‑daily NPH insulin injections in combination with oral glucose‑lowering drugs. Consider pre-mixed (biphasic) preparations that include short‑acting insulin analogues, rather than pre‑mixed (biphasic) preparations that include short‑acting human insulin preparations, if: the person prefers injecting insulin immediately before a meal or hypoglycaemia is a problem or blood glucose levels rise markedly after meals. Consider switching to insulin detemir or insulin glargine from NPH insulin in adults with type 2 diabetes: who do not reach their target HbA1c because of significant hypoglycaemia or who experience significant hypoglycaemia on NPH insulin irrespective of the level of HbA1c reached or who cannot use the device needed to inject NPH insulin but could administer their own insulin safely and accurately if a switch to one of the long‑acting insulin analogues was made or who need help from a carer or healthcare professional to administer insulin injections and for whom switching to one of the long‑acting insulin analogues would reduce the number of daily injections. Monitor adults with type 2 diabetes who are on a basal insulin regimen (NPH insulin, insulin detemir or insulin glargine) for the need for short‑acting insulin before meals (or a pre‑mixed insulin preparation). Monitor adults with type 2 diabetes who are on pre‑mixed (biphasic) insulin for the need for a further injection of short‑acting insulin before meals or for a change to a basal-bolus regimen with NPH insulin or insulin detemir or insulin glargine, if blood glucose control remains inadequate. When starting an insulin for which a biosimilar is available, use the product with the lowest acquisition cost. Ensure the risk of medication errors with insulins is minimised by following the Medicines and Healthcare products Regulatory Agency (MHRA) guidance on minimising the risk of medication error with high strength, fixed combination and biosimilar insulin products, which includes advice for healthcare professionals when starting treatment with a biosimilar. When people are already using an insulin for which a lower cost biosimilar is available, discuss the possibility of switching to the biosimilar. Make a shared decision with the person after discussing their preferences. For a short explanation of why the committee made the 2021 recommendations on biosimilars and how they might affect practice, see the rationale and impact section on long-acting insulin . Loading. Please wait. For guidance on using insulin in combination with SGLT2 inhibitors, see: the section on drug treatment NICE's technology appraisal guidance on canagliflozin, dapagliflozin, and empagliflozin in combination therapy. ## Insulin delivery For guidance on insulin delivery for adults with type 2 diabetes, see the section on insulin delivery in the NICE guideline on type 1 diabetes. # Managing complications ## Periodontitis Advise adults with type 2 diabetes at their annual review that: they are at higher risk of periodontitis if they get periodontitis, managing it can improve their blood glucose control and can reduce their risk of hyperglycaemia. Advise adults with type 2 diabetes to have regular oral health reviews (their oral healthcare or dental team will tell them how often, in line with the NICE guideline on dental checks: intervals between oral health reviews). For guidance for oral healthcare and dental teams on how to provide oral health advice, see the NICE guideline on oral health promotion. For adults with type 2 diabetes who have been diagnosed with periodontitis by an oral healthcare or dental team, offer dental appointments to manage and treat their periodontitis (at a frequency based on their oral health needs). For a short explanation of why the committee made these recommendations, see the rationale and impact section on periodontitis . Full details of the evidence and the committee's discussion are in evidence review D: periodontitis. Loading. Please wait. ## Gastroparesis Think about a diagnosis of gastroparesis in adults with type 2 diabetes who have erratic blood glucose control or unexplained gastric bloating or vomiting, taking into account possible alternative diagnoses. For adults with type 2 diabetes who have vomiting caused by gastroparesis, explain that: there is no strong evidence that any available antiemetic therapy is effective some people have had benefit with domperidone, erythromycin or metoclopramide the strongest evidence for effectiveness is for domperidone, but prescribers must take into account its safety profile, in particular its cardiac risk and potential interactions with other medicines. In December 2015, the use of erythromycin was off-label. See NICE's information on prescribing medicines. To treat vomiting caused by gastroparesis in adults with type 2 diabetes: consider alternating the use of erythromycin and metoclopramide consider domperidone only in exceptional circumstances (if domperidone is the only effective treatment) and in accordance with MHRA guidance on domperidone. In December 2015, the use of erythromycin was off-label. See NICE's information on prescribing medicines. If gastroparesis is suspected, consider referring adults with type 2 diabetes to specialist services if: the differential diagnosis is in doubt or the person has persistent or severe vomiting. ## Painful diabetic neuropathy For guidance on managing painful diabetic peripheral neuropathy in adults with type 2 diabetes, see the NICE guideline on neuropathic pain in adults. ## Autonomic neuropathy Think about the possibility of contributory sympathetic nervous system damage in adults with type 2 diabetes who lose the warning signs of hypoglycaemia. Think about the possibility of autonomic neuropathy affecting the gut in adults with type 2 diabetes who have unexplained diarrhoea that happens particularly at night. For adults with type 2 diabetes and autonomic neuropathy who are taking tricyclic drugs and antihypertensive drug treatments, be aware of the increased likelihood of side effects such as orthostatic hypotension. For guidance on safe prescribing of antidepressants (such as tricyclic drugs) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. For adults with type 2 diabetes who have unexplained bladder‑emptying problems, investigate the possibility of autonomic neuropathy affecting the bladder. In managing autonomic neuropathy symptoms, include specific interventions indicated by the manifestations (for example, for abnormal sweating or nocturnal diarrhoea). ## Diabetic foot problems For guidance on preventing and managing foot problems in adults with type 2 diabetes, see the NICE guideline on diabetic foot problems. ## Chronic kidney disease For adults with chronic kidney disease (CKD) and type 2 diabetes, offer an angiotensin receptor blocker (ARB) or an angiotensin‑converting enzyme (ACE) inhibitor (titrated to the highest licensed dose that the person can tolerate) if albumin-to-creatinine ratio (ACR) is 3 mg/mmol or more, as recommended in the section on pharmacotherapy for CKD in adults, children, and young people with related persistent proteinuria in the NICE guideline on chronic kidney disease. For adults with type 2 diabetes and CKD who are taking an ARB or an ACE inhibitor (titrated to the highest licensed dose that they can tolerate), offer an SGLT2 inhibitor (in addition to the ARB or ACE inhibitor) if: ACR is over 30 mg/mmol and they meet the criteria in the marketing authorisation (including relevant estimated glomerular filtration rate thresholds).In November 2021, not all SGLT2 inhibitors were licensed for this indication. See NICE's information on prescribing medicines. For adults with type 2 diabetes and CKD who are taking an ARB or an ACE inhibitor (titrated to the highest licensed dose that they can tolerate), consider an SGLT2 inhibitor (in addition to the ARB or ACE inhibitor) if: ACR is between 3 and 30 mg/mmol and they meet the criteria in the marketing authorisation (including relevant eGFR thresholds). In November 2021, not all SGLT2 inhibitors were licensed for this indication. See NICE's information on prescribing medicines. For guidance on dapagliflozin for adults with CKD, see NICE's technology appraisal guidance on dapagliflozin for treating chronic kidney disease. For further guidance on managing kidney disease in adults with type 2 diabetes, see the NICE guideline on chronic kidney disease. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on SGLT2 inhibitors for adults with type 2 diabetes and chronic kidney disease . Full details of the evidence and the committee's discussion are in evidence review A: SGLT2 inhibitors for people with chronic kidney disease and type 2 diabetes. Loading. Please wait. ## Erectile dysfunction Offer men with type 2 diabetes the opportunity to discuss erectile dysfunction as part of their annual review. Assess, educate and support men with type 2 diabetes who have problematic erectile dysfunction, addressing contributory factors such as cardiovascular disease as well as possible treatment options. Consider a phosphodiesterase‑5 inhibitor to treat problematic erectile dysfunction in men with type 2 diabetes. Initially choose the drug with the lowest acquisition cost and take into account any contraindications. After discussion, refer men with type 2 diabetes to a service offering other medical, surgical or psychological management of erectile dysfunction if treatment (including a phosphodiesterase‑5 inhibitor, as appropriate) has been unsuccessful. ## Eye disease When adults are diagnosed with type 2 diabetes, refer them immediately to the local eye screening service. Encourage adults to attend eye screening, and explain that it will help them to keep their eyes healthy and help to prevent problems with their vision. Explain that the screening service is effective at identifying problems so that they can be treated early. Arrange emergency review by an ophthalmologist for: sudden loss of vision rubeosis iridis pre-retinal or vitreous haemorrhage retinal detachment. Refer to an ophthalmologist in accordance with the UK National Screening Committee criteria and timelines for any large sudden unexplained drop in visual acuity. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster. ## Atherosclerotic cardiovascular disease This includes coronary heart disease, acute coronary syndrome, previous myocardial infarction, stable angina, previous coronary or other revascularisation, cerebrovascular disease (ischaemic stroke and transient ischaemic attack) and peripheral arterial disease. ## Consultant-led multidisciplinary team A consultant-led multidisciplinary team may include a wide range of staff based in primary, secondary and community care. ## Continuous glucose monitoring This covers both real-time continuous glucose monitoring (rtCGM) and intermittently scanned continuous glucose monitoring (isCGM, commonly referred to as 'flash'). A continuous glucose monitor is a device that measures blood glucose levels and sends the readings to a display device or smartphone. ## High risk of developing cardiovascular disease Adults with type 2 diabetes who have: QRISK2 more than 10% in adults aged 40 and over or an elevated lifetime risk of cardiovascular disease (defined as the presence of 1 or more cardiovascular risk factors in someone under 40). Cardiovascular disease risk factors: hypertension, dyslipidaemia, smoking, obesity, and family history (in a first-degree relative) of premature cardiovascular disease. ## Insulin glargine The recommendations in this guideline also apply to any current or future biosimilar product of insulin glargine that has an appropriate marketing authorisation that allows the use of the biosimilar in the same indication. ## Multiple daily injections Two or more daily insulin injections, which could either be a basal-bolus regimen or more than one daily insulin injection. ## Periodontitis A chronic inflammatory gum disease that destroys the supporting tissues of the teeth (the periodontium). Gingivitis is a milder form of periodontal disease than periodontitis. However, gingivitis still causes inflammation in the gum, and if not treated it can lead to periodontitis. ## Severe hypoglycaemia Episodes of hypoglycaemia that require assistance from another person to treat. ## Recurrent hypoglycaemia Frequent events of hypoglycaemia that occur each week or month and have an impact on quality of life. ## Very low carbohydrate and ketogenic diets A very low carbohydrate diet has 20 to 50 grams per day of carbohydrate or less than 10% of a 2000 kcal/day diet. A ketogenic diet is a very low carbohydrate, high fat diet that is designed to induce ketosis.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## The effects of stopping or switching drug treatments to control blood glucose levels In adults with type 2 diabetes, what are the effects of stopping and/or switching drug treatments to control blood glucose levels, and what criteria should inform the decision? There is a lack of evidence on the effects of stopping and/or switching drug treatments to control blood glucose levels. The current practice of 'stopping rules' is typically motivated by either inadequate blood glucose control (rising HbA1c levels) or intolerable side effects. There is limited understanding of the short- and long‑term effects of stopping a therapy and switching to another in terms of diabetes control (HbA1c levels), hypoglycaemic risk, weight gain, and cardiovascular morbidity and mortality. In addition, there is limited understanding of how quickly consideration should be given to stopping and switching to another drug treatment and, if stopping and switching may be needed, what the optimal sequencing is of drug treatments. Randomised controlled trials examining these different issues would help to improve diabetes care. ## Non-metformin-based drug treatment combinations to control blood glucose levels In adults with type 2 diabetes, what treatment combinations (for example, glucagon‑like peptide‑1 mimetics and insulin combination therapy with meglitinides) are most effective when initial drug treatment with non‑metformin monotherapy fails to adequately control blood glucose levels? Although it is recognised that metformin therapy is suitable for most adults with type 2 diabetes, its use is contraindicated or not tolerated in approximately 15% of individuals. To date, research evidence has largely focused on metformin‑based treatment combinations. Given the progressive nature of the condition, in which intensification of blood glucose lowering drug therapies are indicated over time, there is little evidence, for some adults, to guide management strategies on treatment combinations that do not include metformin. Randomised controlled trials are therefore needed to better understand the treatment choices that are available which improve blood glucose control and long‑term risks of complications associated with diabetes. ## Drug treatment for when blood glucose levels are inadequately controlled by 3 oral antidiabetic drugs or insulin combinations When blood glucose levels are inadequately controlled by 3 oral antidiabetic drugs and/or insulin combinations, which blood glucose lowering therapies should be used to control blood glucose levels? As the incidence of type 2 diabetes increases in the younger population and as blood glucose control declines naturally over time, it is likely that further intensification of therapies would be needed. Currently, there is evidence up to second intensification of drug therapies, that is, when 2 or more non‑insulin‑based treatment combinations fail to adequately control blood glucose levels. Randomised controlled trials are needed to improve understanding of alternative treatment options for adults at second intensification whose blood glucose is inadequately controlled with insulin and/or triple non‑insulin‑based drug therapies. ## Self-monitoring of blood glucose levels What is the optimal frequency for self‑monitoring of blood glucose in adults with type 2 diabetes? There is limited evidence in relation to the long‑term effects (at least 5 years) of blood glucose lowering therapies, particularly newer agents in terms of efficacy and adverse events (for example, cardiovascular outcomes). Randomised controlled trials and prospective longitudinal studies are needed to better understand the long‑term efficacy and safety issues surrounding these medicines. # Other recommendations for research ## Effectiveness of SGLT2 inhibitors for different ethnic groups What is the clinical and cost effectiveness of SGLT2 inhibitors in adults with type 2 diabetes and chronic kidney disease, stratified across different ethnic groups? For a short explanation of why the committee made the recommendation for research, see the rationale on SGLT2 inhibitors for adults with type 2 diabetes and chronic kidney disease . Full details of the evidence and the committee's discussion are in evidence review A: SGLT2 inhibitors for people with chronic kidney disease and type 2 diabetes. Loading. Please wait. ## Effectiveness of SGLT2 inhibitors for adults with a urine albumin-to-creatinine ratio (ACR) below 3 mg/mmol What is the clinical and cost effectiveness of SGLT2 inhibitors in adults with type 2 diabetes, chronic kidney disease and a urine ACR of less than 3 mg/mmol? For a short explanation of why the committee made the recommendation for research, see the rationale on SGLT2 inhibitors for adults with type 2 diabetes and chronic kidney disease . Full details of the evidence and the committee's discussion are in evidence review A: SGLT2 inhibitors for people with chronic kidney disease and type 2 diabetes. Loading. Please wait. ## Long-term outcomes associated with blood glucose lowering agents In adults with type 2 diabetes, what are the long‑term effects of blood glucose lowering therapies such as dipeptidyl peptidase‑4 (DPP‑4) inhibitors, sodium–glucose cotransporter‑2 (SGLT2) inhibitors and meglitinides? ## Using routinely collected real-world data to assess the effectiveness of continuous glucose monitoring Based on routinely collected real-world data, what is the effectiveness and cost effectiveness of CGM devices to improve glycaemic control in adults with type 2 diabetes? For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale section on continuous glucose monitoring. Full details of the evidence and the committee's discussion are in evidence review C: continuous glucose monitoring in adults with type 2 diabetes. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Continuous glucose monitoring Recommendations 1.6.17 to 1.6.26 ## Why the committee made the recommendations The committee discussed how continuous glucose monitoring (CGM) could potentially be useful for many people with type 2 diabetes. They were aware of examples from current practice in which adults who have insulin-treated type 2 diabetes and use intermittently scanned CGM (isCGM) have had good outcomes. Because of the additional cost associated with CGM and the large number of adults with type 2 diabetes, the committee used both the evidence and their clinical experience to decide who would gain the most benefit from using CGM. There was evidence that intermittently scanned CGM (isCGM) was cost effective for adults with type 2 diabetes using insulin, but no evidence for populations not using insulin, so the committee agreed to restrict their recommendations to that subpopulation. People who have recurrent or severe hypoglycaemic events were identified as one of the groups likely to benefit most from isCGM, because hypoglycaemic events were considered to be one of the most important and concerning outcomes for adults with type 2 diabetes who are using insulin. The committee decided that the number of hypoglycaemic events was a more effective indicator of someone who would benefit from isCGM than specific HbA1c target values, because target values can vary between people. The evidence also indicated minimal effects of isCGM on HbA1c values. The committee agreed that people with impaired hypoglycaemic awareness would also benefit from isCGM. However, they did not recommend specific methods for assessing impaired hypoglycaemic awareness. This is because validated methods for assessing impaired hypoglycaemic awareness in people with type 2 diabetes (such as the GOLD or Clarke scores) are not always available in primary care. People who use insulin and have a condition or disability that restricts their ability to self-monitor blood glucose levels should also be offered isCGM. This is because having access to isGCM means they will no longer have to rely on others to monitor their diabetes, potentially increasing their independence. For people with learning disabilities, this recommendation is in line with similar guidance for type 1 diabetes set out in the NHS RightCare Pathway, which specifies reasonable adjustments for people with a learning disability who have diabetes. People who are advised to self-measure using capillary blood glucose monitoring more than 8 times a day should also be offered isCGM. This is in line with the funding requirements for NHS England's flash glucose monitoring: national arrangements for funding of relevant diabetes patients. Although the funding requirements are specifically for people with type 1 diabetes, the committee thought that this criterion was also important for people with type 2 diabetes who have to monitor their blood glucose levels multiple times a day. People who need help from a care worker or other healthcare professional to administer their insulin injections should also be offered isCGM, even if they only use once-daily insulin injections. isCGM will help care workers to record a person's blood glucose levels quickly. And for people who have multiple home care visits per day, blood glucose levels can be recorded at each visit. This will help them to adjust their insulin levels to reduce the risk of hypoglycaemic events between home visits. It may also reduce the number of hospital admissions for this group. The committee discussed how short-term use of isCGM may still be useful for some people. It may help people to understand when they have hypoglycaemic episodes, which would help them to develop a more effective treatment plan. There was no evidence that real-time CGM (rtCGM) was cost effective for people with type 2 diabetes, so the committee agreed it could not be recommended for all adults with type 2 diabetes (whether or not they used insulin). They noted, however, that prices of rtCGM have reduced over the past few years, and if this continues to happen there may come a time when it is no more expensive than isCGM. At this point, rtCGM would be an appropriate alternative for people who meet the criteria for isCGM. The committee did not make a recommendation on using specific devices because CGM technologies are changing very quickly and this recommendation would soon be out of date. Local healthcare services are better placed to assess which devices are evidence-based and suitable for use at any given time. The committee discussed how self-monitoring of blood glucose should still take place, albeit less frequently, even when a person is using CGM. The ability to self-monitor blood glucose levels allows people to ensure the accuracy of the CGM device. The committee also recommended keeping capillary blood glucose monitoring as a back-up for situations such as when the technology fails. The committee decided to highlight that CGM should be provided by a team who have expertise in its use. To ensure that CGM is effective, healthcare professionals need to have the skills to interpret and communicate the data effectively. As well as healthcare professionals having a clear understanding of CGM, it is also crucial that people with type 2 diabetes who are using CGM have education about the technology. This will increase the likelihood that people will scan and report the results frequently, allowing people to understand and manage their diabetes effectively. Although many people will choose CGM if offered, there are some people who either cannot be offered it or do not want to use it. Because it is still important for these people to monitor their blood glucose levels, the committee made a recommendation to reinforce the importance of offering capillary blood glucose monitoring instead. The committee did not make a recommendation on how long CGM should be used because there was no evidence on this, and they did not want to stop people accessing CGM for short periods if they and their healthcare professional thought they could benefit from this. Using CGM for a short period of time may help some people to understand when they have hypoglycaemic episodes, thereby helping them to develop a more effective treatment plan. Despite the positive recommendations on CGM, the committee were concerned that existing health inequalities may still lead to lower uptake of CGM in some groups of people. To address this, the committee made a recommendation outlining actions for commissioners, providers and healthcare professionals. The committee highlighted the importance of routinely reviewing a person's use of CGM. This will establish whether it is providing clinical benefits and whether the monitor is being used correctly. Making people aware that their use of CGM will be continually reviewed is important so they know it is not a guaranteed long-term option. The committee also made a recommendation for research on using routinely collected real-world data to assess the effectiveness and cost effectiveness of CGM. They agreed that this has the potential to show the direct effects of the technology used by people with type 2 diabetes instead of interpreting it through the results of clinical trials. Increased monitoring of routine healthcare data including registries and audits would ensure that findings from a broader population are captured. ## How the recommendations might affect practice The recommendations are likely to increase the number of adults with type 2 diabetes who are offered CGM, particularly those who have issues with hypoglycaemia. This will have associated cost implications: It may save the NHS time, because healthcare professionals do not have to meet people who are using CGM as often as people who use capillary blood glucose monitoring. There should be fewer hypoglycaemic events to manage. The committee did not expect a significant resource impact related to education and monitoring for the CGM devices. Return to recommendations # First-line drug treatment Recommendations 1.7.3 to 1.7.13 ## Why the committee made the recommendations The evidence from the clinical trials looking at cardiovascular benefits, the network meta-analyses, and the economic modelling, showed that some treatments were effective at improving cardiovascular outcomes and were likely to be cost effective. All of these trials recruited people with established cardiovascular disease, and some also included people with a high risk of developing cardiovascular disease. However, for people without high cardiovascular risk, the committee agreed there was more uncertainty over whether the same level of cardiovascular benefits seen in the high-risk groups could be applied to a lower risk population. They decided that they could not justify changing the recommendations for people at lower risk based on this evidence. Therefore, they retained the 2015 recommendations outlining the drug treatment options for people in the lower risk group. The committee agreed it was important to assess people's cardiovascular status and risk to help determine which treatments are suitable for them. They used a definition for the established cardiovascular disease group (adults with type 2 diabetes and chronic heart failure or established atherosclerotic cardiovascular disease) that reflected the people included in all the clinical trials and modelled as a subgroup in the economic model. To assess whether people are at high risk of developing cardiovascular disease, the committee recommended using the QRISK2 tool because this is recommended in the NICE guideline on cardiovascular disease: risk assessment and reduction, including lipid modification for adults with type 2 diabetes, and the factors covered by this tool were similar to those used in the trials and economic model to define this population. In addition, this tool is widely used in current practice in the NHS. Lifetime cardiovascular risk may be underestimated in people aged under 40 using this tool, so the committee also included risk factors to consider for this age group. This definition was broadly aligned to the subgroup of people with high cardiovascular risk without established cardiovascular disease who were included in the model. The evidence showed that SGLT2 inhibitors as a class of drugs were most likely to be cost effective in combination with metformin, although the incremental cost-effectiveness ratio (ICER) varied between different drugs in the class and in different scenarios in the model. The exception to this was dapagliflozin, which was cost effective at a threshold of £20,000 per quality-adjusted life year in the base-case analysis and across a range of model scenarios. However, the committee agreed there was too much uncertainty in the clinical data, and therefore the economic modelling, for them to be confident that these different ICERs represented true underlying differences in cost effectiveness. There were also varying levels of certainty in the clinical trials and the network meta-analyses about: which individual SGLT2 inhibitors were effective at improving cardiovascular outcomes whether there were real differences in cardiovascular benefits between the different SGLT2 inhibitors.For hospitalisation for heart failure, empagliflozin, canagliflozin and dapagliflozin produced a clinically meaningful reduction compared with placebo in the random effects network meta-analysis model. However, in the sensitivity analyses using a fixed effect model, ertugliflozin also showed a clinically meaningful reduction compared with placebo (which reflects the original clinical trial data). The network meta-analysis could not differentiate between the SGLT2 inhibitors. For the 3‑point MACE outcome (a composite of major adverse cardiovascular events), only canagliflozin and empagliflozin produced a statistically significant reduction compared with placebo. However, the network meta-analyses again could not differentiate between SGLT2 inhibitors. For all-cause mortality and cardiovascular mortality, empagliflozin showed a clinically meaningful reduction compared with placebo and the other SGLT2 inhibitors. The network meta-analysis could not differentiate between the other SGLT2 inhibitors. For non-fatal myocardial infarction and non-fatal stroke, the network meta-analysis could not differentiate between empagliflozin, canagliflozin, ertugliflozin or placebo. The data for dapagliflozin was reported differently and could not be included in the network meta-analyses. In the clinical trial data, dapagliflozin could not be differentiated from placebo for myocardial infarction and was not meaningfully different from placebo for stroke. Finally, only dapagliflozin showed a clinically meaningful reduction in severe hypoglycaemia compared with placebo. However, the remaining SGLT2 inhibitors could not be differentiated from each other or from placebo in the network meta-analysis. Taking the cost effectiveness and clinical results into account, the committee decided against recommending only dapagliflozin and instead made recommendations for the SGLT2 inhibitors as a class. However, they recognised that there was greater uncertainty around the cardiovascular benefits associated with ertugliflozin than there was for empagliflozin, canagliflozin and dapagliflozin. This was because ertugliflozin did not consistently show a reduction in heart failure compared with placebo in the network meta-analyses (it depended on the model used), and it was not statistically significantly better than placebo for the 3‑point MACE outcome. The committee therefore decided to refer to 'SGLT2 inhibitors with proven cardiovascular benefit' in the recommendations. This was to enable prescribers to select a particular drug from the class of SGLT2 inhibitors that they thought was clinically appropriate for each person, while allowing the recommendation to remain current even if additional evidence or new SGLT2 inhibitors become available. The committee agreed there was more certainty of cardiovascular benefits in adults with type 2 diabetes and chronic heart failure or established atherosclerotic cardiovascular disease because they were participants in all the included trials, while people at high risk of developing cardiovascular disease were included in fewer trials. So, they recommended dual therapy with an SGLT2 inhibitor with proven cardiovascular benefit in addition to metformin for both groups, but only as an option to consider for people without established cardiovascular disease, to reflect the lower certainty. For people without a high risk of developing cardiovascular disease who do not have chronic heart failure or established atherosclerotic cardiovascular disease, metformin monotherapy remains the recommended first-line treatment option, based on the 2015 recommendation. When starting first-line dual therapy, the committee noted the importance of introducing the drugs sequentially. This enables any side effects and intolerances from the first drug to be identified before the second drug is introduced. In line with current practice, the committee recommended starting with metformin and then adding the SGLT2 inhibitor without delay once metformin tolerability is established, to avoid people remaining on metformin alone for prolonged periods. Some people will have established cardiovascular disease or a high risk of developing cardiovascular disease, but not be able to take an SGLT2 inhibitor. As GLP‑1 mimetics were not cost-effective options in this situation (see the rationale and impact section on why GLP-1 mimetics were not recommended as first-line treatment), the committee agreed that these people would be offered metformin alone as a first-line treatment (see recommendation 1.7.3). People who cannot tolerate metformin or for whom it is contraindicated were not included as a separate group in the economic model because the evidence was taken from trials that did not separate results by whether the person was able to take metformin or not. Most people in these trials were expected to be able to take metformin. The committee agreed with the assumption that people who cannot tolerate metformin or for whom it is contraindicated would be offered the next most effective and cost-effective treatment options after metformin. In the economic model scenario, when another drug was used in place of metformin for people with established cardiovascular disease or at high risk of developing cardiovascular disease, SGLT2 inhibitors were the class of drugs that were most likely to be cost effective. The committee therefore prioritised this class of drugs for these people. As before, there was greater certainty in the results for people with established cardiovascular disease compared with those at high risk of developing cardiovascular disease, and the rationale for referring to SGLT2 inhibitors with proven cardiovascular benefit also applies here. Some people will have established cardiovascular disease or a high risk of developing cardiovascular disease, but not be able to take an SGLT2 inhibitor or metformin. There was no evidence specifically for this group so the committee made the same assumption as above (that these people would take the next most effective and cost-effective treatment). The committee did not recommend a specific drug for these people because GLP‑1 mimetics were not cost-effective options in this situation (see the rationale and impact section on why GLP-1 mimetics were not recommended as first-line treatment). They agreed that in practice prescribers would use their clinical judgement to choose an appropriate treatment from the remaining options, based on the individual clinical circumstances and needs of the person with type 2 diabetes (see recommendation 1.7.1). The committee noted some particularly important safety considerations to take into account before an adult with type 2 diabetes starts on an SGLT2 inhibitor. The committee highlighted these because the SGLT2 inhibitors are comparatively new drugs and clinical experience with them is low in primary care, but the new recommendations are expected to greatly increase their use in this setting. In the committee's experience there have been multiple instances of avoidable diabetic ketoacidosis (DKA) resulting in hospital admission. The committee highlighted some factors that might put someone at higher risk of DKA, but the list is not intended to be exhaustive. Addressing modifiable risk factors before starting an SGLT2 inhibitor could reduce the risk of DKA and make the drug safer for the person with type 2 diabetes. The committee were aware that adults with type 2 diabetes who are overweight or obese may wish to try a ketogenic diet to reverse or reduce the severity of their diabetes or induce remission. However, the committee agreed, based on their experience, that there may be an increased risk of DKA associated with SGLT2 inhibitors and such diets. It is important to tell people about these risks and to advise them to discuss any planned change to a very low carbohydrate or ketogenic diet with their healthcare professional first. The committee did not recommend a GLP‑1 mimetic as first-line treatment for the following reasons: GLP‑1 mimetics were not cost effective as a class at this (or any) stage of treatment for people with a high risk of developing cardiovascular disease or with established cardiovascular disease. Although the ICERs for injectable semaglutide for the various modelled scenarios and stages of treatment fell within a similar range to the ICERs for the individual SGLT2 inhibitors, there was more certainty that the SGLT2s were cost effective as a class. In contrast, the ICERs for injectable semaglutide increased significantly in a sensitivity analysis, highlighting the uncertainty surrounding the results. There were differences in clinical effectiveness between the injectable and oral forms of semaglutide compared with placebo for some outcomes, such as all-cause mortality, based on the evidence from the trials. However, the committee agreed it was uncertain whether the observed differences in effect were real or might be related to the relatively small size and low event rates in these trials compared with other trials included in the review, which resulted in wide 95% confidence intervals around the effect estimates for some outcomes. The committee concluded that the factors above combined to give such a high level of uncertainty around the clinical and cost effectiveness of injectable semaglutide that they could not make a positive recommendation for its use. ## How the recommendations might affect practice The recommendations to offer SGLT2 inhibitors with metformin to adults with type 2 diabetes and chronic heart failure or established atherosclerotic cardiovascular disease at first-line treatment (or if they are already taking metformin monotherapy) are expected to lead to a change in practice and increase the number of people taking SGLT2 inhibitors at the beginning of their treatment. This is also expected to be the case for people with a high risk of developing cardiovascular disease, as this category is expected to cover a large proportion of adults with type 2 diabetes. In current practice, these people would not be offered combination therapy with an SGLT2 inhibitor until additional treatment is needed to control their HbA1c to below their individually agreed threshold for intervention, and then only if they met the criteria in the relevant NICE technology appraisals for being prescribed an SGLT2 inhibitor. Overall, this recommendation is expected to greatly increase the number of people taking SGLT2 inhibitors and is likely to have a substantial resource impact. The number of adults with type 2 diabetes and chronic heart failure or established atherosclerotic cardiovascular disease or a high risk of developing cardiovascular disease who cannot tolerate metformin, or for whom metformin is contraindicated, are expected to be relatively low. The new recommendations are likely to see a change in practice as more people start taking an SGLT2 inhibitor, and this will likely be associated with a resource impact. The recommendations about how to begin combination therapy, factors to check before a person starts on an SGLT2 inhibitor, and topics to cover in a conversation with the person, are not expected to significantly increase consultation time or be a change in practice because these should already form part of the prescribing process. Checking that the person is not at increased risk of DKA when they are prescribed an SGLT2 inhibitor should help reduce the number of people who experience DKA and thereby reduce unnecessary hospital admissions. Return to recommendations # Reviewing drug treatments Recommendations 1.7.14 to 1.7.16 ## Why the committee made the recommendations The committee agreed that when changes to treatment are being considered it is important to review existing treatment options first. Stopping medications that have not worked, for example, in controlling blood glucose or weight loss, and optimising current treatments may remove the need to prescribe additional drugs. However, some drugs, such as SGLT2 inhibitors, may be continued because they provide additional cardiovascular protective benefits. In particular, there might be reasons, such as problems with adherence or adverse effects, that might make existing treatments less effective or ineffective. Addressing these might mean that adding a new drug is unnecessary. The list of factors to think about as part of optimisation is not exhaustive but includes those that the committee thought were particularly important. The committee agreed that it is important to revisit advice about diet and lifestyle because part of this discussion is to ensure the person is supported with both non-pharmacological and pharmacological interventions to improve their current health and prognosis. Reviews should also take into account a person's current clinical circumstances (as detailed in recommendation 1.7.1 on choosing drug treatments). This will help ensure that appropriate treatment options are considered if the person's clinical situation has changed: for example, if it has improved because of weight loss or if they have developed chronic heart failure or atherosclerotic cardiovascular disease. When people with an elevated lifetime risk of cardiovascular disease turn 40, their cardiovascular risk may appear to drop when it is assessed using QRISK2. However, this is due to switching from assessing lifetime risk to a 10-year risk calculation rather than an actual decrease in cardiovascular risk. SGLT2 inhibitor treatment should not be stopped for this reason alone. Based on the evidence and the economic model, the benefits of SGLT2 inhibitors were not confined to first-line treatment for people with elevated cardiovascular risk or chronic heart failure or established atherosclerotic cardiovascular disease. To ensure that people who are already on drug therapy (including those people who have started first-line treatment, and those people who are further along the treatment pathway and are taking dual or triple therapy) for type 2 diabetes can have an SGLT2 inhibitor if their level of cardiovascular risk is sufficiently high or they have chronic heart failure or established atherosclerotic cardiovascular disease, the committee included a separate recommendation on SGLT2 inhibitors for these people. As explained in the rationale for recommendations on first-line treatment, the committee specified SGLT2 inhibitors with proven cardiovascular benefits. This recommendation also takes into account that adults with type 2 diabetes may develop these conditions (or an increase in their risk) over time. If that happens, an SGLT2 inhibitor could then be of benefit to them. The committee agreed that it was very important to highlight that it may be more appropriate to replace an existing therapy with an SGLT2 inhibitor than to add to it, depending on the person's circumstances. This is because they were aware that treatment optimisation as detailed in recommendation 1.7.14 is not always carried out in practice. ## How the recommendations might affect practice The recommendation about reviewing drug treatment is not expected to be a change in practice or to need substantial additional resources because these conversations should already take place. However, the wider use of SGLT2 inhibitors in people who are already being treated for type 2 diabetes and who have or develop high cardiovascular risk or chronic heart failure or established atherosclerotic cardiovascular disease is expected to lead to an increase in resource use. Return to recommendations # Treatment options if further interventions are needed Recommendations 1.7.17 to 1.7.23 ## Why the committee did not make any new recommendations in 2022 The committee did not make any new recommendations on further treatment options. They agreed that for later stages of treatment, separate recommendations were not needed for people at high risk of developing cardiovascular disease or with chronic heart failure or established atherosclerotic cardiovascular disease. This was for several reasons. Firstly, the evidence and the economic model continued to show that an SGLT2 inhibitor was likely to be the most cost-effective option for these people. Secondly, the recommendations they had made on first-line treatment using an SGLT2 inhibitor (either with metformin, or alone if metformin is contraindicated or not tolerated) and for switching or adding this drug at later stages meant that these people would be able to access an SGLT2 inhibitor without adding this consideration to the existing 2015 recommendations. Finally, the alternative treatment options for people with and without increased cardiovascular risk remained the same for later treatment stages. Therefore, the committee agreed to retain the existing 2015 recommendations for treatment options if further interventions are needed, without making any changes based on cardiovascular risk. To simplify treatment options, the committee merged recommendations for people in whom metformin is contraindicated or not tolerated into the existing 2015 recommendations where possible, and added the NICE technology appraisals as bullet points to the relevant existing recommendations. The evidence reviewed in this update was limited to the cardiovascular benefits of GLP‑1 mimetics and the committee agreed that this was only generalisable to people with a high risk of developing cardiovascular disease or with chronic heart failure or established atherosclerotic cardiovascular disease. As for first-line treatment, GLP-1 mimetics as a class were not cost-effective options for later stages of treatment, and there was too much uncertainty in the clinical and cost effectiveness to support recommending injectable semaglutide (see the rationale and impact section on first-line drug treatment). The committee did not look at clinical- and cost-effectiveness evidence for the use of GLP‑1 mimetics to control blood glucose levels. As a result, the committee were unable to update the 2015 GLP‑1 mimetic recommendations in this update. However, the committee were concerned that, as written, the 2015 recommendation on GLP1‑mimetics would mean that people taking newer drugs with proven cardiovascular benefit, such as SGLT2 inhibitors, would have to switch to a combination of metformin, a sulfonylurea and a GLP‑1 mimetic. They agreed that this might be clinically inappropriate and not in keeping with current clinical practice, so they amended recommendation 1.7.21 to remove the requirement for this specific combination of treatment options. The rest of the recommendation and the other recommendations for GLP‑1 mimetics were out of scope for this update, so the criteria for accessing a GLP‑1 mimetic remain unchanged. These recommendations set tight limits on who should be offered a GLP‑1 mimetic, based on the lack of cost effectiveness of this treatment for most people in the 2015 guideline. ## How the recommendations might affect practice Since no new drug options have been added to later stages of treatment, these recommendations are not expected to lead to an increase in resource impact over that detailed above for starting drug treatment with metformin and an SGLT2 inhibitor, or an SGLT2 inhibitor alone, or for people who are already on drug therapy when an SGLT2 inhibitor is or becomes appropriate based on their cardiovascular risk. Removing the previous restriction limiting the use of GLP‑1 mimetics to combination therapy with metformin and a sulfonylurea may increase the use of GLP‑1 mimetics at later stages of the treatment pathway by making additional combinations of triple therapy that include GLP‑1 mimetics available to eligible people. However, these drugs are already widely used in some areas and this change may bring the guideline into line with current practice. Return to recommendations # Long-acting insulin Recommendations 1.7.30 to 1.7.32 ## Why the committee made the recommendations Biosimilars have the potential to offer the NHS considerable cost savings. To gain approval for use, biosimilar medicines have to be shown to be safe and as effective as the original reference medicine, and have the same quality. Based on this understanding, the committee noted it was appropriate when starting a new prescription of an insulin where a biosimilar is available, to use the one with the lowest cost. Additionally, people may be using an insulin for which a lower cost biosimilar is available. In such cases, the committee recommended discussing with people the possibility of switching to the biosimilar. This could happen at the person's routine review. They also agreed that switching to the biosimilar should be carefully planned, taking into consideration the dose-switching protocols, monitoring and the person's concerns about switching from their existing regimen, and a shared decision reached. Healthcare professionals should also refer to the summary of product characteristics for further information when considering switching to biosimilars. Return to recommendations # SGLT2 inhibitors for adults with type 2 diabetes and chronic kidney disease Recommendations 1.8.16 to 1.8.20 ## Why the committee made the recommendations Strong evidence from well-conducted randomised controlled trials showed that SGLT2 inhibitors reduced the risk of chronic kidney disease (CKD) progression, mortality and cardiovascular events in adults with type 2 diabetes and CKD. Economic modelling for people with an albumin-to-creatinine ratio (ACR) above 30 mg/mol at baseline showed that SGLT2 inhibitors were likely to be both more effective and cost saving in this group compared with standard treatment. People with a baseline ACR of 3 mg/mmol to 30 mg/mmol will experience fewer cardiovascular events and events relating to CKD progression than people with a higher ACR. Because of this, SGLT2 inhibitors would prevent fewer events for this group in absolute terms, even if the relative effect was the same. Economic modelling showed that SGLT2 inhibitors were still likely to be both more effective and cost saving in people with a baseline ACR of between 3 mg/mol and 30 mg/mol compared with standard treatment. However, there was more uncertainty around the clinical and cost effectiveness in this group than in people with a baseline ACR over 30 mg/mmol. Because of this, SGLT2 inhibitors may not be suitable for everyone with a baseline ACR of between 3 mg/mmol and 30 mg/mmol, and the committee made a different recommendation for this group. There was no evidence specifically looking at the effectiveness of SGLT2 inhibitors for people with a baseline ACR of less than 3 mg/mol, so the committee made a recommendation for research for this group. The committee cautioned that SGLT2 inhibitors are not suitable for everyone and should only be used within their marketing authorisation. Some ethnic groups have a higher risk of micro- and macrovascular complications and so may benefit more from SGLT2 inhibitors. However, no evidence was found that stratified data by ethnicity. To address this gap, the committee made a recommendation for research. For an explanation of why the committee recommended angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors, see the section on pharmacotherapy in NICE's guideline on chronic kidney disease. ## How the recommendations might affect practice The recommendations will lead to a significant change in practice, since SGLT2 inhibitors will be prescribed more widely. This will result in a substantial cost impact. The committee noted, however, that there was likely to be a long-term cost saving from reduced downstream treatment costs, as SGLT2 inhibitors slow CKD progression and reduce the number of cardiovascular and end-stage renal events. Return to recommendations # Periodontitis Recommendations 1.8.1 to 1.8.4 ## Why the committee made the recommendations The evidence showed that people with diabetes are at increased risk of periodontitis, and that non-surgical periodontal treatment can improve diabetes control. However, in the committee's experience, people with diabetes are often unaware of this and may not be having regular oral health reviews. To address this, the committee recommended routinely discussing the risk of periodontitis at annual reviews, alongside eye disease and foot problems. The evidence also showed that periodontal treatment is cost effective for people with type 2 diabetes, assuming improvements in HbA1c are maintained. This was tested with health economic modelling in a range of different scenarios. There were some scenarios where periodontal treatment was not cost effective, but the committee did not think these scenarios reflected real-world practice. ## How the recommendations might affect practice For oral healthcare professionals, the long-term impact of the recommendations is uncertain. The recommendations specify that people should follow existing NICE guidelines on oral health. However, the recommendations may also increase awareness of periodontitis, leading to a possible short-term increase in the number of oral health reviews. Any increase in the number of oral health reviews will potentially impact on services, as NHS dental services already have capacity issues. A short-term increase in the number of oral health reviews will also lead to a short-term increase in costs. However, there is likely to be a larger long-term reduction in costs from the improvement to oral health and diabetes control. Oral healthcare and dental teams will need clear advice on what they need to do for people with diabetes. They will need clear care pathways to improve quality of care and service delivery, in line with the NHS England commissioning standard on dental care for people with diabetes. Many people do not have regular oral health reviews, even if they are eligible for free NHS dental care. People are eligible for free dental care if they are: pregnant mothers with babies under 1 year old -n low income benefits, or under 20 and dependent on someone who is receiving low income benefits having treatment in an NHS hospital by the hospital dentist. The recommendations may encourage more people with diabetes to have regular oral health reviews. Combined with proactive engagement and enhanced support for people with diabetes, this may broaden access to dental and oral healthcare and help to reduce oral health inequalities. Return to recommendations# Context Type 2 diabetes is a chronic metabolic condition characterised by insulin resistance (that is, the body's inability to effectively use insulin) and insufficient pancreatic insulin production, resulting in high blood glucose levels (hyperglycaemia). Type 2 diabetes is commonly associated with obesity, physical inactivity, raised blood pressure, periodontitis, disturbed blood lipid levels and a tendency to develop thrombosis, and is therefore recognised to have an increased cardiovascular risk. It is associated with long‑term microvascular and macrovascular complications, together with reduced quality of life and life expectancy. In 2019, approximately 3.2 million adults in the UK had diagnosed diabetes. About 90% of these people had type 2 diabetes. Type 2 diabetes is more common in people of African, African‑Caribbean and South Asian family background. It can occur in all age groups and is increasingly being diagnosed in adolescents and young adults. Multiple vascular risk factors and wide‑ranging complications make diabetes care complex and time-consuming, and many areas of healthcare services must be involved for optimal management. Necessary lifestyle changes, and the complexities and possible side effects of therapy, make structured education and self‑management important aspects of diabetes care. Diabetes care is estimated to account for at least 5% of UK healthcare expenditure, and up to 10% of NHS expenditure. This guideline contains recommendations for managing type 2 diabetes in adults, and focuses on education, dietary advice, managing cardiovascular risk, managing blood glucose levels, and identifying and managing long‑term complications. The guideline does not cover diagnosis, secondary diabetes, type 1 diabetes in adults, diabetes in pregnancy or diabetes in children and young people.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines\xa0explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Individualised care\n\nAdopt an individualised approach to diabetes care that is tailored to the needs and circumstances of adults with type 2 diabetes, taking into account their personal preferences, comorbidities and risks from polypharmacy, and their likelihood of benefiting from long-term interventions. Such an approach is especially important in the context of multimorbidity. [2015, amended 2022]\n\nReassess the person's needs and circumstances at each review and think about whether to stop any medicines that are not effective. \n\nTake into account any disabilities, including visual impairment, when planning and delivering care for adults with type 2 diabetes. \n\n# Education\n\nOffer structured education to adults with type\xa02 diabetes and their family members or carers (as appropriate) at the time of diagnosis, with annual reinforcement and review. Explain to people that structured education is an integral part of diabetes care. \n\nEnsure that any structured education programme for adults with type\xa02 diabetes:\n\nis evidence-based, and suits the needs of the person\n\nhas specific aims and learning objectives, and supports the person and their family members and carers to develop attitudes, beliefs, knowledge and skills to self-manage diabetes\n\nhas a structured curriculum that is theory driven, evidence-based and resource-effective, has supporting materials and is written down\n\nis delivered by trained educators who:\n\n\n\nhave an understanding of educational theory appropriate to the age and needs of the person\n\nare trained and competent to deliver the principles and content of the programme\n\n\n\nis quality assured, and reviewed by trained, competent, independent assessors who measure it against criteria that ensure consistency\n\nhas outcomes that are audited regularly. \n\nEnsure that education programmes for adults with type\xa02 diabetes provide the necessary resources to support the educators, and that educators are properly trained and given time to develop and maintain their skills. \n\nOffer adults with type\xa02 diabetes group education programmes as the preferred option. Provide an alternative of equal standard for people who are unable or prefer not to take part in group education. \n\nEnsure that education programmes for adults with type\xa02 diabetes meet the cultural, linguistic, cognitive and literacy needs of people in the local area. \n\nEnsure that all members of the diabetes healthcare team are familiar with the education programmes available locally for adults with type\xa02 diabetes, and that these programmes are integrated with the rest of the care pathway. \n\nEnsure that adults with type\xa02 diabetes and their family members and carers (as appropriate) have the opportunity to contribute to the design and provision of local education programmes for adults with type\xa02 diabetes. \n\n# Dietary advice and bariatric surgery\n\nProvide individualised and ongoing nutritional advice from a healthcare professional with specific expertise and competencies in nutrition. \n\nProvide dietary advice in a form sensitive to the person's needs, culture and beliefs, being sensitive to their willingness to change and the effects on their quality of life. \n\nEncourage adults with type\xa02 diabetes to follow the same healthy eating advice as the general population, which includes:\n\neating high-fibre, low-glycaemic-index sources of carbohydrate, such as fruit, vegetables, wholegrains and pulses\n\nchoosing low-fat dairy products\n\neating oily fish\n\ncontrolling their intake of saturated and trans fatty acids. \n\nIntegrate dietary advice with a personalised diabetes management plan, including other aspects of lifestyle modification such as increasing physical activity and losing weight. \n\nFor adults with type\xa02 diabetes who are overweight, discuss and agree an initial body weight loss target of 5% to 10%. Remember that a small amount of weight loss may still be beneficial, and a larger amount will have advantageous metabolic impact in the long term. \n\nIndividualise recommendations for carbohydrate and alcohol intake, and meal patterns. Make reducing the risk of hypoglycaemia a particular aim for people using insulin or an insulin secretagogue. \n\nAdvise adults with type\xa02 diabetes that they can substitute a limited amount of sucrose-containing foods for other carbohydrate in the meal plan but should take care to avoid excess energy intake. \n\nDiscourage adults with type\xa02 diabetes from using foods marketed specifically for people with diabetes. \n\nWhen adults with type\xa02 diabetes are admitted as inpatients to hospital or any other care setting, implement a meal planning system that provides consistency in the carbohydrate content of meals and snacks. \n\nFor recommendations on lifestyle advice, see the NICE guidelines on preventing excess weight gain, weight management, obesity, physical activity and tobacco. \n\nFor recommendations on bariatric surgery for people with recent-onset type\xa02 diabetes, see the section on bariatric surgery for people with recent-onset type 2 diabetes in the NICE guideline on obesity. \n\n# Diagnosing and managing hypertension\n\nThe recommendations on diagnosing and managing hypertension have been removed. For recommendations on hypertension in people with type\xa02 diabetes, see the NICE guideline on hypertension in adults. Diagnosis, treatment and monitoring of hypertension is broadly the same for people with type\xa02 diabetes as for other people. When a different approach is needed for people with type\xa02 diabetes, this is specified in the hypertension guideline.\n\n# Antiplatelet therapy\n\nDo not offer antiplatelet therapy (aspirin or clopidogrel) to adults with type\xa02 diabetes without cardiovascular disease. \n\nFor guidance on the primary and secondary prevention of cardiovascular disease in adults with type\xa02 diabetes, see the NICE guidelines on cardiovascular disease and acute coronary syndromes. \n\n# Blood glucose management\n\n## HbA1c measurement and targets\n\nMeasure HbA1c levels in adults with type\xa02 diabetes every:\n\nto 6\xa0months (tailored to individual needs) until HbA1c is stable on unchanging therapy\n\nmonths once the HbA1c level and blood glucose lowering therapy are stable. \n\nMeasure HbA1c using methods calibrated according to International Federation of Clinical Chemistry (IFCC) standardisation. \n\nIf HbA1c monitoring is invalid because of disturbed erythrocyte turnover or abnormal haemoglobin type, estimate trends in blood glucose control using one of the following:\n\nquality-controlled plasma glucose profiles\n\ntotal glycated haemoglobin estimation (if abnormal haemoglobins)\n\nfructosamine estimation. \n\nInvestigate unexplained discrepancies between HbA1c and other glucose measurements. Seek advice from a team with specialist expertise in diabetes or clinical biochemistry. \n\nNICE has produced a patient decision aid on agreeing HbA1c targets, which also covers factors to weigh up when discussing HbA1c targets with patients.\n\nDiscuss and agree an individual HbA1c target with adults with type\xa02 diabetes (see recommendations 1.6.6 to 1.6.10). Encourage them to reach their target and maintain it, unless any resulting adverse effects (including hypoglycaemia), or their efforts to achieve their target impair their quality of life. Think about using the NICE patient decision aid on weighing up HbA1c targets to support these discussions. [2015, amended 2022]\n\nOffer lifestyle advice and drug treatment to support adults with type\xa02 diabetes to reach and maintain their HbA1c target (see the sections on dietary advice and bariatric surgery and choosing drug treatments). For more information about supporting adherence, see the NICE guideline on medicines adherence. \n\nFor adults whose type\xa02 diabetes is managed either by lifestyle and diet, or lifestyle and diet combined with a single drug not associated with hypoglycaemia, support them to aim for an HbA1c level of 48\xa0mmol/mol (6.5%). For adults on a drug associated with hypoglycaemia, support them to aim for an HbA1c level of 53\xa0mmol/mol (7.0%). \n\nIn adults with type\xa02 diabetes, if HbA1c levels are not adequately controlled by a single drug and rise to 58\xa0mmol/mol (7.5%) or higher:\n\nreinforce advice about diet, lifestyle and adherence to drug treatment and\n\nsupport the person to aim for an HbA1c level of 53\xa0mmol/mol (7.0%) and\n\nintensify drug treatment. \n\nConsider relaxing the target HbA1c level (see recommendations 1.6.7 and 1.6.8 and NICE's patient decision aid) on a case-by-case basis and in discussion with adults with type\xa02 diabetes, with particular consideration for people who are older or frailer, if:\n\nthey are unlikely to achieve longer-term risk-reduction benefits, for example, people with a reduced life expectancy\n\ntight blood glucose control would put them at high risk if they developed hypoglycaemia, for example, if they are at risk of falling, they have impaired awareness of hypoglycaemia, or they drive or operate machinery as part of their job\n\nintensive management would not be appropriate, for example if they have significant comorbidities. [2015, amended 2022]\n\nIf adults with type\xa02 diabetes reach an HbA1c level that is lower than their target and they are not experiencing hypoglycaemia, encourage them to maintain it. Be aware that there are other possible reasons for a low HbA1c level, for example deteriorating renal function or sudden weight loss. \n\nFor guidance on HbA1c targets for women with type\xa02 diabetes who are pregnant or planning to become pregnant, see the NICE guideline on diabetes in pregnancy. \n\n## Self-monitoring of capillary blood glucose\n\nThese recommendations relate to self-monitoring by capillary blood glucose monitoring.\n\nTake the Driver and Vehicle Licensing Agency (DVLA)'s Assessing fitness to drive: a guide for medical professionals into account when offering self‑monitoring of capillary blood glucose levels for adults with type\xa02 diabetes. [2015, amended 2022]\n\nDo not routinely offer self-monitoring of capillary blood glucose levels for adults with type\xa02 diabetes unless:\n\nthe person is on insulin or\n\nthere is evidence of hypoglycaemic episodes or\n\nthe person is on oral medication that may increase their risk of hypoglycaemia while driving or operating machinery or\n\nthe person is pregnant or is planning to become pregnant (see the NICE guideline on diabetes in pregnancy). [2015, amended 2022]\n\nConsider short-term self-monitoring of capillary blood glucose levels in adults with type\xa02 diabetes, reviewing treatment as necessary:\n\nwhen starting treatment with oral or intravenous corticosteroids or\n\nto confirm suspected hypoglycaemia. [2015, amended 2022]\n\nBe aware that adults with type\xa02 diabetes who have acute intercurrent illness are at risk of worsening hyperglycaemia. Review treatment as necessary. \n\nIf adults with type\xa02 diabetes are self-monitoring their capillary blood glucose levels, carry out a structured assessment at least annually. The assessment should include:\n\nthe person's self-monitoring skills\n\nthe quality and frequency of testing\n\nchecking that the person knows how to interpret the blood glucose results and what action to take\n\nthe impact on the person's quality of life\n\nthe continued benefit to the person\n\nthe equipment used. [2015, amended 2022]\n\n## Continuous glucose monitoring\n\nOffer intermittently scanned continuous glucose monitoring (isCGM, commonly referred to as 'flash') to adults with type\xa02 diabetes on multiple daily insulin injections if any of the following apply:\n\nthey have recurrent hypoglycaemia or severe hypoglycaemia\n\nthey have impaired hypoglycaemia awareness\n\nthey have a condition or disability (including a learning disability or cognitive impairment) that means they cannot self-monitor their blood glucose by capillary blood glucose monitoring but could use an isCGM device (or have it scanned for them)\n\nthey would otherwise be advised to self-measure at least 8 times a day. For guidance on continuous glucose monitoring (CGM) for pregnant women, see the NICE guideline on diabetes in pregnancy. \n\nOffer isCGM to adults with insulin-treated type\xa02 diabetes who would otherwise need help from a care worker or healthcare professional to monitor their blood glucose. \n\nConsider real-time continuous glucose monitoring (rtCGM) as an alternative to isCGM for adults with insulin-treated type\xa02 diabetes if it is available for the same or lower cost. \n\nCGM should be provided by a team with expertise in its use, as part of supporting people to self-manage their diabetes. \n\nAdvise adults with type\xa02 diabetes who are using CGM that they will still need to take capillary blood glucose measurements (although they can do this less often). Explain that is because:\n\nthey will need to use capillary blood glucose measurements to check the accuracy of their CGM device\n\nthey will need capillary blood glucose monitoring as a back-up (for example when their blood glucose levels are changing quickly or if the device stops working). Provide them with enough test strips to take capillary blood glucose measurements as needed. \n\nIf a person is offered rtCGM or isCGM but cannot or does not want to use any of these devices, offer capillary blood glucose monitoring. \n\nEnsure CGM is part of the education provided to adults with type\xa02 diabetes who are using it (see the section on education). \n\nMonitor and review the person's use of CGM as part of reviewing their diabetes care plan (see the section on individualised care). \n\nIf there are concerns about the way a person is using the CGM device:\n\nask if they are having problems using their device\n\nlook at ways to address any problems and concerns to improve their use of the device, including further education and emotional and psychological support. \n\nCommissioners, providers and healthcare professionals should address inequalities in CGM access and uptake by:\n\nmonitoring who is using CGM\n\nidentifying groups who are eligible but who have a lower uptake\n\nmaking plans to engage with these groups to encourage them to consider CGM. \n\nFor a short explanation of why the committee made these recommendations see the rationale and impact section on continuous glucose monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: continuous glucose monitoring in adults with type\xa02 diabetes.\n\nLoading. Please wait.\n\n# Drug treatment\n\nRecommendations in this section that cover dipeptidyl peptidase‑4 (DPP‑4) inhibitors, glucagon‑like peptide‑1 (GLP‑1) mimetics, sulfonylureas and sodium–glucose cotransporter‑2 (SGLT2) inhibitors refer to each of these groups of drugs at class level unless otherwise stated.\n\nNICE technology appraisals for SGLT2 inhibitors recommend the use of these medicines only in specific populations and in certain circumstances. The 2022 update of this guideline looked at the clinical- and cost-effectiveness evidence for SGLT2 inhibitors in people with cardiovascular disease or at high risk of developing cardiovascular disease. The guideline recommends SGLT2 inhibitors in a wider population than the technology appraisals that were published before February\xa02022.\n\n## Choosing drug treatments\n\nWe have produced a visual summary to provide an overview of the recommendations and additional information to support medicines choice.\n\nDiscuss with adults with type\xa02 diabetes the benefits and risks of drug treatment and the options available. Base the choice of drug treatments on:\n\nthe person's individual clinical circumstances, for example comorbidities, contraindications, weight, and risks from polypharmacy\n\nthe person's individual preferences and needs\n\nthe effectiveness of the drug treatments in terms of metabolic response and cardiovascular and renal protection\n\nsafety and tolerability of the drug treatment\n\nmonitoring requirements\n\nthe licensed indications or combinations available\n\ncost (if 2\xa0drugs in the same class are appropriate, choose the option with the lowest acquisition cost). [2015, amended 2022]See the NICE guideline on shared decision making and the section on safety of medicines for diabetes before and during pregnancy in the NICE guideline on diabetes in pregnancy.\n\n## Rescue therapy at any phase of treatment\n\nIf an adult with type\xa02 diabetes is symptomatically hyperglycaemic, consider insulin (see the section on insulin-based treatments) or a sulfonylurea, and review treatment when blood glucose control has been achieved. \n\n## First-line drug treatment\n\nAlso see the visual summary on first-line drug treatment for an overview of the recommendations and additional information to support medicines choice.\n\nFor adults with type\xa02 diabetes and chronic kidney disease, follow recommendations on SGLT2 inhibitors in the section on chronic kidney disease in this guideline.\n\nOffer standard-release metformin as first-line drug treatment to adults with type\xa02 diabetes. \n\nAssess the person's cardiovascular status and risk to determine whether they have chronic heart failure or established atherosclerotic cardiovascular disease or are at high risk of developing cardiovascular disease.See the recommendations on using risk scores and QRISK2 to assess cardiovascular disease risk in adults with type\xa02 diabetes in NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification. \n\nBased on the cardiovascular risk assessment for the person with type\xa02 diabetes:\n\nIf they have chronic heart failure or established atherosclerotic cardiovascular disease, offer an SGLT2 inhibitor with proven cardiovascular benefit in addition to metformin.\n\nIf they are at high risk of developing cardiovascular disease, consider an SGLT2 inhibitor with proven cardiovascular benefit in addition to metformin. \n\nSee the rationale and impact section on first-line drug treatment\xa0 for an explanation of 'proven cardiovascular benefit'\n\nLoading. Please wait.\n\nWhen starting an adult with type\xa02 diabetes on dual therapy with metformin and an SGLT2 inhibitor as first-line therapy, introduce the drugs sequentially, starting with metformin and checking tolerability. Start the SGLT2 inhibitor as soon as metformin tolerability is confirmed. \n\nGradually increase the dose of standard-release metformin over several weeks to minimise the risk of gastrointestinal side effects in adults with type\xa02 diabetes. \n\nIf an adult with type\xa02 diabetes experiences gastrointestinal side effects with standard‑release metformin, consider a trial of modified‑release metformin. \n\nFor first-line drug treatment in adults with type\xa02 diabetes, if metformin is contraindicated or not tolerated:\n\nIf they have chronic heart failure or established atherosclerotic cardiovascular disease, offer an SGLT2 inhibitor with proven cardiovascular benefit.\n\nIf they are at high risk of developing cardiovascular disease, consider an SGLT2 inhibitor with proven cardiovascular benefit. \n\nFor first-line drug treatment in adults with type\xa02 diabetes, if metformin is contraindicated or not tolerated and if they are not in either of the groups in recommendation 1.7.9, consider:\n\na DPP‑4 inhibitor or\n\npioglitazone or\n\na sulfonylurea or\n\nan SGLT2 inhibitor for people who meet the criteria in NICE's technology appraisal guidance on canagliflozin, dapagliflozin and empagliflozin as monotherapies or ertugliflozin as monotherapy or with metformin for treating type\xa02 diabetes. [2015, amended 2022]\n\nBefore starting an SGLT2 inhibitor, check whether the person may be at increased risk of diabetic ketoacidosis (DKA), for example if:\n\nthey have had a previous episode of DKA\n\nthey are unwell with intercurrent illness\n\nthey are following a very low carbohydrate or ketogenic diet. \n\nAddress modifiable risks for DKA before starting an SGLT2 inhibitor. For example, for people who are following a very low carbohydrate or ketogenic diet, they may need to delay treatment until they have changed their diet. \n\nAdvise adults with type\xa02 diabetes who are taking an SGLT2 inhibitor about the need to minimise their risk of DKA by not starting a very low carbohydrate or ketogenic diet without discussing it with their healthcare professional, because they may need to suspend SGLT2 inhibitor treatment. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on first-line drug treatment\xa0.\n\nFull details of the evidence and the committee's decision are in evidence review B: pharmacological therapies with cardiovascular and other benefits in people with type\xa02 diabetes.\n\nLoading. Please wait.\n\n## Reviewing drug treatments\n\nWhen reviewing or considering changing treatments for adults with type\xa02 diabetes, think about and discuss the following with the person:\n\nhow to optimise their current treatment regimen before thinking about changing treatments, taking into account factors such as:\n\n\n\nadverse effects\n\nadherence to existing medicines\n\nthe need to revisit advice about diet and lifestyle\n\nprescribed doses and formulations\n\n\n\nstopping medicines that have had no impact on glycaemic control or weight, unless there is an additional clinical benefit, such as cardiovascular or renal protection, from continued treatment (see the note below on off-label use)\n\nwhether switching rather than adding drugs could be effective\n\nthe considerations about treatment choice in recommendation 1.7.1. In February\xa02022, using ertugliflozin to reduce cardiovascular risk when blood glucose is well controlled was off-label. See NICE's information on prescribing medicines.Also see the recommendations on medication review in the NICE guideline on medicines optimisation and on reviewing medicines and supporting adherence in the NICE guideline on medicines adherence.\n\nFor adults with type 2 diabetes who start taking an SGLT2 inhibitor before they are 40 because they have an elevated lifetime risk of cardiovascular disease, do not stop the SGLT2 inhibitor when they turn 40 even if their QRISK2 score is below 10%. Only stop the SGLT2 inhibitor if the person's circumstances have changed and the SGLT2 inhibitor is no longer appropriate. \n\nFor adults with type\xa02 diabetes at any stage after they have started first-line treatment:\n\nIf they have or develop chronic heart failure or established atherosclerotic cardiovascular disease, offer an SGLT2 inhibitor with proven cardiovascular benefit in addition to current treatment or replace an existing drug with the SGLT2 inhibitor.\n\nIf they are or become at high risk of developing cardiovascular disease, consider adding an SGLT2 inhibitor with proven cardiovascular benefit to current treatment or replacing an existing drug with the SGLT2 inhibitor.Take into account the person's current treatment regimen and preferences and make a shared decision about switching treatments or adding an SGLT2 inhibitor, as appropriate (also see recommendations 1.7.12 and 1.7.13 on starting an SGLT2 inhibitor). In February\xa02022, using ertugliflozin to reduce cardiovascular risk when blood glucose is well controlled was off-label. See NICE's information on prescribing medicines.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reviewing drug treatments\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: pharmacological therapies with cardiovascular and other benefits in people with type\xa02 diabetes.\n\nLoading. Please wait.\n\n## Treatment options if further interventions are needed\n\nAlso see our visual summary on treatment options if further interventions are needed for an overview of the recommendations and additional information to support medicines choice.\n\nIntroduce drugs used in combination therapy in a stepwise manner, checking for tolerability and effectiveness of each drug. \n\nFor adults with type\xa02 diabetes, if monotherapy has not continued to control HbA1c to below the person's individually agreed threshold for further intervention, consider adding:\n\na DPP‑4 inhibitor or\n\npioglitazone or\n\na sulfonylurea or\n\nan SGLT2 inhibitor for people who meet the criteria in NICE's technology appraisal guidance on canagliflozin in combination therapy, ertugliflozin as monotherapy or with metformin, or dapagliflozin or empagliflozin in combination therapy. [2015, amended 2022]\n\nFor adults with type\xa02 diabetes, if dual therapy with metformin and another oral drug has not continued to control HbA1c to below the person's individually agreed threshold for further intervention consider either:\n\ntriple therapy by adding a DPP‑4 inhibitor, pioglitazone or a sulfonylurea or an SGLT2 inhibitor for people who meet the criteria in NICE's technology appraisal guidance on canagliflozin in combination therapy, dapagliflozin in triple therapy, empagliflozin in combination therapy, or ertugliflozin with metformin and a dipeptidyl peptidase-4 inhibitor\xa0or\n\nstarting insulin-based treatment (see the section on insulin-based treatments). [2015, amended 2022]\n\nIn adults with type\xa02 diabetes, if metformin is contraindicated or not tolerated and dual therapy with 2\xa0oral drugs has not continued to control HbA1c to below the person's individually agreed threshold for intervention, consider insulin-based treatment (see the section on insulin-based treatments). [2015, amended 2022]\n\nIf triple therapy with metformin and 2\xa0other oral drugs is not effective, not tolerated or contraindicated, consider triple therapy by switching one drug for a GLP‑1 mimetic for adults with type\xa02 diabetes who:\n\nhave a body mass index (BMI) of 35\xa0kg/m2 or higher (adjust accordingly for people from Black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity or\n\nhave a BMI lower than 35\xa0kg/m2\xa0and:\n\n\n\nfor whom insulin therapy would have significant occupational implications or\n\nweight loss would benefit other significant obesity-related comorbidities. [2015, amended 2022]\n\n\n\nOnly continue GLP‑1 mimetic therapy if the adult with type\xa02 diabetes has had a beneficial metabolic response (a reduction of at least 11\xa0mmol/mol [1.0%] in HbA1c and weight loss of at least 3% of initial body weight in 6\xa0months). \n\nFor adults with type\xa02 diabetes, only offer combination therapy with a GLP‑1 mimetic and insulin along with specialist care advice and ongoing support from a consultant-led multidisciplinary team. \n\nFor a short explanation of why the committee did not make any new 2022 recommendations, see the rationale and impact section on treatment options if further interventions are needed\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: pharmacological therapies with cardiovascular and other benefits in people with type\xa02 diabetes.\n\nLoading. Please wait.\n\n## Insulin-based treatments\n\nFor adults with type\xa02 diabetes starting insulin therapy, provide a structured programme using active insulin dose titration that encompasses:\n\ninjection technique, including rotating injection sites and avoiding repeated injections at the same point within sites\n\ncontinuing telephone support\n\nself-monitoring\n\ndose titration to target levels\n\ndietary advice\n\nthe DVLA's Assessing fitness to drive: a guide for medical professionals\n\nmanaging hypoglycaemia\n\nmanaging acute changes in plasma glucose control\n\nsupport from an appropriately trained and experienced healthcare professional. \n\nFor adults with type\xa02 diabetes starting insulin therapy, continue to offer metformin for people without contraindications or intolerance. Review the continued need for other blood glucose lowering therapies. \n\nStart insulin therapy for adults with type\xa02 diabetes from a choice of the following insulin types and regimens:\n\nOffer neutral protamine Hagedorn (NPH) insulin injected once or twice daily according to need.\n\nConsider starting both NPH and short‑acting insulin (particularly if the person's HbA1c is 75\xa0mmol/mol [9.0%] or higher), administered either:\n\n\n\nseparately or\n\nas a pre-mixed (biphasic) human insulin preparation.\n\n\n\nConsider, as an alternative to NPH insulin, using insulin detemir or insulin glargine if:\n\n\n\nthe person needs help from a carer or healthcare professional to inject insulin, and use of insulin detemir or insulin glargine would reduce the frequency of injections from twice to once daily or\n\nthe person's lifestyle is restricted by recurrent symptomatic hypoglycaemic episodes or\n\nthe person would otherwise need twice‑daily NPH insulin injections in combination with oral glucose‑lowering drugs.\n\n\n\nConsider pre-mixed (biphasic) preparations that include short‑acting insulin analogues, rather than pre‑mixed (biphasic) preparations that include short‑acting human insulin preparations, if:\n\n\n\nthe person prefers injecting insulin immediately before a meal or\n\nhypoglycaemia is a problem or\n\nblood glucose levels rise markedly after meals. \n\n\n\nConsider switching to insulin detemir or insulin glargine from NPH insulin in adults with type\xa02 diabetes:\n\nwho do not reach their target HbA1c because of significant hypoglycaemia or\n\nwho experience significant hypoglycaemia on NPH insulin irrespective of the level of HbA1c reached or\n\nwho cannot use the device needed to inject NPH insulin but could administer their own insulin safely and accurately if a switch to one of the long‑acting insulin analogues was made or\n\nwho need help from a carer or healthcare professional to administer insulin injections and for whom switching to one of the long‑acting insulin analogues would reduce the number of daily injections. \n\nMonitor adults with type\xa02 diabetes who are on a basal insulin regimen (NPH insulin, insulin detemir or insulin glargine) for the need for short‑acting insulin before meals (or a pre‑mixed [biphasic] insulin preparation). \n\nMonitor adults with type\xa02 diabetes who are on pre‑mixed (biphasic) insulin for the need for a further injection of short‑acting insulin before meals or for a change to a basal-bolus regimen with NPH insulin or insulin detemir or insulin glargine, if blood glucose control remains inadequate. \n\nWhen starting an insulin for which a biosimilar is available, use the product with the lowest acquisition cost. \n\nEnsure the risk of medication errors with insulins is minimised by following the Medicines and Healthcare products Regulatory Agency (MHRA) guidance on minimising the risk of medication error with high strength, fixed combination and biosimilar insulin products, which includes advice for healthcare professionals when starting treatment with a biosimilar. \n\nWhen people are already using an insulin for which a lower cost biosimilar is available, discuss the possibility of switching to the biosimilar. Make a shared decision with the person after discussing their preferences. \n\nFor a short explanation of why the committee made the 2021 recommendations on biosimilars and how they might affect practice, see the rationale and impact section on long-acting insulin\xa0.\n\nLoading. Please wait.\n\nFor guidance on using insulin in combination with SGLT2 inhibitors, see:\n\nthe section on drug treatment\n\nNICE's technology appraisal guidance on canagliflozin, dapagliflozin, and empagliflozin in combination therapy.\n\n## Insulin delivery\n\nFor guidance on insulin delivery for adults with type\xa02 diabetes, see the section on insulin delivery in the NICE guideline on type\xa01 diabetes. \n\n# Managing complications\n\n## Periodontitis\n\nAdvise adults with type\xa02 diabetes at their annual review that:\n\nthey are at higher risk of periodontitis\n\nif they get periodontitis, managing it can improve their blood glucose control and can reduce their risk of hyperglycaemia. \n\nAdvise adults with type\xa02 diabetes to have regular oral health reviews (their oral healthcare or dental team will tell them how often, in line with the NICE guideline on dental checks: intervals between oral health reviews). \n\nFor guidance for oral healthcare and dental teams on how to provide oral health advice, see the NICE guideline on oral health promotion. \n\nFor adults with type\xa02 diabetes who have been diagnosed with periodontitis by an oral healthcare or dental team, offer dental appointments to manage and treat their periodontitis (at a frequency based on their oral health needs). \n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on periodontitis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: periodontitis.\n\nLoading. Please wait.\n\n## Gastroparesis\n\nThink about a diagnosis of gastroparesis in adults with type\xa02 diabetes who have erratic blood glucose control or unexplained gastric bloating or vomiting, taking into account possible alternative diagnoses. [2009, amended 2015]\n\nFor adults with type\xa02 diabetes who have vomiting caused by gastroparesis, explain that:\n\nthere is no strong evidence that any available antiemetic therapy is effective\n\nsome people have had benefit with domperidone, erythromycin or metoclopramide\n\nthe strongest evidence for effectiveness is for domperidone, but prescribers must take into account its safety profile, in particular its cardiac risk and potential interactions with other medicines. In December\xa02015, the use of erythromycin was off-label. See NICE's information on prescribing medicines.\n\nTo treat vomiting caused by gastroparesis in adults with type\xa02 diabetes:\n\nconsider alternating the use of erythromycin and metoclopramide\n\nconsider domperidone only in exceptional circumstances (if domperidone is the only effective treatment) and in accordance with MHRA guidance on domperidone. In December\xa02015, the use of erythromycin was off-label. See NICE's information on prescribing medicines.\n\nIf gastroparesis is suspected, consider referring adults with type\xa02 diabetes to specialist services if:\n\nthe differential diagnosis is in doubt or\n\nthe person has persistent or severe vomiting. \n\n## Painful diabetic neuropathy\n\nFor guidance on managing painful diabetic peripheral neuropathy in adults with type\xa02 diabetes, see the NICE guideline on neuropathic pain in adults. \n\n## Autonomic neuropathy\n\nThink about the possibility of contributory sympathetic nervous system damage in adults with type\xa02 diabetes who lose the warning signs of hypoglycaemia. [2009, amended 2015]\n\nThink about the possibility of autonomic neuropathy affecting the gut in adults with type\xa02 diabetes who have unexplained diarrhoea that happens particularly at night. [2009, amended 2015]\n\nFor adults with type\xa02 diabetes and autonomic neuropathy who are taking tricyclic drugs and antihypertensive drug treatments, be aware of the increased likelihood of side effects such as orthostatic hypotension. For guidance on safe prescribing of antidepressants (such as tricyclic drugs) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. \n\nFor adults with type\xa02 diabetes who have unexplained bladder‑emptying problems, investigate the possibility of autonomic neuropathy affecting the bladder. \n\nIn managing autonomic neuropathy symptoms, include specific interventions indicated by the manifestations (for example, for abnormal sweating or nocturnal diarrhoea). \n\n## Diabetic foot problems\n\nFor guidance on preventing and managing foot problems in adults with type\xa02 diabetes, see the NICE guideline on diabetic foot problems. \n\n## Chronic kidney disease\n\nFor adults with chronic kidney disease (CKD) and type\xa02 diabetes, offer an angiotensin receptor blocker (ARB) or an angiotensin‑converting enzyme (ACE) inhibitor (titrated to the highest licensed dose that the person can tolerate) if albumin-to-creatinine ratio (ACR) is 3\xa0mg/mmol or more, as recommended in the section on pharmacotherapy for CKD in adults, children, and young people with related persistent proteinuria in the NICE guideline on chronic kidney disease. \n\nFor adults with type\xa02 diabetes and CKD who are taking an ARB or an ACE inhibitor (titrated to the highest licensed dose that they can tolerate), offer an SGLT2 inhibitor (in addition to the ARB or ACE inhibitor) if:\n\nACR is over 30\xa0mg/mmol and\n\nthey meet the criteria in the marketing authorisation (including relevant estimated glomerular filtration rate [eGFR] thresholds).In November\xa02021, not all SGLT2 inhibitors were licensed for this indication. See NICE's information on prescribing medicines. \n\nFor adults with type\xa02 diabetes and CKD who are taking an ARB or an ACE inhibitor (titrated to the highest licensed dose that they can tolerate), consider an SGLT2 inhibitor (in addition to the ARB or ACE inhibitor) if:\n\nACR is between 3 and 30\xa0mg/mmol and\n\nthey meet the criteria in the marketing authorisation (including relevant eGFR thresholds). In November\xa02021, not all SGLT2 inhibitors were licensed for this indication. See NICE's information on prescribing medicines. \n\nFor guidance on dapagliflozin for adults with CKD, see NICE's technology appraisal guidance on dapagliflozin for treating chronic kidney disease. \n\nFor further guidance on managing kidney disease in adults with type\xa02 diabetes, see the NICE guideline on chronic kidney disease. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on SGLT2 inhibitors for adults with type\xa02 diabetes and chronic kidney disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: SGLT2 inhibitors for people with chronic kidney disease and type\xa02 diabetes.\n\nLoading. Please wait.\n\n## Erectile dysfunction\n\nOffer men with type\xa02 diabetes the opportunity to discuss erectile dysfunction as part of their annual review. \n\nAssess, educate and support men with type\xa02 diabetes who have problematic erectile dysfunction, addressing contributory factors such as cardiovascular disease as well as possible treatment options. \n\nConsider a phosphodiesterase‑5 inhibitor to treat problematic erectile dysfunction in men with type\xa02 diabetes. Initially choose the drug with the lowest acquisition cost and take into account any contraindications. \n\nAfter discussion, refer men with type\xa02 diabetes to a service offering other medical, surgical or psychological management of erectile dysfunction if treatment (including a phosphodiesterase‑5 inhibitor, as appropriate) has been unsuccessful. \n\n## Eye disease\n\nWhen adults are diagnosed with type\xa02 diabetes, refer them immediately to the local eye screening service. [2009, amended 2020]\n\nEncourage adults to attend eye screening, and explain that it will help them to keep their eyes healthy and help to prevent problems with their vision. Explain that the screening service is effective at identifying problems so that they can be treated early. \n\nArrange emergency review by an ophthalmologist for:\n\nsudden loss of vision\n\nrubeosis iridis\n\npre-retinal or vitreous haemorrhage\n\nretinal detachment. \n\nRefer to an ophthalmologist in accordance with the UK National Screening Committee criteria and timelines for any large sudden unexplained drop in visual acuity. [2009, amended 2020]\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Atherosclerotic cardiovascular disease\n\nThis includes coronary heart disease, acute coronary syndrome, previous myocardial infarction, stable angina, previous coronary or other revascularisation, cerebrovascular disease (ischaemic stroke and transient ischaemic attack) and peripheral arterial disease.\n\n## Consultant-led multidisciplinary team\n\nA consultant-led multidisciplinary team may include a wide range of staff based in primary, secondary and community care.\n\n## Continuous glucose monitoring\n\nThis covers both real-time continuous glucose monitoring (rtCGM) and intermittently scanned continuous glucose monitoring (isCGM, commonly referred to as 'flash').\n\nA continuous glucose monitor is a device that measures blood glucose levels and sends the readings to a display device or smartphone.\n\n## High risk of developing cardiovascular disease\n\nAdults with type\xa02 diabetes who have:\n\nQRISK2 more than 10% in adults aged\xa040 and over or\n\nan elevated lifetime risk of cardiovascular disease (defined as the presence of 1 or more cardiovascular risk factors in someone under\xa040).\n\nCardiovascular disease risk factors: hypertension, dyslipidaemia, smoking, obesity, and family history (in a first-degree relative) of premature cardiovascular disease.\n\n## Insulin glargine\n\nThe recommendations in this guideline also apply to any current or future biosimilar product of insulin glargine that has an appropriate marketing authorisation that allows the use of the biosimilar in the same indication.\n\n## Multiple daily injections\n\nTwo or more daily insulin injections, which could either be a basal-bolus regimen or more than one daily insulin injection.\n\n## Periodontitis\n\nA chronic inflammatory gum disease that destroys the supporting tissues of the teeth (the periodontium).\n\nGingivitis is a milder form of periodontal disease than periodontitis. However, gingivitis still causes inflammation in the gum, and if not treated it can lead to periodontitis.\n\n## Severe hypoglycaemia\n\nEpisodes of hypoglycaemia that require assistance from another person to treat.\n\n## Recurrent hypoglycaemia\n\nFrequent events of hypoglycaemia that occur each week or month and have an impact on quality of life.\n\n## Very low carbohydrate and ketogenic diets\n\nA very low carbohydrate diet has 20\xa0to 50\xa0grams per day of carbohydrate or less than 10% of a 2000\xa0kcal/day diet. A ketogenic diet is a very low carbohydrate, high fat diet that is designed to induce ketosis.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## The effects of stopping or switching drug treatments to control blood glucose levels\n\nIn adults with type\xa02 diabetes, what are the effects of stopping and/or switching drug treatments to control blood glucose levels, and what criteria should inform the decision? \n\nThere is a lack of evidence on the effects of stopping and/or switching drug treatments to control blood glucose levels. The current practice of 'stopping rules' is typically motivated by either inadequate blood glucose control (rising HbA1c levels) or intolerable side effects. There is limited understanding of the short- and long‑term effects of stopping a therapy and switching to another in terms of diabetes control (HbA1c levels), hypoglycaemic risk, weight gain, and cardiovascular morbidity and mortality. In addition, there is limited understanding of how quickly consideration should be given to stopping and switching to another drug treatment and, if stopping and switching may be needed, what the optimal sequencing is of drug treatments. Randomised controlled trials examining these different issues would help to improve diabetes care.\n\n## Non-metformin-based drug treatment combinations to control blood glucose levels\n\nIn adults with type\xa02 diabetes, what treatment combinations (for example, glucagon‑like peptide‑1 [GLP‑1] mimetics and insulin combination therapy with meglitinides) are most effective when initial drug treatment with non‑metformin monotherapy fails to adequately control blood glucose levels? \n\nAlthough it is recognised that metformin therapy is suitable for most adults with type\xa02 diabetes, its use is contraindicated or not tolerated in approximately 15% of individuals. To date, research evidence has largely focused on metformin‑based treatment combinations. Given the progressive nature of the condition, in which intensification of blood glucose lowering drug therapies are indicated over time, there is little evidence, for some adults, to guide management strategies on treatment combinations that do not include metformin. Randomised controlled trials are therefore needed to better understand the treatment choices that are available which improve blood glucose control and long‑term risks of complications associated with diabetes.\n\n## Drug treatment for when blood glucose levels are inadequately controlled by 3 oral antidiabetic drugs or insulin combinations\n\nWhen blood glucose levels are inadequately controlled by 3\xa0oral antidiabetic drugs and/or insulin combinations, which blood glucose lowering therapies should be used to control blood glucose levels? [2015, amended 2021]\n\nAs the incidence of type\xa02 diabetes increases in the younger population and as blood glucose control declines naturally over time, it is likely that further intensification of therapies would be needed. Currently, there is evidence up to second intensification of drug therapies, that is, when 2 or more non‑insulin‑based treatment combinations fail to adequately control blood glucose levels. Randomised controlled trials are needed to improve understanding of alternative treatment options for adults at second intensification whose blood glucose is inadequately controlled with insulin and/or triple non‑insulin‑based drug therapies.\n\n## Self-monitoring of blood glucose levels\n\nWhat is the optimal frequency for self‑monitoring of blood glucose in adults with type\xa02 diabetes? \n\nThere is limited evidence in relation to the long‑term effects (at least 5\xa0years) of blood glucose lowering therapies, particularly newer agents in terms of efficacy and adverse events (for example, cardiovascular outcomes). Randomised controlled trials and prospective longitudinal studies are needed to better understand the long‑term efficacy and safety issues surrounding these medicines.\n\n# Other recommendations for research\n\n## Effectiveness of SGLT2 inhibitors for different ethnic groups\n\nWhat is the clinical and cost effectiveness of SGLT2 inhibitors in adults with type 2 diabetes and chronic kidney disease, stratified across different ethnic groups? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on SGLT2 inhibitors for adults with type\xa02 diabetes and chronic kidney disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: SGLT2 inhibitors for people with chronic kidney disease and type\xa02 diabetes.\n\nLoading. Please wait.\n\n## Effectiveness of SGLT2 inhibitors for adults with a urine albumin-to-creatinine ratio (ACR) below 3\xa0mg/mmol\n\nWhat is the clinical and cost effectiveness of SGLT2 inhibitors in adults with type 2 diabetes, chronic kidney disease and a urine ACR of less than 3\xa0mg/mmol? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on SGLT2 inhibitors for adults with type\xa02 diabetes and chronic kidney disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: SGLT2 inhibitors for people with chronic kidney disease and type\xa02 diabetes.\n\nLoading. Please wait.\n\n## Long-term outcomes associated with blood glucose lowering agents\n\nIn adults with type\xa02 diabetes, what are the long‑term effects of blood glucose lowering therapies such as dipeptidyl peptidase‑4 (DPP‑4) inhibitors, sodium–glucose cotransporter‑2 (SGLT2) inhibitors and meglitinides? \n\n## Using routinely collected real-world data to assess the effectiveness of continuous glucose monitoring\n\nBased on routinely collected real-world data, what is the effectiveness and cost effectiveness of CGM devices to improve glycaemic control in adults with type\xa02 diabetes? \n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale section on continuous glucose monitoring.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: continuous glucose monitoring in adults with type\xa02 diabetes.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Continuous glucose monitoring\n\nRecommendations 1.6.17 to 1.6.26\n\n## Why the committee made the recommendations\n\nThe committee discussed how continuous glucose monitoring (CGM) could potentially be useful for many people with type\xa02 diabetes. They were aware of examples from current practice in which adults who have insulin-treated type\xa02 diabetes and use intermittently scanned CGM (isCGM) have had good outcomes. Because of the additional cost associated with CGM and the large number of adults with type\xa02 diabetes, the committee used both the evidence and their clinical experience to decide who would gain the most benefit from using CGM.\n\nThere was evidence that intermittently scanned CGM (isCGM) was cost effective for adults with type\xa02 diabetes using insulin, but no evidence for populations not using insulin, so the committee agreed to restrict their recommendations to that subpopulation.\n\nPeople who have recurrent or severe hypoglycaemic events were identified as one of the groups likely to benefit most from isCGM, because hypoglycaemic events were considered to be one of the most important and concerning outcomes for adults with type\xa02 diabetes who are using insulin. The committee decided that the number of hypoglycaemic events was a more effective indicator of someone who would benefit from isCGM than specific HbA1c target values, because target values can vary between people. The evidence also indicated minimal effects of isCGM on HbA1c values.\n\nThe committee agreed that people with impaired hypoglycaemic awareness would also benefit from isCGM. However, they did not recommend specific methods for assessing impaired hypoglycaemic awareness. This is because validated methods for assessing impaired hypoglycaemic awareness in people with type\xa02 diabetes (such as the GOLD or Clarke scores) are not always available in primary care.\n\nPeople who use insulin and have a condition or disability that restricts their ability to self-monitor blood glucose levels should also be offered isCGM. This is because having access to isGCM means they will no longer have to rely on others to monitor their diabetes, potentially increasing their independence. For people with learning disabilities, this recommendation is in line with similar guidance for type\xa01 diabetes set out in the NHS RightCare Pathway, which specifies reasonable adjustments for people with a learning disability who have diabetes.\n\nPeople who are advised to self-measure using capillary blood glucose monitoring more than 8 times a day should also be offered isCGM. This is in line with the funding requirements for NHS England's flash glucose monitoring: national arrangements for funding of relevant diabetes patients. Although the funding requirements are specifically for people with type\xa01 diabetes, the committee thought that this criterion was also important for people with type\xa02 diabetes who have to monitor their blood glucose levels multiple times a day.\n\nPeople who need help from a care worker or other healthcare professional to administer their insulin injections should also be offered isCGM, even if they only use once-daily insulin injections. isCGM will help care workers to record a person's blood glucose levels quickly. And for people who have multiple home care visits per day, blood glucose levels can be recorded at each visit. This will help them to adjust their insulin levels to reduce the risk of hypoglycaemic events between home visits. It may also reduce the number of hospital admissions for this group.\n\nThe committee discussed how short-term use of isCGM may still be useful for some people. It may help people to understand when they have hypoglycaemic episodes, which would help them to develop a more effective treatment plan.\n\nThere was no evidence that real-time CGM (rtCGM) was cost effective for people with type\xa02 diabetes, so the committee agreed it could not be recommended for all adults with type\xa02 diabetes (whether or not they used insulin). They noted, however, that prices of rtCGM have reduced over the past few years, and if this continues to happen there may come a time when it is no more expensive than isCGM. At this point, rtCGM would be an appropriate alternative for people who meet the criteria for isCGM.\n\nThe committee did not make a recommendation on using specific devices because CGM technologies are changing very quickly and this recommendation would soon be out of date. Local healthcare services are better placed to assess which devices are evidence-based and suitable for use at any given time.\n\nThe committee discussed how self-monitoring of blood glucose should still take place, albeit less frequently, even when a person is using CGM. The ability to self-monitor blood glucose levels allows people to ensure the accuracy of the CGM device. The committee also recommended keeping capillary blood glucose monitoring as a back-up for situations such as when the technology fails.\n\nThe committee decided to highlight that CGM should be provided by a team who have expertise in its use. To ensure that CGM is effective, healthcare professionals need to have the skills to interpret and communicate the data effectively. As well as healthcare professionals having a clear understanding of CGM, it is also crucial that people with type\xa02 diabetes who are using CGM have education about the technology. This will increase the likelihood that people will scan and report the results frequently, allowing people to understand and manage their diabetes effectively.\n\nAlthough many people will choose CGM if offered, there are some people who either cannot be offered it or do not want to use it. Because it is still important for these people to monitor their blood glucose levels, the committee made a recommendation to reinforce the importance of offering capillary blood glucose monitoring instead.\n\nThe committee did not make a recommendation on how long CGM should be used because there was no evidence on this, and they did not want to stop people accessing CGM for short periods if they and their healthcare professional thought they could benefit from this. Using CGM for a short period of time may help some people to understand when they have hypoglycaemic episodes, thereby helping them to develop a more effective treatment plan.\n\nDespite the positive recommendations on CGM, the committee were concerned that existing health inequalities may still lead to lower uptake of CGM in some groups of people. To address this, the committee made a recommendation outlining actions for commissioners, providers and healthcare professionals.\n\nThe committee highlighted the importance of routinely reviewing a person's use of CGM. This will establish whether it is providing clinical benefits and whether the monitor is being used correctly. Making people aware that their use of CGM will be continually reviewed is important so they know it is not a guaranteed long-term option.\n\nThe committee also made a recommendation for research on using routinely collected real-world data to assess the effectiveness and cost effectiveness of CGM. They agreed that this has the potential to show the direct effects of the technology used by people with type\xa02 diabetes instead of interpreting it through the results of clinical trials. Increased monitoring of routine healthcare data including registries and audits would ensure that findings from a broader population are captured.\n\n## How the recommendations might affect practice\n\nThe recommendations are likely to increase the number of adults with type\xa02 diabetes who are offered CGM, particularly those who have issues with hypoglycaemia. This will have associated cost implications:\n\nIt may save the NHS time, because healthcare professionals do not have to meet people who are using CGM as often as people who use capillary blood glucose monitoring.\n\nThere should be fewer hypoglycaemic events to manage. The committee did not expect a significant resource impact related to education and monitoring for the CGM devices.\n\nReturn to recommendations\n\n# First-line drug treatment\n\nRecommendations 1.7.3 to 1.7.13\n\n## Why the committee made the recommendations\n\nThe evidence from the clinical trials looking at cardiovascular benefits, the network meta-analyses, and the economic modelling, showed that some treatments were effective at improving cardiovascular outcomes and were likely to be cost effective. All of these trials recruited people with established cardiovascular disease, and some also included people with a high risk of developing cardiovascular disease. However, for people without high cardiovascular risk, the committee agreed there was more uncertainty over whether the same level of cardiovascular benefits seen in the high-risk groups could be applied to a lower risk population. They decided that they could not justify changing the recommendations for people at lower risk based on this evidence. Therefore, they retained the 2015 recommendations outlining the drug treatment options for people in the lower risk group.\n\nThe committee agreed it was important to assess people's cardiovascular status and risk to help determine which treatments are suitable for them. They used a definition for the established cardiovascular disease group (adults with type\xa02 diabetes and chronic heart failure or established atherosclerotic cardiovascular disease) that reflected the people included in all the clinical trials and modelled as a subgroup in the economic model.\n\nTo assess whether people are at high risk of developing cardiovascular disease, the committee recommended using the QRISK2 tool because this is recommended in the NICE guideline on cardiovascular disease: risk assessment and reduction, including lipid modification for adults with type\xa02 diabetes, and the factors covered by this tool were similar to those used in the trials and economic model to define this population. In addition, this tool is widely used in current practice in the NHS.\n\nLifetime cardiovascular risk may be underestimated in people aged under\xa040 using this tool, so the committee also included risk factors to consider for this age group. This definition was broadly aligned to the subgroup of people with high cardiovascular risk without established cardiovascular disease who were included in the model.\n\nThe evidence showed that SGLT2 inhibitors as a class of drugs were most likely to be cost effective in combination with metformin, although the incremental cost-effectiveness ratio (ICER) varied between different drugs in the class and in different scenarios in the model. The exception to this was dapagliflozin, which was cost effective at a threshold of £20,000 per quality-adjusted life year in the base-case analysis and across a range of model scenarios. However, the committee agreed there was too much uncertainty in the clinical data, and therefore the economic modelling, for them to be confident that these different ICERs represented true underlying differences in cost effectiveness.\n\nThere were also varying levels of certainty in the clinical trials and the network meta-analyses about:\n\nwhich individual SGLT2 inhibitors were effective at improving cardiovascular outcomes\n\nwhether there were real differences in cardiovascular benefits between the different SGLT2 inhibitors.For hospitalisation for heart failure, empagliflozin, canagliflozin and dapagliflozin produced a clinically meaningful reduction compared with placebo in the random effects network meta-analysis model. However, in the sensitivity analyses using a fixed effect model, ertugliflozin also showed a clinically meaningful reduction compared with placebo (which reflects the original clinical trial data). The network meta-analysis could not differentiate between the SGLT2 inhibitors.\n\nFor the 3‑point MACE outcome (a composite of major adverse cardiovascular events), only canagliflozin and empagliflozin produced a statistically significant reduction compared with placebo. However, the network meta-analyses again could not differentiate between SGLT2 inhibitors.\n\nFor all-cause mortality and cardiovascular mortality, empagliflozin showed a clinically meaningful reduction compared with placebo and the other SGLT2 inhibitors. The network meta-analysis could not differentiate between the other SGLT2 inhibitors.\n\nFor non-fatal myocardial infarction and non-fatal stroke, the network meta-analysis could not differentiate between empagliflozin, canagliflozin, ertugliflozin or placebo. The data for dapagliflozin was reported differently and could not be included in the network meta-analyses. In the clinical trial data, dapagliflozin could not be differentiated from placebo for myocardial infarction and was not meaningfully different from placebo for stroke.\n\nFinally, only dapagliflozin showed a clinically meaningful reduction in severe hypoglycaemia compared with placebo. However, the remaining SGLT2 inhibitors could not be differentiated from each other or from placebo in the network meta-analysis.\n\nTaking the cost effectiveness and clinical results into account, the committee decided against recommending only dapagliflozin and instead made recommendations for the SGLT2 inhibitors as a class. However, they recognised that there was greater uncertainty around the cardiovascular benefits associated with ertugliflozin than there was for empagliflozin, canagliflozin and dapagliflozin. This was because ertugliflozin did not consistently show a reduction in heart failure compared with placebo in the network meta-analyses (it depended on the model used), and it was not statistically significantly better than placebo for the 3‑point MACE outcome. The committee therefore decided to refer to 'SGLT2 inhibitors with proven cardiovascular benefit' in the recommendations. This was to enable prescribers to select a particular drug from the class of SGLT2 inhibitors that they thought was clinically appropriate for each person, while allowing the recommendation to remain current even if additional evidence or new SGLT2 inhibitors become available.\n\nThe committee agreed there was more certainty of cardiovascular benefits in adults with type\xa02 diabetes and chronic heart failure or established atherosclerotic cardiovascular disease because they were participants in all the included trials, while people at high risk of developing cardiovascular disease were included in fewer trials. So, they recommended dual therapy with an SGLT2 inhibitor with proven cardiovascular benefit in addition to metformin for both groups, but only as an option to consider for people without established cardiovascular disease, to reflect the lower certainty. For people without a high risk of developing cardiovascular disease who do not have chronic heart failure or established atherosclerotic cardiovascular disease, metformin monotherapy remains the recommended first-line treatment option, based on the 2015 recommendation.\n\nWhen starting first-line dual therapy, the committee noted the importance of introducing the drugs sequentially. This enables any side effects and intolerances from the first drug to be identified before the second drug is introduced. In line with current practice, the committee recommended starting with metformin and then adding the SGLT2 inhibitor without delay once metformin tolerability is established, to avoid people remaining on metformin alone for prolonged periods.\n\nSome people will have established cardiovascular disease or a high risk of developing cardiovascular disease, but not be able to take an SGLT2 inhibitor. As GLP‑1 mimetics were not cost-effective options in this situation (see the rationale and impact section on why GLP-1 mimetics were not recommended as first-line treatment), the committee agreed that these people would be offered metformin alone as a first-line treatment (see recommendation\xa01.7.3).\n\nPeople who cannot tolerate metformin or for whom it is contraindicated were not included as a separate group in the economic model because the evidence was taken from trials that did not separate results by whether the person was able to take metformin or not. Most people in these trials were expected to be able to take metformin. The committee agreed with the assumption that people who cannot tolerate metformin or for whom it is contraindicated would be offered the next most effective and cost-effective treatment options after metformin.\n\nIn the economic model scenario, when another drug was used in place of metformin for people with established cardiovascular disease or at high risk of developing cardiovascular disease, SGLT2 inhibitors were the class of drugs that were most likely to be cost effective. The committee therefore prioritised this class of drugs for these people. As before, there was greater certainty in the results for people with established cardiovascular disease compared with those at high risk of developing cardiovascular disease, and the rationale for referring to SGLT2 inhibitors with proven cardiovascular benefit also applies here.\n\nSome people will have established cardiovascular disease or a high risk of developing cardiovascular disease, but not be able to take an SGLT2 inhibitor or metformin. There was no evidence specifically for this group so the committee made the same assumption as above (that these people would take the next most effective and cost-effective treatment). The committee did not recommend a specific drug for these people because GLP‑1 mimetics were not cost-effective options in this situation (see the rationale and impact section on why GLP-1 mimetics were not recommended as first-line treatment). They agreed that in practice prescribers would use their clinical judgement to choose an appropriate treatment from the remaining options, based on the individual clinical circumstances and needs of the person with type\xa02 diabetes (see recommendation\xa01.7.1).\n\nThe committee noted some particularly important safety considerations to take into account before an adult with type\xa02 diabetes starts on an SGLT2 inhibitor. The committee highlighted these because the SGLT2 inhibitors are comparatively new drugs and clinical experience with them is low in primary care, but the new recommendations are expected to greatly increase their use in this setting. In the committee's experience there have been multiple instances of avoidable diabetic ketoacidosis (DKA) resulting in hospital admission. The committee highlighted some factors that might put someone at higher risk of DKA, but the list is not intended to be exhaustive. Addressing modifiable risk factors before starting an SGLT2 inhibitor could reduce the risk of DKA and make the drug safer for the person with type\xa02 diabetes.\n\nThe committee were aware that adults with type\xa02 diabetes who are overweight or obese may wish to try a ketogenic diet to reverse or reduce the severity of their diabetes or induce remission. However, the committee agreed, based on their experience, that there may be an increased risk of DKA associated with SGLT2 inhibitors and such diets. It is important to tell people about these risks and to advise them to discuss any planned change to a very low carbohydrate or ketogenic diet with their healthcare professional first.\n\nThe committee did not recommend a GLP‑1 mimetic as first-line treatment for the following reasons:\n\nGLP‑1 mimetics were not cost effective as a class at this (or any) stage of treatment for people with a high risk of developing cardiovascular disease or with established cardiovascular disease.\n\nAlthough the ICERs for injectable semaglutide for the various modelled scenarios and stages of treatment fell within a similar range to the ICERs for the individual SGLT2 inhibitors, there was more certainty that the SGLT2s were cost effective as a class. In contrast, the ICERs for injectable semaglutide increased significantly in a sensitivity analysis, highlighting the uncertainty surrounding the results.\n\nThere were differences in clinical effectiveness between the injectable and oral forms of semaglutide compared with placebo for some outcomes, such as all-cause mortality, based on the evidence from the trials. However, the committee agreed it was uncertain whether the observed differences in effect were real or might be related to the relatively small size and low event rates in these trials compared with other trials included in the review, which resulted in wide 95% confidence intervals around the effect estimates for some outcomes.\n\nThe committee concluded that the factors above combined to give such a high level of uncertainty around the clinical and cost effectiveness of injectable semaglutide that they could not make a positive recommendation for its use.\n\n## How the recommendations might affect practice\n\nThe recommendations to offer SGLT2 inhibitors with metformin to adults with type\xa02 diabetes and chronic heart failure or established atherosclerotic cardiovascular disease at first-line treatment (or if they are already taking metformin monotherapy) are expected to lead to a change in practice and increase the number of people taking SGLT2 inhibitors at the beginning of their treatment. This is also expected to be the case for people with a high risk of developing cardiovascular disease, as this category is expected to cover a large proportion of adults with type\xa02 diabetes. In current practice, these people would not be offered combination therapy with an SGLT2 inhibitor until additional treatment is needed to control their HbA1c to below their individually agreed threshold for intervention, and then only if they met the criteria in the relevant NICE technology appraisals for being prescribed an SGLT2 inhibitor. Overall, this recommendation is expected to greatly increase the number of people taking SGLT2 inhibitors and is likely to have a substantial resource impact.\n\nThe number of adults with type\xa02 diabetes and chronic heart failure or established atherosclerotic cardiovascular disease or a high risk of developing cardiovascular disease who cannot tolerate metformin, or for whom metformin is contraindicated, are expected to be relatively low. The new recommendations are likely to see a change in practice as more people start taking an SGLT2 inhibitor, and this will likely be associated with a resource impact.\n\nThe recommendations about how to begin combination therapy, factors to check before a person starts on an SGLT2 inhibitor, and topics to cover in a conversation with the person, are not expected to significantly increase consultation time or be a change in practice because these should already form part of the prescribing process. Checking that the person is not at increased risk of DKA when they are prescribed an SGLT2 inhibitor should help reduce the number of people who experience DKA and thereby reduce unnecessary hospital admissions.\n\nReturn to recommendations\n\n# Reviewing drug treatments\n\nRecommendations 1.7.14 to 1.7.16\n\n## Why the committee made the recommendations\n\nThe committee agreed that when changes to treatment are being considered it is important to review existing treatment options first. Stopping medications that have not worked, for example, in controlling blood glucose or weight loss, and optimising current treatments may remove the need to prescribe additional drugs. However, some drugs, such as SGLT2 inhibitors, may be continued because they provide additional cardiovascular protective benefits. In particular, there might be reasons, such as problems with adherence or adverse effects, that might make existing treatments less effective or ineffective. Addressing these might mean that adding a new drug is unnecessary.\n\nThe list of factors to think about as part of optimisation is not exhaustive but includes those that the committee thought were particularly important. The committee agreed that it is important to revisit advice about diet and lifestyle because part of this discussion is to ensure the person is supported with both non-pharmacological and pharmacological interventions to improve their current health and prognosis.\n\nReviews should also take into account a person's current clinical circumstances (as detailed in recommendation\xa01.7.1 on choosing drug treatments). This will help ensure that appropriate treatment options are considered if the person's clinical situation has changed: for example, if it has improved because of weight loss or if they have developed chronic heart failure or atherosclerotic cardiovascular disease.\n\nWhen people with an elevated lifetime risk of cardiovascular disease turn 40, their cardiovascular risk may appear to drop when it is assessed using QRISK2. However, this is due to switching from assessing lifetime risk to a 10-year risk calculation rather than an actual decrease in cardiovascular risk. SGLT2 inhibitor treatment should not be stopped for this reason alone.\n\nBased on the evidence and the economic model, the benefits of SGLT2 inhibitors were not confined to first-line treatment for people with elevated cardiovascular risk or chronic heart failure or established atherosclerotic cardiovascular disease. To ensure that people who are already on drug therapy (including those people who have started first-line treatment, and those people who are further along the treatment pathway and are taking dual or triple therapy) for type\xa02 diabetes can have an SGLT2 inhibitor if their level of cardiovascular risk is sufficiently high or they have chronic heart failure or established atherosclerotic cardiovascular disease, the committee included a separate recommendation on SGLT2 inhibitors for these people. As explained in the rationale for recommendations on first-line treatment, the committee specified SGLT2 inhibitors with proven cardiovascular benefits.\n\nThis recommendation also takes into account that adults with type\xa02 diabetes may develop these conditions (or an increase in their risk) over time. If that happens, an SGLT2 inhibitor could then be of benefit to them. The committee agreed that it was very important to highlight that it may be more appropriate to replace an existing therapy with an SGLT2 inhibitor than to add to it, depending on the person's circumstances. This is because they were aware that treatment optimisation as detailed in recommendation 1.7.14 is not always carried out in practice.\n\n## How the recommendations might affect practice\n\nThe recommendation about reviewing drug treatment is not expected to be a change in practice or to need substantial additional resources because these conversations should already take place. However, the wider use of SGLT2 inhibitors in people who are already being treated for type\xa02 diabetes and who have or develop high cardiovascular risk or chronic heart failure or established atherosclerotic cardiovascular disease is expected to lead to an increase in resource use.\n\nReturn to recommendations\n\n# Treatment options if further interventions are needed\n\nRecommendations 1.7.17 to 1.7.23\n\n## Why the committee did not make any new recommendations in 2022\n\nThe committee did not make any new recommendations on further treatment options. They agreed that for later stages of treatment, separate recommendations were not needed for people at high risk of developing cardiovascular disease or with chronic heart failure or established atherosclerotic cardiovascular disease. This was for several reasons.\n\nFirstly, the evidence and the economic model continued to show that an SGLT2 inhibitor was likely to be the most cost-effective option for these people. Secondly, the recommendations they had made on first-line treatment using an SGLT2 inhibitor (either with metformin, or alone if metformin is contraindicated or not tolerated) and for switching or adding this drug at later stages meant that these people would be able to access an SGLT2 inhibitor without adding this consideration to the existing 2015 recommendations.\n\nFinally, the alternative treatment options for people with and without increased cardiovascular risk remained the same for later treatment stages. Therefore, the committee agreed to retain the existing 2015 recommendations for treatment options if further interventions are needed, without making any changes based on cardiovascular risk.\n\nTo simplify treatment options, the committee merged recommendations for people in whom metformin is contraindicated or not tolerated into the existing 2015 recommendations where possible, and added the NICE technology appraisals as bullet points to the relevant existing recommendations.\n\nThe evidence reviewed in this update was limited to the cardiovascular benefits of GLP‑1 mimetics and the committee agreed that this was only generalisable to people with a high risk of developing cardiovascular disease or with chronic heart failure or established atherosclerotic cardiovascular disease. As for first-line treatment, GLP-1 mimetics as a class were not cost-effective options for later stages of treatment, and there was too much uncertainty in the clinical and cost effectiveness to support recommending injectable semaglutide (see the rationale and impact section on first-line drug treatment).\n\nThe committee did not look at clinical- and cost-effectiveness evidence for the use of GLP‑1 mimetics to control blood glucose levels. As a result, the committee were unable to update the 2015 GLP‑1 mimetic recommendations in this update. However, the committee were concerned that, as written, the 2015 recommendation on GLP1‑mimetics would mean that people taking newer drugs with proven cardiovascular benefit, such as SGLT2 inhibitors, would have to switch to a combination of metformin, a sulfonylurea and a GLP‑1 mimetic. They agreed that this might be clinically inappropriate and not in keeping with current clinical practice, so they amended recommendation\xa01.7.21 to remove the requirement for this specific combination of treatment options. The rest of the recommendation and the other recommendations for GLP‑1 mimetics were out of scope for this update, so the criteria for accessing a GLP‑1 mimetic remain unchanged. These recommendations set tight limits on who should be offered a GLP‑1 mimetic, based on the lack of cost effectiveness of this treatment for most people in the 2015 guideline.\n\n## How the recommendations might affect practice\n\nSince no new drug options have been added to later stages of treatment, these recommendations are not expected to lead to an increase in resource impact over that detailed above for starting drug treatment with metformin and an SGLT2 inhibitor, or an SGLT2 inhibitor alone, or for people who are already on drug therapy when an SGLT2 inhibitor is or becomes appropriate based on their cardiovascular risk.\n\nRemoving the previous restriction limiting the use of GLP‑1 mimetics to combination therapy with metformin and a sulfonylurea may increase the use of GLP‑1 mimetics at later stages of the treatment pathway by making additional combinations of triple therapy that include GLP‑1 mimetics available to eligible people. However, these drugs are already widely used in some areas and this change may bring the guideline into line with current practice.\n\nReturn to recommendations\n\n# Long-acting insulin\n\nRecommendations 1.7.30 to 1.7.32\n\n## Why the committee made the recommendations\n\nBiosimilars have the potential to offer the NHS considerable cost savings. To gain approval for use, biosimilar medicines have to be shown to be safe and as effective as the original reference medicine, and have the same quality. Based on this understanding, the committee noted it was appropriate when starting a new prescription of an insulin where a biosimilar is available, to use the one with the lowest cost.\n\nAdditionally, people may be using an insulin for which a lower cost biosimilar is available. In such cases, the committee recommended discussing with people the possibility of switching to the biosimilar. This could happen at the person's routine review. They also agreed that switching to the biosimilar should be carefully planned, taking into consideration the dose-switching protocols, monitoring and the person's concerns about switching from their existing regimen, and a shared decision reached. Healthcare professionals should also refer to the summary of product characteristics for further information when considering switching to biosimilars.\n\nReturn to recommendations\n\n# SGLT2 inhibitors for adults with type\xa02 diabetes and chronic kidney disease\n\nRecommendations 1.8.16 to 1.8.20\n\n## Why the committee made the recommendations\n\nStrong evidence from well-conducted randomised controlled trials showed that SGLT2 inhibitors reduced the risk of chronic kidney disease (CKD) progression, mortality and cardiovascular events in adults with type\xa02 diabetes and CKD.\n\nEconomic modelling for people with an albumin-to-creatinine ratio (ACR) above 30\xa0mg/mol at baseline showed that SGLT2 inhibitors were likely to be both more effective and cost saving in this group compared with standard treatment.\n\nPeople with a baseline ACR of 3\xa0mg/mmol to 30\xa0mg/mmol will experience fewer cardiovascular events and events relating to CKD progression than people with a higher ACR. Because of this, SGLT2 inhibitors would prevent fewer events for this group in absolute terms, even if the relative effect was the same. Economic modelling showed that SGLT2 inhibitors were still likely to be both more effective and cost saving in people with a baseline ACR of between 3\xa0mg/mol and 30\xa0mg/mol compared with standard treatment. However, there was more uncertainty around the clinical and cost effectiveness in this group than in people with a baseline ACR over 30\xa0mg/mmol. Because of this, SGLT2 inhibitors may not be suitable for everyone with a baseline ACR of between 3\xa0mg/mmol and 30\xa0mg/mmol, and the committee made a different recommendation for this group.\n\nThere was no evidence specifically looking at the effectiveness of SGLT2 inhibitors for people with a baseline ACR of less than 3\xa0mg/mol, so the committee made a recommendation for research for this group.\n\nThe committee cautioned that SGLT2 inhibitors are not suitable for everyone and should only be used within their marketing authorisation.\n\nSome ethnic groups have a higher risk of micro- and macrovascular complications and so may benefit more from SGLT2 inhibitors. However, no evidence was found that stratified data by ethnicity. To address this gap, the committee made a recommendation for research.\n\nFor an explanation of why the committee recommended angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors, see the section on pharmacotherapy in NICE's guideline on chronic kidney disease.\n\n## How the recommendations might affect practice\n\nThe recommendations will lead to a significant change in practice, since SGLT2 inhibitors will be prescribed more widely. This will result in a substantial cost impact. The committee noted, however, that there was likely to be a long-term cost saving from reduced downstream treatment costs, as SGLT2 inhibitors slow CKD progression and reduce the number of cardiovascular and end-stage renal events.\n\nReturn to recommendations\n\n# Periodontitis\n\nRecommendations 1.8.1 to 1.8.4\n\n## Why the committee made the recommendations\n\nThe evidence showed that people with diabetes are at increased risk of periodontitis, and that non-surgical periodontal treatment can improve diabetes control. However, in the committee's experience, people with diabetes are often unaware of this and may not be having regular oral health reviews. To address this, the committee recommended routinely discussing the risk of periodontitis at annual reviews, alongside eye disease and foot problems.\n\nThe evidence also showed that periodontal treatment is cost effective for people with type 2 diabetes, assuming improvements in HbA1c are maintained. This was tested with health economic modelling in a range of different scenarios. There were some scenarios where periodontal treatment was not cost effective, but the committee did not think these scenarios reflected real-world practice.\n\n## How the recommendations might affect practice\n\nFor oral healthcare professionals, the long-term impact of the recommendations is uncertain. The recommendations specify that people should follow existing NICE guidelines on oral health. However, the recommendations may also increase awareness of periodontitis, leading to a possible short-term increase in the number of oral health reviews. Any increase in the number of oral health reviews will potentially impact on services, as NHS dental services already have capacity issues.\n\nA short-term increase in the number of oral health reviews will also lead to a short-term increase in costs. However, there is likely to be a larger long-term reduction in costs from the improvement to oral health and diabetes control.\n\nOral healthcare and dental teams will need clear advice on what they need to do for people with diabetes. They will need clear care pathways to improve quality of care and service delivery, in line with the NHS England commissioning standard on dental care for people with diabetes.\n\nMany people do not have regular oral health reviews, even if they are eligible for free NHS dental care. People are eligible for free dental care if they are:\n\npregnant\n\nmothers with babies under 1 year old\n\non low income benefits, or under 20 and dependent on someone who is receiving low income benefits\n\nhaving treatment in an NHS hospital by the hospital dentist.\n\nThe recommendations may encourage more people with diabetes to have regular oral health reviews. Combined with proactive engagement and enhanced support for people with diabetes, this may broaden access to dental and oral healthcare and help to reduce oral health inequalities.\n\nReturn to recommendations", 'Context': "Type\xa02 diabetes is a chronic metabolic condition characterised by insulin resistance (that is, the body's inability to effectively use insulin) and insufficient pancreatic insulin production, resulting in high blood glucose levels (hyperglycaemia). Type\xa02 diabetes is commonly associated with obesity, physical inactivity, raised blood pressure, periodontitis, disturbed blood lipid levels and a tendency to develop thrombosis, and is therefore recognised to have an increased cardiovascular risk. It is associated with long‑term microvascular and macrovascular complications, together with reduced quality of life and life expectancy.\n\nIn 2019, approximately 3.2\xa0million adults in the UK had diagnosed diabetes. About 90% of these people had type\xa02 diabetes. Type\xa02 diabetes is more common in people of African, African‑Caribbean and South Asian family background. It can occur in all age groups and is increasingly being diagnosed in adolescents and young adults.\n\nMultiple vascular risk factors and wide‑ranging complications make diabetes care complex and time-consuming, and many areas of healthcare services must be involved for optimal management. Necessary lifestyle changes, and the complexities and possible side effects of therapy, make structured education and self‑management important aspects of diabetes care. Diabetes care is estimated to account for at least 5% of UK healthcare expenditure, and up to 10% of NHS expenditure.\n\nThis guideline contains recommendations for managing type\xa02 diabetes in adults, and focuses on education, dietary advice, managing cardiovascular risk, managing blood glucose levels, and identifying and managing long‑term complications. The guideline does not cover diagnosis, secondary diabetes, type\xa01 diabetes in adults, diabetes in pregnancy or diabetes in children and young people."}	https://www.nice.org.uk/guidance/ng28	This guideline covers care and management for adults (aged 18 and over) with type 2 diabetes. It focuses on patient education, dietary advice, managing cardiovascular risk, managing blood glucose levels, and identifying and managing long-term complications.
dcedbee6c125b4ff50d85eca79c4b2ca305d3614	nice	COVID-19 rapid guideline: vaccine-induced immune thrombocytopenia and thrombosis (VITT)	COVID-19 rapid guideline: vaccine-induced immune thrombocytopenia and thrombosis (VITT) This guideline covers vaccine-induced immune thrombocytopenia and thrombosis (VITT), a syndrome which has been reported in rare cases after COVID-19 vaccination. VITT may also be called vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) or thrombotic thrombocytopenic syndrome (TTS). Because VITT is a new condition, there is limited evidence available to inform clinical management, identification and management of the condition is evolving quickly as the case definition becomes clearer. This guideline was produced to support clinicians to diagnose and manage this newly recognised syndrome. # Recommendations How to use this guideline Introduction Identifying suspected VITT Investigations and diagnosis Initial investigations Further care when VITT is unlikely Further investigations for probable VITT Management Person-centred care Managing thrombosis Anticoagulants Additional considerations for treating thrombosis Managing the VITT immune response Initial treatment Further treatments Intensive treatment for people with signs of poor prognosis Ongoing management Patient-centred care Monitoring response and treating relapse Reporting cases Further vaccination Equality considerations Equalities impact assessment during scoping Equalities impact assessment during guideline development Methods and processes	{'Recommendations': 'How to use this guideline\n\nIntroduction\n\nIdentifying suspected VITT\n\nInvestigations and diagnosis\n\n\n\nInitial investigations\n\nFurther care when VITT is unlikely\n\nFurther investigations for probable VITT\n\n\n\nManagement\n\n\n\nPerson-centred care\n\nManaging thrombosis\n\n\n\nAnticoagulants\n\nAdditional considerations for treating thrombosis\n\n\n\nManaging the VITT immune response\n\n\n\nInitial treatment\n\nFurther treatments\n\nIntensive treatment for people with signs of poor prognosis\n\n\n\nOngoing management\n\n\n\nPatient-centred care\n\nMonitoring response and treating relapse\n\n\n\n\n\nReporting cases\n\nFurther vaccination\n\nEquality considerations\n\n\n\nEqualities impact assessment during scoping\n\nEqualities impact assessment during guideline development\n\n\n\nMethods and processes'}	https://www.nice.org.uk/guidance/ng200	This guideline covers vaccine-induced immune thrombocytopenia and thrombosis (VITT), a syndrome which has been reported in rare cases after COVID-19 vaccination. VITT may also be called vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) or thrombotic thrombocytopenic syndrome (TTS). Because VITT is a new condition, there is limited evidence available to inform clinical management, identification and management of the condition is evolving quickly as the case definition becomes clearer. This guideline was produced to support clinicians to diagnose and manage this newly recognised syndrome.
3fde33116993782cd4dd6a60678da8dcdb3da05b	nice	Multiple sclerosis in adults: management	Multiple sclerosis in adults: management This guideline covers diagnosing and managing multiple sclerosis in people aged 18 and over. It aims to improve the quality of life for people with multiple sclerosis by promoting prompt and effective symptom management and relapse treatment, and comprehensive reviews. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Diagnosing multiple sclerosis ## Recognising multiple sclerosis See also NICE's guideline on suspected neurological conditions: recognition and referral for advice for non-specialists on initial assessment of symptoms and signs that might indicate a neurological condition. Be aware that people with multiple sclerosis (MS) may present with a wide range of symptoms affecting different parts of the body. The most common are: loss or reduction of vision in 1 eye with painful eye movements double vision ascending sensory disturbance and/or weakness altered sensation or pain travelling down the back and sometimes into the limbs when bending the neck forwards (Lhermitte's sign) progressive difficulties with balance and gait. Be aware that usually people with MS present with neurological symptoms or signs as described in recommendation 1.1.1, and: are often aged under 50 and may have a history of previous neurological symptoms and have symptoms that have evolved over more than 24 hours and have symptoms that may persist over several days or weeks and then improve and do not have fever or infection. Do not routinely suspect MS if a person's main symptoms are fatigue, depression, dizziness or vague sensory phenomena, unless they have a history or evidence of focal neurological symptoms or signs. ## Initial assessment Before referring a person suspected of having MS to a neurologist, confirm that this is a neurological episode by taking a history, undertaking a physical examination and excluding alternative, more common diagnoses. ## Referral and diagnosis Refer people suspected of having MS for diagnosis by a consultant neurologist or a specialist under their supervision. Contact the consultant neurologist directly if you think a person needs to be seen urgently. Diagnose MS using a combination of history, examination, MRI and laboratory findings, and by following the 2017 revised McDonald criteria. This should include: assessing that symptoms are consistent with an inflammatory demyelinating process; for example, headache is not suggestive of MS excluding alternative diagnoses (targeted laboratory tests may be indicated if the history, examination or MRI findings are atypical) establishing that lesions on MRI scans have developed at different times and are in different anatomical locations for a diagnosis of relapsing–remitting MS looking for cerebrospinal fluid-specific oligoclonal bands if there is no clinical or radiological evidence of lesions developing at different times establishing progressive neurological deterioration over 1 year or more for a diagnosis of primary progressive MS. If the McDonald criteria are not met but MS is suspected or the person has confirmed clinically isolated syndrome (see the 2017 McDonald criteria for a definition of clinically isolated syndrome): Plan a review to reassess the possibility of MS. Discuss the timing of this and future reviews with the person (for example, annually). Provide information and ensure that the person knows who to contact for advice if they develop further neurological symptoms or if current symptoms worsen. Do not diagnose MS on the basis of MRI findings alone. Offer people with confirmed MS information and advice on resources and support. For further details, see the section on information and support at the time of diagnosis. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnosing multiple sclerosis . Full details of the committee's discussion are in the committee discussion for diagnostic criteria. Loading. Please wait. ## Optic neuritis and neuromyelitis optica spectrum disorder If a person has an episode of isolated, optic neuritis, confirmed by an ophthalmologist, refer them to a consultant neurologist for further assessment. Diagnosis of neuromyelitis optica spectrum disorder should be made by an appropriate specialist based on established up‑to‑date criteria. # Providing information and support For advice on communication and information follow the recommendations in NICE's guideline on patient experience in adult NHS services. For advice on shared decision making, follow the recommendations in NICE's guideline on shared decision making. ## Information and support at the time of diagnosis The consultant neurologist should ensure that people with MS, and with their agreement their family members or carers, are offered oral and written information at the time of diagnosis. This should include, but not be limited to, information about: what MS is treatments, including disease‑modifying therapies symptom management how support groups, local services, social services and national charities are organised and how to get in touch with them -nline resources legal requirements such as notifying the Driver and Vehicle Licensing Agency (DVLA; see the DVLA webpage on multiple sclerosis and driving) and legal rights including social care, employment rights and benefits. Discuss with the person with MS and their family members or carers whether they have social care needs and if so refer them to social services for assessment. Ensure the needs of children of people with MS are addressed. Offer the person with MS a face‑to‑face follow‑up appointment with a healthcare professional with expertise in MS to take place within 6 weeks of diagnosis. ## Ongoing information and support Explain to people with MS that they should have a comprehensive review of their care at least once a year and what this should cover (see the section on comprehensive review). Advise them to ask their healthcare professional for a review if it has not taken place. Review information, support and social care needs regularly. Continue to offer information and support to people with MS or their family members or carers even if this has been declined previously. Ensure people with MS and their family members or carers have a management plan that includes who to contact if their symptoms change significantly. Explain to people with MS that the possible causes of symptom changes include: another illness such as an infection further relapse change of disease status (for example progression). Talk to people with MS and their family members or carers about the possibility that the condition might lead to cognitive problems. Provide ongoing information and support tailored to the person's changing needs or circumstances, for example, when planning to have children, if their MS is changing to a more progressive phase or as their MS becomes more advanced. Explain to carers (including young carers) about their right to a carer's assessment and tell them about other sources of information and support that may be available (see NICE's guideline on supporting adult carers and the Young Carers Regulations 2015). ## Information and support for people planning to have children or who are pregnant Ask the person with MS soon after diagnosis and at regular intervals if they have any plans for starting or extending their family now or in the future, either through pregnancy or adoption. Explain to people with MS that they should discuss with their healthcare professionals if they are planning to start or extend their family or become pregnant. In particular, ensure that people taking disease-modifying treatments understand that they should tell their healthcare professionals straight away if they are trying to become pregnant or if they become pregnant. Explain to people with MS, and their partners if appropriate, that MS should not stop them from planning a family. Offer the opportunity to talk with a healthcare professional with knowledge of MS to answer any questions they have. For example, this may include discussing the following: that fertility is not affected by MS that pregnancy can be well managed in people with MS the risk of the child developing MS taking vitamin D and folic acid supplements before and during pregnancy (see NICE's guidelines on vitamin D and maternal and child nutrition) possible changes to medicine use before and during pregnancy that pregnancy does not increase the risk of disease progression that relapses may decrease during pregnancy and may increase 3 to 6 months after childbirth before returning to pre-pregnancy rates that birth options and pain relief choices available (including epidurals) should not be affected by MS that breastfeeding is safe unless the person with MS is taking certain disease-modifying treatments support that may be available with caring for and supporting children. Discuss caring for a child and the possible impact of MS symptoms, such as fatigue, and how these could be managed. ## Information and support for people as MS becomes more advanced, including those approaching the end of their life Give people with MS that is becoming more advanced and their family members or carers information and support covering: social isolation and feelings of depression mobility aids and home adaptations -ther support available, such as legal rights including social care, employment rights and benefits, and the right to a carer's assessment (see recommendation 1.2.6). Explain to people with advanced MS and their family members or carers about the services available (for example, occupational therapy, palliative care and social services) and give them support to access them if needed. For advice on identifying people who may be approaching the end of their life and providing information and support, follow the recommendations in NICE's guideline on end of life care for adults. When appropriate, explain to the person with MS (and their family members or carers if the person wishes) about advance care planning and power of attorney. Think about discussing advance care planning early if you expect the person's ability to communicate, cognitive status or mental capacity will deteriorate. Follow the recommendations on advance care planning in NICE's guideline on decision making and mental capacity. For a short explanation of why the committee made the 2022 recommendations and how they might affect practice, see the rationale and impact section on providing information and support . Full details of the evidence and the committee's discussion are in evidence review A: information and support for patients, their families and carers. Loading. Please wait. # Coordination of care For general advice on continuity of care and relationships follow the recommendations in NICE's guideline on patient experience in adult NHS services. Offer the person with MS an appropriate single point of contact with knowledge of MS services to coordinate care and help them access services. Care for people with MS using a coordinated multidisciplinary approach. Involve professionals who can best meet the needs of the person with MS and who have expertise in managing MS including: MS nurses consultant neurologists physiotherapists with expertise in MS and occupational therapists speech and language therapists, psychologists, dietitians, social care, continence specialists and specialist neuropharmacists or specialist MS pharmacists consultants in rehabilitation medicine primary healthcare team. For a short explanation of why the committee made the 2022 recommendation and how it might affect practice, see the rationale and impact section on coordination of care . Full details of the evidence and the committee's discussion are in evidence review B: coordination of care. Loading. Please wait. # Modifiable risk factors for relapse or progression of MS ## Exercise Encourage people with MS to exercise. Advise them that regular exercise may have beneficial effects on their MS and does not have any harmful effects on their MS. ## Smoking Advise people with MS not to smoke and explain that it will increase the progression of disability. (See NICE's guideline on tobacco: preventing uptake, promoting quitting and treating dependence.) ## Vaccinations Offer vaccinations in line with advice from the Joint Committee on Vaccinations and Immunisation and the Green Book: Immunisation against infectious disease for people with MS and their carers. # MS symptom management and rehabilitation The guideline does not make recommendations for all symptoms that occur in people with MS. Some symptoms are addressed in other NICE guidelines and these are referenced where relevant. Determine how often the person with MS will need to be seen based on: their needs, and those of their family and carers and the frequency of visits needed for different types of treatment (such as review of disease‑modifying therapies, rehabilitation and symptom management). When prescribing medicines for symptom management in people with MS, ensure that local arrangements for prescribing, supply and treatment review follow NICE's guideline on medicines optimisation. ## Fatigue Ask people with MS if they are experiencing fatigue, sudden tiredness or a change in their energy levels affecting their daily living. Do not assume that the person's fatigue is always caused by MS. Assess for other causes and manage these or refer the person for management if indicated. Other causes of fatigue may include: sleep problems symptoms of MS, such as pain, spasticity and bladder dysfunction side effects of medicines illnesses, such as infections, anaemia and thyroid dysfunction anxiety and depression (see NICE's guidelines on generalised anxiety disorder and panic disorder in adults and depression in adults with a chronic physical health problem). Explain that MS‑related fatigue may be brought on by heat or biological, physical and emotional stress. Offer people with MS and fatigue a personalised discussion about how they can be supported to self-manage their fatigue. This could include: identifying goals and priorities advice on conserving their energy reviewing lifestyle factors such as diet and exercise using stress management and wellbeing approaches such as mindfulness and cognitive behavioural techniques to help with day-to-day activities. Advise people that aerobic, resistive and balance exercises, including yoga and pilates, may be helpful in treating MS‑related fatigue. Explain to people that there is no evidence that a specific diet will improve fatigue in people with MS, but that a healthy diet will benefit their general health. For people with MS with moderately impaired mobility (an EDSS score of greater than or equal to 4), consider a combination of: a programme of supervised aerobic and moderate progressive resistance activity and cognitive behavioural techniques. Do not use vitamin B12 injections to treat fatigue in people with MS. Do not offer hyperbaric oxygen to treat fatigue in people with MS. See also the section on non-pharmacological management of mobility problems and fatigue. For a short explanation of why the committee made the 2022 recommendations and how they might affect practice, see the rationale and impact section on assessment and non-pharmacological management of fatigue . Full details of the evidence and the committee's discussion are in evidence review C: non-pharmacological management of fatigue. Loading. Please wait. Discuss with the person with MS whether a medicine to treat fatigue might be an option for them. Explain that there are potential risks, benefits and safety concerns for the possible treatment options. If a person with MS wishes to try a medicine for fatigue, refer them to a specialist to fully discuss the treatment options. Use shared decision making to decide whether to try a medicine for fatigue and which would be most suitable. Taking into account the needs, priorities and preferences of the person with MS, and the risks and benefits of each treatment, consider any of the following: amantadine: see the BNF for amantadine dosages modafinil, except in people who are pregnant or planning pregnancy: see the Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on modafinil for advice on monitoring and cautions for use, including cardiovascular monitoring before and during treatment follow the MHRA safety advice on modafinil and pregnancy for people who are able to get pregnant, including explaining the risks, advising on effective contraception and explaining that modafinil may reduce the effectiveness of steroidal contraceptives use the lowest effective dose selective serotonin reuptake inhibitor (SSRI): use the lowest dose recommended for licensed indications see also, the section on making decisions about prescribing in NICE's guideline on medicines associated with dependence or withdrawal symptoms. In June 2022 this was an off-label use of amantadine, modafinil and SSRIs. See NICE's information on prescribing medicines. Regularly review treatment to monitor effectiveness, safety and acceptability, adjust the dose, and decide whether to continue or stop the medicine: Agree the frequency of review with the person with MS, taking into account the medicine that they are taking, the need for dose adjustments and the person's preferences and circumstances. For more information, see the section on medication review in NICE's guideline on medicines optimisation and, for reviewing SSRIs, see the section on reviewing medicines in NICE's guideline on medicines associated with dependence or withdrawal symptoms. When the person with MS is on a stable dose of a medicine for fatigue, subsequent prescriptions may be issued by another prescriber as part of a shared-care agreement under the direction of the initiating specialist prescriber. For more information about shared care, see NHS England's guidance on responsibility for prescribing between primary and secondary/tertiary care. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pharmacological management of fatigue . Full details of the evidence and the committee's discussion are in evidence review D: pharmacological management of fatigue. Loading. Please wait. ## Mobility problems See also recommendation 1.4.1 for advice on encouraging exercise in people with MS. For guidance on functional electrical stimulation for drop foot, see the NICE interventional procedures guidance on functional electrical stimulation for drop foot of central neurological origin. Ensure people with MS and mobility problems have access to an assessment to establish individual goals and discuss ways to achieve them. This would usually involve rehabilitation specialists and physiotherapists with expertise in MS. Do not offer fampridine to treat mobility problems in people with MS. Fampridine is a clinically effective treatment for some people, but it is not cost effective at the current list price. This recommendation does not apply to people who have already started treatment with fampridine in the NHS, who should be able to continue treatment until they and their NHS clinician think it appropriate to stop. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on pharmacological management of mobility problems . Full details of the evidence and the committee's discussion are in evidence review E: pharmacological management of mobility. Loading. Please wait. Consider vestibular rehabilitation for people with MS who have fatigue or mobility problems associated with limited standing balance. Consider supervised exercise programmes involving moderate progressive resistance training and aerobic exercise to treat people with MS who have mobility problems or fatigue. Help the person with MS continue to exercise, for example, by referring them to a physiotherapist with expertise in MS or to exercise referral schemes. If more than 1 of the interventions recommended for mobility or fatigue are suitable, offer treatment based on which the person prefers and whether they can continue the activity after the treatment programme ends. Encourage people with MS to keep exercising after treatment programmes end for longer-term benefits (see NICE's guideline on behaviour change: individual approaches). ## Spasticity Suspect spasticity when a person with MS presents with any of the following: involuntary muscle movements (spasms) muscle stiffness pain and restriction with certain movements or positions causing difficulty in performing various activities a change in their mobility or upper limb function. Assess people with MS and suspected spasticity for factors that might worsen spasticity, for example, pressure ulcers, bladder and bowel dysfunction and infections, poor posture or positioning, and pain. Provide support and information to help people with MS, and their families and carers if appropriate, to prevent and manage these factors. Discuss with the person the balance between the benefits and harms of treating spasticity. In particular, explain that some people use their spasticity to maintain their posture and ability to stand, walk or transfer, and that treatment with muscle relaxants may adversely affect this. Consider oral baclofen as a first-line drug treatment to treat spasticity in people with MS who have specific treatment goals such as improving mobility or easing pain and discomfort. Take into account any contraindications, comorbidities and the person's preferences. If oral baclofen is not tolerated or does not provide adequate relief, consider gabapentin as a second-line option to treat spasticity in people with MS. For guidance on safe prescribing of gabapentin and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. In June 2022, this was an off-label use of gabapentin. See NICE's information on prescribing medicines. See also the 2019 MHRA drug safety update on pregabalin, gabapentin and risk of abuse and dependence. When using oral baclofen or gabapentin to treat spasticity in people with MS, explain to the person that they should: increase the dose gradually in at least 2‑week increments to optimise symptom improvement or until they reach the maximum dose they can tolerate stop taking the medicine if there is no benefit at the maximum tolerated dose (explain that baclofen can cause harm if stopped suddenly and that special precautions may be needed when stopping specific medicines) have their medicines reviewed at least annually once the optimal dose has been reached. See the BNF and the summary of product characteristics for baclofen and gabapentin for advice on optimising dosage and stopping treatment and, if relevant, treating people with renal impairment and older people. For more information on reviewing and withdrawing gabapentin, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. Consider a combination of oral baclofen and gabapentin for people with MS if: individual medicines do not provide adequate relief or side effects from individual medicines prevent the dose being increased. See the BNF and the summary of product characteristics for baclofen and gabapentin. Use caution when using these medicines in combination because of the risk of severe respiratory depression (see the 2017 MHRA advice on gabapentin: risk of severe respiratory depression). For guidance on safe prescribing of gabapentin and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.In June 2022, this was an off-label use of gabapentin. See NICE's information on prescribing medicines. See also the 2019 MHRA drug safety update on pregabalin, gabapentin and risk of abuse and dependence. If spasticity is causing significant impairments in mobility, posture or function and initial treatments are unsuccessful, refer to a multidisciplinary team experienced in the management of spasticity for assessment and treatment planning. For guidance on THC:CBD spray for treating spasticity in people with MS, see the recommendations on spasticity in NICE's guideline on cannabis-based medicinal products. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on spasticity . Full details of the evidence and the committee's discussion are in evidence review F: pharmacological management of spasticity. Loading. Please wait. ## Oscillopsia Consider gabapentin as a first‑line drug to treat oscillopsia in people with MS. For guidance on safe prescribing of gabapentin and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. In June 2022, this was an off-label use of gabapentin. See NICE's information on prescribing medicines and the 2019 MHRA drug safety update on pregabalin, gabapentin and risk of abuse and dependence. Consider memantine as the second‑line treatment for oscillopsia in people with MS. In June 2022, this was an off-label use of memantine. See NICE's information on prescribing medicines. Refer the person with MS for specialist advice if there is no improvement in oscillopsia after treatment with gabapentin and memantine or if side effects prevent continued use. ## Emotional lability Consider amitriptyline to treat emotional lability (involuntary laughing and crying related to a frontal lobe lesion) in people with MS. For guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. In June 2022, this was an off-label use of amitriptyline. See NICE's information on prescribing medicines. ## Pain Assess and investigate the cause of pain to establish a diagnosis and offer treatment specific to the cause of the pain. Be mindful of the impact of pain on the mental wellbeing of people with MS, and provide advice and support. See NICE's guideline on depression in adults with a chronic physical health problem. Treat neuropathic pain in people with MS and refer people to pain services according to NICE's guideline on neuropathic pain in adults. Be aware that musculoskeletal pain is common in people with MS and is usually secondary to problems with immobility, spasticity and posture. Assess musculoskeletal pain and offer treatment appropriate to the cause, for example see the sections on managing mobility problems and spasticity, and NICE's guideline on low back pain and sciatica in over 16s. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pain . Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of pain. Loading. Please wait. ## Cognitive and memory problems Be aware that the symptoms of MS can include cognitive problems, including memory problems, that the person may not immediately recognise or associate with their MS. Assess cognition as part of the person's comprehensive review. Tailor the assessment to the person's needs, for example, use a clinic interview or brief formal assessment, or consider referral for a full neuropsychological assessment if needed. Be aware that anxiety, depression, difficulty sleeping, fatigue and medication can affect cognition. Assess for and offer management appropriate for these issues in people with MS and cognitive or memory problems (for example, see the section on fatigue and NICE's guidelines on generalised anxiety disorder and panic disorder in adults and depression in adults with a chronic physical health problem). Consider referring people with MS and persisting cognitive impairments to an occupational therapist and/or a neuropsychologist to assess and manage these symptoms according to the person's needs. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on cognitive and memory problems . Full details of the evidence and the committee's discussion are in evidence review H: non-pharmacological management of memory and cognitive problems. Loading. Please wait. ## Ataxia and tremor The evidence was reviewed for the pharmacological management of ataxia and tremor, and the committee made a recommendation for research. For a short explanation of why the committee only made a recommendation for research, see the rationale section on pharmacological management of ataxia and tremor . Full details of the evidence and the committee's discussion are in evidence review I: pharmacological management of ataxia and tremor. Loading. Please wait. ## Dystonia and tremor For guidance on deep brain stimulation for tremor and dystonia, see the NICE interventional procedures guidance on deep brain stimulation for tremor and dystonia (excluding Parkinson's disease). # Comprehensive review Ensure all people with MS have a comprehensive review of all aspects of their care at least once a year. Ensure the comprehensive review is carried out by healthcare professionals with expertise in MS and its complications. Involve different healthcare professionals with expertise in specific areas of the review if needed. Tailor the comprehensive review to the needs of the person with MS assessing: MS symptoms: mobility and balance including falls need for mobility aids including wheelchair assessment use of arms and hands muscle spasms and stiffness tremor bladder, bowel and sexual function (see NICE's guidelines on urinary incontinence in neurological disease and faecal incontinence in adults) sensory symptoms and pain speech and swallowing (see NICE's guideline on nutrition support for adults) vision cognitive symptoms fatigue depression and anxiety (see NICE's guidelines on depression in adults with a chronic physical health problem and generalised anxiety disorder and panic disorder in adults) sleep respiratory function. MS disease course: evidence of progression evidence of active disease relapses in past year eligibility for disease-modifying treatments (see the section on other treatments) the nature and extent of disability (which should be documented). General health: weight smoking, alcohol and recreational drugs exercise access to routine health screening and contraception care of other chronic conditions. Social activity and participation: family and social circumstances driving and access to transport employment (for example, the need for vocational support or rehabilitation) access to daily activities and leisure. Care and carers: personal care needs social care needs access to adaptations and equipment at home. Refer any issues identified during the comprehensive review of the person with MS to members of the MS multidisciplinary team and other appropriate teams so that they can be managed. Ensure people with MS are offered a medicines review in line with NICE's guidelines on medicines adherence and medicines optimisation. Ensure people with MS have their bone health regularly assessed and reviewed in line with NICE's guideline on osteoporosis. Ensure people with MS and severely reduced mobility are regularly assessed and reviewed for risk of contractures (shortening of tendons, muscles or ligaments that limits joint movement). Check people with MS and severely reduced mobility at every contact for areas at risk of pressure ulcers (see NICE's guideline on pressure ulcers). Discuss the care provided by carers and care workers as part of the person's care plan. Ensure that carers (including young carers) know about their right to a carer's assessment (see NICE's guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers and the Young Carers Regulations 2015). Refer people with MS to palliative care services for symptom control and for end of life care when appropriate. # Relapse and exacerbation ## Recognising a relapse Diagnose a relapse of MS if the person: develops new symptoms or has worsening of existing symptomsand these last for more than 24 hours in the absence of infection or any other cause after a stable period of at least 1 month. Before diagnosing a relapse of MS: rule out infection – particularly urinary tract and respiratory infections and discriminate between the relapse and fluctuations in disease or progression. Do not routinely diagnose a relapse of MS if symptoms are present for more than 3 months. ## Treating acute relapse of MS Develop local guidance and pathways for timely treatment of relapses of MS. Ensure follow up is included in the guidance and pathway. Assess and offer treatment for relapses of MS that affect the person's ability to perform their usual tasks, as early as possible and within 14 days of onset of symptoms. Non‑specialists should discuss a person's diagnosis of relapse and whether to offer steroids with a healthcare professional with expertise in MS because not all relapses need treating with steroids. Offer treatment for relapse of MS with oral methylprednisolone 0.5 g daily for 5 days. Consider intravenous methylprednisolone 1 g daily for 3 to 5 days as an alternative for people with MS: in whom oral steroids have failed or not been tolerated or who need admitting to hospital for a severe relapse or monitoring of medical or psychological conditions such as diabetes or depression. Do not prescribe steroids at lower doses than methylprednisolone 0.5 g daily for 5 days to treat an acute relapse of MS. Do not give people with MS a supply of steroids to self‑administer at home for future relapses. ## Information about treating a relapse with steroids Discuss the benefits and risks of steroids with the person with MS, taking into account the effect of the relapse on the person's ability to perform their usual tasks and their wellbeing. Explain the potential complications of high‑dose steroids, for example temporary effects on mental health (such as insomnia, depression, confusion and agitation) and worsening of blood glucose control in people with diabetes. Give the person with MS and their family members or carers (as appropriate) information that they can take away about side effects of high‑dose steroids in a format that is appropriate for them. Ensure that the MS multidisciplinary team is told that the person is having a relapse, because relapse frequency may influence which disease-modifying therapies are chosen and whether they need to be changed. ## Medical, therapy and social care needs at time of relapse or exacerbation Identify whether the person having a relapse of MS or their family members or carers have social care needs and if so refer them to social services for assessment. Offer inpatient treatment to the person having a relapse of MS if their relapse is severe or if it is difficult to meet their medical and social care needs at home. Explain that a relapse of MS may have short‑term effects on cognitive function. Identify whether the person with MS having a relapse or exacerbation needs additional symptom management, rehabilitation or consideration for disease-modifying treatments. # Other treatments ## Disease-modifying treatments NICE has published technology appraisal guidance on disease-modifying treatments for MS. For full details, see NICE's technology appraisal guidance on multiple sclerosis. ## Vitamin D Do not offer vitamin D solely for the purpose of treating MS. ## Omega fatty acids compounds Do not offer omega‑3 or omega‑6 fatty acid compounds to treat MS. Explain that there is no evidence that they affect relapse frequency or progression of MS. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. ## Advanced MS MS is described as 'advanced' when it has progressed to the point where a person is severely affected by their symptoms and has significant ongoing physical or cognitive impairment (this typically happens in the late stages of primary and secondary progressive MS). People with advanced MS are unable to carry out most of their usual activities of daily living independently and need other people to assist them. The term is used to describe the level of burden rather than the type or duration of the MS.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Coordination of care What is the clinical and cost effectiveness of processes of care, including the role of multiple sclerosis (MS) specialist nurses and other healthcare professionals, to improve care coordination and health outcomes in adults with MS? For a short explanation of why the committee made the recommendation for research, see the rationale section on coordination of care . Full details of the evidence and the committee's discussion are in evidence review B: coordination of care. Loading. Please wait. ## Cognitive rehabilitation For adults with MS, including people receiving palliative care, what is the clinical and cost effectiveness of non-pharmacological interventions for memory and cognitive problems? For a short explanation of why the committee made the recommendation for research, see the rationale section on cognitive and memory problems . Full details of the evidence and the committee's discussion are in evidence review H: non-pharmacological management of memory and cognitive problems. Loading. Please wait. ## Outcome measures for cognitive rehabilitation What core outcome measures should be used for studies assessing memory and cognition in people with MS? For a short explanation of why the committee made the recommendation for research, see the rationale section on cognitive and memory problems . Full details of the evidence and the committee's discussion are in evidence review H: non-pharmacological management of memory and cognitive problems. Loading. Please wait. ## Continued relapses Is intravenous methylprednisolone more clinically and cost effective than oral methylprednisolone in people with relapsing–remitting MS and people with secondary progressive MS with continued relapses? ## Mobility What is the optimal frequency, intensity and form of rehabilitation for mobility problems in people with MS? ## Spasticity For adults with MS, including people receiving palliative care, what is the clinical and cost effectiveness of pharmacological interventions for generalised spasticity? For a short explanation of why the committee made the recommendation for research, see the rationale section on spasticity . Full details of the evidence and the committee's discussion are in evidence review F: pharmacological management of spasticity. Loading. Please wait. ## Vitamin D Can vitamin D slow down the progression of disability in MS? # Other recommendations for research ## Information and support What information, education and support do adults with clinically isolated syndrome and their families and carers find most useful? For a short explanation of why the committee made the recommendation for research, see the rationale section on providing information and support . Full details of the evidence and the committee's discussion are in evidence review A: information and support for patients, their families and carers. Loading. Please wait. ## Non-pharmacological management of fatigue For adults with MS, including people receiving palliative care, what is the clinical and cost effectiveness of non-pharmacological interventions for fatigue? For a short explanation of why the committee made the recommendation for research, see the rationale section on assessment and non-pharmacological management of fatigue . Full details of the evidence and the committee's discussion are in evidence review C: non-pharmacological management of fatigue. Loading. Please wait. ## Pharmacological management of fatigue For adults with MS, including people receiving palliative care, what is the clinical and cost effectiveness of pharmacological interventions for fatigue? For a short explanation of why the committee made the recommendation for research, see the rationale section on pharmacological management of fatigue . Full details of the evidence and the committee's discussion are in evidence review D: pharmacological management of fatigue. Loading. Please wait. ## Pain For adults with MS, including people receiving palliative care, what is the clinical and cost effectiveness of non-pharmacological interventions for pain? For a short explanation of why the committee made the recommendation for research, see the rationale section on pain . Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of pain. Loading. Please wait. ## Ataxia and tremor For adults with MS, what is the clinical and cost effectiveness of pharmacological interventions for ataxia and tremor? For a short explanation of why the committee made the recommendation for research, see the rationale section on pharmacological management of ataxia and tremor . Full details of the evidence and the committee's discussion are in evidence review I: pharmacological management of ataxia and tremor. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Diagnosing multiple sclerosis Recommendations 1.1.1 to 1.1.9 ## Why the committee made the recommendations The recommendations were updated to reflect changes to the McDonald criteria, revised 2017 (Thompson AJ, Banwell BL, Barkhof F et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria, The Lancet Neurology), which are expected to speed up diagnosis and reduce the chance of misdiagnosis. The committee agreed that the previous recommendations on diagnosis are still relevant, but made some updates based on their experience and changes to practice since 2014. The committee retained the recommendations on symptoms and features of multiple sclerosis (MS), highlighting that symptoms can be wide-ranging and listing the most common symptoms and those that would make a diagnosis unlikely. The committee agreed that assessments to exclude alternative diagnoses need to be tailored to the person, according to their presenting symptoms. They decided that a list of blood tests would not be helpful and that tests would need to be decided on an individual basis. The committee agreed that a consultant neurologist should be responsible for the diagnosis of MS, using the history, examination, MRI and other test findings, and by following the revised McDonald criteria. To meet the updated criteria, dissemination of lesions in the nervous system in space and time needs to be demonstrated, and all lesions visible on an MRI scan can contribute to the criteria, irrespective of whether they have caused symptoms (symptomatic lesions) or have not caused symptoms (asymptomatic lesions). A positive finding of cerebrospinal fluid oligoclonal bands can now be used in place of dissemination of lesions in some circumstances. The criteria have been developed for people experiencing clinically isolated syndrome, which means that they must present with symptoms suggestive of an inflammatory demyelinating condition. The committee agreed to retain the previous recommendation on reviewing people with suspected MS who do not meet the McDonald criteria, but added the example of reviewing people annually, which is in line with current practice. They agreed that information should be provided so that people understand why they need to be reviewed regularly and who to contact if their symptoms change or they have concerns. The committee supported the importance of providing information and advice on resources at the time of diagnosis. ## How the recommendations might affect practice The recommendations are expected to help to reduce variation between services and clinicians. The recommendations reflect current clinical practice and are not expected to increase the number of referrals or the cost of making a diagnosis and therefore will not have a substantial resource impact. Return to recommendations # Providing information and support Recommendations 1.2.4 and 1.2.9 to 1.2.18 ## Why the committee made the recommendations The committee noted that people who were diagnosed with MS a long time ago may not be offered an annual review. They highlighted the importance of informing people with MS and their carers that they should have a regular comprehensive review so that they can ensure that this takes place at least once a year and covers all of their needs. The evidence showed that MS has a significant impact on carers and that information and support for them was often lacking. Carers are not always aware of the support available to them and often do not have the information they need as circumstances change for the person with MS. The committee agreed that carers should be aware of their right to a carer's assessment and highlighted that this should include assessments for young carers. The committee also noted that the timing of information was important and agreed that information and support should be provided according to the changing needs or circumstances of the person with MS. Considering pregnancy and approaching more advanced disease were identified as particular situations in which information and support needs should be reviewed. The committee made specific recommendations for these groups. No evidence was identified on the information and support needs for people diagnosed with clinically isolated syndrome, and the committee therefore made a recommendation for research on information and support for people with clinically isolated syndrome. Recommendations from the previous version of the guideline were updated and new recommendations added, based on qualitative evidence and the committee's experience. The committee agreed that the recommendations should apply to both women and men planning to start a family, where appropriate, and to people considering adoption as well as those planning pregnancy. The committee agreed that discussions about starting or extending a family should happen early to ensure that people with MS have time to make decisions and plan for the future. They agreed that healthcare professionals should proactively ask about and discuss the person's plans for having children. The committee noted that some people with MS assume that they cannot have children and do not ask for advice. Although there was limited evidence supporting early information giving, the committee agreed that, based on their experience, it is important to start these discussions soon after diagnosis. The committee noted that some disease-modifying treatments should not be taken during pregnancy because of the risk of harm to the unborn baby. Therefore, they highlighted that people taking these treatments need to inform their healthcare professional straight away if they are trying to get pregnant or become pregnant. The evidence showed that people with MS often have concerns about the impact of MS on having a family. The committee agreed that MS should not be a barrier to planning a family, because pregnancies can be well managed and additional support may be available. Many people with MS may feel like they are not able to have children, so the committee agreed that people with MS should be able to discuss the possibilities before making these decisions. The evidence highlighted issues of particular concern to people with MS, such as how MS and treatments can affect pregnancy, whether they can pass MS on to their children and the impact of MS on their labour, birth options and breastfeeding. People also wanted more information on the possible impact that caring for a child might have on their symptoms, such as fatigue, and advice on how to manage this. The committee updated the existing recommendations based on the evidence. Based on their experience, the committee also included a reference to advice on folic acid in the NICE guideline on maternal and child nutrition because they agreed that this would also apply to people with MS. The qualitative evidence showed that feelings of social isolation and depression are common in people with MS, but they often lack information about available services and support. It also showed that people were not always aware of the availability and suitability of home adaptations and mobility aids, and how to obtain them. These are important for maintaining independence as MS progresses. Other areas were also identified where better information and support could improve the experience and wellbeing of people with MS and their carers, including legal rights, employment rights, benefits and carer assessments. Based on the evidence and their experience, the committee agreed that people with advanced MS and their carers need information and support to navigate services so that they can access extra support as their needs change. The committee noted that NICE's guideline on end of life care for adults includes recommendations on providing information and support for people who may be approaching the end of their life. They also agreed that an existing recommendation on advance care planning and power of attorney should be retained because it is still supported by the evidence and it is important to help people plan for their future care. It was updated to include a cross reference to NICE's guideline on decision-making and mental capacity. The committee added that early discussions about advance care planning should be considered for people at risk of deterioration. ## How the recommendations might affect practice The recommendations are in line with current good practice. Overall, the committee did not think these recommendations would have a significant resource impact. Return to recommendations # Coordination of care Recommendation 1.3.1 ## Why the committee made the recommendation The committee updated the 2014 recommendation to emphasise that the point of contact should have knowledge of MS services to coordinate the person's care and help them access relevant healthcare professionals. The available clinical and health economic evidence was limited, so the committee were not able to specify that the point of contact should have knowledge of MS because this may represent a change in practice and a significant resource impact. Instead, a point of contact with access to appropriate healthcare services was specified to allow for different service configurations; for example, the point of contact would be able to access a healthcare professional who can contact the person with MS and respond to their concerns. The committee acknowledged the lack of evidence in this area and made a recommendation for research on coordination of care for people with MS to support future guidance in this area. ## How the recommendation might affect practice The recommendation emphasises that the point of contact should have knowledge of MS services. This should not result in a large change in practice and therefore will not have a significant resource impact. Return to recommendation # Assessment and non-pharmacological management of fatigue Recommendations 1.5.3 to 1.5.9 and 1.5.11 ## Why the committee made the recommendations Although a large number of studies have been published since the previous version of the guideline, the committee agreed that the new evidence was too limited in quality to change most of the existing recommendations. However, the new evidence did further support the 2014 recommendations on managing MS-related fatigue. Fatigue may not always be identified and treated, so the committee agreed by informal consensus that people with MS should be asked about the presence of fatigue. Causes of fatigue other than MS may sometimes be missed, so the committee highlighted the importance of checking for other possible causes, to ensure appropriate management. There was some evidence that fatigue or energy management interventions and wellbeing techniques, such as cognitive behavioural therapy (CBT) and mindfulness, are beneficial. However, the committee agreed that the evidence was not sufficient to recommend formal programmes because of limitations in the studies. Instead, the committee recognised that using elements of these approaches could be helpful and included in discussions about self-management options. Based on their experience, the committee agreed that a fatigue management discussion should be offered, which is routinely provided in current practice. This would be a tailored discussion that could include goals and priorities for each person, advice on energy conservation, review of lifestyle factors and the use of stress reduction and wellbeing techniques, including cognitive behavioural principles for managing day-to-day activities and mindfulness-based techniques. The committee agreed that the previous recommendation on advice about the possible benefits of aerobic, balance and stretching exercises, including yoga, was still supported by the evidence. In addition, there was some evidence of benefit for progressive resistive exercises and pilates. There was a lack of evidence on specific diets, but a recommendation was made to highlight the benefits of following a healthy diet. Diet was also included in the discussion of fatigue management. The committee agreed that the evidence still supported the previous recommendation on considering a programme of aerobic and moderate progressive resistance activity combined with cognitive behavioural techniques to treat fatigue in people with significantly impaired mobility (EDSS score of at least 4). This was based on clinical evidence, modest economic evidence (covering the ExIMS study, 2013) and the original economic analysis from the previous version of the guideline supporting the cost effectiveness of combined exercise programmes. The committee noted that this should be a supervised programme provided to the person with MS, rather than self-directed exercise, and that it should be tailored to the needs and abilities of the person. No randomised controlled trial evidence was identified for hyperbaric oxygen to treat MS-related fatigue in people with MS. The committee were concerned that this intervention is being used despite the lack of evidence, sometimes at the expense of the person with MS or through charities. They agreed that it should not be used, based on the lack of evidence, their clinical experience and the high cost involved. A recommendation for research on identifying clinically and cost-effective interventions for the non-pharmacological management of fatigue was developed to encourage further research in this area. ## How the recommendations might affect practice The recommendations on assessment and offering people a personal tailored discussion about fatigue management do not represent a change in practice. Discussion of fatigue management is provided routinely in current practice by occupational therapists, MS nurses or physiotherapists. It does not typically involve a specific, structured fatigue management programme but includes some elements of fatigue management, such as advice on energy conservation. Similarly, the inclusion of stress and wellbeing techniques does not refer to structured interventions but allows the opportunity to use some elements of these techniques as part of the fatigue management discussion, which the committee agreed are used as part of fatigue management discussions in current practice. Supervised aerobic and moderate progressive resistance programmes with cognitive behavioural techniques for people with an EDSS score of at least 4 was recommended in the 2014 guideline based on clinical- and cost-effectiveness analysis. Physiotherapists and occupational therapists typically apply CBT principles like goal setting as part of exercise interventions in current practice, and this does not need to be a formal CBT intervention delivered by a psychologist. The committee agreed that this would not represent a change in practice. Recommendations covering advice on exercises for MS-related fatigue (which would be self-directed exercise rather than supervised programmes provided to the person with MS) and following the principles of a healthy diet are consistent with current good practice, as is the recommendation not to offer hyperbaric oxygen. As none of the recommendations represent a change in current practice these recommendations are not expected to have a resource impact. Return to recommendations # Pharmacological management of fatigue Recommendations 1.5.12 and 1.5.16 ## Why the committee made the recommendations The evidence for treating fatigue with amantadine, modafinil or selective serotonin reuptake inhibitors (SSRIs) in people with MS was limited but showed some benefit for each medicine. The lack of good evidence comparing the different treatments meant that the committee were unable to recommend one in preference to the others or an order in which these treatments should be considered. However, they agreed that fatigue can have a significant impact on the person's daily activities and that, in their clinical experience, it can improve with pharmacological treatment in some people. Amantadine, modafinil and SSRIs are not licensed for treating fatigue in people with MS and there are safety issues associated with their use, so they should only be started by a specialist in MS. The committee agreed that the potential benefits of effective treatment may outweigh the risks for people whose quality of life is severely affected by fatigue. However, they highlighted that people with MS should be fully informed about the possible risks and benefits, and make a shared decision with a specialist about whether to try a medicine and which would be most suitable, taking into account their needs, priorities and preferences. They agreed that it is important that people can access pharmacological treatment options and that they can be considered before trying non-pharmacological treatments in people for whom a rapid response is a priority. The committee highlighted the particular safety concerns for modafinil, including that it should not be used by people who are pregnant or planning pregnancy, and that precautions should be taken if prescribing it for people able to get pregnant, in line with the 2020 Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on modafinil. The committee noted additional advice for modafinil on monitoring, stopping treatment and cautions for use in the 2014 MHRA safety advice on modafinil and advice in the summary of product characteristics for modafinil and amantadine. Based on their experience, the committee highlighted the importance of starting people on a low dose of modafinil, such as 100 mg once a day. The committee agreed that people taking these medicines would need to have regular reviews to monitor effectiveness and safety, adjust dosages and ensure that treatment is stopped if it is ineffective or the person experiences adverse effects. If treatment is effective and the person is on a stable dose of their medicine, the committee agreed that responsibility for prescribing could be transferred to primary care under a shared-care arrangement. A recommendation for research on the pharmacological management of fatigue was made to support future research in this area. ## How the recommendations might affect practice Amantadine is currently prescribed as the first-line pharmacological treatment, alongside non-pharmacological management options, as a part of a multidisciplinary approach to fatigue. Modafinil and SSRIs are less commonly prescribed. These pharmacological treatments are usually prescribed under the guidance of secondary care specialists. The recommendations may result in a change from current practice, with increased prescribing of modafinil and SSRIs. There may also be an increase in the use of shared-care arrangements for prescribing these medicines in primary care. There may be a resource impact due to cardiovascular monitoring from the increased use of modafinil in a broader range of clinical settings, including primary care. However, the recommendations may result in a decrease in the use of amantadine, which has a greater unit cost than modafinil and SSRIs. Therefore, the overall resource impact of the recommendations is unlikely to be significant. Return to recommendations # Pharmacological management of mobility problems Recommendation 1.5.18 ## Why the committee made the recommendation Fampridine was shown to be effective in treating lack of mobility in some people with MS, but not all. A health economic analysis was carried out for this guideline update, which included modelling an initial 4‑week assessment to identify which people with MS respond to and would then continue fampridine treatment. Based on the current list price, fampridine was not found to be a cost-effective treatment and so the committee made a recommendation to not offer fampridine for the management of mobility problems. ## How the recommendation might affect practice This recommendation does not represent a change in practice and therefore will not have a resource impact. Return to recommendation # Spasticity Recommendations 1.5.24 to 1.5.32 ## Why the committee made the recommendations There was very limited new evidence on pharmacological management of spasticity. Only 1 study comparing intrathecal baclofen to usual care in a post-stroke population was identified. This evidence was insufficient to make any new recommendations or significant changes to the previous guideline recommendations. Therefore, the committee updated the 2014 recommendations based on their experience and knowledge of current practice. The committee agreed that it is important to raise awareness of spasticity and its presentation to ensure that people with MS receive appropriate treatment. They also highlighted that it is important to emphasise that the management of spasticity in MS should be tailored to the needs of the person and their specific treatment goals because spasticity can vary significantly in people with MS and change at different stages in the course of their disease. The committee agreed that the previous recommendation on assessing for and treating factors that may exacerbate symptomatic spasticity should be retained. The committee were aware that some people with MS use their spasticity to support them in maintaining posture when transferring or standing, and they agreed that the treatment of spasticity can have the potential to cause greater levels of disability. It was, therefore, agreed that the balance of risks and harms of treatment need to be fully discussed with the person before agreeing treatment. Although there was no new evidence on specific pharmacological treatments for spasticity, the committee took into account safety concerns for the use of gabapentin (see the 2019 MHRA drug safety update on pregabalin, gabapentin and risk of abuse and dependence) and agreed that it should no longer be recommended as a first-line option. The combination of baclofen and gabapentin is offered when neither agent by itself manages to control symptoms, but this needs to be balanced against the possible side effects. The committee noted that the BNF states that both gabapentin and baclofen can have central nervous system (CNS) depressant effects, which might affect the ability to perform skilled tasks. There is also a potential increased risk of respiratory depression (as advised by the MHRA) when using gabapentin in combination with other CNS depressants, and people with neurological disease (such as MS) may be at higher risk of this. The committee discussed the safety issues for gabapentin and agreed that illegal diversion and misuse are of particular concern. However, they agreed that gabapentin can be an effective treatment and should still be an option for treating spasticity in MS if oral baclofen is not tolerated or unsuccessful. Prescribers should follow the MHRA safety advice on evaluating people for a history of drug abuse and checking for misuse and dependence. The committee noted that gabapentin is now a class C controlled substance and prescribers will need to follow the statutory requirements for its use. Based on their experience, the committee agreed that information should be added to the previous recommendation on using these medicines to clarify the importance of gradually increasing the doses of medicine to reach the optimal dosage. The committee agreed that if a person's treatment goals are not being met by treatment with baclofen or gabapentin (alone or in combination), and appropriate physical assessments and precipitating or prolonging factors have been addressed, other treatment approaches should be considered, which may be delivered by a service dedicated to the more specialist management of spasticity. The committee updated the recommendation in the 2014 guideline on referral to specialist services to include multidisciplinary teams, which is consistent with current clinical practice. A recommendation for research on identifying clinical and cost-effective pharmacological interventions for the management of spasticity was developed to encourage further research in this area. ## How the recommendations might affect practice The recommendations reflect current best practice in the approach to the assessment and management of spasticity in people with MS. The committee recognised that not all clinicians would have direct access to specialist spasticity management services to deliver treatments beyond initial pharmacological approaches. However, services that specialise in the management of spasticity should be available at a regional level, ideally as part of a network. It is not anticipated that the updated recommendations will result in significantly greater resource use to support the assessment and treatment of spasticity in people with MS. There may be resource savings realised through a reduction in complications caused by inappropriate treatment or untreated spasticity. Return to recommendations # Pain Recommendations 1.5.37 to 1.5.40 ## Why the committee made the recommendations The causes of pain in people with MS are varied. It may be neuropathic, caused by MS nerve damage; or secondary to immobility, spasticity or posture issues; or it may be unrelated to MS and caused by other comorbid conditions. Pain is sometimes assumed to be neuropathic in people with MS when it may have a different cause. Based on their experience, the committee agreed that the first step in managing pain is to investigate and establish the cause. If the underlying cause is correctly identified, it will prevent unnecessary treatment and possible side effects, and ensure pain is managed correctly. The committee acknowledged the impact that pain can have on mental health. Pain can severely impair mobility and active lifestyle choices, which may lead to low mood and mental health problems. Low mood may also affect the way the person deals with pain. Therefore, it is important that healthcare professionals are mindful of this complex interaction and that people are offered support and advice if pain is affecting their mental wellbeing. The evidence on non-pharmacological management of pain was limited. The interventions and outcomes were varied, and the study sizes were small. There was some evidence of benefit from interventions such as yoga, relaxation massage, mindfulness, CBT and transcutaneous direct current stimulation and hypnosis with neurofeedback. However, the committee agreed that the evidence was insufficient to make any recommendations for or against particular non-pharmacological interventions. The committee therefore made a recommendation for research on non-pharmacological interventions for pain to support future research in this area. The committee agreed that immobility and problems with posture can often cause or exacerbate pain. It was also acknowledged that spasticity can play a major part in musculoskeletal pain. Therefore, the committee highlighted that musculoskeletal pain should be assessed and treatment offered that is appropriate to and addresses the cause of the pain. ## How the recommendations might affect practice Assessing and investigating the cause of pain is consistent with current best practice. The committee noted that assessment can be done by many different healthcare professionals, such as a rehabilitation physician, a GP, a neurologist, a physiotherapist or an MS nurse. They discussed that this would usually just involve history taking, but for some people further investigations such as scans may be needed. Although there may be costs associated with further investigations, it was agreed that these are likely to be offset by identifying the cause of pain and offering appropriate treatment. Acknowledging the impact of pain on mental health would not result in a change in practice or significant resource impact. Return to recommendations # Cognitive and memory problems Recommendations 1.5.41 to 1.5.44 ## Why the committee made the recommendations There was variation in the interventions covered by the studies on non-pharmacological management of cognitive and memory problems, which made it difficult for the committee to come to any conclusions. They agreed that the evidence was too limited to make recommendations about the types of interventions that should be offered. Current practice for treating cognitive impairments in MS varies, so the committee were not able to make consensus-based recommendations on which interventions would be most appropriate based on their experience. They agreed that a new recommendation for research on cognitive rehabilitation should involve larger trials in this area. A recommendation for research on outcome measures for studies of memory and cognition was also made to encourage the use of particular tests or scales for measuring different cognitive functions and improve the ability to pool and interpret data in the future. Based on their experience, the committee highlighted the need for cognitive symptoms to be assessed as part of the comprehensive review. This assessment is important for people with cognitive symptoms, because their cognitive profile needs to be established before decisions about any interventions can be made, based on their impairments. It was agreed that the type of cognitive assessment needed would differ depending on the person's needs. This might involve a clinical interview with or without carer input or a brief formal neuropsychological assessment. It was noted that a full neuropsychological assessment may be needed in people with a more complex presentation, for example, if fatigue and other disorders may be contributing to cognitive impairments. In the absence of new evidence, the committee agreed that the previous recommendations on cognition and memory problems should be retained and updated based on their experience and agreed by informal consensus. They agreed that medication should be added to the list of factors that may affect cognition, and that appropriate management of these factors should be offered. The committee agreed that the recommendation on referral for assessment and management of cognitive impairment should be updated so that referral can be to an occupational therapist, or a neuropsychologist as needed, rather than both, in line with current practice. Referral and the assessment and management of cognitive impairment should be tailored to the person's individual needs, because the cognitive profile of each person is likely to differ. ## How the recommendations might affect practice Cognitive assessment is usually available if the person has been offered a referral, although there may be some regional differences. It was noted that a simple assessment takes 10 to 15 minutes and does not need specific expertise. This type of assessment may be a change in practice for some services, but it is unlikely to have a significant resource impact. A full, longer neuropsychological assessment is a more costly assessment. However, it was noted that only a very small proportion of people are likely to need this longer assessment and future assessments are not as resource intensive as the baseline assessment. Given that only a small number of people would need this more expensive assessment (fewer than 1% of the MS population) and that it may already be current practice for some services, it was not thought to represent a significant resource impact. Many people with MS already have access to an occupational therapist who is skilled in cognitive assessment and interventions. A proportion will also have access to a neuropsychologist. Return to recommendations # Pharmacological management of ataxia and tremor ## Why the committee did not make recommendations There was a lack of evidence for pharmacological management of ataxia and tremor in people with MS. Only 1 new study was identified, which compared botulinum toxin with a placebo. This study was analysed alongside a similar study included in the previous guideline, but the committee agreed that this evidence was insufficient to make recommendations for or against its use. Botulinum toxin is not generally used in current practice for ataxia and tremor, and this use is off label. A recommendation for research on the pharmacological management of ataxia and tremor was developed to support future research in this area.# Context Multiple sclerosis (MS) is an acquired chronic immune-mediated inflammatory condition of the central nervous system, affecting both the brain and spinal cord. It affects approximately 130,000 people in the UK. It is the most common cause of serious physical disability in adults of working age. People with MS typically develop symptoms in their late 20s, experiencing visual and sensory disturbances, limb weakness, gait problems, and bladder and bowel symptoms. They may initially have partial recovery, but over time develop progressive disability. The cause of MS is unknown. It is believed that an abnormal immune response to environmental triggers in people who are genetically predisposed results in immune-mediated acute, and then chronic, inflammation. The initial phase of inflammation is followed by a phase of progressive degeneration of the affected cells in the nervous system. MS is a potentially highly disabling disorder with considerable personal, social and economic consequences. People with MS live for many years after diagnosis with a significant impact on their ability to work, as well as an adverse and often highly debilitating effect on their quality of life and that of their families. This guideline updates and replaces NICE's 2014 guideline (CG186). It includes updated recommendations on diagnosis, information and support, coordination of care and management of MS-related symptoms. The guideline does not cover all symptoms and problems associated with MS. Some areas are addressed in other NICE guidance, for example, urinary symptoms and swallowing, and these are referenced where appropriate. Many of the interventions used in rehabilitation to alleviate symptoms, such as non-pharmacological interventions for ataxia and tremor, interventions for weakness, cardiorespiratory fitness, sensory loss, visual problems (apart from oscillopsia), and secondary complications of immobility such as deconditioning and contractures, have not been covered because these are beyond the scope of the guideline. Many of these problems are complex and need personalised assessment and management strategies carried out by healthcare professionals with appropriate expertise in rehabilitation and MS. The guideline does not cover the use of disease-modifying treatments. However, NICE has published technology appraisal guidance on these treatments (see the NICE technology appraisal guidance on multiple sclerosis for more information). The guideline is aimed primarily at services provided in primary and secondary care. It does not map out a model of service delivery. Many people with MS may also attend specialised tertiary services, often established to provide and monitor disease-modifying therapies.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Diagnosing multiple sclerosis\n\n## Recognising multiple sclerosis\n\nSee also NICE's guideline on suspected neurological conditions: recognition and referral for advice for non-specialists on initial assessment of symptoms and signs that might indicate a neurological condition.\n\nBe aware that people with multiple sclerosis (MS) may present with a wide range of symptoms affecting different parts of the body. The most common are:\n\nloss or reduction of vision in 1\xa0eye with painful eye movements\n\ndouble vision\n\nascending sensory disturbance and/or weakness\n\naltered sensation or pain travelling down the back and sometimes into the limbs when bending the neck forwards (Lhermitte's sign)\n\nprogressive difficulties with balance and gait. \n\nBe aware that usually people with MS present with neurological symptoms or signs as described in recommendation\xa01.1.1, and:\n\nare often aged under 50 and\n\nmay have a history of previous neurological symptoms and\n\nhave symptoms that have evolved over more than 24\xa0hours and\n\nhave symptoms that may persist over several days or weeks and then improve and\n\ndo not have fever or infection. \n\nDo not routinely suspect MS if a person's main symptoms are fatigue, depression, dizziness or vague sensory phenomena, unless they have a history or evidence of focal neurological symptoms or signs. \n\n## Initial assessment\n\nBefore referring a person suspected of having MS to a neurologist, confirm that this is a neurological episode by taking a history, undertaking a physical examination and excluding alternative, more common diagnoses. \n\n## Referral and diagnosis\n\nRefer people suspected of having MS for diagnosis by a consultant neurologist or a specialist under their supervision. Contact the consultant neurologist directly if you think a person needs to be seen urgently. \n\nDiagnose MS using a combination of history, examination, MRI and laboratory findings, and by following the 2017 revised McDonald criteria. This should include:\n\nassessing that symptoms are consistent with an inflammatory demyelinating process; for example, headache is not suggestive of MS\n\nexcluding alternative diagnoses (targeted laboratory tests may be indicated if the history, examination or MRI findings are atypical)\n\nestablishing that lesions on MRI scans have developed at different times and are in different anatomical locations for a diagnosis of relapsing–remitting MS\n\nlooking for cerebrospinal fluid-specific oligoclonal bands if there is no clinical or radiological evidence of lesions developing at different times\n\nestablishing progressive neurological deterioration over 1\xa0year or more for a diagnosis of primary progressive MS. \n\nIf the McDonald criteria are not met but MS is suspected or the person has confirmed clinically isolated syndrome (see the 2017 McDonald criteria for a definition of clinically isolated syndrome):\n\nPlan a review to reassess the possibility of MS. Discuss the timing of this and future reviews with the person (for example, annually).\n\nProvide information and ensure that the person knows who to contact for advice if they develop further neurological symptoms or if current symptoms worsen. \n\nDo not diagnose MS on the basis of MRI findings alone. \n\nOffer people with confirmed MS information and advice on resources and support. For further details, see the section on information and support at the time of diagnosis. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnosing multiple sclerosis\xa0.\n\nFull details of the committee's discussion are in the committee discussion for diagnostic criteria.\n\nLoading. Please wait.\n\n## Optic neuritis and neuromyelitis optica spectrum disorder\n\nIf a person has an episode of isolated, optic neuritis, confirmed by an ophthalmologist, refer them to a consultant neurologist for further assessment. \n\nDiagnosis of neuromyelitis optica spectrum disorder should be made by an appropriate specialist based on established up‑to‑date criteria. \n\n# Providing information and support\n\nFor advice on communication and information follow the recommendations in NICE's guideline on patient experience in adult NHS services. For advice on shared decision making, follow the recommendations in NICE's guideline on shared decision making.\n\n## Information and support at the time of diagnosis\n\nThe consultant neurologist should ensure that people with MS, and with their agreement their family members or carers, are offered oral and written information at the time of diagnosis. This should include, but not be limited to, information about:\n\nwhat MS is\n\ntreatments, including disease‑modifying therapies\n\nsymptom management\n\nhow support groups, local services, social services and national charities are organised and how to get in touch with them\n\nonline resources\n\nlegal requirements such as notifying the Driver and Vehicle Licensing Agency (DVLA; see the DVLA webpage on multiple sclerosis and driving) and legal rights including social care, employment rights and benefits. [2014, amended 2022]\n\nDiscuss with the person with MS and their family members or carers whether they have social care needs and if so refer them to social services for assessment. Ensure the needs of children of people with MS are addressed. \n\nOffer the person with MS a face‑to‑face follow‑up appointment with a healthcare professional with expertise in MS to take place within 6\xa0weeks of diagnosis. \n\n## Ongoing information and support\n\nExplain to people with MS that they should have a comprehensive review of their care at least once a year and what this should cover (see the section on comprehensive review). Advise them to ask their healthcare professional for a review if it has not taken place. \n\nReview information, support and social care needs regularly. Continue to offer information and support to people with MS or their family members or carers even if this has been declined previously. \n\nEnsure people with MS and their family members or carers have a management plan that includes who to contact if their symptoms change significantly. \n\nExplain to people with MS that the possible causes of symptom changes include:\n\nanother illness such as an infection\n\nfurther relapse\n\nchange of disease status (for example progression). \n\nTalk to people with MS and their family members or carers about the possibility that the condition might lead to cognitive problems. \n\nProvide ongoing information and support tailored to the person's changing needs or circumstances, for example, when planning to have children, if their MS is changing to a more progressive phase or as their MS becomes more advanced. \n\nExplain to carers (including young carers) about their right to a carer's assessment and tell them about other sources of information and support that may be available (see NICE's guideline on supporting adult carers and the Young Carers [Needs Assessment] Regulations 2015). \n\n## Information and support for people planning to have children or who are pregnant\n\nAsk the person with MS soon after diagnosis and at regular intervals if they have any plans for starting or extending their family now or in the future, either through pregnancy or adoption. \n\nExplain to people with MS that they should discuss with their healthcare professionals if they are planning to start or extend their family or become pregnant. In particular, ensure that people taking disease-modifying treatments understand that they should tell their healthcare professionals straight away if they are trying to become pregnant or if they become pregnant. \n\nExplain to people with MS, and their partners if appropriate, that MS should not stop them from planning a family. Offer the opportunity to talk with a healthcare professional with knowledge of MS to answer any questions they have. For example, this may include discussing the following:\n\nthat fertility is not affected by MS\n\nthat pregnancy can be well managed in people with MS\n\nthe risk of the child developing MS\n\ntaking vitamin\xa0D and folic acid supplements before and during pregnancy (see NICE's guidelines on vitamin\xa0D and maternal and child nutrition)\n\npossible changes to medicine use before and during pregnancy\n\nthat pregnancy does not increase the risk of disease progression\n\nthat relapses may decrease during pregnancy and may increase 3 to 6\xa0months after childbirth before returning to pre-pregnancy rates\n\nthat birth options and pain relief choices available (including epidurals) should not be affected by MS\n\nthat breastfeeding is safe unless the person with MS is taking certain disease-modifying treatments\n\nsupport that may be available with caring for and supporting children. \n\nDiscuss caring for a child and the possible impact of MS symptoms, such as fatigue, and how these could be managed. \n\n## Information and support for people as MS becomes more advanced, including those approaching the end of their life\n\nGive people with MS that is becoming more advanced and their family members or carers information and support covering:\n\nsocial isolation and feelings of depression\n\nmobility aids and home adaptations\n\nother support available, such as legal rights including social care, employment rights and benefits, and the right to a carer's assessment (see recommendation\xa01.2.6). \n\nExplain to people with advanced MS and their family members or carers about the services available (for example, occupational therapy, palliative care and social services) and give them support to access them if needed. \n\nFor advice on identifying people who may be approaching the end of their life and providing information and support, follow the recommendations in NICE's guideline on end of life care for adults. \n\nWhen appropriate, explain to the person with MS (and their family members or carers if the person wishes) about advance care planning and power of attorney. Think about discussing advance care planning early if you expect the person's ability to communicate, cognitive status or mental capacity will deteriorate. Follow the recommendations on advance care planning in NICE's guideline on decision making and mental capacity. \n\nFor a short explanation of why the committee made the 2022 recommendations and how they might affect practice, see the rationale and impact section on providing information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: information and support for patients, their families and carers.\n\nLoading. Please wait.\n\n# Coordination of care\n\nFor general advice on continuity of care and relationships follow the recommendations in NICE's guideline on patient experience in adult NHS services.\n\nOffer the person with MS an appropriate single point of contact with knowledge of MS services to coordinate care and help them access services. \n\nCare for people with MS using a coordinated multidisciplinary approach. Involve professionals who can best meet the needs of the person with MS and who have expertise in managing MS including:\n\nMS nurses\n\nconsultant neurologists\n\nphysiotherapists with expertise in MS and occupational therapists\n\nspeech and language therapists, psychologists, dietitians, social care, continence specialists and specialist neuropharmacists or specialist MS pharmacists\n\nconsultants in rehabilitation medicine\n\nprimary healthcare team. [2014, amended 2022]\n\nFor a short explanation of why the committee made the 2022 recommendation and how it might affect practice, see the rationale and impact section on coordination of care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: coordination of care.\n\nLoading. Please wait.\n\n# Modifiable risk factors for relapse or progression of MS\n\n## Exercise\n\nEncourage people with MS to exercise. Advise them that regular exercise may have beneficial effects on their MS and does not have any harmful effects on their MS. \n\n## Smoking\n\nAdvise people with MS not to smoke and explain that it will increase the progression of disability. (See NICE's guideline on tobacco: preventing uptake, promoting quitting and treating dependence.) [2014, amended 2022]\n\n## Vaccinations\n\nOffer vaccinations in line with advice from the Joint Committee on Vaccinations and Immunisation and the Green Book: Immunisation against infectious disease for people with MS and their carers. [2014, amended 2022]\n\n# MS symptom management and rehabilitation\n\nThe guideline does not make recommendations for all symptoms that occur in people with MS. Some symptoms are addressed in other NICE guidelines and these are referenced where relevant.\n\nDetermine how often the person with MS will need to be seen based on:\n\ntheir needs, and those of their family and carers and\n\nthe frequency of visits needed for different types of treatment (such as review of disease‑modifying therapies, rehabilitation and symptom management). \n\nWhen prescribing medicines for symptom management in people with MS, ensure that local arrangements for prescribing, supply and treatment review follow NICE's guideline on medicines optimisation. \n\n## Fatigue\n\nAsk people with MS if they are experiencing fatigue, sudden tiredness or a change in their energy levels affecting their daily living. \n\nDo not assume that the person's fatigue is always caused by MS. Assess for other causes and manage these or refer the person for management if indicated. Other causes of fatigue may include:\n\nsleep problems\n\nsymptoms of MS, such as pain, spasticity and bladder dysfunction\n\nside effects of medicines\n\nillnesses, such as infections, anaemia and thyroid dysfunction\n\nanxiety and depression (see NICE's guidelines on generalised anxiety disorder and panic disorder in adults and depression in adults with a chronic physical health problem). \n\nExplain that MS‑related fatigue may be brought on by heat or biological, physical and emotional stress. \n\nOffer people with MS and fatigue a personalised discussion about how they can be supported to self-manage their fatigue. This could include:\n\nidentifying goals and priorities\n\nadvice on conserving their energy\n\nreviewing lifestyle factors such as diet and exercise\n\nusing stress management and wellbeing approaches such as mindfulness and cognitive behavioural techniques to help with day-to-day activities. \n\nAdvise people that aerobic, resistive and balance exercises, including yoga and pilates, may be helpful in treating MS‑related fatigue. \n\nExplain to people that there is no evidence that a specific diet will improve fatigue in people with MS, but that a healthy diet will benefit their general health. \n\nFor people with MS with moderately impaired mobility (an EDSS [Expanded Disability Status Scale] score of greater than or equal to 4), consider a combination of:\n\na programme of supervised aerobic and moderate progressive resistance activity and\n\ncognitive behavioural techniques. \n\nDo not use vitamin\xa0B12 injections to treat fatigue in people with MS. \n\nDo not offer hyperbaric oxygen to treat fatigue in people with MS. \n\nSee also the section on non-pharmacological management of mobility problems and fatigue.\n\nFor a short explanation of why the committee made the 2022 recommendations and how they might affect practice, see the rationale and impact section on assessment and non-pharmacological management of fatigue\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: non-pharmacological management of fatigue.\n\nLoading. Please wait.\n\nDiscuss with the person with MS whether a medicine to treat fatigue might be an option for them. Explain that there are potential risks, benefits and safety concerns for the possible treatment options. \n\nIf a person with MS wishes to try a medicine for fatigue, refer them to a specialist to fully discuss the treatment options. \n\nUse shared decision making to decide whether to try a medicine for fatigue and which would be most suitable. Taking into account the needs, priorities and preferences of the person with MS, and the risks and benefits of each treatment, consider any of the following:\n\namantadine:\n\n\n\nsee the BNF for amantadine dosages\n\n\n\nmodafinil, except in people who are pregnant or planning pregnancy:\n\n\n\nsee the Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on modafinil for advice on monitoring and cautions for use, including cardiovascular monitoring before and during treatment\n\nfollow the MHRA safety advice on modafinil and pregnancy for people who are able to get pregnant, including explaining the risks, advising on effective contraception and explaining that modafinil may reduce the effectiveness of steroidal contraceptives\n\nuse the lowest effective dose\n\n\n\nselective serotonin reuptake inhibitor (SSRI):\n\n\n\nuse the lowest dose recommended for licensed indications\n\nsee also, the section on making decisions about prescribing in NICE's guideline on medicines associated with dependence or withdrawal symptoms. In June 2022 this was an off-label use of amantadine, modafinil and SSRIs. See NICE's information on prescribing medicines.\n\n\n\nRegularly review treatment to monitor effectiveness, safety and acceptability, adjust the dose, and decide whether to continue or stop the medicine:\n\nAgree the frequency of review with the person with MS, taking into account the medicine that they are taking, the need for dose adjustments and the person's preferences and circumstances.\n\nFor more information, see the section on medication review in NICE's guideline on medicines optimisation and, for reviewing SSRIs, see the section on reviewing medicines in NICE's guideline on medicines associated with dependence or withdrawal symptoms. \n\nWhen the person with MS is on a stable dose of a medicine for fatigue, subsequent prescriptions may be issued by another prescriber as part of a shared-care agreement under the direction of the initiating specialist prescriber. For more information about shared care, see NHS England's guidance on responsibility for prescribing between primary and secondary/tertiary care. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pharmacological management of fatigue\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: pharmacological management of fatigue.\n\nLoading. Please wait.\n\n## Mobility problems\n\nSee also recommendation\xa01.4.1 for advice on encouraging exercise in people with MS.\n\nFor guidance on functional electrical stimulation for drop foot, see the NICE interventional procedures guidance on functional electrical stimulation for drop foot of central neurological origin.\n\nEnsure people with MS and mobility problems have access to an assessment to establish individual goals and discuss ways to achieve them. This would usually involve rehabilitation specialists and physiotherapists with expertise in MS. \n\nDo not offer fampridine to treat mobility problems in people with MS. Fampridine is a clinically effective treatment for some people, but it is not cost effective at the current list price. This recommendation does not apply to people who have already started treatment with fampridine in the NHS, who should be able to continue treatment until they and their NHS clinician think it appropriate to stop.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on pharmacological management of mobility problems\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: pharmacological management of mobility.\n\nLoading. Please wait.\n\nConsider vestibular rehabilitation for people with MS who have fatigue or mobility problems associated with limited standing balance. \n\nConsider supervised exercise programmes involving moderate progressive resistance training and aerobic exercise to treat people with MS who have mobility problems or fatigue. \n\nHelp the person with MS continue to exercise, for example, by referring them to a physiotherapist with expertise in MS or to exercise referral schemes. [2014, amended 2022]\n\nIf more than 1 of the interventions recommended for mobility or fatigue are suitable, offer treatment based on which the person prefers and whether they can continue the activity after the treatment programme ends. \n\nEncourage people with MS to keep exercising after treatment programmes end for longer-term benefits (see NICE's guideline on behaviour change: individual approaches). \n\n## Spasticity\n\nSuspect spasticity when a person with MS presents with any of the following:\n\ninvoluntary muscle movements (spasms)\n\nmuscle stiffness\n\npain and restriction with certain movements or positions causing difficulty in performing various activities\n\na change in their mobility or upper limb function. \n\nAssess people with MS and suspected spasticity for factors that might worsen spasticity, for example, pressure ulcers, bladder and bowel dysfunction and infections, poor posture or positioning, and pain. Provide support and information to help people with MS, and their families and carers if appropriate, to prevent and manage these factors. \n\nDiscuss with the person the balance between the benefits and harms of treating spasticity. In particular, explain that some people use their spasticity to maintain their posture and ability to stand, walk or transfer, and that treatment with muscle relaxants may adversely affect this. \n\nConsider oral baclofen as a first-line drug treatment to treat spasticity in people with MS who have specific treatment goals such as improving mobility or easing pain and discomfort. Take into account any contraindications, comorbidities and the person's preferences. \n\nIf oral baclofen is not tolerated or does not provide adequate relief, consider gabapentin as a second-line option to treat spasticity in people with MS. For guidance on safe prescribing of gabapentin and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. In June 2022, this was an off-label use of gabapentin. See NICE's information on prescribing medicines. See also the 2019 MHRA drug safety update on pregabalin, gabapentin and risk of abuse and dependence.\n\nWhen using oral baclofen or gabapentin to treat spasticity in people with MS, explain to the person that they should:\n\nincrease the dose gradually in at least 2‑week increments to optimise symptom improvement or until they reach the maximum dose they can tolerate\n\nstop taking the medicine if there is no benefit at the maximum tolerated dose (explain that baclofen can cause harm if stopped suddenly and that special precautions may be needed when stopping specific medicines)\n\nhave their medicines reviewed at least annually once the optimal dose has been reached. See the BNF and the summary of product characteristics for baclofen and gabapentin for advice on optimising dosage and stopping treatment and, if relevant, treating people with renal impairment and older people. For more information on reviewing and withdrawing gabapentin, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nConsider a combination of oral baclofen and gabapentin for people with MS if:\n\nindividual medicines do not provide adequate relief or\n\nside effects from individual medicines prevent the dose being increased. See the BNF and the summary of product characteristics for baclofen and gabapentin. Use caution when using these medicines in combination because of the risk of severe respiratory depression (see the 2017 MHRA advice on gabapentin: risk of severe respiratory depression). For guidance on safe prescribing of gabapentin and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.In June 2022, this was an off-label use of gabapentin. See NICE's information on prescribing medicines. See also the 2019 MHRA drug safety update on pregabalin, gabapentin and risk of abuse and dependence.\n\nIf spasticity is causing significant impairments in mobility, posture or function and initial treatments are unsuccessful, refer to a multidisciplinary team experienced in the management of spasticity for assessment and treatment planning. \n\nFor guidance on THC:CBD spray for treating spasticity in people with MS, see the recommendations on spasticity in NICE's guideline on cannabis-based medicinal products. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on spasticity\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: pharmacological management of spasticity.\n\nLoading. Please wait.\n\n## Oscillopsia\n\nConsider gabapentin as a first‑line drug to treat oscillopsia in people with MS. For guidance on safe prescribing of gabapentin and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. In June 2022, this was an off-label use of gabapentin. See NICE's information on prescribing medicines and the 2019 MHRA drug safety update on pregabalin, gabapentin and risk of abuse and dependence.\n\nConsider memantine as the second‑line treatment for oscillopsia in people with MS. In June 2022, this was an off-label use of memantine. See NICE's information on prescribing medicines.\n\nRefer the person with MS for specialist advice if there is no improvement in oscillopsia after treatment with gabapentin and memantine or if side effects prevent continued use. \n\n## Emotional lability\n\nConsider amitriptyline to treat emotional lability (involuntary laughing and crying related to a frontal lobe lesion) in people with MS. For guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. In June 2022, this was an off-label use of amitriptyline. See NICE's information on prescribing medicines.\n\n## Pain\n\nAssess and investigate the cause of pain to establish a diagnosis and offer treatment specific to the cause of the pain. \n\nBe mindful of the impact of pain on the mental wellbeing of people with MS, and provide advice and support. See NICE's guideline on depression in adults with a chronic physical health problem. \n\nTreat neuropathic pain in people with MS and refer people to pain services according to NICE's guideline on neuropathic pain in adults. \n\nBe aware that musculoskeletal pain is common in people with MS and is usually secondary to problems with immobility, spasticity and posture. Assess musculoskeletal pain and offer treatment appropriate to the cause, for example see the sections on managing mobility problems and spasticity, and NICE's guideline on low back pain and sciatica in over 16s. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of pain.\n\nLoading. Please wait.\n\n## Cognitive and memory problems\n\nBe aware that the symptoms of MS can include cognitive problems, including memory problems, that the person may not immediately recognise or associate with their MS. \n\nAssess cognition as part of the person's comprehensive review. Tailor the assessment to the person's needs, for example, use a clinic interview or brief formal assessment, or consider referral for a full neuropsychological assessment if needed. \n\nBe aware that anxiety, depression, difficulty sleeping, fatigue and medication can affect cognition. Assess for and offer management appropriate for these issues in people with MS and cognitive or memory problems (for example, see the section on fatigue and NICE's guidelines on generalised anxiety disorder and panic disorder in adults and depression in adults with a chronic physical health problem). \n\nConsider referring people with MS and persisting cognitive impairments to an occupational therapist and/or a neuropsychologist to assess and manage these symptoms according to the person's needs. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on cognitive and memory problems\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: non-pharmacological management of memory and cognitive problems.\n\nLoading. Please wait.\n\n## Ataxia and tremor\n\nThe evidence was reviewed for the pharmacological management of ataxia and tremor, and the committee made a recommendation for research.\n\nFor a short explanation of why the committee only made a recommendation for research, see the rationale section on pharmacological management of ataxia and tremor\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: pharmacological management of ataxia and tremor.\n\nLoading. Please wait.\n\n## Dystonia and tremor\n\nFor guidance on deep brain stimulation for tremor and dystonia, see the NICE interventional procedures guidance on deep brain stimulation for tremor and dystonia (excluding Parkinson's disease).\n\n# Comprehensive review\n\nEnsure all people with MS have a comprehensive review of all aspects of their care at least once a year. \n\nEnsure the comprehensive review is carried out by healthcare professionals with expertise in MS and its complications. Involve different healthcare professionals with expertise in specific areas of the review if needed. \n\nTailor the comprehensive review to the needs of the person with MS assessing:\n\nMS symptoms:\n\n\n\nmobility and balance including falls\n\nneed for mobility aids including wheelchair assessment\n\nuse of arms and hands\n\nmuscle spasms and stiffness\n\ntremor\n\nbladder, bowel and sexual function (see NICE's guidelines on urinary incontinence in neurological disease and faecal incontinence in adults)\n\nsensory symptoms and pain\n\nspeech and swallowing (see NICE's guideline on nutrition support for adults)\n\nvision\n\ncognitive symptoms\n\nfatigue\n\ndepression and anxiety (see NICE's guidelines on depression in adults with a chronic physical health problem and generalised anxiety disorder and panic disorder in adults)\n\nsleep\n\nrespiratory function.\n\n\n\nMS disease course:\n\n\n\nevidence of progression\n\nevidence of active disease\n\nrelapses in past year\n\neligibility for disease-modifying treatments (see the section on other treatments)\n\nthe nature and extent of disability (which should be documented).\n\n\n\nGeneral health:\n\n\n\nweight\n\nsmoking, alcohol and recreational drugs\n\nexercise\n\naccess to routine health screening and contraception\n\ncare of other chronic conditions.\n\n\n\nSocial activity and participation:\n\n\n\nfamily and social circumstances\n\ndriving and access to transport\n\nemployment (for example, the need for vocational support or rehabilitation)\n\naccess to daily activities and leisure.\n\n\n\nCare and carers:\n\n\n\npersonal care needs\n\nsocial care needs\n\naccess to adaptations and equipment at home. [2014, amended 2022]\n\n\n\nRefer any issues identified during the comprehensive review of the person with MS to members of the MS multidisciplinary team and other appropriate teams so that they can be managed. \n\nEnsure people with MS are offered a medicines review in line with NICE's guidelines on medicines adherence and medicines optimisation. \n\nEnsure people with MS have their bone health regularly assessed and reviewed in line with NICE's guideline on osteoporosis. \n\nEnsure people with MS and severely reduced mobility are regularly assessed and reviewed for risk of contractures (shortening of tendons, muscles or ligaments that limits joint movement). \n\nCheck people with MS and severely reduced mobility at every contact for areas at risk of pressure ulcers (see NICE's guideline on pressure ulcers). \n\nDiscuss the care provided by carers and care workers as part of the person's care plan. Ensure that carers (including young carers) know about their right to a carer's assessment (see NICE's guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers and the Young Carers [Needs Assessment] Regulations 2015). [2014 amended 2022]\n\nRefer people with MS to palliative care services for symptom control and for end of life care when appropriate. \n\n# Relapse and exacerbation\n\n## Recognising a relapse\n\nDiagnose a relapse of MS if the person:\n\ndevelops new symptoms or\n\nhas worsening of existing symptomsand these last for more than 24\xa0hours in the absence of infection or any other cause after a stable period of at least 1\xa0month. \n\nBefore diagnosing a relapse of MS:\n\nrule out infection – particularly urinary tract and respiratory infections and\n\ndiscriminate between the relapse and fluctuations in disease or progression. \n\nDo not routinely diagnose a relapse of MS if symptoms are present for more than 3\xa0months. \n\n## Treating acute relapse of MS\n\nDevelop local guidance and pathways for timely treatment of relapses of MS. Ensure follow up is included in the guidance and pathway. \n\nAssess and offer treatment for relapses of MS that affect the person's ability to perform their usual tasks, as early as possible and within 14\xa0days of onset of symptoms. \n\nNon‑specialists should discuss a person's diagnosis of relapse and whether to offer steroids with a healthcare professional with expertise in MS because not all relapses need treating with steroids. \n\nOffer treatment for relapse of MS with oral methylprednisolone 0.5\xa0g daily for 5\xa0days. \n\nConsider intravenous methylprednisolone 1\xa0g daily for 3\xa0to 5\xa0days as an alternative for people with MS:\n\nin whom oral steroids have failed or not been tolerated or\n\nwho need admitting to hospital for a severe relapse or monitoring of medical or psychological conditions such as diabetes or depression. \n\nDo not prescribe steroids at lower doses than methylprednisolone 0.5\xa0g daily for 5\xa0days to treat an acute relapse of MS. \n\nDo not give people with MS a supply of steroids to self‑administer at home for future relapses. \n\n## Information about treating a relapse with steroids\n\nDiscuss the benefits and risks of steroids with the person with MS, taking into account the effect of the relapse on the person's ability to perform their usual tasks and their wellbeing. \n\nExplain the potential complications of high‑dose steroids, for example temporary effects on mental health (such as insomnia, depression, confusion and agitation) and worsening of blood glucose control in people with diabetes. \n\nGive the person with MS and their family members or carers (as appropriate) information that they can take away about side effects of high‑dose steroids in a format that is appropriate for them. \n\nEnsure that the MS multidisciplinary team is told that the person is having a relapse, because relapse frequency may influence which disease-modifying therapies are chosen and whether they need to be changed. \n\n## Medical, therapy and social care needs at time of relapse or exacerbation\n\nIdentify whether the person having a relapse of MS or their family members or carers have social care needs and if so refer them to social services for assessment. \n\nOffer inpatient treatment to the person having a relapse of MS if their relapse is severe or if it is difficult to meet their medical and social care needs at home. \n\nExplain that a relapse of MS may have short‑term effects on cognitive function. \n\nIdentify whether the person with MS having a relapse or exacerbation needs additional symptom management, rehabilitation or consideration for disease-modifying treatments. [2014 amended 2022]\n\n# Other treatments\n\n## Disease-modifying treatments\n\nNICE has published technology appraisal guidance on disease-modifying treatments for MS. For full details, see NICE's technology appraisal guidance on multiple sclerosis.\n\n## Vitamin\xa0D\n\nDo not offer vitamin\xa0D solely for the purpose of treating MS. \n\n## Omega fatty acids compounds\n\nDo not offer omega‑3 or omega‑6 fatty acid compounds to treat MS. Explain that there is no evidence that they affect relapse frequency or progression of MS. \n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Advanced MS\n\nMS is described as 'advanced' when it has progressed to the point where a person is severely affected by their symptoms and has significant ongoing physical or cognitive impairment (this typically happens in the late stages of primary and secondary progressive MS). People with advanced MS are unable to carry out most of their usual activities of daily living independently and need other people to assist them. The term is used to describe the level of burden rather than the type or duration of the MS.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Coordination of care\n\nWhat is the clinical and cost effectiveness of processes of care, including the role of multiple sclerosis (MS) specialist nurses and other healthcare professionals, to improve care coordination and health outcomes in adults with MS? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on coordination of care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: coordination of care.\n\nLoading. Please wait.\n\n## Cognitive rehabilitation\n\nFor adults with MS, including people receiving palliative care, what is the clinical and cost effectiveness of non-pharmacological interventions for memory and cognitive problems? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on cognitive and memory problems\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: non-pharmacological management of memory and cognitive problems.\n\nLoading. Please wait.\n\n## Outcome measures for cognitive rehabilitation\n\nWhat core outcome measures should be used for studies assessing memory and cognition in people with MS?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on cognitive and memory problems\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: non-pharmacological management of memory and cognitive problems.\n\nLoading. Please wait.\n\n## Continued relapses\n\nIs intravenous methylprednisolone more clinically and cost effective than oral methylprednisolone in people with relapsing–remitting MS and people with secondary progressive MS with continued relapses? \n\n## Mobility\n\nWhat is the optimal frequency, intensity and form of rehabilitation for mobility problems in people with MS? \n\n## Spasticity\n\nFor adults with MS, including people receiving palliative care, what is the clinical and cost effectiveness of pharmacological interventions for generalised spasticity? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on spasticity\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: pharmacological management of spasticity.\n\nLoading. Please wait.\n\n## Vitamin\xa0D\n\nCan vitamin\xa0D slow down the progression of disability in MS? \n\n# Other recommendations for research\n\n## Information and support\n\nWhat information, education and support do adults with clinically isolated syndrome and their families and carers find most useful? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on providing information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: information and support for patients, their families and carers.\n\nLoading. Please wait.\n\n## Non-pharmacological management of fatigue\n\nFor adults with MS, including people receiving palliative care, what is the clinical and cost effectiveness of non-pharmacological interventions for fatigue? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on assessment and non-pharmacological management of fatigue\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: non-pharmacological management of fatigue.\n\nLoading. Please wait.\n\n## Pharmacological management of fatigue\n\nFor adults with MS, including people receiving palliative care, what is the clinical and cost effectiveness of pharmacological interventions for fatigue? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pharmacological management of fatigue\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: pharmacological management of fatigue.\n\nLoading. Please wait.\n\n## Pain\n\nFor adults with MS, including people receiving palliative care, what is the clinical and cost effectiveness of non-pharmacological interventions for pain? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of pain.\n\nLoading. Please wait.\n\n## Ataxia and tremor\n\nFor adults with MS, what is the clinical and cost effectiveness of pharmacological interventions for ataxia and tremor? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pharmacological management of ataxia and tremor\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: pharmacological management of ataxia and tremor.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Diagnosing multiple sclerosis\n\nRecommendations 1.1.1 to 1.1.9\n\n## Why the committee made the recommendations\n\nThe recommendations were updated to reflect changes to the McDonald criteria, revised 2017 (Thompson AJ, Banwell BL, Barkhof F et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria, The Lancet Neurology), which are expected to speed up diagnosis and reduce the chance of misdiagnosis. The committee agreed that the previous recommendations on diagnosis are still relevant, but made some updates based on their experience and changes to practice since 2014.\n\nThe committee retained the recommendations on symptoms and features of multiple sclerosis (MS), highlighting that symptoms can be wide-ranging and listing the most common symptoms and those that would make a diagnosis unlikely.\n\nThe committee agreed that assessments to exclude alternative diagnoses need to be tailored to the person, according to their presenting symptoms. They decided that a list of blood tests would not be helpful and that tests would need to be decided on an individual basis.\n\nThe committee agreed that a consultant neurologist should be responsible for the diagnosis of MS, using the history, examination, MRI and other test findings, and by following the revised McDonald criteria. To meet the updated criteria, dissemination of lesions in the nervous system in space and time needs to be demonstrated, and all lesions visible on an MRI scan can contribute to the criteria, irrespective of whether they have caused symptoms (symptomatic lesions) or have not caused symptoms (asymptomatic lesions). A positive finding of cerebrospinal fluid oligoclonal bands can now be used in place of dissemination of lesions in some circumstances. The criteria have been developed for people experiencing clinically isolated syndrome, which means that they must present with symptoms suggestive of an inflammatory demyelinating condition.\n\nThe committee agreed to retain the previous recommendation on reviewing people with suspected MS who do not meet the McDonald criteria, but added the example of reviewing people annually, which is in line with current practice. They agreed that information should be provided so that people understand why they need to be reviewed regularly and who to contact if their symptoms change or they have concerns.\n\nThe committee supported the importance of providing information and advice on resources at the time of diagnosis.\n\n## How the recommendations might affect practice\n\nThe recommendations are expected to help to reduce variation between services and clinicians. The recommendations reflect current clinical practice and are not expected to increase the number of referrals or the cost of making a diagnosis and therefore will not have a substantial resource impact.\n\nReturn to recommendations\n\n# Providing information and support\n\nRecommendations 1.2.4 and 1.2.9 to 1.2.18\n\n## Why the committee made the recommendations\n\nThe committee noted that people who were diagnosed with MS a long time ago may not be offered an annual review. They highlighted the importance of informing people with MS and their carers that they should have a regular comprehensive review so that they can ensure that this takes place at least once a year and covers all of their needs.\n\nThe evidence showed that MS has a significant impact on carers and that information and support for them was often lacking. Carers are not always aware of the support available to them and often do not have the information they need as circumstances change for the person with MS. The committee agreed that carers should be aware of their right to a carer's assessment and highlighted that this should include assessments for young carers.\n\nThe committee also noted that the timing of information was important and agreed that information and support should be provided according to the changing needs or circumstances of the person with MS. Considering pregnancy and approaching more advanced disease were identified as particular situations in which information and support needs should be reviewed. The committee made specific recommendations for these groups.\n\nNo evidence was identified on the information and support needs for people diagnosed with clinically isolated syndrome, and the committee therefore made a recommendation for research on information and support for people with clinically isolated syndrome.\n\nRecommendations from the previous version of the guideline were updated and new recommendations added, based on qualitative evidence and the committee's experience. The committee agreed that the recommendations should apply to both women and men planning to start a family, where appropriate, and to people considering adoption as well as those planning pregnancy.\n\nThe committee agreed that discussions about starting or extending a family should happen early to ensure that people with MS have time to make decisions and plan for the future. They agreed that healthcare professionals should proactively ask about and discuss the person's plans for having children. The committee noted that some people with MS assume that they cannot have children and do not ask for advice. Although there was limited evidence supporting early information giving, the committee agreed that, based on their experience, it is important to start these discussions soon after diagnosis.\n\nThe committee noted that some disease-modifying treatments should not be taken during pregnancy because of the risk of harm to the unborn baby. Therefore, they highlighted that people taking these treatments need to inform their healthcare professional straight away if they are trying to get pregnant or become pregnant.\n\nThe evidence showed that people with MS often have concerns about the impact of MS on having a family. The committee agreed that MS should not be a barrier to planning a family, because pregnancies can be well managed and additional support may be available. Many people with MS may feel like they are not able to have children, so the committee agreed that people with MS should be able to discuss the possibilities before making these decisions.\n\nThe evidence highlighted issues of particular concern to people with MS, such as how MS and treatments can affect pregnancy, whether they can pass MS on to their children and the impact of MS on their labour, birth options and breastfeeding. People also wanted more information on the possible impact that caring for a child might have on their symptoms, such as fatigue, and advice on how to manage this. The committee updated the existing recommendations based on the evidence. Based on their experience, the committee also included a reference to advice on folic acid in the NICE guideline on maternal and child nutrition because they agreed that this would also apply to people with MS.\n\nThe qualitative evidence showed that feelings of social isolation and depression are common in people with MS, but they often lack information about available services and support. It also showed that people were not always aware of the availability and suitability of home adaptations and mobility aids, and how to obtain them. These are important for maintaining independence as MS progresses. Other areas were also identified where better information and support could improve the experience and wellbeing of people with MS and their carers, including legal rights, employment rights, benefits and carer assessments.\n\nBased on the evidence and their experience, the committee agreed that people with advanced MS and their carers need information and support to navigate services so that they can access extra support as their needs change.\n\nThe committee noted that NICE's guideline on end of life care for adults includes recommendations on providing information and support for people who may be approaching the end of their life. They also agreed that an existing recommendation on advance care planning and power of attorney should be retained because it is still supported by the evidence and it is important to help people plan for their future care. It was updated to include a cross reference to NICE's guideline on decision-making and mental capacity. The committee added that early discussions about advance care planning should be considered for people at risk of deterioration.\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current good practice. Overall, the committee did not think these recommendations would have a significant resource impact.\n\nReturn to recommendations\n\n# Coordination of care\n\nRecommendation 1.3.1\n\n## Why the committee made the recommendation\n\nThe committee updated the 2014 recommendation to emphasise that the point of contact should have knowledge of MS services to coordinate the person's care and help them access relevant healthcare professionals. The available clinical and health economic evidence was limited, so the committee were not able to specify that the point of contact should have knowledge of MS because this may represent a change in practice and a significant resource impact. Instead, a point of contact with access to appropriate healthcare services was specified to allow for different service configurations; for example, the point of contact would be able to access a healthcare professional who can contact the person with MS and respond to their concerns. The committee acknowledged the lack of evidence in this area and made a recommendation for research on coordination of care for people with MS to support future guidance in this area.\n\n## How the recommendation might affect practice\n\nThe recommendation emphasises that the point of contact should have knowledge of MS services. This should not result in a large change in practice and therefore will not have a significant resource impact.\n\nReturn to recommendation\n\n# Assessment and non-pharmacological management of fatigue\n\nRecommendations 1.5.3 to 1.5.9 and 1.5.11\n\n## Why the committee made the recommendations\n\nAlthough a large number of studies have been published since the previous version of the guideline, the committee agreed that the new evidence was too limited in quality to change most of the existing recommendations. However, the new evidence did further support the 2014 recommendations on managing MS-related fatigue.\n\nFatigue may not always be identified and treated, so the committee agreed by informal consensus that people with MS should be asked about the presence of fatigue. Causes of fatigue other than MS may sometimes be missed, so the committee highlighted the importance of checking for other possible causes, to ensure appropriate management.\n\nThere was some evidence that fatigue or energy management interventions and wellbeing techniques, such as cognitive behavioural therapy (CBT) and mindfulness, are beneficial. However, the committee agreed that the evidence was not sufficient to recommend formal programmes because of limitations in the studies. Instead, the committee recognised that using elements of these approaches could be helpful and included in discussions about self-management options.\n\nBased on their experience, the committee agreed that a fatigue management discussion should be offered, which is routinely provided in current practice. This would be a tailored discussion that could include goals and priorities for each person, advice on energy conservation, review of lifestyle factors and the use of stress reduction and wellbeing techniques, including cognitive behavioural principles for managing day-to-day activities and mindfulness-based techniques.\n\nThe committee agreed that the previous recommendation on advice about the possible benefits of aerobic, balance and stretching exercises, including yoga, was still supported by the evidence. In addition, there was some evidence of benefit for progressive resistive exercises and pilates.\n\nThere was a lack of evidence on specific diets, but a recommendation was made to highlight the benefits of following a healthy diet. Diet was also included in the discussion of fatigue management.\n\nThe committee agreed that the evidence still supported the previous recommendation on considering a programme of aerobic and moderate progressive resistance activity combined with cognitive behavioural techniques to treat fatigue in people with significantly impaired mobility (EDSS [Expanded Disability Status Scale] score of at least 4). This was based on clinical evidence, modest economic evidence (covering the ExIMS study, 2013) and the original economic analysis from the previous version of the guideline supporting the cost effectiveness of combined exercise programmes. The committee noted that this should be a supervised programme provided to the person with MS, rather than self-directed exercise, and that it should be tailored to the needs and abilities of the person.\n\nNo randomised controlled trial evidence was identified for hyperbaric oxygen to treat MS-related fatigue in people with MS. The committee were concerned that this intervention is being used despite the lack of evidence, sometimes at the expense of the person with MS or through charities. They agreed that it should not be used, based on the lack of evidence, their clinical experience and the high cost involved.\n\nA recommendation for research on identifying clinically and cost-effective interventions for the non-pharmacological management of fatigue was developed to encourage further research in this area.\n\n## How the recommendations might affect practice\n\nThe recommendations on assessment and offering people a personal tailored discussion about fatigue management do not represent a change in practice. Discussion of fatigue management is provided routinely in current practice by occupational therapists, MS nurses or physiotherapists. It does not typically involve a specific, structured fatigue management programme but includes some elements of fatigue management, such as advice on energy conservation. Similarly, the inclusion of stress and wellbeing techniques does not refer to structured interventions but allows the opportunity to use some elements of these techniques as part of the fatigue management discussion, which the committee agreed are used as part of fatigue management discussions in current practice.\n\nSupervised aerobic and moderate progressive resistance programmes with cognitive behavioural techniques for people with an EDSS score of at least 4 was recommended in the 2014 guideline based on clinical- and cost-effectiveness analysis. Physiotherapists and occupational therapists typically apply CBT principles like goal setting as part of exercise interventions in current practice, and this does not need to be a formal CBT intervention delivered by a psychologist. The committee agreed that this would not represent a change in practice.\n\nRecommendations covering advice on exercises for MS-related fatigue (which would be self-directed exercise rather than supervised programmes provided to the person with MS) and following the principles of a healthy diet are consistent with current good practice, as is the recommendation not to offer hyperbaric oxygen.\n\nAs none of the recommendations represent a change in current practice these recommendations are not expected to have a resource impact.\n\nReturn to recommendations\n\n# Pharmacological management of fatigue\n\nRecommendations 1.5.12 and 1.5.16\n\n## Why the committee made the recommendations\n\nThe evidence for treating fatigue with amantadine, modafinil or selective serotonin reuptake inhibitors (SSRIs) in people with MS was limited but showed some benefit for each medicine. The lack of good evidence comparing the different treatments meant that the committee were unable to recommend one in preference to the others or an order in which these treatments should be considered. However, they agreed that fatigue can have a significant impact on the person's daily activities and that, in their clinical experience, it can improve with pharmacological treatment in some people.\n\nAmantadine, modafinil and SSRIs are not licensed for treating fatigue in people with MS and there are safety issues associated with their use, so they should only be started by a specialist in MS. The committee agreed that the potential benefits of effective treatment may outweigh the risks for people whose quality of life is severely affected by fatigue. However, they highlighted that people with MS should be fully informed about the possible risks and benefits, and make a shared decision with a specialist about whether to try a medicine and which would be most suitable, taking into account their needs, priorities and preferences. They agreed that it is important that people can access pharmacological treatment options and that they can be considered before trying non-pharmacological treatments in people for whom a rapid response is a priority.\n\nThe committee highlighted the particular safety concerns for modafinil, including that it should not be used by people who are pregnant or planning pregnancy, and that precautions should be taken if prescribing it for people able to get pregnant, in line with the 2020 Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on modafinil. The committee noted additional advice for modafinil on monitoring, stopping treatment and cautions for use in the 2014 MHRA safety advice on modafinil and advice in the summary of product characteristics for modafinil and amantadine. Based on their experience, the committee highlighted the importance of starting people on a low dose of modafinil, such as 100\xa0mg once a day.\n\nThe committee agreed that people taking these medicines would need to have regular reviews to monitor effectiveness and safety, adjust dosages and ensure that treatment is stopped if it is ineffective or the person experiences adverse effects. If treatment is effective and the person is on a stable dose of their medicine, the committee agreed that responsibility for prescribing could be transferred to primary care under a shared-care arrangement.\n\nA recommendation for research on the pharmacological management of fatigue was made to support future research in this area.\n\n## How the recommendations might affect practice\n\nAmantadine is currently prescribed as the first-line pharmacological treatment, alongside non-pharmacological management options, as a part of a multidisciplinary approach to fatigue. Modafinil and SSRIs are less commonly prescribed. These pharmacological treatments are usually prescribed under the guidance of secondary care specialists. The recommendations may result in a change from current practice, with increased prescribing of modafinil and SSRIs. There may also be an increase in the use of shared-care arrangements for prescribing these medicines in primary care.\n\nThere may be a resource impact due to cardiovascular monitoring from the increased use of modafinil in a broader range of clinical settings, including primary care. However, the recommendations may result in a decrease in the use of amantadine, which has a greater unit cost than modafinil and SSRIs. Therefore, the overall resource impact of the recommendations is unlikely to be significant.\n\nReturn to recommendations\n\n# Pharmacological management of mobility problems\n\nRecommendation 1.5.18\n\n## Why the committee made the recommendation\n\nFampridine was shown to be effective in treating lack of mobility in some people with MS, but not all. A health economic analysis was carried out for this guideline update, which included modelling an initial 4‑week assessment to identify which people with MS respond to and would then continue fampridine treatment. Based on the current list price, fampridine was not found to be a cost-effective treatment and so the committee made a recommendation to not offer fampridine for the management of mobility problems.\n\n## How the recommendation might affect practice\n\nThis recommendation does not represent a change in practice and therefore will not have a resource impact.\n\nReturn to recommendation\n\n# Spasticity\n\nRecommendations 1.5.24 to 1.5.32\n\n## Why the committee made the recommendations\n\nThere was very limited new evidence on pharmacological management of spasticity. Only 1 study comparing intrathecal baclofen to usual care in a post-stroke population was identified. This evidence was insufficient to make any new recommendations or significant changes to the previous guideline recommendations. Therefore, the committee updated the 2014 recommendations based on their experience and knowledge of current practice.\n\nThe committee agreed that it is important to raise awareness of spasticity and its presentation to ensure that people with MS receive appropriate treatment. They also highlighted that it is important to emphasise that the management of spasticity in MS should be tailored to the needs of the person and their specific treatment goals because spasticity can vary significantly in people with MS and change at different stages in the course of their disease. The committee agreed that the previous recommendation on assessing for and treating factors that may exacerbate symptomatic spasticity should be retained.\n\nThe committee were aware that some people with MS use their spasticity to support them in maintaining posture when transferring or standing, and they agreed that the treatment of spasticity can have the potential to cause greater levels of disability. It was, therefore, agreed that the balance of risks and harms of treatment need to be fully discussed with the person before agreeing treatment.\n\nAlthough there was no new evidence on specific pharmacological treatments for spasticity, the committee took into account safety concerns for the use of gabapentin (see the 2019 MHRA drug safety update on pregabalin, gabapentin and risk of abuse and dependence) and agreed that it should no longer be recommended as a first-line option. The combination of baclofen and gabapentin is offered when neither agent by itself manages to control symptoms, but this needs to be balanced against the possible side effects. The committee noted that the BNF states that both gabapentin and baclofen can have central nervous system (CNS) depressant effects,\u202fwhich might affect the ability to perform skilled tasks. There is also a potential increased risk of respiratory depression (as advised by the MHRA) when using gabapentin in combination with other CNS depressants, and people with neurological disease (such as MS) may be at higher risk of this. The committee discussed the safety issues for gabapentin and agreed that illegal diversion and misuse are of particular concern. However, they agreed that gabapentin can be an effective treatment and should still be an option for treating spasticity in MS if oral baclofen is not tolerated or unsuccessful. Prescribers should follow the MHRA safety advice on evaluating people for a history of drug abuse and checking for misuse and dependence. The committee noted that gabapentin is now a class\xa0C controlled substance and prescribers will need to follow the statutory requirements for its use.\n\nBased on their experience, the committee agreed that information should be added to the previous recommendation on using these medicines to clarify the importance of gradually increasing the doses of medicine to reach the optimal dosage.\n\nThe committee agreed that if a person's treatment goals are not being met by treatment with baclofen or gabapentin (alone or in combination), and appropriate physical assessments and precipitating or prolonging factors have been addressed, other treatment approaches should be considered, which may be delivered by a service dedicated to the more specialist management of spasticity. The committee updated the recommendation in the 2014 guideline on referral to specialist services to include multidisciplinary teams, which is consistent with current clinical practice.\n\nA recommendation for research on identifying clinical and cost-effective pharmacological interventions for the management of spasticity was developed to encourage further research in this area.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current best practice in the approach to the assessment and management of spasticity in people with MS. The committee recognised that not all clinicians would have direct access to specialist spasticity management services to deliver treatments beyond initial pharmacological approaches. However, services that specialise in the management of spasticity should be available at a regional level, ideally as part of a network.\n\nIt is not anticipated that the updated recommendations will result in significantly greater resource use to support the assessment and treatment of spasticity in people with MS. There may be resource savings realised through a reduction in complications caused by inappropriate treatment or untreated spasticity.\n\nReturn to recommendations\n\n# Pain\n\nRecommendations 1.5.37 to 1.5.40\n\n## Why the committee made the recommendations\n\nThe causes of pain in people with MS are varied. It may be neuropathic, caused by MS nerve damage; or secondary to immobility, spasticity or posture issues; or it may be unrelated to MS and caused by other comorbid conditions. Pain is sometimes assumed to be neuropathic in people with MS when it may have a different cause. Based on their experience, the committee agreed that the first step in managing pain is to investigate and establish the cause. If the underlying cause is correctly identified, it will prevent unnecessary treatment and possible side effects, and ensure pain is managed correctly.\n\nThe committee acknowledged the impact that pain can have on mental health. Pain can severely impair mobility and active lifestyle choices, which may lead to low mood and mental health problems. Low mood may also affect the way the person deals with pain. Therefore, it is important that healthcare professionals are mindful of this complex interaction and that people are offered support and advice if pain is affecting their mental wellbeing.\n\nThe evidence on non-pharmacological management of pain was limited. The interventions and outcomes were varied, and the study sizes were small. There was some evidence of benefit from interventions such as yoga, relaxation massage, mindfulness, CBT and transcutaneous direct current stimulation and hypnosis with neurofeedback. However, the committee agreed that the evidence was insufficient to make any recommendations for or against particular non-pharmacological interventions. The committee therefore made a recommendation for research on non-pharmacological interventions for pain to support future research in this area.\n\nThe committee agreed that immobility and problems with posture can often cause or exacerbate pain. It was also acknowledged that spasticity can play a major part in musculoskeletal pain. Therefore, the committee highlighted that musculoskeletal pain should be assessed and treatment offered that is appropriate to and addresses the cause of the pain.\n\n## How the recommendations might affect practice\n\nAssessing and investigating the cause of pain is consistent with current best practice. The committee noted that assessment can be done by many different healthcare professionals, such as a rehabilitation physician, a GP, a neurologist, a physiotherapist or an MS nurse. They discussed that this would usually just involve history taking, but for some people further investigations such as scans may be needed. Although there may be costs associated with further investigations, it was agreed that these are likely to be offset by identifying the cause of pain and offering appropriate treatment.\n\nAcknowledging the impact of pain on mental health would not result in a change in practice or significant resource impact.\n\nReturn to recommendations\n\n# Cognitive and memory problems\n\nRecommendations 1.5.41 to 1.5.44\n\n## Why the committee made the recommendations\n\nThere was variation in the interventions covered by the studies on non-pharmacological management of cognitive and memory problems, which made it difficult for the committee to come to any conclusions. They agreed that the evidence was too limited to make recommendations about the types of interventions that should be offered. Current practice for treating cognitive impairments in MS varies, so the committee were not able to make consensus-based recommendations on which interventions would be most appropriate based on their experience. They agreed that a new recommendation for research on cognitive rehabilitation should involve larger trials in this area. A recommendation for research on outcome measures for studies of memory and cognition was also made to encourage the use of particular tests or scales for measuring different cognitive functions and improve the ability to pool and interpret data in the future.\n\nBased on their experience, the committee highlighted the need for cognitive symptoms to be assessed as part of the comprehensive review. This assessment is important for people with cognitive symptoms, because their cognitive profile needs to be established before decisions about any interventions can be made, based on their impairments. It was agreed that the type of cognitive assessment needed would differ depending on the person's needs. This might involve a clinical interview with or without carer input or a brief formal neuropsychological assessment. It was noted that a full neuropsychological assessment may be needed in people with a more complex presentation, for example, if fatigue and other disorders may be contributing to cognitive impairments.\n\nIn the absence of new evidence, the committee agreed that the previous recommendations on cognition and memory problems should be retained and updated based on their experience and agreed by informal consensus. They agreed that medication should be added to the list of factors that may affect cognition, and that appropriate management of these factors should be offered.\n\nThe committee agreed that the recommendation on referral for assessment and management of cognitive impairment should be updated so that referral can be to an occupational therapist, or a neuropsychologist as needed, rather than both, in line with current practice. Referral and the assessment and management of cognitive impairment should be tailored to the person's individual needs, because the cognitive profile of each person is likely to differ.\n\n## How the recommendations might affect practice\n\nCognitive assessment is usually available if the person has been offered a referral, although there may be some regional differences. It was noted that a simple assessment takes 10\xa0to 15\xa0minutes and does not need specific expertise. This type of assessment may be a change in practice for some services, but it is unlikely to have a significant resource impact. A full, longer neuropsychological assessment is a more costly assessment. However, it was noted that only a very small proportion of people are likely to need this longer assessment and future assessments are not as resource intensive as the baseline assessment. Given that only a small number of people would need this more expensive assessment (fewer than 1% of the MS population) and that it may already be current practice for some services, it was not thought to represent a significant resource impact.\n\nMany people with MS already have access to an occupational therapist who is skilled in cognitive assessment and interventions. A proportion will also have access to a neuropsychologist.\n\nReturn to recommendations\n\n# Pharmacological management of ataxia and tremor\n\n## Why the committee did not make recommendations\n\nThere was a lack of evidence for pharmacological management of ataxia and tremor in people with MS. Only 1 new study was identified, which compared botulinum toxin with a placebo. This study was analysed alongside a similar study included in the previous guideline, but the committee agreed that this evidence was insufficient to make recommendations for or against its use. Botulinum toxin is not generally used in current practice for ataxia and tremor, and this use is off label. A recommendation for research on the pharmacological management of ataxia and tremor was developed to support future research in this area.", 'Context': "Multiple sclerosis (MS) is an acquired chronic immune-mediated inflammatory condition of the central nervous system, affecting both the brain and spinal cord. It affects approximately 130,000\xa0people in the UK. It is the most common cause of serious physical disability in adults of working age.\n\nPeople with MS typically develop symptoms in their late 20s, experiencing visual and sensory disturbances, limb weakness, gait problems, and bladder and bowel symptoms. They may initially have partial recovery, but over time develop progressive disability.\n\nThe cause of MS is unknown. It is believed that an abnormal immune response to environmental triggers in people who are genetically predisposed results in immune-mediated acute, and then chronic, inflammation. The initial phase of inflammation is followed by a phase of progressive degeneration of the affected cells in the nervous system. MS is a potentially highly disabling disorder with considerable personal, social and economic consequences. People with MS live for many years after diagnosis with a significant impact on their ability to work, as well as an adverse and often highly debilitating effect on their quality of life and that of their families.\n\nThis guideline updates and replaces NICE's 2014 guideline (CG186). It includes updated recommendations on diagnosis, information and support, coordination of care and management of MS-related symptoms. The guideline does not cover all symptoms and problems associated with MS. Some areas are addressed in other NICE guidance, for example, urinary symptoms and swallowing, and these are referenced where appropriate. Many of the interventions used in rehabilitation to alleviate symptoms, such as non-pharmacological interventions for ataxia and tremor, interventions for weakness, cardiorespiratory fitness, sensory loss, visual problems (apart from oscillopsia), and secondary complications of immobility such as deconditioning and contractures, have not been covered because these are beyond the scope of the guideline. Many of these problems are complex and need personalised assessment and management strategies carried out by healthcare professionals with appropriate expertise in rehabilitation and MS.\n\nThe guideline does not cover the use of disease-modifying treatments. However, NICE has published technology appraisal guidance on these treatments (see the NICE technology appraisal guidance on multiple sclerosis for more information).\n\nThe guideline is aimed primarily at services provided in primary and secondary care. It does not map out a model of service delivery. Many people with MS may also attend specialised tertiary services, often established to provide and monitor disease-modifying therapies."}	https://www.nice.org.uk/guidance/ng220	This guideline covers diagnosing and managing multiple sclerosis in people aged 18 and over. It aims to improve the quality of life for people with multiple sclerosis by promoting prompt and effective symptom management and relapse treatment, and comprehensive reviews.
5c7adf6817bb7ec8217d9a9314ff0309fd6f3902	nice	Durvalumab for maintenance treatment of unresectable non-small-cell lung cancer after platinum-based chemoradiation	Durvalumab for maintenance treatment of unresectable non-small-cell lung cancer after platinum-based chemoradiation Evidence-based recommendations on durvalumab (Imfinzi) for locally advanced unresectable non-small-cell lung cancer after platinum-based chemoradiation in adults. # Recommendations Durvalumab is recommended as an option for treating locally advanced unresectable non-small-cell lung cancer (NSCLC) in adults whose tumours express programmed cell death ligand 1 (PD‑L1) on 1% or more of cells and whose disease has not progressed after platinum-based chemoradiation, only if: they have had concurrent platinum-based chemoradiation the company provides durvalumab according to the commercial arrangement. Why the committee made these recommendations This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for durvalumab for treating locally advanced unresectable NSCLC in adults whose tumours express PD‑L1 on 1% or more of cells and whose disease has not progressed following platinum-based chemoradiation (NICE technology appraisal guidance 578). The new evidence includes longer term data from the PACIFIC clinical trial and from people having treatment in the NHS while this treatment was available in the Cancer Drugs Fund. It shows that people having durvalumab live longer than those who have standard care, defined as routine surveillance and an annual CT scan. While a different modelling approach would have been preferred, the cost-effectiveness estimates for durvalumab were considered sufficiently plausible. They are within what NICE considers to be an acceptable use of NHS resources. So, durvalumab is recommended.# Information about durvalumab # Marketing authorisation indication Durvalumab (Imfinzi, AstraZeneca) is 'indicated for the treatment of locally advanced, unresectable non-small-cell lung cancer (NSCLC) in adults whose tumours express programmed cell death ligand 1 (PD‑L1) on 1% or more of tumour cells and whose disease has not progressed following platinum-based chemoradiation therapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for durvalumab. # Price Ths list price of durvalumab is £2,466 per 500 mg per 10‑ml infusion vial (excluding VAT; BNF online, accessed April 2022). The company has a commercial arrangement. This makes durvalumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. This review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal of durvalumab. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from the PACIFIC trial, comprising progression-free survival, overall survival and subsequent treatments. In addition, data was collected on durvalumab in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset. The appraisal committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see the ERG report, pages 10 and 11). It discussed the following issues, and took them into account in its decision making: the generalisability of the PACIFIC trial to clinical practice, in terms of programmed cell death ligand 1 (PD‑L1) status and dosing regimen the model structure used by the company the progression-free survival extrapolations in the durvalumab arm and their effect on modelled overall survival the duration of treatment effect for durvalumab subsequent treatments taken after durvalumab. # Clinical need ## Durvalumab is a valued treatment option for people with locally advanced unresectable NSCLC Locally advanced unresectable non-small-cell lung cancer (NSCLC) is a highly heterogeneous disease with complex symptoms. Durvalumab is indicated for use in people whose tumours express PD‑L1 on at least 1% of tumour cells and whose disease has not progressed after platinum-based chemoradiation. In the original appraisal, the committee agreed that these people would otherwise have standard care, and that this was the appropriate comparator. Standard care involves surveillance every 6 months for 2 years, and a volume chest CT scan at least every year. The committee was aware that locally advanced unresectable NSCLC is a distressing condition, and that treatment options are limited. It noted that people with unresectable NSCLC and their carers welcome treatments that improve symptoms and survival without negatively affecting quality of life. People having durvalumab value the survival benefit in a setting where overall survival is otherwise still low despite advances in chemotherapy and radiotherapy. The clinical experts advised that since its introduction in the Cancer Drugs Fund durvalumab has become standard care in this setting and has led to more people having concurrent chemoradiation when it is considered suitable. The committee considered that durvalumab is a valued treatment option among people with NSCLC and the clinicians who manage the condition. # Clinical evidence ## Durvalumab lengthens progression-free survival and overall survival compared with standard care The main clinical evidence for durvalumab came from a subgroup of people in an ongoing randomised controlled trial (PACIFIC). PACIFIC compared the efficacy and safety of durvalumab with standard care (placebo) in people with locally advanced unresectable NSCLC who had had at least 2 cycles of concurrent chemoradiation therapy. A cohort of people in PACIFIC whose cancers expressed PD‑L1 on 1% or more of tumour cells provided the evidence for this appraisal. Progression-free survival was statistically significantly longer in the durvalumab arm than the standard care arm. At the 5-year data cut, median progression-free survival was 24.9 months in the durvalumab arm and 5.5 months in the standard care arm. The hazard ratio was 0.47 (95% confidence interval 0.35 to 0.64). Durvalumab also lengthened overall survival compared with standard care in PACIFIC. Median overall survival in the durvalumab arm was 63.1 months while in the standard care arm it was 29.6 months. The hazard ratio for overall survival was 0.61 (95% CI 0.44 to 0.85). The data from the SACT dataset, which was collected while durvalumab was available on the Cancer Drugs Fund, supported the generalisability of the PACIFIC trial data to NHS practice. The overall survival rates from the SACT PD-L1 of 1% or more cohort (n=522) at 12 and 24 months were comparable to those in PACIFIC. The committee concluded that, for those people whose tumours express PD‑L1 on 1% or more of cells, durvalumab lengthens progression-free and overall survival compared with standard care. ## The PACIFIC trial is only generalisable to people who have had concurrent chemoradiation The marketing authorisation for durvalumab is for people whose cancer has not progressed after platinum-based chemoradiation. There are 2 main types of chemoradiation, sequential and concurrent. The PACIFIC trial (see section 3.2) only recruited people who had 2 or more cycles of concurrent platinum-based chemoradiation, and explicitly excluded people who had had sequential chemoradiation. In the original appraisal, clinical experts explained that people who have concurrent chemoradiation may be in better health than those having sequential chemoradiation. Concurrent chemoradiation may also produce better outcomes than sequential chemoradiation. The original appraisal committee considered that, because the PACIFIC trial was not generalisable to those who had had sequential chemoradiation, the appraisal would be optimised to only those having had concurrent chemoradiation. The population in the company's submission for the current appraisal reflected this. ## The PACIFIC trial is generalisable to NHS practice, despite some uncertainty around people whose tumours have unknown PD-L1 status In the Cancer Drugs Fund, people could have durvalumab if their tumour PD‑L1 status could not be determined despite a clear intent and reasonable attempt to do so. The clinical experts stated that it was not always possible to do lung cancer biopsies, either because the tumour is not accessible or there is not enough sample tissue available. This can lead to an inability to determine PD‑L1 status. The company anticipated that the option of offering durvalumab to people whose tumours were PD‑L1 unknown is likely to continue if durvalumab is recommended for routine commissioning. In the SACT cohort, 12% of people who had durvalumab had an unknown tumour PD‑L1 status. The ERG explained that this population would have included some people whose tumours express PD‑L1 on less than 1% of tumour cells (were PD‑L1 negative). Because durvalumab is less efficacious in these people, there may be a reduction in the overall efficacy of durvalumab in clinical practice compared with the trial. This was because the PACIFIC cohort of interest (see section 3.2) did not include people whose tumour PD‑L1 status was unknown. The clinical experts explained that the 12% PD‑L1 unknown figure was slightly higher than their clinical experience but that it was plausible. A clinical expert also noted that, within the population whose tumours are PD‑L1 unknown, the proportion of people whose tumours were actually PD‑L1 negative would be around 25%. As such, the overall reduction in durvalumab efficacy was likely to be small. The committee noted that overall survival at 24 months was similar in the full SACT cohort (67%) and the SACT cohort when data from people with tumours with PD‑L1 unknown status was removed (68%). This suggested that including the PD‑L1 unknown population had a minimal effect on treatment outcomes. The committee noted that people whose tumour PD‑L1 status was unknown were outside of the NICE scope for the appraisal. The possibility that these people would have durvalumab in clinical practice added some uncertainty to the generalisability of the PACIFIC trial. However, the committee concluded that any effect on the cost-effectiveness results was likely to be small. ## The weight-based dose and fixed dose of durvalumab are likely to have similar efficacy In the PACIFIC trial people had durvalumab at a dose of 10 mg per kg every 2 weeks. A second, fixed dosing regimen of 1,500 mg every 4 weeks has since been added to the marketing authorisation. In its submission the company stated that the fixed dose was now standard clinical practice in the UK, and it therefore incorporated it into its base-case economic model. The company cited a European Medicines Agency report which concluded there were no anticipated clinically significant differences in efficacy and safety between the 2 dosing regimens. However, the ERG questioned whether the fixed dose could lead to reduced efficacy in certain people. The clinical experts described how the switch to the 4‑weekly fixed dose was widespread and had improved people's quality of life and helped increase chemotherapy day unit capacity. They noted that other immunotherapies had been switched from weight-based to fixed dosing with no apparent decrease in efficacy. The nominated deputy for the Cancer Drugs Fund clinical lead stated that it was likely that most of the SACT cohort would have had the fixed dose. The similar survival between the SACT dataset and the PACIFIC trial (in which people had a weight-based dose) therefore supported equivalency of the dosing regimens. The committee concluded that although it had not seen direct clinical-effectiveness evidence for the new dosing regimen, it was unlikely to have a large effect on the clinical and cost effectiveness of durvalumab. # The company's economic model ## The company's state transition approach is not preferred, but is acceptable for decision making The company's economic model used the same approach as in the original appraisal. It was a state transition model with 3 health states: progression-free disease, progressed disease and death. Health-state occupancy over time was informed by transition probabilities which were calculated from extrapolations of progression-free survival, time to progression and post-progression survival data from the PACIFIC trial. Progression-free survival and time to progression were extrapolated separately for each arm. The distribution used for progression-free survival in each arm was also used for time to progression. Post-progression survival was extrapolated from pooled data from both arms. The ERG in the original appraisal raised concerns that extrapolation of post-progression survival added uncertainty because it was based on a small sample size made up of those whose disease progressed early, and who may have different survival to those whose disease progressed later. The ERG in the current appraisal had requested that a partitioned survival model be provided by the company to allow assessment of any potential bias in the state transition model. It considered that without this the company had not fully explored the most appropriate method to model the survival outcomes from PACIFIC. The company responded that a partitioned survival model would have had significant limitations because all standard parametric extrapolations of progression-free survival and overall survival crossed. This meant that, under that modelling approach, more people would be progression-free than were alive, which is not possible. The company therefore did not provide the partitioned survival model as requested. The committee considered that a partitioned survival model would have been preferable for consistency with previous appraisals, and because it would have allowed overall survival to be modelled directly from the trial data. It considered that the crossing of progression-free survival and overall survival curves suggested that more flexible parametric models should have been explored by the company. However, the committee concluded that, in the absence of preferable alternative approaches, the state transition model was acceptable for decision making. ## The durvalumab survival extrapolations are only plausible when treatment effect waning is applied The company selected a generalised gamma distribution to extrapolate progression-free survival and, by extension, time to progression in the durvalumab arm. It also submitted a scenario using the Gompertz distribution. The ERG stated that the generalised gamma distribution in the durvalumab arm resulted in modelled overall survival being higher than the PACIFIC trial at 5 years. At the same time, the company's generalised gamma distribution for progression-free survival and time to progression in the standard care arm underestimated overall survival compared with PACIFIC at 5 years. However, the ERG explained that none of the alternative standard parametric distributions provided better internal consistency with the PACIFIC data for the standard care arm. The committee was concerned that the company's base-case model overestimated the survival benefit of durvalumab. For the durvalumab arm, it considered that the Gompertz distribution, while providing a relatively good fit to the PACIFIC trial data, generated implausible long-term progression-free survival estimates. Finally, it considered that the other standard parametric distributions tested by the company underestimated progression-free survival compared with the PACIFIC trial. The committee therefore concluded that all the progression-free survival distributions tested by the company for durvalumab either did not fit the PACIFIC data well, or resulted in implausible long-term predictions. In the absence of alternatives, it concluded that it would consider all scenarios thought to be potentially plausible by the company and ERG (generalised gamma, Gompertz and log-normal) during decision making, with treatment effect waning assumptions applied (see section 3.8). ## It is appropriate to consider both 3- and 5-year waning scenarios because the true effect is likely between them The company had not modelled any additional treatment effect waning, defined as the convergence of the risk of disease progression or death in the durvalumab arm with that of the standard care arm, in its base case. It stated that any treatment effect waning was already captured by its chosen extrapolations, because these were based on the 5-year data from PACIFIC. The clinical experts explained that for people with locally advanced NSCLC, most disease progression happens before 3 years and that progression is very unlikely after 5 years. The clinical experts noted that they had limited experience with people who were 5 years on from starting durvalumab treatment. However, they felt that the risk of disease progression or death would likely not be different at 5 years between somebody who had had durvalumab and somebody who had not had it. The ERG considered that there would be a waning of treatment effect by 3 years for progression-free survival and 5 years for overall survival, and that this was not captured by the generalised gamma distribution. It noted that if this distribution was used, additional treatment effect waning should be modelled. The company pointed out that the estimate of relative effectiveness towards the end of the trial was uncertain due to the small number of remaining patients. It also provided scenario analyses with treatment effect waning at 7.5 and 10 years after starting treatment for the generalised gamma distribution. The ERG's 2 preferred base cases were the generalised gamma extrapolation with treatment effect waning at 3 and 5 years after starting treatment respectively, stating that the true effect was probably somewhere in between. The committee understood that other recent appraisals of fixed-duration immunotherapies in NSCLC had assumed treatment effect durations lasting between 3 and 5 years after stopping treatment. It noted that the ERG's 3-year waning base case produced overall survival estimates which matched the PACIFIC data well, while the 5-year waning base case was more in keeping with previous appraisals and the clinical expert feedback. The committee concluded that both 3- and 5-year treatment effect waning scenarios, applied to the generalised gamma, Gompertz and log-normal progression-free survival distributions (see section 3.7), were appropriate for decision making. ## Subsequent treatment assumptions should be based on the PACIFIC data to align costs and effects in the model The company modelled subsequent treatments based on their distribution and duration in the PACIFIC trial. Some of the people in the PACIFIC trial had immunotherapy after stopping durvalumab, which would not currently happen in the NHS. The ERG was concerned that this could bias the model in favour of durvalumab. The company position was that people in the durvalumab arm had less subsequent immunotherapy, and for a shorter time, than those in the standard care arm. This meant that any such effect would be minimised. The company also cited treatment switching analyses, using a rank preserving structural failure time model and modified 2‑stage method. These showed that, among people in PACIFIC with any tumour PD‑L1 status, removing the effect of subsequent immunotherapy from the durvalumab arm did not affect the hazard ratio substantially. The company therefore stated that including the costs of subsequent immunotherapies was conservative, and submitted a scenario analysis showing that removing these costs greatly lowered the incremental cost-effectiveness ratio (ICER) for durvalumab. The nominated deputy to the Cancer Drugs Fund clinical lead explained that, if durvalumab was recommended in this indication, NHS England would likely offer some flexibility for people who have completed a course of durvalumab without disease progression to then have further immunotherapies if their lung cancer recurred. This would depend on how soon disease progression occurred after completing a course of durvalumab. The clinical experts welcomed NHS England's position on subsequent immunotherapy treatment for some people. The committee noted this but considered that there was uncertainty about subsequent immunotherapy usage after durvalumab in the future. It concluded that subsequent treatment assumptions should be based on the data from the PACIFIC trial so that the data on costs and effects were aligned in the model. # Cost-effectiveness estimate ## The most plausible ICERs for durvalumab are likely within the range considered to be a cost-effective use of NHS resources The company's base-case ICER was generated using the generalised gamma distribution to extrapolate progression-free survival and time to progression in the durvalumab arm and was considerably lower than £20,000 per quality-adjusted life year (QALY) gained. Because there are confidential discounts for some of the subsequent treatments, the exact ICERs cannot be reported here. The committee considered scenarios with the following assumptions: The generalised gamma, Gompertz and log-normal distributions for extrapolating progression-free survival and time to progression in the durvalumab arm (see section 3.7) A treatment effect lasting 3 and 5 years after starting treatment (see section 3.8).The ICERs for all of the scenarios were between £20,000 and £30,000 per QALY gained, within the upper end of the range NICE normally considers a cost-effective use of NHS resources. # Other factors No equality or social value judgement issues were identified. NICE's advice about life-extending treatments for people with a short life expectancy did not apply. Durvalumab is not innovative because all benefits of the technology are captured in the QALYs. # Conclusion ## Durvalumab is recommended for routine commissioning for people with locally advanced unresectable NSCLC which has PD-L1 of 1% or more New evidence was considered from the PACIFIC trial and the Cancer Drugs Fund SACT data. The committee recognised that there was residual uncertainty in the ICERs, stemming largely from the state transition model structure that the company used. However, taking this uncertainty into account, it considered that all estimates of cost effectiveness for durvalumab compared with standard care generated by the model, were below what is considered to be a cost-effective use of NHS resources. Durvalumab is therefore recommended as an option for treating locally advanced unresectable NSCLC in adults whose tumours express PD‑L1 on 1% or more of cells and whose disease has not progressed after platinum-based chemoradiation, only if they have had concurrent platinum-based chemoradiation.	{'Recommendations': 'Durvalumab is recommended as an option for treating locally advanced unresectable non-small-cell lung cancer (NSCLC) in adults whose tumours express programmed cell death ligand\xa01 (PD‑L1) on 1% or more of cells and whose disease has not progressed after platinum-based chemoradiation, only if:\n\nthey have had concurrent platinum-based chemoradiation\n\nthe company provides durvalumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for durvalumab for treating locally advanced unresectable NSCLC in adults whose tumours express PD‑L1 on 1% or more of cells and whose disease has not progressed following platinum-based chemoradiation (NICE technology appraisal guidance 578).\n\nThe new evidence includes longer term data from the PACIFIC clinical trial and from people having treatment in the NHS while this treatment was available in the Cancer Drugs Fund. It shows that people having durvalumab live longer than those who have standard care, defined as routine surveillance and an annual CT scan.\n\nWhile a different modelling approach would have been preferred, the cost-effectiveness estimates for durvalumab were considered sufficiently plausible. They are within what NICE considers to be an acceptable use of NHS resources. So, durvalumab is recommended.', 'Information about durvalumab': "# Marketing authorisation indication\n\nDurvalumab (Imfinzi, AstraZeneca) is 'indicated for the treatment of locally advanced, unresectable non-small-cell lung cancer (NSCLC) in adults whose tumours express programmed cell death ligand\xa01 (PD‑L1) on 1% or more of tumour cells and whose disease has not progressed following platinum-based chemoradiation therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for durvalumab.\n\n# Price\n\nThs list price of durvalumab is £2,466 per 500\xa0mg per 10‑ml infusion vial (excluding VAT; BNF online, accessed April\xa02022).\n\nThe company has a commercial arrangement. This makes durvalumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThis review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal of durvalumab. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from the PACIFIC trial, comprising progression-free survival, overall survival and subsequent treatments. In addition, data was collected on durvalumab in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset.\n\nThe appraisal committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see the ERG report, pages 10 and 11). It discussed the following issues, and took them into account in its decision making:\n\nthe generalisability of the PACIFIC trial to clinical practice, in terms of programmed cell death ligand\xa01 (PD‑L1) status and dosing regimen\n\nthe model structure used by the company\n\nthe progression-free survival extrapolations in the durvalumab arm and their effect on modelled overall survival\n\nthe duration of treatment effect for durvalumab\n\nsubsequent treatments taken after durvalumab.\n\n# Clinical need\n\n## Durvalumab is a valued treatment option for people with locally advanced unresectable NSCLC\n\nLocally advanced unresectable non-small-cell lung cancer (NSCLC) is a highly heterogeneous disease with complex symptoms. Durvalumab is indicated for use in people whose tumours express PD‑L1 on at least 1% of tumour cells and whose disease has not progressed after platinum-based chemoradiation. In the original appraisal, the committee agreed that these people would otherwise have standard care, and that this was the appropriate comparator. Standard care involves surveillance every 6\xa0months for 2\xa0years, and a volume chest CT scan at least every year. The committee was aware that locally advanced unresectable NSCLC is a distressing condition, and that treatment options are limited. It noted that people with unresectable NSCLC and their carers welcome treatments that improve symptoms and survival without negatively affecting quality of life. People having durvalumab value the survival benefit in a setting where overall survival is otherwise still low despite advances in chemotherapy and radiotherapy. The clinical experts advised that since its introduction in the Cancer Drugs Fund durvalumab has become standard care in this setting and has led to more people having concurrent chemoradiation when it is considered suitable. The committee considered that durvalumab is a valued treatment option among people with NSCLC and the clinicians who manage the condition.\n\n# Clinical evidence\n\n## Durvalumab lengthens progression-free survival and overall survival compared with standard care\n\nThe main clinical evidence for durvalumab came from a subgroup of people in an ongoing randomised controlled trial (PACIFIC). PACIFIC compared the efficacy and safety of durvalumab with standard care (placebo) in people with locally advanced unresectable NSCLC who had had at least 2\xa0cycles of concurrent chemoradiation therapy. A cohort of people in PACIFIC whose cancers expressed PD‑L1 on 1% or more of tumour cells provided the evidence for this appraisal. Progression-free survival was statistically significantly longer in the durvalumab arm than the standard care arm. At the 5-year data cut, median progression-free survival was 24.9\xa0months in the durvalumab arm and 5.5\xa0months in the standard care arm. The hazard ratio was 0.47 (95% confidence interval [CI] 0.35 to 0.64). Durvalumab also lengthened overall survival compared with standard care in PACIFIC. Median overall survival in the durvalumab arm was 63.1\xa0months while in the standard care arm it was 29.6\xa0months. The hazard ratio for overall survival was 0.61 (95% CI 0.44 to 0.85). The data from the SACT dataset, which was collected while durvalumab was available on the Cancer Drugs Fund, supported the generalisability of the PACIFIC trial data to NHS practice. The overall survival rates from the SACT PD-L1 of 1% or more cohort (n=522) at 12 and 24\xa0months were comparable to those in PACIFIC. The committee concluded that, for those people whose tumours express PD‑L1 on 1% or more of cells, durvalumab lengthens progression-free and overall survival compared with standard care.\n\n## The PACIFIC trial is only generalisable to people who have had concurrent chemoradiation\n\nThe marketing authorisation for durvalumab is for people whose cancer has not progressed after platinum-based chemoradiation. There are 2 main types of chemoradiation, sequential and concurrent. The PACIFIC trial (see section 3.2) only recruited people who had 2 or more cycles of concurrent platinum-based chemoradiation, and explicitly excluded people who had had sequential chemoradiation. In the original appraisal, clinical experts explained that people who have concurrent chemoradiation may be in better health than those having sequential chemoradiation. Concurrent chemoradiation may also produce better outcomes than sequential chemoradiation. The original appraisal committee considered that, because the PACIFIC trial was not generalisable to those who had had sequential chemoradiation, the appraisal would be optimised to only those having had concurrent chemoradiation. The population in the company's submission for the current appraisal reflected this.\n\n## The PACIFIC trial is generalisable to NHS practice, despite some uncertainty around people whose tumours have unknown PD-L1 status\n\nIn the Cancer Drugs Fund, people could have durvalumab if their tumour PD‑L1 status could not be determined despite a clear intent and reasonable attempt to do so. The clinical experts stated that it was not always possible to do lung cancer biopsies, either because the tumour is not accessible or there is not enough sample tissue available. This can lead to an inability to determine PD‑L1 status. The company anticipated that the option of offering durvalumab to people whose tumours were PD‑L1 unknown is likely to continue if durvalumab is recommended for routine commissioning. In the SACT cohort, 12% of people who had durvalumab had an unknown tumour PD‑L1 status. The ERG explained that this population would have included some people whose tumours express PD‑L1 on less than 1% of tumour cells (were PD‑L1 negative). Because durvalumab is less efficacious in these people, there may be a reduction in the overall efficacy of durvalumab in clinical practice compared with the trial. This was because the PACIFIC cohort of interest (see section\xa03.2) did not include people whose tumour PD‑L1 status was unknown. The clinical experts explained that the 12% PD‑L1 unknown figure was slightly higher than their clinical experience but that it was plausible. A clinical expert also noted that, within the population whose tumours are PD‑L1 unknown, the proportion of people whose tumours were actually PD‑L1 negative would be around 25%. As such, the overall reduction in durvalumab efficacy was likely to be small. The committee noted that overall survival at 24\xa0months was similar in the full SACT cohort (67%) and the SACT cohort when data from people with tumours with PD‑L1 unknown status was removed (68%). This suggested that including the PD‑L1 unknown population had a minimal effect on treatment outcomes. The committee noted that people whose tumour PD‑L1 status was unknown were outside of the NICE scope for the appraisal. The possibility that these people would have durvalumab in clinical practice added some uncertainty to the generalisability of the PACIFIC trial. However, the committee concluded that any effect on the cost-effectiveness results was likely to be small.\n\n## The weight-based dose and fixed dose of durvalumab are likely to have similar efficacy\n\nIn the PACIFIC trial people had durvalumab at a dose of 10\xa0mg per kg every 2\xa0weeks. A second, fixed dosing regimen of 1,500\xa0mg every 4\xa0weeks has since been added to the marketing authorisation. In its submission the company stated that the fixed dose was now standard clinical practice in the UK, and it therefore incorporated it into its base-case economic model. The company cited a European Medicines Agency report which concluded there were no anticipated clinically significant differences in efficacy and safety between the 2 dosing regimens. However, the ERG questioned whether the fixed dose could lead to reduced efficacy in certain people. The clinical experts described how the switch to the 4‑weekly fixed dose was widespread and had improved people's quality of life and helped increase chemotherapy day unit capacity. They noted that other immunotherapies had been switched from weight-based to fixed dosing with no apparent decrease in efficacy. The nominated deputy for the Cancer Drugs Fund clinical lead stated that it was likely that most of the SACT cohort would have had the fixed dose. The similar survival between the SACT dataset and the PACIFIC trial (in which people had a weight-based dose) therefore supported equivalency of the dosing regimens. The committee concluded that although it had not seen direct clinical-effectiveness evidence for the new dosing regimen, it was unlikely to have a large effect on the clinical and cost effectiveness of durvalumab.\n\n# The company's economic model\n\n## The company's state transition approach is not preferred, but is acceptable for decision making\n\nThe company's economic model used the same approach as in the original appraisal. It was a state transition model with 3 health states: progression-free disease, progressed disease and death. Health-state occupancy over time was informed by transition probabilities which were calculated from extrapolations of progression-free survival, time to progression and post-progression survival data from the PACIFIC trial. Progression-free survival and time to progression were extrapolated separately for each arm. The distribution used for progression-free survival in each arm was also used for time to progression. Post-progression survival was extrapolated from pooled data from both arms. The ERG in the original appraisal raised concerns that extrapolation of post-progression survival added uncertainty because it was based on a small sample size made up of those whose disease progressed early, and who may have different survival to those whose disease progressed later. The ERG in the current appraisal had requested that a partitioned survival model be provided by the company to allow assessment of any potential bias in the state transition model. It considered that without this the company had not fully explored the most appropriate method to model the survival outcomes from PACIFIC. The company responded that a partitioned survival model would have had significant limitations because all standard parametric extrapolations of progression-free survival and overall survival crossed. This meant that, under that modelling approach, more people would be progression-free than were alive, which is not possible. The company therefore did not provide the partitioned survival model as requested. The committee considered that a partitioned survival model would have been preferable for consistency with previous appraisals, and because it would have allowed overall survival to be modelled directly from the trial data. It considered that the crossing of progression-free survival and overall survival curves suggested that more flexible parametric models should have been explored by the company. However, the committee concluded that, in the absence of preferable alternative approaches, the state transition model was acceptable for decision making.\n\n## The durvalumab survival extrapolations are only plausible when treatment effect waning is applied\n\nThe company selected a generalised gamma distribution to extrapolate progression-free survival and, by extension, time to progression in the durvalumab arm. It also submitted a scenario using the Gompertz distribution. The ERG stated that the generalised gamma distribution in the durvalumab arm resulted in modelled overall survival being higher than the PACIFIC trial at 5\xa0years. At the same time, the company's generalised gamma distribution for progression-free survival and time to progression in the standard care arm underestimated overall survival compared with PACIFIC at 5\xa0years. However, the ERG explained that none of the alternative standard parametric distributions provided better internal consistency with the PACIFIC data for the standard care arm. The committee was concerned that the company's base-case model overestimated the survival benefit of durvalumab. For the durvalumab arm, it considered that the Gompertz distribution, while providing a relatively good fit to the PACIFIC trial data, generated implausible long-term progression-free survival estimates. Finally, it considered that the other standard parametric distributions tested by the company underestimated progression-free survival compared with the PACIFIC trial. The committee therefore concluded that all the progression-free survival distributions tested by the company for durvalumab either did not fit the PACIFIC data well, or resulted in implausible long-term predictions. In the absence of alternatives, it concluded that it would consider all scenarios thought to be potentially plausible by the company and ERG (generalised gamma, Gompertz and log-normal) during decision making, with treatment effect waning assumptions applied (see section 3.8).\n\n## It is appropriate to consider both 3- and 5-year waning scenarios because the true effect is likely between them\n\nThe company had not modelled any additional treatment effect waning, defined as the convergence of the risk of disease progression or death in the durvalumab arm with that of the standard care arm, in its base case. It stated that any treatment effect waning was already captured by its chosen extrapolations, because these were based on the 5-year data from PACIFIC. The clinical experts explained that for people with locally advanced NSCLC, most disease progression happens before 3\xa0years and that progression is very unlikely after 5\xa0years. The clinical experts noted that they had limited experience with people who were 5\xa0years on from starting durvalumab treatment. However, they felt that the risk of disease progression or death would likely not be different at 5\xa0years between somebody who had had durvalumab and somebody who had not had it. The ERG considered that there would be a waning of treatment effect by 3 years for progression-free survival and 5 years for overall survival, and that this was not captured by the generalised gamma distribution. It noted that if this distribution was used, additional treatment effect waning should be modelled. The company pointed out that the estimate of relative effectiveness towards the end of the trial was uncertain due to the small number of remaining patients. It also provided scenario analyses with treatment effect waning at 7.5 and 10\xa0years after starting treatment for the generalised gamma distribution. The ERG's 2 preferred base cases were the generalised gamma extrapolation with treatment effect waning at 3 and 5\xa0years after starting treatment respectively, stating that the true effect was probably somewhere in between. The committee understood that other recent appraisals of fixed-duration immunotherapies in NSCLC had assumed treatment effect durations lasting between 3 and 5\xa0years after stopping treatment. It noted that the ERG's 3-year waning base case produced overall survival estimates which matched the PACIFIC data well, while the 5-year waning base case was more in keeping with previous appraisals and the clinical expert feedback. The committee concluded that both 3- and 5-year treatment effect waning scenarios, applied to the generalised gamma, Gompertz and log-normal progression-free survival distributions (see section 3.7), were appropriate for decision making.\n\n## Subsequent treatment assumptions should be based on the PACIFIC data to align costs and effects in the model\n\nThe company modelled subsequent treatments based on their distribution and duration in the PACIFIC trial. Some of the people in the PACIFIC trial had immunotherapy after stopping durvalumab, which would not currently happen in the NHS. The ERG was concerned that this could bias the model in favour of durvalumab. The company position was that people in the durvalumab arm had less subsequent immunotherapy, and for a shorter time, than those in the standard care arm. This meant that any such effect would be minimised. The company also cited treatment switching analyses, using a rank preserving structural failure time model and modified 2‑stage method. These showed that, among people in PACIFIC with any tumour PD‑L1 status, removing the effect of subsequent immunotherapy from the durvalumab arm did not affect the hazard ratio substantially. The company therefore stated that including the costs of subsequent immunotherapies was conservative, and submitted a scenario analysis showing that removing these costs greatly lowered the incremental cost-effectiveness ratio (ICER) for durvalumab. The nominated deputy to the Cancer Drugs Fund clinical lead explained that, if durvalumab was recommended in this indication, NHS England would likely offer some flexibility for people who have completed a course of durvalumab without disease progression to then have further immunotherapies if their lung cancer recurred. This would depend on how soon disease progression occurred after completing a course of durvalumab. The clinical experts welcomed NHS England's position on subsequent immunotherapy treatment for some people. The committee noted this but considered that there was uncertainty about subsequent immunotherapy usage after durvalumab in the future. It concluded that subsequent treatment assumptions should be based on the data from the PACIFIC trial so that the data on costs and effects were aligned in the model.\n\n# Cost-effectiveness estimate\n\n## The most plausible ICERs for durvalumab are likely within the range considered to be a cost-effective use of NHS resources\n\nThe company's base-case ICER was generated using the generalised gamma distribution to extrapolate progression-free survival and time to progression in the durvalumab arm and was considerably lower than £20,000 per quality-adjusted life year (QALY) gained. Because there are confidential discounts for some of the subsequent treatments, the exact ICERs cannot be reported here. The committee considered scenarios with the following assumptions:\n\nThe generalised gamma, Gompertz and log-normal distributions for extrapolating progression-free survival and time to progression in the durvalumab arm (see section 3.7)\n\nA treatment effect lasting 3 and 5\xa0years after starting treatment (see section 3.8).The ICERs for all of the scenarios were between £20,000 and £30,000 per QALY gained, within the upper end of the range NICE normally considers a cost-effective use of NHS resources.\n\n# Other factors\n\nNo equality or social value judgement issues were identified.\n\nNICE's advice about life-extending treatments for people with a short life expectancy did not apply.\n\nDurvalumab is not innovative because all benefits of the technology are captured in the QALYs.\n\n# Conclusion\n\n## Durvalumab is recommended for routine commissioning for people with locally advanced unresectable NSCLC which has PD-L1 of 1% or more\n\nNew evidence was considered from the PACIFIC trial and the Cancer Drugs Fund SACT data. The committee recognised that there was residual uncertainty in the ICERs, stemming largely from the state transition model structure that the company used. However, taking this uncertainty into account, it considered that all estimates of cost effectiveness for durvalumab compared with standard care generated by the model, were below what is considered to be a cost-effective use of NHS resources. Durvalumab is therefore recommended as an option for treating locally advanced unresectable NSCLC in adults whose tumours express PD‑L1 on 1% or more of cells and whose disease has not progressed after platinum-based chemoradiation, only if they have had concurrent platinum-based chemoradiation."}	https://www.nice.org.uk/guidance/ta798	Evidence-based recommendations on durvalumab (Imfinzi) for locally advanced unresectable non-small-cell lung cancer after platinum-based chemoradiation in adults.
c48ec609a09162c0565a54e721dc535b827becbd	nice	Reducing sexually transmitted infections	Reducing sexually transmitted infections This guideline covers interventions to prevent sexually transmitted infections (STIs) in people aged 16 and over. It aims to reduce the transmission of all STIs, including HIV, and includes ways to help increase the uptake of STI testing and vaccines for human papillomavirus (HPV) and hepatitis A and B. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. These recommendations should be read together with relevant NICE guidance on sexual health and contraception (see the NICE topic page on sexual health). # Reducing the risk of people getting and transmitting sexually transmitted infections (STIs) ## Accessing sexual health services Form a network of services, including online services, providing sexual healthcare for an area. Ensure that: everyone is signposted to, and can access, the care they need local pathways are in place to link people, including underserved communities, to the best possible care details of the network are kept up to date and all staff understand what each service offers. Determine the most appropriate settings for services and interventions in consultation with groups with greater sexual health or access needs (see also recommendations in section 1.2). Include online and non-clinical settings. Reduce barriers to services for groups with greater sexual health or access needs by: emphasising confidentiality, empathy and a non-judgemental approach -ffering access to a professional translator or interpreter instead of waiting for the person to ask, to ensure they are fully able to communicate and to understand the discussion making sure staff understand that services are free and available to everyone regardless of where they live (or are from), and they do not refuse access to someone who is entitled to the service supporting people to attend appointments and engage with treatment providing outreach activities.Take into account guidance on making services more welcoming and inclusive, such as the Department of Health and Social Care's 'You're welcome' quality criteria or UK Health Security Agency's (previously Public Health England) Inclusion health: applying all our health. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on accessing sexual health services . Full details of the evidence and the committee's discussion are in: evidence review A: interventions to reduce the acquisition and transmission of STIs in higher risk groups evidence review B: qualitative evidence synthesis for the acceptability of interventions for reducing or preventing the acquisition and transmission of STIs. Loading. Please wait. ## Meeting the needs of groups with greater sexual health or access needs Target interventions at groups with greater sexual health or access needs. Identify local needs and priorities using data from the Joint Strategic Needs Assessment (JSNA) and other data sources. Engage with groups with greater sexual health or access needs to understand how best to meet their sexual health and wellbeing needs. Take into account factors such as existing barriers to access (for example, for people with learning difficulties, or because of their gender or sexuality), language and other socioeconomic factors, including deprivation. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on meeting the needs of groups with greater sexual health or access needs . Full details of the evidence and the committee's discussion are in: evidence review A: interventions to reduce the acquisition and transmission of STIs in higher risk groups evidence review B: qualitative evidence synthesis for the acceptability of interventions for reducing or preventing the acquisition and transmission of STIs. Loading. Please wait. ## Co-producing interventions to reduce STI transmission Co-produce (plan, design, implement and evaluate) services and interventions in consultation with the groups that they are for, in line with NICE's guideline on community engagement. Ensure that interventions are culturally competent. This includes being delivered in a suitable language for people whose main language is not English. It might also involve recognising that people may be engaged in activities that are stigmatised by their communities (therefore, discretion may be particularly important for them). Ensure that interventions include some or all of the following components: information and education about: STIs the impact of alcohol and drugs on sexual decision making information about: sexual health services available, including that they are free, confidential and open access the rates of STIs to explain why some groups are at higher risk the impact of stigma sex-positive approaches to providing advice on the consistent and correct use of barrier methods, including providing external condoms in different sizes and textures, and internal condoms (see NICE's guideline on sexually transmitted infections: condom distribution schemes) risk assessment and risk-reduction activities, for example developing personalised risk-reduction plans, identifying triggers and setting goals Information–Motivation–Behavioural skills (IMB) model approaches and motivational interviewing techniques to guide conversations about risk reduction or safer-sex practices and address informational, motivational and skills-based barriers to change activities to increase sexual self-efficacy (for example, talking about sexual consent, negotiating the use of barrier methods and negotiating sexual preferences) and broader self-efficacy (for example, self-esteem) activities exploring the links between emotion and sexual behaviour, and coping skills (for example, using cognitive behavioural approaches) a plan for follow up (for example, repeated contact to review progress or make new plans). Take into account the recommendations in the NICE guidance on behaviour change (see the NICE topic page on behaviour change) when co-producing interventions to reduce STIs. Tailor interventions to the needs of the groups identified. Take into account safety concerns (such as sexual violence or coercion), stigma and discrimination. See also the NICE guideline on domestic violence and abuse: multi-agency working. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on co-producing interventions to reduce STI transmission . Full details of the evidence and the committee's discussion are in: evidence review A: interventions to reduce the acquisition and transmission of STIs in higher risk groups evidence review B: qualitative evidence synthesis for the acceptability of interventions for reducing or preventing the acquisition and transmission of STIs. Loading. Please wait. ## Delivering and evaluating interventions to reduce STI transmission Deliver interventions to reduce STIs across a range of services, including within broader support interventions and community services (for example, in drug and alcohol services, abortion care services, HIV care and mental health services). Think about whether one-to-one or group delivery is the most appropriate for the community the intervention is aimed at, and the content and aims of the intervention. Take into account people's preferences and any resource impact. Ensure that people have the opportunity to have interventions that are delivered by peers or other trusted people they can relate to, who share a cultural or group background with the target group. When delivering interventions: Avoid making assumptions about people or judging them. This could include using inclusive language (until the person expresses a preference) and recognising a range of relationships and sexual behaviours. Be sex and identity positive (for example, by using gender-affirming language and being respectful of their sex life). Focus on self-worth and empowering people to have autonomy over their bodies and their sexual decision making. Commissioners and providers should regularly evaluate interventions, including the methods used to co-produce them, to determine their effectiveness and acceptability and identify gaps to make service improvements across the pathway. For example, this could be done through a health equity audit. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on delivering and evaluating interventions to reduce STI transmission . Full details of the evidence and the committee's discussion are in: evidence review A: interventions to reduce the acquisition and transmission of STIs in higher risk groups evidence review B: qualitative evidence synthesis for the acceptability of interventions for reducing or preventing the acquisition and transmission of STIs. Loading. Please wait. # Improving uptake and increasing the frequency of STI testing ## Self-sampling Offer a range of STI testing options based on local need, including remote self-sampling, in-person attendance at specialist clinics or in community pharmacies, primary care, and outreach services. Offer people without symptoms remote self-sampling as an alternative option to clinic attendance. Self-sampling should test for the same infections as those tested for at the clinic. Ensure that local service websites give up-to-date information on which testing options are available in their area. Ensure that self-sampling kits meet the NHS Accessible Information Standard and are inclusive (for example, addressing the needs of trans and gender-diverse people, and making instructions and guidance available in different languages or different formats such as diagrams, photos, or videos targeted at people with learning difficulties). Widen access to self-sampling kits. For example, by having a system for people to order a kit online or by phone, or providing self-sampling kits through 'pop-up' or outreach services. Monitor the provision and return rates of kits to identify any groups that have low rates of accessing or returning them. Take action to try to address the reasons for the low rates. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on self-sampling to improve the uptake and increase the frequency of STI testing . Full details of the evidence and the committee's discussion are in: evidence review C: effectiveness, acceptability and cost effectiveness of strategies to improve uptake of STI testing evidence D: effective and cost-effective interventions to increase frequent STI testing in very high-risk groups. Loading. Please wait. ## Tailoring interventions Tailor interventions and information to the target users of the service. Where possible, ensure that interventions are available for other groups who may be excluded by this targeting. (See also recommendation 1.1.10.) Recognise people's individual needs. Be aware that membership of a particular group does not imply that a person is necessarily at higher risk of an STI. Address this with cultural sensitivity and competency within the context of sex-positive approaches. Consider personalising automated recall messages using low-level tailoring, for example adding the name of the person and clinician to the message. However, be aware of any potential risks of personalising messages, such as where there may be safety concerns. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on tailoring interventions to improve the uptake and increase the frequency of STI testing . Full details of the evidence and the committee's discussion are in: evidence review C: effectiveness, acceptability and cost effectiveness of strategies to improve uptake of STI testing. Loading. Please wait. # Partner notification Advise people diagnosed with an STI about the importance and benefits of partner notification, the possibility of sex partners being infected even if asymptomatic, and the risk of reinfection. Encourage them to engage in partner notification, regardless of where they are tested, and discuss the different methods of partner notification with them. Help people decide how to notify their sex partners. Discuss ways of having these potentially difficult conversations and suggest ways to deliver this information. Discuss the best method of partner notification in light of the person's relationship status and other circumstances. Alternative methods of disclosure may need to be used in different contexts (for example, those who may be at risk of domestic violence, or if the person expresses a need for anonymity). If a person feels unable to tell their sex partners about the STI or is showing signs of difficulty dealing with their diagnosis, refer them to specialist sexual health services that can offer them more support with partner notification. Ensure that there is a clear referral pathway to specialist sexual health services that can help with partner notification so that people can be referred seamlessly and without the need for self-referral. Partner notification on behalf of a person with an STI should be carried out by professionals with expertise in contact tracing and counselling in line with the British Association for Sexual Health and HIV (BASHH) statement on partner notification for sexually transmitted infections. Consider how geospatial networking apps (for example, Grindr or Tinder) may be used for partner notification, for example by: suggesting that people who use geospatial networking apps to find sex partners use the apps to notify partners about contacting a sexual health service for STI testing using app profiles to inform contacts of their need to be tested when notifying partners on behalf of a person with an STI. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on partner notification . Full details of the evidence and the committee's discussion are in evidence review E: partner notification methods to prevent or reduce STIs. Loading. Please wait. # HPV and hepatitis A and B vaccination in gay, bisexual and other men who have sex with men Be aware that gay, bisexual and other men who have sex with men are not the only groups eligible for human papillomavirus (HPV), hepatitis A and hepatitis B vaccination (see NHS information on HPV vaccine eligibility, hepatitis A vaccine eligibility and hepatitis B vaccine eligibility). Consult local gay, bisexual and other men who have sex with men to identify their needs and the barriers to vaccine uptake and course completion. Opportunistically promote HPV, hepatitis A and hepatitis B vaccination with gay, bisexual and other men who have sex with men who are eligible for the vaccines. Give them information on HPV, hepatitis A and hepatitis B vaccination, including: the diseases and their potential severity the risks and benefits of vaccination, including individual benefits and, if relevant, population benefits (protecting other people in their community) the importance of having all doses of a vaccination course. Where possible, consider providing HPV and hepatitis vaccination during other routine health appointments for gay, bisexual and other men who have sex with men. Identify gay, bisexual and other men who have sex with men who do not return for follow-up vaccinations (second and third doses), and send reminders that highlight the importance of completing the course. See also the NICE guideline on vaccine uptake in the general population. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on HPV and hepatitis A and B vaccination in gay, bisexual and other men who have sex with men . Full details of the evidence and the committee's discussion are in evidence review F: increasing uptake of hepatitis A, hepatitis B and HPV vaccinations in gay, bisexual and other men who have sex with men. Loading. Please wait. # Pre-exposure prophylaxis for HIV These recommendations should be read together with NICE's guideline on HIV testing: increasing uptake among people who may have undiagnosed HIV. ## Raising awareness of pre-exposure prophylaxis for HIV Raise awareness of pre-exposure prophylaxis (PrEP) among local groups with greater sexual health or access needs: Use methods designed to target specific populations (for example, social media and relevant local organisations or groups). Follow the advice in NICE's guideline on community engagement. Pay particular attention to groups in which PrEP is less well-known or uptake is lower, such as trans people, cisgender women, young people (aged 16 to 24), people with a Black African or Caribbean family background and people from a lower socioeconomic status background. Give relevant local community groups support and information resources to help them raise awareness of PrEP and increase trust in services. Ensure that people in groups with greater sexual health or access needs understand that PrEP is for HIV prevention only and that it does not protect against other STIs, therefore barrier methods are also important. See NICE's guideline on sexually transmitted infections: condom distribution schemes. Co-produce materials that target specific information gaps and causes of stigma within the target population. Use peer support to normalise PrEP use, reduce all forms of stigma (originating from the person themselves, professionals and the wider society) and increase trust in services. Tell trans people undergoing medical transition that there are no clinically significant interactions expected between PrEP and the common hormones used in this process, and that using PrEP is not expected to affect their transition. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on raising awareness of PrEP for HIV . Full details of the evidence and the committee's discussion are in evidence review G: effectiveness, cost effectiveness, acceptability and unintended consequences of PrEP for HIV. Loading. Please wait. ## Service design for PrEP services Ensure that services offering PrEP are welcoming and accessible (see recommendation 1.1.5) for all the different population groups who are eligible, for example by co-designing services with the key population groups. Ensure that tailoring services to specific communities does not exclude or alienate other eligible groups. Raise awareness among healthcare professionals (particularly those in primary care, community settings and gender identity clinics) about which groups of people are eligible for PrEP. This could be done through continuing education or through commissioning (for example, through local networks ). Provide protected time for healthcare professionals who have day-to-day contact with people eligible for PrEP to have training on relevant issues. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on service design for PrEP services . Full details of the evidence and the committee's discussion are in evidence review G: effectiveness, cost effectiveness, acceptability and unintended consequences of PrEP for HIV. Loading. Please wait. ## Access to PrEP services Services that do not provide PrEP should connect people who are interested in PrEP and eligible for it to a service that can prescribe it. Ensure there are clear referral pathways between services that do not provide PrEP and those that do. Make provision for people who want to be referred to services outside their local area or community. See also recommendation 1.1.3. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on access to PrEP services . Full details of the evidence and the committee's discussion are in evidence review G: effectiveness, cost effectiveness, acceptability and unintended consequences of PrEP for HIV. Loading. Please wait. ## Prescribing PrEP Recommendations 1.5.13 to 1.5.19 support recommendations in the British HIV Association (BHIVA) and BASHH guidelines on the use of PrEP for HIV and should be implemented with reference to them. Offer PrEP to people at higher risk of HIV, using the criteria in the BHIVA/BASHH guidelines. Support people who are taking PrEP, for example in decisions around the use of barrier methods and attending follow-up appointments. Continue to offer them all other relevant sexual health services, such as information, behavioural support and condom provision. Support people who are taking PrEP to get regular HIV testing and STI screening (every 3 months). Give people taking PrEP tailored information and education on effectiveness, adherence, side effects and monitoring risks (see NICE's guideline on shared decision making). Follow up people taking PrEP in line with the good practice points and monitoring recommendations in the BHIVA/BASHH guidelines. Monitor the kidney function of people taking PrEP, and any other adverse health events. Help people taking PrEP to maximise adherence to treatment. Follow the general principles in NICE's guideline on medicines adherence and address factors specific to the use of PrEP, including those listed in the BHIVA/BASHH guidelines. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prescribing PrEP . Full details of the evidence and the committee's discussion are in evidence review G: effectiveness, cost effectiveness, acceptability and unintended consequences of PrEP for HIV. Loading. Please wait. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local Act Personal Care and Support Jargon Buster. ## Groups with greater sexual health or access needs These groups have higher rates of sex partner change or less contact with the healthcare system than average. People are most at risk of STIs if they are involved in higher rates of condomless sex with multiple partners or frequently change partners. There may be more people practising these behaviours in some groups than others, but this does not mean that everyone in the group is necessarily at higher risk. For example, gay, bisexual and other men who have sex with men are a higher risk group for STIs and HIV, but this does not mean that every person in that group is at higher risk. Some people find it more difficult to access sexual health services because of the location of services (most services are in urban rather than rural settings) or because they do not know that they are eligible for free services (for example, some refugees or asylum seekers may not know this). Others may find it difficult to access services either because they do not know about them, because of physical accessibility issues, or because of language barriers, learning difficulties or stigma. ## Pre-exposure prophylaxis (PrEP) A medicine that people at risk of HIV take to prevent them getting HIV. Normally it involves taking tablets every day (daily PrEP) but in some cases, it may mean taking tablets at particular times (event-based or on-demand PrEP). ## Remote self-sampling The person collects a sample themselves outside the clinic environment (for example, a swab or a urine sample) and sends it to a lab for analysis. This is different to self-testing, for which the person conducts the test and reads and interprets the result themselves. ## Sex-positive approaches Being non-judgemental, openly communicating and reducing embarrassment around sex and sexuality. Recognising the diversity of sexual experiences that exists and that sex can be an important and pleasurable part of many people's lives. ## Sexual self-efficacy A person's sense of control over their sexual life and sexual health, and their ability as an individual to have safe, consensual and satisfying sex.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Availability of PrEP What is the effectiveness and cost effectiveness of providing pre-exposure prophylaxis (PrEP) outside sexual health services, and does this reach eligible population groups different from those who do access sexual health services? For a short explanation of why the committee made this recommendation for research, see the rationale section on access to PrEP services . Full details of the evidence and the committee's discussion are in evidence review G: effectiveness, cost effectiveness, acceptability and unintended consequences of PrEP for HIV. Loading. Please wait. ## Mode of PrEP delivery What are the effectiveness, cost effectiveness, availability (eligibility status), adherence considerations, and short- and long-term adverse effects (including impact on bone density) of different modes of delivery, particularly long-acting PrEP (such as injections), including in women? For a short explanation of why the committee made this recommendation for research, see the rationale section on prescribing PrEP . Full details of the evidence and the committee's discussion are in evidence review G: effectiveness, cost effectiveness, acceptability and unintended consequences of PrEP for HIV. Loading. Please wait. ## Delivering effective sexual health services as part of other services How can sexual health services best be delivered together with other services (for example, drug and alcohol services)? For a short explanation of why the committee made this recommendation for research, see the rationale section on delivering and evaluating interventions to reduce sexually transmitted infection (STI) transmission . Full details of the evidence and the committee's discussion are in: evidence review A: interventions to reduce the acquisition and transmission of STIs in higher risk groups evidence review B: qualitative evidence synthesis for the acceptability of interventions for reducing or preventing the acquisition and transmission of STIs. Loading. Please wait. ## Tailoring outreach services How can outreach be tailored to specific groups to increase their access to sexual health services and their uptake of STI testing? For a short explanation of why the committee made this recommendation for research, see the rationale section on meeting the needs of groups with greater sexual health or access needs . Full details of the evidence and the committee's discussion are in: evidence review A: interventions to reduce the acquisition and transmission of STIs in higher risk groups evidence review B: qualitative evidence synthesis for the acceptability of interventions for reducing or preventing the acquisition and transmission of STIs. Loading. Please wait. ## Reducing stigma What are the most effective and cost-effective methods of reducing the stigma associated with accessing sexual health services? For a short explanation of why the committee made this recommendation for research, see the rationale and impact section on co-producing interventions to reduce STI transmission . Full details of the evidence and the committee's discussion are in: evidence review A: interventions to reduce the acquisition and transmission of STIs in higher risk groups evidence review B: qualitative evidence synthesis for the acceptability of interventions for reducing or preventing the acquisition and transmission of STIs evidence review D: effective and cost-effective interventions to increase frequent STI testing in very high risk groups. Loading. Please wait. # Other recommendations for research ## Value of incentives What incentives are effective and cost effective in increasing STI testing and diagnosis, and what, if any, are the adverse and unintended consequences? For a short explanation of why the committee made this recommendation for research, see the rationale section on self-sampling to improve the uptake and increase the frequency of STI testing . Full details of the evidence and the committee's discussion are in: evidence review C: effectiveness, acceptability and cost effectiveness of strategies to improve uptake of STI testing evidence review D: effective and cost-effective interventions to increase frequent STI testing in very high risk groups. Loading. Please wait. ## Vaccination course completion What factors affect whether people complete the full course of hepatitis A and B or human papillomavirus (HPV) vaccinations and how do people think they might be encouraged to complete it? For a short explanation of why the committee made this recommendation for research, see the rationale section on HPV and hepatitis A and B vaccination in gay, bisexual and other men who have sex with men . Full details of the evidence and the committee's discussion are in evidence review F: increasing uptake of hepatitis A, hepatitis B and human papillomavirus (HPV) vaccinations in gay, bisexual and other men who have sex with men. Loading. Please wait. ## Eligibility for PrEP What is the cost effectiveness of providing PrEP to people who do not report recent condomless sex? For a short explanation of why the committee made this recommendation for research, see the rationale section on raising awareness of pre-exposure prophylaxis for HIV . Full details of the evidence and the committee's discussion are in evidence review G: effectiveness, cost effectiveness, acceptability and unintended consequences of PrEP for HIV. Loading. Please wait. ## Remote self-sampling Have people's attitudes to remote self-sampling and regular testing for STIs changed as a result of self-sampling for COVID‑19? What are the effectiveness and adverse outcomes of self-sampling for people with symptoms, if remote triage (for example, phone triage) indicates that this is appropriate? For a short explanation of why the committee made this recommendation for research, see the rationale section on self-sampling to improve the uptake and increase the frequency of STI testing . Full details of the evidence and the committee's discussion are in: evidence review C: effectiveness, acceptability and cost effectiveness of strategies to improve uptake of STI testing evidence review D: effective and cost-effective interventions to increase frequent STI testing in very high risk groups. Loading. Please wait. ## Delivering effective sexual health services What are the experiences of LGBT+ people in accessing STI testing services, including online? For a short explanation of why the committee made this recommendation for research, see the rationale section on tailoring interventions to improve the uptake and increase the frequency of STI testing . Full details of the evidence and the committee's discussion are in: evidence review C: effectiveness, acceptability and cost effectiveness of strategies to improve uptake of STI testing evidence review D: effective and cost-effective interventions to increase frequent STI testing in very high risk groups. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice or services. # Accessing sexual health services Recommendations 1.1.1 to 1.1.3 ## Why the committee made the recommendations The committee considered who should be offered interventions and when, noting that often, the people who most need support with their sexual health and wellbeing are those least likely to access services. They also noted that people who do access services may be doing so because they have had sex that they perceive to have been unsafe. The committee noted the importance of sexual history taking in this context. They agreed this could help to identify issues such as sexual violence and exploitation, coercion, and drug and alcohol use in the context of sex. They noted the British Association for Sexual Health and HIV (BASHH) 2019 UK National Guideline for consultations requiring sexual history taking as an example of good practice. The committee recognised the value of collaborative working and the importance of supporting people to access services that already deliver suitable interventions. However, they also acknowledged regional variations in provision and that many tailored interventions for higher risk minority groups do not exist outside London. They agreed that the responsibility should be on services to support people in accessing the service that is right for them rather than just leaving it up to the person. They agreed that a single service was unlikely to meet the needs of every person and highlighted the importance of networks of services and clear pathways into them. The committee noted that some people did not realise that services were confidential and open access (that is, they are free for anyone to use). Those people might not access services because they thought they were not entitled to do so, that they would have to pay, or that their data might be shared with other organisations. Therefore, the committee agreed it was important to ensure that staff and people who use services know about this. ## How the recommendations might affect practice or services Existing clinic appointments could be used to identify people with greater sexual health or access needs and signpost them to appropriate services. However, additional appointment time would be needed for conversations about sexual wellbeing and risk reduction, particularly if brief motivational interviewing, cognitive behavioural therapy or condom-focused interventions are used. Changing settings in which services are delivered could have a cost impact because services may need to be moved or started up, but reducing barriers to access those services need not be resource intensive. The committee noted that fairly simple changes can make a large difference to people's ability to access services. Return to recommendations # Meeting the needs of groups with greater sexual health or access needs Recommendations 1.1.4 and 1.1.5 ## Why the committee made the recommendations The committee discussed how the wider determinants of health can influence sexual health and wellbeing. These include stigma, discrimination faced by those who are part of a minority group, housing instability, poverty, substance use, mental health and intimate partner violence. They agreed that it is important to consider the social, cultural, emotional and economic aspects of a person's life when seeking to address their sexual risk behaviour. The committee also recognised that sexually transmitted infection (STI) incidence is just 1 aspect of sexual health, and that taking a broad perspective that encompasses wider aspects of sexual wellbeing is important. The committee agreed that interventions and services should be targeted at people with greater sexual health and access needs because that represents the most effective and cost-effective strategy. They discussed the complexity of reaching individual people with greater sexual health and access needs rather than targeting everyone in higher risk groups because not all people in higher risk groups need sexual health support or interventions. However, by targeting higher risk groups, individuals needing help would benefit. The committee recognised that local areas vary in their cultural and demographic profiles and agreed that data from various sources (including the Joint Strategic Needs Assessment and relevant health equity audits) should be used to commission and provide services to meet local need. They agreed that although it was important to engage with groups with greater sexual health or access needs, in many cases it would be challenging to do so. The committee discussed the evidence specific to each of the higher risk groups and agreed that interventions should be tailored to the needs of specific groups, such as gay, bisexual and other men who have sex with men, or trans people. However, they noted that the degree of intersectionality and the likely variation in experiences and identities within these groups made group-specific recommendations somewhat problematic. They agreed that there was little evidence about how to tailor outreach services to best meet the needs of specific groups to improve their access to sexual health services and uptake of STI testing, although expert testimony provided some promising examples. Therefore, they made a recommendation for research on tailoring outreach services. The committee also considered the evidence for culturally relevant interventions and agreed that interventions should be culturally competent. The committee discussed the expert testimony about the inclusion health agenda and their own expertise and experience of reducing barriers to services for people from underserved groups (those who existing services are not accessible to). They noted that a key part of service accessibility was about avoiding assumptions about things like gender or sexuality, or being judgemental about people's relationships or sexual practices. The committee noted that staff may need additional training to do this. ## How the recommendations might affect services Targeting interventions at groups in which greater sexual health needs have been identified locally will make the use of resources more efficient by ensuring that they are used where they are most needed. Identifying groups will make use of existing data, for example from the JSNA or from STI diagnosis data, and will not have a large resource impact. However, the committee agreed that this could be challenging because the data may be limited or not as robust. Engaging with groups with greater needs is already good practice in sexual health and should not have an impact on resources. Return to recommendations # Co-producing interventions to reduce STI transmission Recommendations 1.1.6 to 1.1.10 ## Why the committee made the recommendations Committee members suggested that the most effective way to ensure that interventions and services meet the needs of specific groups, communities or cultures is to plan, design and implement them in consultation with the people who will be using them (co-production). This was supported by the broader evidence and expert testimony. It helps to ensure that they are culturally sensitive and appropriate to the group they are for. They noted that further research was needed to understand and reduce the stigma associated with accessing sexual health services, and therefore made a recommendation for research on the most effective and cost-effective methods of reducing stigma. The committee considered evidence for a range of interventions designed to reduce sexual risk and prevent STIs. The evidence was mixed, with some studies showing no effect on sexual health outcomes and other studies showing a positive impact on condom use, STI incidence and sexual health knowledge. No single intervention type emerged as consistently or substantially effective. Motivation-based approaches, cognitive behavioural therapy and cognitive approaches, condom-focused approaches and culturally relevant interventions all performed comparatively well compared with no intervention. Based on this evidence and their experience, the committee agreed that interventions should aim to adopt a multi-model approach by incorporating components from some or all of these approaches, and that people designing interventions should look at NICE's guidance on behaviour change. The committee also agreed that all interventions should be sex and identity positive – that is, they should recognise the broad range of people's sex lives and their identities without being judgemental. The committee noted the evidence for condom-focused approaches and agreed that condom use is a fundamental method of preventing STIs. Therefore, supporting people to use condoms correctly and consistently is important. They agreed that condom-positive approaches would be most effective, with a focus on pleasure, the wide variety of condoms available, the importance of fit and feel, barriers to use and strategies for negotiating use. They also noted the importance of both internal and external condoms. They agreed that demonstrations of condom use were also valuable, particularly if people were given the opportunity to practise. The committee agreed that motivation-based approaches such as motivational interviewing were useful for risk-reduction interventions but recognised that the evidence for their effectiveness was mixed. They heard expert testimony from organisations delivering motivation-based interventions, which helped them to better understand how well these approaches work, who they may be most suited to and the best way to deliver them. The committee agreed that, given the challenging life contexts in which many people with greater sexual health needs live, it is important to offer people support to develop their understanding of the link between emotions and sexual wellbeing, stress management and coping skills, and that these should be incorporated into sexual risk reduction interventions. They discussed that cognitive behavioural approaches were particularly useful for addressing psychological aspects of sexual wellbeing and the evidence to some extent supported this. ## How the recommendations might affect services The committee agreed that co-produced interventions were far more likely to be effective and therefore cost effective because they would be better suited to the people they were serving. They agreed that although co-production does have a resource impact compared with usual planning and commissioning, it need not be significant and it is already widely used in other areas of the public sector. Return to recommendations # Delivering and evaluating interventions to reduce STI transmission Recommendations 1.1.11 to 1.1.15 ## Why the committee made the recommendations The setting of interventions is important. The committee discussed current sexual health provision across primary care, sexual health services and third sector organisations and agreed that people should be able to attend the service most suited to them. They also agreed that online services were an integral and important part of this. The committee also discussed the importance of Making Every Contact Count. They agreed that 1 of the ways that people could be encouraged to use sexual health services was to provide them as part of broader support services, for example drug and alcohol services, HIV care and mental health services. They agreed it was important to take into account that people's sexual health is only 1 aspect of their overall wellbeing. The committee were unaware of research about the most effective ways to deliver sexual health services together with other services and made a recommendation for research on delivering effective sexual health services as part of other services. The committee agreed that co-producing interventions would help people to decide if interventions were best delivered in one-to-one or group settings (this might also relate to considerations about safety and stigma). The committee considered the evidence for peer delivery and, in combination with their experience, agreed that interventions were best delivered by peers if possible. The committee clarified their understanding of peers as people with a shared identity with the target group or another person who they could relate to, and that the ability to empathise and understand the person's needs and life context was crucial. Committee members with experience of commissioning and delivering peer-led interventions emphasised the value and effectiveness of this approach. The committee agreed that it was important for people delivering interventions to do so in ways that respected people's identities and choices, for example by using gender-neutral pronouns until a person expressed a preferred pronoun. They also discussed the importance of using those pronouns in written records – currently most written records have limited options and use a 'tick box' approach to gender and sexual identity. The committee agreed that because the interventions were not based on strong evidence that it was important to evaluate them regularly and use the results of the evaluation to improve services and pathways. They noted that resources were available that could help with this, such as the UK Health Security Agency's (previously Public Health England) sexual health, reproductive health and HIV services: evaluation resources. ## How the recommendations might affect services Increased awareness of personal risk may lead to more people accessing STI testing services, which may affect service capacity and allocation of resources in clinics that deliver STI testing. However, the committee expect sexual health services in general to be providing cost-effective interventions and care, so even if more people using them increases costs, that is likely to be a cost-effective use of resources. Evaluating interventions should already be inbuilt into all intervention delivery and therefore will not have a resource impact. Return to recommendations # Self-sampling to improve the uptake and increase the frequency of STI testing Recommendations 1.2.1 to 1.2.6 ## Why the committee made the recommendations The committee were satisfied that the evidence supports the use of STI testing outside clinical services using self-sampling kits for people who are asymptomatic. They agreed that it encourages people who have previously never engaged with sexual health services to come forward for testing, so widening access to these kits would be a good thing. They noted that being able to access kits from a variety of locations could increase uptake. Possible locations include community pharmacies, which are already an integral part of test kit provision in some areas. However, these services would need to be commissioned. The committee agreed that local service websites needed to be kept up to date about available options so that people knew what was available in their area and how to access it. However, they noted that the 'digital divide' could potentially widen health inequalities because not everyone who might want to order a remote self-sampling kit would necessarily have access to online ordering services. They also agreed that knowing who was accessing remote self-sampling would highlight groups where there may be inequalities in uptake. Services could then be tailored to address this. There is regional variation in whether remote self-sampling is offered and how many kits are available. In locations that do offer it, not everyone who is eligible can have a test kit. This is because the demand for these kits is often greater than the supply and kits are not always returned, so there is some concern about wasting money if the return rate is low. As a result, the committee were aware that some areas were capping the number of kits available, creating a tension between widening access and limiting the number of kits. The committee therefore agreed that services should monitor kit return rates in different populations to ensure they were meeting the populations' needs. They also noted that there can be unintended consequences as a result of not having direct contact with a clinician. For example, a person with a positive test may not go to a service and there might be a missed opportunity to treat an STI and to start partner notification. They agreed remote self-sampling was an important option for testing, but not the only option. In committee members' experiences, self-sampling is suitable for STIs, but tests that need a blood sample, such as syphilis, are more challenging to complete so are more likely to be returned in an unsuitable state for analysis. Antibodies from previous infections can also result in initially reactive results that need confirmation through a test at a clinic. In spite of this, they agreed that the tests offered through self-sampling should be the same as those offered in clinic so that people using the service would not be at a disadvantage. They concluded that remote self-sampling should be part of a suite of testing options and be aimed primarily at people without symptoms. Committee members highlighted the self-efficacy needed to access, complete and return tests and to understand the implications of the results. They discussed how some people might have difficulty accessing the right tests for their anatomy or understanding the instructions. Therefore, they agreed on the importance of ensuring that kits meet accessibility and inclusivity standards. They noted the usefulness of resources such as BASHH guidance for the design of self-sampling packs and associated support for self-sampling processes within sexually transmitted infection and blood borne virus testing. The committee were aware that during the COVID‑19 pandemic, some areas had used remote self-sampling after telephone triage for people who had symptoms. The evidence was unclear about this, so the committee made a recommendation for research to assess the effectiveness and adverse outcomes of self-sampling for people with symptoms. Overall, they agreed that it was better to attend a clinic if symptoms were present, but acknowledged that in extenuating circumstances (for example, during the COVID‑19 pandemic), using self-sampling kits even for some symptomatic people was better than not testing them at all. They were interested to know whether people's attitudes to home-based self-sampling and regular testing for STIs had changed as a result of the self-sampling for COVID‑19 that most people have undertaken, and made a recommendation for research on people's attitudes to remote self-sampling. The committee agreed that increasing the uptake of testing was only 1 part of the solution and that re-testing and prompt treatment were also important aspects of STI prevention. They noted the BASHH standards for the management of sexually transmitted infections specify that people should be offered an appointment within 2 days of contacting the service. The committee discussed the lack of evidence for the value of incentives in encouraging uptake of STI testing, but agreed there needed to be further research on this and made a recommendation for research on the value of incentives. They also discussed the lack of evidence for improving the uptake of testing in people from very high-risk groups such as sex workers and men who engage in group sex under the influence of stimulant drugs (such as methamphetamine or mephedrone), typically with multiple partners (so-called chemsex). Although there was a lack of evidence, the committee agreed that the recommendations they had made would be applicable to these groups. ## How the recommendations might affect services The committee agreed that most local areas are already providing some kind of asymptomatic remote self-sampling service, often as part of larger collaboratives. However, they noted that recommendations to widen access to this might have a cost impact. Although remote self-sampling is a cheaper method of testing than in clinic, the extra positive cases detected mean there will be an overall increase in costs. It would be important to monitor things like return rates for kits and positive test result rates to determine whether broader testing was identifying more people with STIs. They were also satisfied that the evidence supported a strategy of offering remote self-sampling as being cost effective compared with clinic only testing, but that this was very sensitive to the return rate of the self-sampling kits. Return to recommendations # Tailoring interventions to improve the uptake and increase the frequency of STI testing Recommendations 1.2.7 to 1.2.9 ## Why the committee made the recommendations The committee agreed that it was important to target information to the groups identified in the recommendations on preventing transmission (for example, a website could be tailored towards particular communities that are at higher risk), and that the same considerations about co-producing information materials with the target groups and communities meant that information about testing would be more likely to make an impact. But they were also aware that this should not exclude other groups. The committee reiterated that people providing services need to look at those using services holistically rather than assuming they are at risk because they are members of a group with a high incidence of STIs. The evidence showed that individually tailored interventions were effective, whereas motivational interventions without tailoring were not. The committee thought that this was consistent with previous discussions about cultural competence in targeting interventions to specific groups. They decided that detailed and specific tailoring may be too resource intensive in practice, so favoured low-level personalisation such as adding names and demographic-specific information to communications. They noted that 'opt-in' automated recall messages are already widely used, but additional safety concerns may need to be taken into account when personalising those messages. The committee were interested in the experiences of LGBT+ people in accessing STI testing services, including online services, and made a recommendation for research on delivering effective sexual health services. They believed this could improve services for LGBT+ people in the future. The committee discussed the lack of evidence for improving the uptake of testing in people from very high-risk groups such as sex workers and men who engage in sex under the influence of stimulant drugs (such as methamphetamine or mephedrone), typically with multiple partners (so-called chemsex). Although there was a lack of evidence, the committee agreed that the recommendations they had made would be applicable to these groups. ## How the recommendations might affect services The committee agreed that low-level tailoring of interventions would mostly involve modifying things that are already being done and need not have a substantial resource impact. Return to recommendations # Partner notification Recommendations 1.3.1 to 1.3.6 ## Why the committee made the recommendations The committee acknowledged that any type of partner notification is beneficial. It is 1 of the most important ways of preventing reinfection and reducing the transmission of STIs. It also ensures that partners have the opportunity to be tested and, if necessary, have their STI treated. They noted the importance of discussing these benefits with people newly diagnosed with an STI, including both the personal benefits and benefits to their sexual partners. The committee noted the importance of making people aware of the different partner notification methods, and providing information about the methods available to them may support their decision making. The quantitative and qualitative evidence supported the committee's view that patient-led referral to sexual health services may be particularly beneficial for both index patients and their partners. They also recognised the benefits of other methods of partner notification, such as provider referral or online partner notification in certain contexts (for example, if the person feels unable to make the referral themselves). The committee recognised that partner notification could lead to negative responses from partners, including the potential for violence. Although experiences of violence or compromised patient safety were not reported in any of the included qualitative studies, the committee agreed that they remain a potentially adverse consequence that needs to be taken into account. They therefore discussed the need for recommendations about patient safety and patient choice, and acknowledged that there may be situations in which partner notification is not appropriate. The committee also noted that their clinical responsibility was to the index patient and not their sex partners, although the needs and preferences of partners being notified remain important. The committee considered other potential harms of partner notification, including unintended disclosure of relationship, sexuality or STI status. They recognised the importance of anonymity and confidentiality for all partner notification methods but did not consider it necessary to make specific recommendations about patient confidentiality because this is standard practice for all healthcare professionals. However, the committee agreed that when telling people about the partner notification methods available, it is important to highlight the option to maintain anonymity. They noted that provider referral may be the most appropriate method when the person expresses a desire to remain anonymous. The committee discussed anonymous sex arranged using geospatial networking apps and websites and how this made partner notification difficult. They noted that there was a potential to use these apps for partner tracing and notification if the person did not know their partner's name or contact details. They agreed that this could be done by the person themselves, and were aware that some services set up profiles on these apps for the purposes of anonymous partner notification. ## How the recommendations might affect practice These recommendations are already within the scope of practice of services that undertake partner notification, so there should be no additional cost. Some services may need to improve their practices in this area, which may have a modest resource impact (for example, increasing the length of appointments). Return to recommendations # HPV and hepatitis A and B vaccination in gay, bisexual and other men who have sex with men Recommendations 1.4.1 to 1.4.5 ## Why the committee made the recommendations The committee were aware that a NICE guideline on improving vaccine uptake in the general population was being developed and agreed that it would be important to consider the recommendations in that guideline when thinking about human papilloma virus (HPV) and hepatitis vaccinations. They also noted that the scope of this guideline asked very specifically about vaccinations for gay, bisexual and other men who have sex with men but that the eligibility criteria for these vaccinations were broader than just that group. The committee saw very little evidence about the effectiveness of interventions to increase the initial uptake of HPV and hepatitis vaccinations, and less evidence on whether interventions improved course completion. As a result, they felt unable to recommend specific interventions to increase vaccine uptake, and therefore made a recommendation for research on vaccination course completion. The committee saw qualitative evidence about the perceived barriers to vaccination among gay, bisexual and other men who have sex with men and agreed that this supported their expertise and experience. On this basis, they agreed on the need to encourage all healthcare professionals to opportunistically discuss vaccination and explain the importance of completing the full course of vaccinations. They also discussed that many gay, bisexual and other men who have sex with men still find it difficult to discuss their sexual health needs with healthcare professionals, so it was important for organisations to consider ways to make services more accessible. They agreed that the Department of Health and Social Care's 'You're welcome' quality criteria, although specifically aimed at young people, modelled good practice that could also be used for other groups (see also recommendation 1.1.3). They noted that in their view and experience, many men did not return for their follow-up vaccines. They agreed that it was important to highlight this, and the need to follow those men up, by making a recommendation. Although they did not see any evidence to support it, the committee agreed that in their experience, uptake might be increased by providing these vaccines during other routine health appointments for gay, bisexual and other men who have sex with men. However, they acknowledged that this will be limited by the availability of vaccines in alternative settings. ## How the recommendations might affect practice The committee agreed that these recommendations would not have a large impact on resource use. Sexual health services should already be providing information about vaccination to gay, bisexual and other men who have sex with men who are eligible for vaccination, and many primary care providers already offer these vaccines. Providing vaccinations alongside existing services should be a more efficient method of delivery, where this is possible. The committee also noted that because these vaccines had already been assessed as being cost effective by the Joint Committee on Vaccination and Immunisation, an increase in the number of people being vaccinated should also be cost effective. Return to recommendations # Raising awareness of pre-exposure prophylaxis for HIV Recommendations 1.5.1 to 1.5.6 ## Why the committee made the recommendations The committee agreed that increasing uptake of pre-exposure prophylaxis for HIV (PrEP) among eligible populations was the highest priority. The evidence showed differing experiences and beliefs about PrEP for different populations, so they wanted to target populations that had negative experiences or are less engaged. With this in mind, they agreed that local groups with greater sexual health or access needs were an appropriate target for awareness raising, in line with NICE's guideline on community engagement and HIV Prevention England's PrEP health promotion campaign guidance. They agreed that particular attention needed to be paid to groups in which uptake of PrEP is lower, such as cisgender women with a Black African family background. They cautioned that it was also very important to make sure that people knew that PrEP was for HIV prevention specifically and that it did not protect against other STIs. The committee noted that the eligibility criteria for PrEP currently restricted it to people who reported recent condomless sex. They were therefore interested in whether providing PrEP to people who do not report recent condomless sex would also be cost effective, and made a recommendation for research on eligibility for PrEP. The evidence showed that people are more likely to trust those from their own community or group when it came to information about PrEP. So the committee agreed that engaging with peers was a good way to normalise PrEP use and reduce both stigma and mistrust in services. They noted qualitative findings (from research predating more widespread use of PrEP) that stereotyped people who use PrEP as promiscuous or reckless. They also agreed that co-producing materials with those communities and groups could help to challenge stigma. The committee noted that trans people in qualitative studies frequently expressed concerns about potential interactions between PrEP and gender-affirming hormones and the possibility of PrEP interfering with their transition. The committee reported information from the University of Liverpool's HIV drug interaction checker, which they agreed was robust based on communication with the University of Liverpool about the methodology underpinning the checker. This showed that there were no interactions expected, and thought that education was needed to raise awareness of the safety of PrEP for those undergoing medical transition. The committee agreed it was important to use this information to reassure potential PrEP users because participants with these concerns expressed that they would prioritise their transition above HIV prevention and may avoid PrEP because of this uncertainty. The committee noted the importance of the Department of Health and Social Care's Towards zero: the HIV action plan for England (2022 to 2025), which was published after this guideline was drafted. They agreed that the action plan was consistent with this guideline and welcomed it. ## How the recommendations might affect practice and services Additional resources will be needed to train healthcare professionals on the needs of populations eligible for PrEP. If the total time allotted for training does not increase, this training will come at the expense of other training options. Existing appointments can be used to identify people eligible for PrEP and signpost them to appropriate services, but this might add to the time needed for each appointment to cover the additional conversations about PrEP. Return to recommendations # Service design for PrEP services Recommendations 1.5.7 to 1.5.9 ## Why the committee made the recommendations The committee were concerned that access to services is a barrier to PrEP uptake. The evidence suggested that this is because PrEP is only provided at sexual health clinics (in line with current NHS England commissioning policy) and that some groups are less likely to seek healthcare in this setting. Conversely, some committee members thought that PrEP should only be prescribed by healthcare professionals with knowledge of it and training in sexual health, which would generally mean only in a sexual health clinic. The committee agreed that it is important that healthcare professionals in primary care, community settings and gender identity clinics are aware of who is eligible for PrEP, regardless of whether the setting provides it. This means that they will be better able to refer eligible people to services where PrEP can be provided. They agreed that healthcare professionals needed training about this. They acknowledged that some populations face particular barriers to accessing PrEP services in sexual health clinics. The qualitative evidence indicated that some groups, particularly LGBT+ people, thought that healthcare professionals did not understand their sexual practices and individual risk factors. This led to them feeling uncomfortable discussing sexual health and being worried about feeling judged, therefore making it harder for them to start conversations about PrEP. ## How the recommendations might affect practice and services Additional resources will be needed to train healthcare professionals on the needs of populations eligible for PrEP. If the total time allotted for training does not increase, this training will come at the expense of other training options. Increased uptake of PrEP is likely to have an impact on service capacity and allocation of resources in clinics that deliver PrEP and provide monitoring and testing for PrEP users. Clinics may need additional funding or expansion of services to meet increased demand. However, PrEP itself is a highly cost-effective intervention and therefore this should be a cost-effective use of resources. Return to recommendations # Access to PrEP services Recommendations 1.5.10 to 1.5.12 ## Why the committee made the recommendations In addition to making existing services more accessible, the committee were interested in the possibility of offering PrEP in other settings. However, they agreed that more evidence was needed on the effectiveness of doing this before they could recommend specific actions, therefore they made a recommendation for research on the availability of PrEP. They thought that, for now, increasing awareness of eligibility and enabling wider services to refer people to PrEP clinics was more important than prescribing PrEP in other settings. They agreed that there needs to be clear pathways for healthcare professionals who cannot or do not provide PrEP to support people in accessing services that prescribe it, and that the responsibility for this should lie with the healthcare professional. The committee agreed that this meant it was important for people to be able to access services outside of their local area or community. ## How the recommendations might affect practice and services Additional resources will be needed to train healthcare professionals on the needs of populations eligible for PrEP. If the total time allotted for training does not increase, this training will come at the expense of other training options. Existing appointments can be used to identify people eligible for PrEP and signpost them to appropriate services, but this might add to the time needed for each appointment to cover the additional conversations about PrEP. Return to recommendations # Prescribing PrEP Recommendations 1.5.13 to 1.5.19 ## Why the committee made the recommendations The committee recognised the evidence for the effectiveness of PrEP and thought that it was important for all groups outlined in the BASHH/BHIVA (British HIV Association) guidelines to be able to access it according to the risk criteria in these guidelines. The committee agreed that the available economic evidence showed PrEP to be cost effective in a population of gay, bisexual and other men who have sex with men at higher risk of HIV (matching the criteria in the BASHH/BHIVA guidance). They also agreed that the findings should be generalisable to other populations at equivalent risk of HIV, as both the potential benefits and costs in those populations should be similar. The evidence also suggested that PrEP would remain cost effective in these populations regardless of potential unintended consequences (such as changes in condom use). Therefore, they were confident that these potential consequences did not need to result in any restrictions made to people eligible for PrEP. The committee recognised from the evidence that the effectiveness of PrEP directly corresponded to adherence, so it is vital that people taking it are made aware of this and given support to take it as prescribed (see NICE's guideline on medicines adherence). They recognised that some people might experience barriers to adherence, so promoting knowledge and understanding about PrEP would be important for these people. The committee agreed that anyone taking PrEP needed knowledge of the risks involved (HIV, antiretroviral drug resistance) in not adhering to the treatment. The committee recognised the importance of adherence to PrEP, the risk of adverse events and the potential relationship between these. So they agreed that clinical follow up of anyone taking PrEP was important and that the BASHH/BHIVA good practice points could be followed. The committee agreed that people who buy their own PrEP should also be able to access clinical follow up and monitoring via NHS services. The committee were also interested in the potential adherence benefits of offering long-acting PrEP (for example, by injection) and noted that some people may prefer it to taking tablets on a daily or frequent basis (depending on the kind of PrEP they are using). However, they thought there was insufficient evidence to recommend long-acting PrEP and that research was needed to establish whether it is as effective as daily (or frequent) PrEP tablets. Therefore, they made a recommendation for research on mode of PrEP delivery. The evidence also suggested some adverse effects associated with PrEP use (such as kidney or gastrointestinal symptoms). The committee recognised that people needed to be made aware of these so they could make an informed choice and manage their symptoms (see NICE's guideline on shared decision making). They noted that the evidence for increased risk of kidney problems corresponded to their own knowledge of how PrEP works pharmacologically. They therefore agreed that monitoring the renal health of those taking PrEP was important. Although the committee were aware of evidence showing that bone-mineral density will rebound after stopping PrEP, there was a lack of data on this for young people who have not yet reached their peak bone density (see the recommendation for research on mode of PrEP delivery). The committee discussed the risk of antiretroviral therapy resistance in prescribing PrEP to people who were HIV positive and strongly supported current guidelines about the importance of regular HIV testing and the requirement for a negative HIV test before prescribing. The committee noted that ongoing research seemed to be showing an association between people taking PrEP and an increase in STI rates, but they emphasised that it was not clear whether there was any causal link. They discussed several other plausible reasons for the association and agreed that it will be important to see how the evidence develops. They agreed on the value of providing condoms and behavioural support to this high-risk population, and that they should have regular screening for other STIs. ## How the recommendations might affect practice and services Increased uptake of PrEP is likely to have an impact on service capacity and allocation of resources in clinics that deliver PrEP and provide monitoring and testing for PrEP users. Clinics may need additional funding or expansion of services to meet increased demand. However, PrEP itself is a highly cost-effective intervention and therefore this should be a cost-effective use of resources. Return to recommendations# Context Sexually transmitted infections (STIs) can affect personal wellbeing, mental health and relationships. They can also lead to serious health problems including pelvic inflammatory disease, ectopic pregnancy and infertility. The rates of STIs are highest in young people aged 15 to 24; people from a Black family background; and gay, bisexual and other men who have sex with men. In 2020, there were 3,482,700 consultations at sexual health services and 317,901 diagnoses of new STIs in England. This was a decrease of 10% and 32%, respectively, compared with 2019, but this largely reflects the rapid reconfiguration of sexual health service delivery in response to the COVID‑19 pandemic. But the number of internet consultations doubled from 511,979 to 1,062,157 over the same period. Sexual health services carried out 1,649,429 sexual health screens (tests for chlamydia, gonorrhoea, syphilis or HIV) in 2020, a 25% decrease compared with 2019. New HIV diagnoses have declined over the past decade, with a substantial decrease during 2019 (4,139 cases, a 10% fall from 4,580 in 2018). This recent reduction has been mostly driven by fewer HIV diagnoses among gay and bisexual men, which have decreased by 47% since 2014. There is also an ongoing human papillomavirus (HPV) vaccination programme for gay, bisexual and other men who have sex with men. The vaccine is recommended for all men up to and including the age of 45 who have sex with men. Social and sexual networking apps have made it easier to buy recreational drugs. People who use drugs during sex are more likely to report unsafe sexual behaviours than those who do not. Mycoplasma genitalium is being increasingly recognised as a public health concern because of its relatively high prevalence (1% to 2% of the general population) and high levels of antimicrobial resistance, along with already recognised drug-resistant gonorrhoea. Sexually transmitted infections are a major public health concern and are costly to healthcare services. Although the COVID‑19 pandemic has reduced the diagnosis rates of STIs, this has coincided with a decrease in sexual health screening caused by the disruption to service provision. The overall trends continue to rise. Together with new evidence identified, this highlights the need for an updated guideline on this topic.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThese recommendations should be read together with relevant NICE guidance on sexual health and contraception (see the NICE topic page on sexual health).\n\n# Reducing the risk of people getting and transmitting sexually transmitted infections (STIs)\n\n## Accessing sexual health services\n\nForm a network of services, including online services, providing sexual healthcare for an area. Ensure that:\n\neveryone is signposted to, and can access, the care they need\n\nlocal pathways are in place to link people, including underserved communities, to the best possible care\n\ndetails of the network are kept up to date and all staff understand what each service offers.\n\nDetermine the most appropriate settings for services and interventions in consultation with groups with greater sexual health or access needs (see also recommendations in section\xa01.2). Include online and non-clinical settings.\n\nReduce barriers to services for groups with greater sexual health or access needs by:\n\nemphasising confidentiality, empathy and a non-judgemental approach\n\noffering access to a professional translator or interpreter instead of waiting for the person to ask, to ensure they are fully able to communicate and to understand the discussion\n\nmaking sure staff understand that services are free and available to everyone regardless of where they live (or are from), and they do not refuse access to someone who is entitled to the service\n\nsupporting people to attend appointments and engage with treatment\n\nproviding outreach activities.Take into account guidance on making services more welcoming and inclusive, such as the Department of Health and Social Care's 'You're welcome' quality criteria or UK Health Security Agency's (previously Public Health England) Inclusion health: applying all our health.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on accessing sexual health services\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: interventions to reduce the acquisition and transmission of STIs in higher risk groups\n\nevidence review\xa0B: qualitative evidence synthesis for the acceptability of interventions for reducing or preventing the acquisition and transmission of STIs.\n\nLoading. Please wait.\n\n## Meeting the needs of groups with greater sexual health or access needs\n\nTarget interventions at groups with greater sexual health or access needs. Identify local needs and priorities using data from the Joint Strategic Needs Assessment (JSNA) and other data sources.\n\nEngage with groups with greater sexual health or access needs to understand how best to meet their sexual health and wellbeing needs. Take into account factors such as existing barriers to access (for example, for people with learning difficulties, or because of their gender or sexuality), language and other socioeconomic factors, including deprivation.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on meeting the needs of groups with greater sexual health or access needs\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: interventions to reduce the acquisition and transmission of STIs in higher risk groups\n\nevidence review\xa0B: qualitative evidence synthesis for the acceptability of interventions for reducing or preventing the acquisition and transmission of STIs.\n\nLoading. Please wait.\n\n## Co-producing interventions to reduce STI transmission\n\nCo-produce (plan, design, implement and evaluate) services and interventions in consultation with the groups that they are for, in line with NICE's guideline on community engagement.\n\nEnsure that interventions are culturally competent. This includes being delivered in a suitable language for people whose main language is not English. It might also involve recognising that people may be engaged in activities that are stigmatised by their communities (therefore, discretion may be particularly important for them).\n\nEnsure that interventions include some or all of the following components:\n\ninformation and education about:\n\n\n\nSTIs\n\nthe impact of alcohol and drugs on sexual decision making\n\n\n\ninformation about:\n\n\n\nsexual health services available, including that they are free, confidential and open access\n\nthe rates of STIs to explain why some groups are at higher risk\n\nthe impact of stigma\n\n\n\nsex-positive approaches to providing advice on the consistent and correct use of barrier methods, including providing external condoms in different sizes and textures, and internal condoms (see NICE's guideline on sexually transmitted infections: condom distribution schemes)\n\nrisk assessment and risk-reduction activities, for example developing personalised risk-reduction plans, identifying triggers and setting goals\n\nInformation–Motivation–Behavioural skills (IMB) model approaches and motivational interviewing techniques to guide conversations about risk reduction or safer-sex practices and address informational, motivational and skills-based barriers to change\n\nactivities to increase sexual self-efficacy (for example, talking about sexual consent, negotiating the use of barrier methods and negotiating sexual preferences) and broader self-efficacy (for example, self-esteem)\n\nactivities exploring the links between emotion and sexual behaviour, and coping skills (for example, using cognitive behavioural approaches)\n\na plan for follow up (for example, repeated contact to review progress or make new plans).\n\nTake into account the recommendations in the NICE guidance on behaviour change (see the NICE topic page on behaviour change) when co-producing interventions to reduce STIs.\n\nTailor interventions to the needs of the groups identified. Take into account safety concerns (such as sexual violence or coercion), stigma and discrimination. See also the NICE guideline on domestic violence and abuse: multi-agency working.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on co-producing interventions to reduce STI transmission\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: interventions to reduce the acquisition and transmission of STIs in higher risk groups\n\nevidence review\xa0B: qualitative evidence synthesis for the acceptability of interventions for reducing or preventing the acquisition and transmission of STIs.\n\nLoading. Please wait.\n\n## Delivering and evaluating interventions to reduce STI transmission\n\nDeliver interventions to reduce STIs across a range of services, including within broader support interventions and community services (for example, in drug and alcohol services, abortion care services, HIV care and mental health services).\n\nThink about whether one-to-one or group delivery is the most appropriate for the community the intervention is aimed at, and the content and aims of the intervention. Take into account people's preferences and any resource impact.\n\nEnsure that people have the opportunity to have interventions that are delivered by peers or other trusted people they can relate to, who share a cultural or group background with the target group.\n\nWhen delivering interventions:\n\nAvoid making assumptions about people or judging them. This could include using inclusive language (until the person expresses a preference) and recognising a range of relationships and sexual behaviours.\n\nBe sex and identity positive (for example, by using gender-affirming language and being respectful of their sex life). Focus on self-worth and empowering people to have autonomy over their bodies and their sexual decision making.\n\nCommissioners and providers should regularly evaluate interventions, including the methods used to co-produce them, to determine their effectiveness and acceptability and identify gaps to make service improvements across the pathway. For example, this could be done through a health equity audit.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on delivering and evaluating interventions to reduce STI transmission\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: interventions to reduce the acquisition and transmission of STIs in higher risk groups\n\nevidence review\xa0B: qualitative evidence synthesis for the acceptability of interventions for reducing or preventing the acquisition and transmission of STIs.\n\nLoading. Please wait.\n\n# Improving uptake and increasing the frequency of STI testing\n\n## Self-sampling\n\nOffer a range of STI testing options based on local need, including remote self-sampling, in-person attendance at specialist clinics or in community pharmacies, primary care, and outreach services.\n\nOffer people without symptoms remote self-sampling as an alternative option to clinic attendance. Self-sampling should test for the same infections as those tested for at the clinic.\n\nEnsure that local service websites give up-to-date information on which testing options are available in their area.\n\nEnsure that self-sampling kits meet the NHS Accessible Information Standard and are inclusive (for example, addressing the needs of trans and gender-diverse people, and making instructions and guidance available in different languages or different formats such as diagrams, photos, or videos targeted at people with learning difficulties).\n\nWiden access to self-sampling kits. For example, by having a system for people to order a kit online or by phone, or providing self-sampling kits through 'pop-up' or outreach services.\n\nMonitor the provision and return rates of kits to identify any groups that have low rates of accessing or returning them. Take action to try to address the reasons for the low rates.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on self-sampling to improve the uptake and increase the frequency of STI testing\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0C: effectiveness, acceptability and cost effectiveness of strategies to improve uptake of STI testing\n\nevidence\xa0D: effective and cost-effective interventions to increase frequent STI testing in very high-risk groups.\n\nLoading. Please wait.\n\n## Tailoring interventions\n\nTailor interventions and information to the target users of the service. Where possible, ensure that interventions are available for other groups who may be excluded by this targeting. (See also recommendation 1.1.10.)\n\nRecognise people's individual needs. Be aware that membership of a particular group does not imply that a person is necessarily at higher risk of an STI. Address this with cultural sensitivity and competency within the context of sex-positive approaches.\n\nConsider personalising automated recall messages using low-level tailoring, for example adding the name of the person and clinician to the message. However, be aware of any potential risks of personalising messages, such as where there may be safety concerns.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on tailoring interventions to improve the uptake and increase the frequency of STI testing\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0C: effectiveness, acceptability and cost effectiveness of strategies to improve uptake of STI testing.\n\nLoading. Please wait.\n\n# Partner notification\n\nAdvise people diagnosed with an STI about the importance and benefits of partner notification, the possibility of sex partners being infected even if asymptomatic, and the risk of reinfection. Encourage them to engage in partner notification, regardless of where they are tested, and discuss the different methods of partner notification with them.\n\nHelp people decide how to notify their sex partners. Discuss ways of having these potentially difficult conversations and suggest ways to deliver this information. Discuss the best method of partner notification in light of the person's relationship status and other circumstances. Alternative methods of disclosure may need to be used in different contexts (for example, those who may be at risk of domestic violence, or if the person expresses a need for anonymity).\n\nIf a person feels unable to tell their sex partners about the STI or is showing signs of difficulty dealing with their diagnosis, refer them to specialist sexual health services that can offer them more support with partner notification.\n\nEnsure that there is a clear referral pathway to specialist sexual health services that can help with partner notification so that people can be referred seamlessly and without the need for self-referral.\n\nPartner notification on behalf of a person with an STI should be carried out by professionals with expertise in contact tracing and counselling in line with the British Association for Sexual Health and HIV (BASHH) statement on partner notification for sexually transmitted infections.\n\nConsider how geospatial networking apps (for example, Grindr or Tinder) may be used for partner notification, for example by:\n\nsuggesting that people who use geospatial networking apps to find sex partners use the apps to notify partners about contacting a sexual health service for STI testing\n\nusing app profiles to inform contacts of their need to be tested when notifying partners on behalf of a person with an STI.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on partner notification\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: partner notification methods to prevent or reduce STIs.\n\nLoading. Please wait.\n\n# HPV and hepatitis\xa0A and\xa0B vaccination in gay, bisexual and other men who have sex with men\n\nBe aware that gay, bisexual and other men who have sex with men are not the only groups eligible for human papillomavirus (HPV), hepatitis\xa0A and hepatitis\xa0B vaccination (see NHS information on HPV vaccine eligibility, hepatitis\xa0A vaccine eligibility and hepatitis\xa0B vaccine eligibility).\n\nConsult local gay, bisexual and other men who have sex with men to identify their needs and the barriers to vaccine uptake and course completion.\n\nOpportunistically promote HPV, hepatitis\xa0A and hepatitis\xa0B vaccination with gay, bisexual and other men who have sex with men who are eligible for the vaccines. Give them information on HPV, hepatitis\xa0A and hepatitis\xa0B vaccination, including:\n\nthe diseases and their potential severity\n\nthe risks and benefits of vaccination, including individual benefits and, if relevant, population benefits (protecting other people in their community)\n\nthe importance of having all doses of a vaccination course.\n\nWhere possible, consider providing HPV and hepatitis vaccination during other routine health appointments for gay, bisexual and other men who have sex with men.\n\nIdentify gay, bisexual and other men who have sex with men who do not return for follow-up vaccinations (second and third doses), and send reminders that highlight the importance of completing the course.\n\nSee also the NICE guideline on vaccine uptake in the general population.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on HPV and hepatitis\xa0A and\xa0B vaccination in gay, bisexual and other men who have sex with men\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: increasing uptake of hepatitis\xa0A, hepatitis\xa0B and HPV vaccinations in gay, bisexual and other men who have sex with men.\n\nLoading. Please wait.\n\n# Pre-exposure prophylaxis for HIV\n\nThese recommendations should be read together with NICE's guideline on HIV testing: increasing uptake among people who may have undiagnosed HIV.\n\n## Raising awareness of pre-exposure prophylaxis for HIV\n\nRaise awareness of pre-exposure prophylaxis (PrEP) among local groups with greater sexual health or access needs:\n\nUse methods designed to target specific populations (for example, social media and relevant local organisations or groups).\n\nFollow the advice in NICE's guideline on community engagement.\n\nPay particular attention to groups in which PrEP is less well-known or uptake is lower, such as trans people, cisgender women, young people (aged 16\xa0to\xa024), people with a Black African or Caribbean family background and people from a lower socioeconomic status background.\n\nGive relevant local community groups support and information resources to help them raise awareness of PrEP and increase trust in services.\n\nEnsure that people in groups with greater sexual health or access needs understand that PrEP is for HIV prevention only and that it does not protect against other STIs, therefore barrier methods are also important. See NICE's guideline on sexually transmitted infections: condom distribution schemes.\n\nCo-produce materials that target specific information gaps and causes of stigma within the target population.\n\nUse peer support to normalise PrEP use, reduce all forms of stigma (originating from the person themselves, professionals and the wider society) and increase trust in services.\n\nTell trans people undergoing medical transition that there are no clinically significant interactions expected between PrEP and the common hormones used in this process, and that using PrEP is not expected to affect their transition.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on raising awareness of PrEP for HIV\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: effectiveness, cost effectiveness, acceptability and unintended consequences of PrEP for HIV.\n\nLoading. Please wait.\n\n## Service design for PrEP services\n\nEnsure that services offering PrEP are welcoming and accessible (see recommendation 1.1.5) for all the different population groups who are eligible, for example by co-designing services with the key population groups. Ensure that tailoring services to specific communities does not exclude or alienate other eligible groups.\n\nRaise awareness among healthcare professionals (particularly those in primary care, community settings and gender identity clinics) about which groups of people are eligible for PrEP. This could be done through continuing education or through commissioning (for example, through local networks [see recommendation 1.1.3]).\n\nProvide protected time for healthcare professionals who have day-to-day contact with people eligible for PrEP to have training on relevant issues.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on service design for PrEP services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: effectiveness, cost effectiveness, acceptability and unintended consequences of PrEP for HIV.\n\nLoading. Please wait.\n\n## Access to PrEP services\n\nServices that do not provide PrEP should connect people who are interested in PrEP and eligible for it to a service that can prescribe it.\n\nEnsure there are clear referral pathways between services that do not provide PrEP and those that do.\n\nMake provision for people who want to be referred to services outside their local area or community.\n\nSee also recommendation 1.1.3.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on access to PrEP services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: effectiveness, cost effectiveness, acceptability and unintended consequences of PrEP for HIV.\n\nLoading. Please wait.\n\n## Prescribing PrEP\n\nRecommendations 1.5.13 to 1.5.19 support recommendations in the British HIV Association (BHIVA) and BASHH guidelines on the use of PrEP for HIV and should be implemented with reference to them.\n\nOffer PrEP to people at higher risk of HIV, using the criteria in the BHIVA/BASHH guidelines.\n\nSupport people who are taking PrEP, for example in decisions around the use of barrier methods and attending follow-up appointments. Continue to offer them all other relevant sexual health services, such as information, behavioural support and condom provision.\n\nSupport people who are taking PrEP to get regular HIV testing and STI screening (every 3\xa0months).\n\nGive people taking PrEP tailored information and education on effectiveness, adherence, side effects and monitoring risks (see NICE's guideline on shared decision making).\n\nFollow up people taking PrEP in line with the good practice points and monitoring recommendations in the BHIVA/BASHH guidelines.\n\nMonitor the kidney function of people taking PrEP, and any other adverse health events.\n\nHelp people taking PrEP to maximise adherence to treatment. Follow the general principles in NICE's guideline on medicines adherence and address factors specific to the use of PrEP, including those listed in the BHIVA/BASHH guidelines.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prescribing PrEP\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: effectiveness, cost effectiveness, acceptability and unintended consequences of PrEP for HIV.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local Act Personal Care and Support Jargon Buster.\n\n## Groups with greater sexual health or access needs\n\nThese groups have higher rates of sex partner change or less contact with the healthcare system than average.\n\nPeople are most at risk of STIs if they are involved in higher rates of condomless sex with multiple partners or frequently change partners. There may be more people practising these behaviours in some groups than others, but this does not mean that everyone in the group is necessarily at higher risk. For example, gay, bisexual and other men who have sex with men are a higher risk group for STIs and HIV, but this does not mean that every person in that group is at higher risk.\n\nSome people find it more difficult to access sexual health services because of the location of services (most services are in urban rather than rural settings) or because they do not know that they are eligible for free services (for example, some refugees or asylum seekers may not know this). Others may find it difficult to access services either because they do not know about them, because of physical accessibility issues, or because of language barriers, learning difficulties or stigma.\n\n## Pre-exposure prophylaxis (PrEP)\n\nA medicine that people at risk of HIV take to prevent them getting HIV. Normally it involves taking tablets every day (daily PrEP) but in some cases, it may mean taking tablets at particular times (event-based or on-demand PrEP).\n\n## Remote self-sampling\n\nThe person collects a sample themselves outside the clinic environment (for example, a swab or a urine sample) and sends it to a lab for analysis. This is different to self-testing, for which the person conducts the test and reads and interprets the result themselves.\n\n## Sex-positive approaches\n\nBeing non-judgemental, openly communicating and reducing embarrassment around sex and sexuality. Recognising the diversity of sexual experiences that exists and that sex can be an important and pleasurable part of many people's lives.\n\n## Sexual self-efficacy\n\nA person's sense of control over their sexual life and sexual health, and their ability as an individual to have safe, consensual and satisfying sex.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Availability of PrEP\n\nWhat is the effectiveness and cost effectiveness of providing pre-exposure prophylaxis (PrEP) outside sexual health services, and does this reach eligible population groups different from those who do access sexual health services?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on access to PrEP services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: effectiveness, cost effectiveness, acceptability and unintended consequences of PrEP for HIV.\n\nLoading. Please wait.\n\n## Mode of PrEP delivery\n\nWhat are the effectiveness, cost effectiveness, availability (eligibility status), adherence considerations, and short- and long-term adverse effects (including impact on bone density) of different modes of delivery, particularly long-acting PrEP (such as injections), including in women?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on prescribing PrEP\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: effectiveness, cost effectiveness, acceptability and unintended consequences of PrEP for HIV.\n\nLoading. Please wait.\n\n## Delivering effective sexual health services as part of other services\n\nHow can sexual health services best be delivered together with other services (for example, drug and alcohol services)?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on delivering and evaluating interventions to reduce sexually transmitted infection (STI) transmission\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: interventions to reduce the acquisition and transmission of STIs in higher risk groups\n\nevidence review\xa0B: qualitative evidence synthesis for the acceptability of interventions for reducing or preventing the acquisition and transmission of STIs.\n\nLoading. Please wait.\n\n## Tailoring outreach services\n\nHow can outreach be tailored to specific groups to increase their access to sexual health services and their uptake of STI testing?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on meeting the needs of groups with greater sexual health or access needs\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: interventions to reduce the acquisition and transmission of STIs in higher risk groups\n\nevidence review\xa0B: qualitative evidence synthesis for the acceptability of interventions for reducing or preventing the acquisition and transmission of STIs.\n\nLoading. Please wait.\n\n## Reducing stigma\n\nWhat are the most effective and cost-effective methods of reducing the stigma associated with accessing sexual health services?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale and impact section on co-producing interventions to reduce STI transmission\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: interventions to reduce the acquisition and transmission of STIs in higher risk groups\n\nevidence review\xa0B: qualitative evidence synthesis for the acceptability of interventions for reducing or preventing the acquisition and transmission of STIs\n\nevidence review\xa0D: effective and cost-effective interventions to increase frequent STI testing in very high risk groups.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Value of incentives\n\nWhat incentives are effective and cost effective in increasing STI testing and diagnosis, and what, if any, are the adverse and unintended consequences?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on self-sampling to improve the uptake and increase the frequency of STI testing\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0C: effectiveness, acceptability and cost effectiveness of strategies to improve uptake of STI testing\n\nevidence review\xa0D: effective and cost-effective interventions to increase frequent STI testing in very high risk groups.\n\nLoading. Please wait.\n\n## Vaccination course completion\n\nWhat factors affect whether people complete the full course of hepatitis\xa0A and\xa0B or human papillomavirus (HPV) vaccinations and how do people think they might be encouraged to complete it?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on HPV and hepatitis\xa0A and\xa0B vaccination in gay, bisexual and other men who have sex with men\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: increasing uptake of hepatitis\xa0A, hepatitis\xa0B and human papillomavirus (HPV) vaccinations in gay, bisexual and other men who have sex with men.\n\nLoading. Please wait.\n\n## Eligibility for PrEP\n\nWhat is the cost effectiveness of providing PrEP to people who do not report recent condomless sex?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on raising awareness of pre-exposure prophylaxis for HIV\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: effectiveness, cost effectiveness, acceptability and unintended consequences of PrEP for HIV.\n\nLoading. Please wait.\n\n## Remote self-sampling\n\nHave people's attitudes to remote self-sampling and regular testing for STIs changed as a result of self-sampling for COVID‑19?\n\nWhat are the effectiveness and adverse outcomes of self-sampling for people with symptoms, if remote triage (for example, phone triage) indicates that this is appropriate?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on self-sampling to improve the uptake and increase the frequency of STI testing\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0C: effectiveness, acceptability and cost effectiveness of strategies to improve uptake of STI testing\n\nevidence review\xa0D: effective and cost-effective interventions to increase frequent STI testing in very high risk groups.\n\nLoading. Please wait.\n\n## Delivering effective sexual health services\n\nWhat are the experiences of LGBT+ people in accessing STI testing services, including online?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on tailoring interventions to improve the uptake and increase the frequency of STI testing\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0C: effectiveness, acceptability and cost effectiveness of strategies to improve uptake of STI testing\n\nevidence review\xa0D: effective and cost-effective interventions to increase frequent STI testing in very high risk groups.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice or services.\n\n# Accessing sexual health services\n\nRecommendations 1.1.1 to 1.1.3\n\n## Why the committee made the recommendations\n\nThe committee considered who should be offered interventions and when, noting that often, the people who most need support with their sexual health and wellbeing are those least likely to access services. They also noted that people who do access services may be doing so because they have had sex that they perceive to have been unsafe. The committee noted the importance of sexual history taking in this context. They agreed this could help to identify issues such as sexual violence and exploitation, coercion, and drug and alcohol use in the context of sex. They noted the British Association for Sexual Health and HIV (BASHH) 2019 UK National Guideline for consultations requiring sexual history taking as an example of good practice.\n\nThe committee recognised the value of collaborative working and the importance of supporting people to access services that already deliver suitable interventions. However, they also acknowledged regional variations in provision and that many tailored interventions for higher risk minority groups do not exist outside London. They agreed that the responsibility should be on services to support people in accessing the service that is right for them rather than just leaving it up to the person. They agreed that a single service was unlikely to meet the needs of every person and highlighted the importance of networks of services and clear pathways into them.\n\nThe committee noted that some people did not realise that services were confidential and open access (that is, they are free for anyone to use). Those people might not access services because they thought they were not entitled to do so, that they would have to pay, or that their data might be shared with other organisations. Therefore, the committee agreed it was important to ensure that staff and people who use services know about this.\n\n## How the recommendations might affect practice or services\n\nExisting clinic appointments could be used to identify people with greater sexual health or access needs and signpost them to appropriate services. However, additional appointment time would be needed for conversations about sexual wellbeing and risk reduction, particularly if brief motivational interviewing, cognitive behavioural therapy or condom-focused interventions are used.\n\nChanging settings in which services are delivered could have a cost impact because services may need to be moved or started up, but reducing barriers to access those services need not be resource intensive. The committee noted that fairly simple changes can make a large difference to people's ability to access services.\n\nReturn to recommendations\n\n# Meeting the needs of groups with greater sexual health or access needs\n\nRecommendations 1.1.4 and 1.1.5\n\n## Why the committee made the recommendations\n\nThe committee discussed how the wider determinants of health can influence sexual health and wellbeing. These include stigma, discrimination faced by those who are part of a minority group, housing instability, poverty, substance use, mental health and intimate partner violence. They agreed that it is important to consider the social, cultural, emotional and economic aspects of a person's life when seeking to address their sexual risk behaviour. The committee also recognised that sexually transmitted infection (STI) incidence is just 1\xa0aspect of sexual health, and that taking a broad perspective that encompasses wider aspects of sexual wellbeing is important.\n\nThe committee agreed that interventions and services should be targeted at people with greater sexual health and access needs because that represents the most effective and cost-effective strategy. They discussed the complexity of reaching individual people with greater sexual health and access needs rather than targeting everyone in higher risk groups because not all people in higher risk groups need sexual health support or interventions. However, by targeting higher risk groups, individuals needing help would benefit. The committee recognised that local areas vary in their cultural and demographic profiles and agreed that data from various sources (including the Joint Strategic Needs Assessment [JSNA] and relevant health equity audits) should be used to commission and provide services to meet local need. They agreed that although it was important to engage with groups with greater sexual health or access needs, in many cases it would be challenging to do so.\n\nThe committee discussed the evidence specific to each of the higher risk groups and agreed that interventions should be tailored to the needs of specific groups, such as gay, bisexual and other men who have sex with men, or trans people. However, they noted that the degree of intersectionality and the likely variation in experiences and identities within these groups made group-specific recommendations somewhat problematic. They agreed that there was little evidence about how to tailor outreach services to best meet the needs of specific groups to improve their access to sexual health services and uptake of STI testing, although expert testimony provided some promising examples. Therefore, they made a recommendation for research on tailoring outreach services. The committee also considered the evidence for culturally relevant interventions and agreed that interventions should be culturally competent.\n\nThe committee discussed the expert testimony about the inclusion health agenda and their own expertise and experience of reducing barriers to services for people from underserved groups (those who existing services are not accessible to). They noted that a key part of service accessibility was about avoiding assumptions about things like gender or sexuality, or being judgemental about people's relationships or sexual practices. The committee noted that staff may need additional training to do this.\n\n## How the recommendations might affect services\n\nTargeting interventions at groups in which greater sexual health needs have been identified locally will make the use of resources more efficient by ensuring that they are used where they are most needed. Identifying groups will make use of existing data, for example from the JSNA or from STI diagnosis data, and will not have a large resource impact. However, the committee agreed that this could be challenging because the data may be limited or not as robust. Engaging with groups with greater needs is already good practice in sexual health and should not have an impact on resources.\n\nReturn to recommendations\n\n# Co-producing interventions to reduce STI transmission\n\nRecommendations 1.1.6 to 1.1.10\n\n## Why the committee made the recommendations\n\nCommittee members suggested that the most effective way to ensure that interventions and services meet the needs of specific groups, communities or cultures is to plan, design and implement them in consultation with the people who will be using them (co-production). This was supported by the broader evidence and expert testimony. It helps to ensure that they are culturally sensitive and appropriate to the group they are for. They noted that further research was needed to understand and reduce the stigma associated with accessing sexual health services, and therefore made a recommendation for research\xa0on the most effective and cost-effective methods of reducing stigma.\n\nThe committee considered evidence for a range of interventions designed to reduce sexual risk and prevent STIs. The evidence was mixed, with some studies showing no effect on sexual health outcomes and other studies showing a positive impact on condom use, STI incidence and sexual health knowledge. No single intervention type emerged as consistently or substantially effective. Motivation-based approaches, cognitive behavioural therapy and cognitive approaches, condom-focused approaches and culturally relevant interventions all performed comparatively well compared with no intervention. Based on this evidence and their experience, the committee agreed that interventions should aim to adopt a multi-model approach by incorporating components from some or all of these approaches, and that people designing interventions should look at NICE's guidance on behaviour change. The committee also agreed that all interventions should be sex and identity positive – that is, they should recognise the broad range of people's sex lives and their identities without being judgemental.\n\nThe committee noted the evidence for condom-focused approaches and agreed that condom use is a fundamental method of preventing STIs. Therefore, supporting people to use condoms correctly and consistently is important. They agreed that condom-positive approaches would be most effective, with a focus on pleasure, the wide variety of condoms available, the importance of fit and feel, barriers to use and strategies for negotiating use. They also noted the importance of both internal and external condoms. They agreed that demonstrations of condom use were also valuable, particularly if people were given the opportunity to practise.\n\nThe committee agreed that motivation-based approaches such as motivational interviewing were useful for risk-reduction interventions but recognised that the evidence for their effectiveness was mixed. They heard expert testimony from organisations delivering motivation-based interventions, which helped them to better understand how well these approaches work, who they may be most suited to and the best way to deliver them.\n\nThe committee agreed that, given the challenging life contexts in which many people with greater sexual health needs live, it is important to offer people support to develop their understanding of the link between emotions and sexual wellbeing, stress management and coping skills, and that these should be incorporated into sexual risk reduction interventions. They discussed that cognitive behavioural approaches were particularly useful for addressing psychological aspects of sexual wellbeing and the evidence to some extent supported this.\n\n## How the recommendations might affect services\n\nThe committee agreed that co-produced interventions were far more likely to be effective and therefore cost effective because they would be better suited to the people they were serving. They agreed that although co-production does have a resource impact compared with usual planning and commissioning, it need not be significant and it is already widely used in other areas of the public sector.\n\nReturn to recommendations\n\n# Delivering and evaluating interventions to reduce STI transmission\n\nRecommendations 1.1.11 to 1.1.15\n\n## Why the committee made the recommendations\n\nThe setting of interventions is important. The committee discussed current sexual health provision across primary care, sexual health services and third sector organisations and agreed that people should be able to attend the service most suited to them. They also agreed that online services were an integral and important part of this.\n\nThe committee also discussed the importance of Making Every Contact Count. They agreed that 1\xa0of the ways that people could be encouraged to use sexual health services was to provide them as part of broader support services, for example drug and alcohol services, HIV care and mental health services. They agreed it was important to take into account that people's sexual health is only 1\xa0aspect of their overall wellbeing. The committee were unaware of research about the most effective ways to deliver sexual health services together with other services and made a recommendation for research on delivering effective sexual health services as part of other services.\n\nThe committee agreed that co-producing interventions would help people to decide if interventions were best delivered in one-to-one or group settings (this might also relate to considerations about safety and stigma).\n\nThe committee considered the evidence for peer delivery and, in combination with their experience, agreed that interventions were best delivered by peers if possible. The committee clarified their understanding of peers as people with a shared identity with the target group or another person who they could relate to, and that the ability to empathise and understand the person's needs and life context was crucial. Committee members with experience of commissioning and delivering peer-led interventions emphasised the value and effectiveness of this approach.\n\nThe committee agreed that it was important for people delivering interventions to do so in ways that respected people's identities and choices, for example by using gender-neutral pronouns until a person expressed a preferred pronoun. They also discussed the importance of using those pronouns in written records – currently most written records have limited options and use a 'tick box' approach to gender and sexual identity.\n\nThe committee agreed that because the interventions were not based on strong evidence that it was important to evaluate them regularly and use the results of the evaluation to improve services and pathways. They noted that resources were available that could help with this, such as the UK Health Security Agency's (previously Public Health England) sexual health, reproductive health and HIV services: evaluation resources.\n\n## How the recommendations might affect services\n\nIncreased awareness of personal risk may lead to more people accessing STI testing services, which may affect service capacity and allocation of resources in clinics that deliver STI testing. However, the committee expect sexual health services in general to be providing cost-effective interventions and care, so even if more people using them increases costs, that is likely to be a cost-effective use of resources.\n\nEvaluating interventions should already be inbuilt into all intervention delivery and therefore will not have a resource impact.\n\nReturn to recommendations\n\n# Self-sampling to improve the uptake and increase the frequency of STI testing\n\nRecommendations 1.2.1 to 1.2.6\n\n## Why the committee made the recommendations\n\nThe committee were satisfied that the evidence supports the use of STI testing outside clinical services using self-sampling kits for people who are asymptomatic. They agreed that it encourages people who have previously never engaged with sexual health services to come forward for testing, so widening access to these kits would be a good thing. They noted that being able to access kits from a variety of locations could increase uptake. Possible locations include community pharmacies, which are already an integral part of test kit provision in some areas. However, these services would need to be commissioned.\n\nThe committee agreed that local service websites needed to be kept up to date about available options so that people knew what was available in their area and how to access it. However, they noted that the 'digital divide' could potentially widen health inequalities because not everyone who might want to order a remote self-sampling kit would necessarily have access to online ordering services. They also agreed that knowing who was accessing remote self-sampling would highlight groups where there may be inequalities in uptake. Services could then be tailored to address this.\n\nThere is regional variation in whether remote self-sampling is offered and how many kits are available. In locations that do offer it, not everyone who is eligible can have a test kit. This is because the demand for these kits is often greater than the supply and kits are not always returned, so there is some concern about wasting money if the return rate is low. As a result, the committee were aware that some areas were capping the number of kits available, creating a tension between widening access and limiting the number of kits. The committee therefore agreed that services should monitor kit return rates in different populations to ensure they were meeting the populations' needs. They also noted that there can be unintended consequences as a result of not having direct contact with a clinician. For example, a person with a positive test may not go to a service and there might be a missed opportunity to treat an STI and to start partner notification. They agreed remote self-sampling was an important option for testing, but not the only option.\n\nIn committee members' experiences, self-sampling is suitable for STIs, but tests that need a blood sample, such as syphilis, are more challenging to complete so are more likely to be returned in an unsuitable state for analysis. Antibodies from previous infections can also result in initially reactive results that need confirmation through a test at a clinic. In spite of this, they agreed that the tests offered through self-sampling should be the same as those offered in clinic so that people using the service would not be at a disadvantage. They concluded that remote self-sampling should be part of a suite of testing options and be aimed primarily at people without symptoms.\n\nCommittee members highlighted the self-efficacy needed to access, complete and return tests and to understand the implications of the results. They discussed how some people might have difficulty accessing the right tests for their anatomy or understanding the instructions. Therefore, they agreed on the importance of ensuring that kits meet accessibility and inclusivity standards. They noted the usefulness of resources such as BASHH guidance for the design of self-sampling packs and associated support for self-sampling processes within sexually transmitted infection and blood borne virus testing.\n\nThe committee were aware that during the COVID‑19 pandemic, some areas had used remote self-sampling after telephone triage for people who had symptoms. The evidence was unclear about this, so the committee made a recommendation for research to assess the effectiveness and adverse outcomes of self-sampling for people with symptoms. Overall, they agreed that it was better to attend a clinic if symptoms were present, but acknowledged that in extenuating circumstances (for example, during the COVID‑19 pandemic), using self-sampling kits even for some symptomatic people was better than not testing them at all. They were interested to know whether people's attitudes to home-based self-sampling and regular testing for STIs had changed as a result of the self-sampling for COVID‑19 that most people have undertaken, and made a recommendation for research on people's attitudes to remote self-sampling.\n\nThe committee agreed that increasing the uptake of testing was only 1\xa0part of the solution and that re-testing and prompt treatment were also important aspects of STI prevention. They noted the BASHH standards for the management of sexually transmitted infections specify that people should be offered an appointment within 2\xa0days of contacting the service.\n\nThe committee discussed the lack of evidence for the value of incentives in encouraging uptake of STI testing, but agreed there needed to be further research on this and made a recommendation for research on the value of incentives. They also discussed the lack of evidence for improving the uptake of testing in people from very high-risk groups such as sex workers and men who engage in group sex under the influence of stimulant drugs (such as methamphetamine or mephedrone), typically with multiple partners (so-called chemsex). Although there was a lack of evidence, the committee agreed that the recommendations they had made would be applicable to these groups.\n\n## How the recommendations might affect services\n\nThe committee agreed that most local areas are already providing some kind of asymptomatic remote self-sampling service, often as part of larger collaboratives. However, they noted that recommendations to widen access to this might have a cost impact. Although remote self-sampling is a cheaper method of testing than in clinic, the extra positive cases detected mean there will be an overall increase in costs. It would be important to monitor things like return rates for kits and positive test result rates to determine whether broader testing was identifying more people with STIs. They were also satisfied that the evidence supported a strategy of offering remote self-sampling as being cost effective compared with clinic only testing, but that this was very sensitive to the return rate of the self-sampling kits.\n\nReturn to recommendations\n\n# Tailoring interventions to improve the uptake and increase the frequency of STI testing\n\nRecommendations 1.2.7 to 1.2.9\n\n## Why the committee made the recommendations\n\nThe committee agreed that it was important to target information to the groups identified in the recommendations on preventing transmission (for example, a website could be tailored towards particular communities that are at higher risk), and that the same considerations about co-producing information materials with the target groups and communities meant that information about testing would be more likely to make an impact. But they were also aware that this should not exclude other groups.\n\nThe committee reiterated that people providing services need to look at those using services holistically rather than assuming they are at risk because they are members of a group with a high incidence of STIs.\n\nThe evidence showed that individually tailored interventions were effective, whereas motivational interventions without tailoring were not. The committee thought that this was consistent with previous discussions about cultural competence in targeting interventions to specific groups. They decided that detailed and specific tailoring may be too resource intensive in practice, so favoured low-level personalisation such as adding names and demographic-specific information to communications. They noted that 'opt-in' automated recall messages are already widely used, but additional safety concerns may need to be taken into account when personalising those messages.\n\nThe committee were interested in the experiences of LGBT+ people in accessing STI testing services, including online services, and made a recommendation for research on delivering effective sexual health services. They believed this could improve services for LGBT+ people in the future.\n\nThe committee discussed the lack of evidence for improving the uptake of testing in people from very high-risk groups such as sex workers and men who engage in sex under the influence of stimulant drugs (such as methamphetamine or mephedrone), typically with multiple partners (so-called chemsex). Although there was a lack of evidence, the committee agreed that the recommendations they had made would be applicable to these groups.\n\n## How the recommendations might affect services\n\nThe committee agreed that low-level tailoring of interventions would mostly involve modifying things that are already being done and need not have a substantial resource impact.\n\nReturn to recommendations\n\n# Partner notification\n\nRecommendations 1.3.1 to 1.3.6\n\n## Why the committee made the recommendations\n\nThe committee acknowledged that any type of partner notification is beneficial. It is 1\xa0of the most important ways of preventing reinfection and reducing the transmission of STIs. It also ensures that partners have the opportunity to be tested and, if necessary, have their STI treated. They noted the importance of discussing these benefits with people newly diagnosed with an STI, including both the personal benefits and benefits to their sexual partners.\n\nThe committee noted the importance of making people aware of the different partner notification methods, and providing information about the methods available to them may support their decision making. The quantitative and qualitative evidence supported the committee's view that patient-led referral to sexual health services may be particularly beneficial for both index patients and their partners. They also recognised the benefits of other methods of partner notification, such as provider referral or online partner notification in certain contexts (for example, if the person feels unable to make the referral themselves).\n\nThe committee recognised that partner notification could lead to negative responses from partners, including the potential for violence. Although experiences of violence or compromised patient safety were not reported in any of the included qualitative studies, the committee agreed that they remain a potentially adverse consequence that needs to be taken into account. They therefore discussed the need for recommendations about patient safety and patient choice, and acknowledged that there may be situations in which partner notification is not appropriate. The committee also noted that their clinical responsibility was to the index patient and not their sex partners, although the needs and preferences of partners being notified remain important.\n\nThe committee considered other potential harms of partner notification, including unintended disclosure of relationship, sexuality or STI status. They recognised the importance of anonymity and confidentiality for all partner notification methods but did not consider it necessary to make specific recommendations about patient confidentiality because this is standard practice for all healthcare professionals. However, the committee agreed that when telling people about the partner notification methods available, it is important to highlight the option to maintain anonymity. They noted that provider referral may be the most appropriate method when the person expresses a desire to remain anonymous.\n\nThe committee discussed anonymous sex arranged using geospatial networking apps and websites and how this made partner notification difficult. They noted that there was a potential to use these apps for partner tracing and notification if the person did not know their partner's name or contact details. They agreed that this could be done by the person themselves, and were aware that some services set up profiles on these apps for the purposes of anonymous partner notification.\n\n## How the recommendations might affect practice\n\nThese recommendations are already within the scope of practice of services that undertake partner notification, so there should be no additional cost. Some services may need to improve their practices in this area, which may have a modest resource impact (for example, increasing the length of appointments).\n\nReturn to recommendations\n\n# HPV and hepatitis\xa0A and\xa0B vaccination in gay, bisexual and other men who have sex with men\n\nRecommendations 1.4.1 to 1.4.5\n\n## Why the committee made the recommendations\n\nThe committee were aware that a NICE guideline on improving vaccine uptake in the general population was being developed and agreed that it would be important to consider the recommendations in that guideline when thinking about human papilloma virus (HPV) and hepatitis vaccinations. They also noted that the scope of this guideline asked very specifically about vaccinations for gay, bisexual and other men who have sex with men but that the eligibility criteria for these vaccinations were broader than just that group. The committee saw very little evidence about the effectiveness of interventions to increase the initial uptake of HPV and hepatitis vaccinations, and less evidence on whether interventions improved course completion. As a result, they felt unable to recommend specific interventions to increase vaccine uptake, and therefore made a recommendation for research on vaccination course completion.\n\nThe committee saw qualitative evidence about the perceived barriers to vaccination among gay, bisexual and other men who have sex with men and agreed that this supported their expertise and experience. On this basis, they agreed on the need to encourage all healthcare professionals to opportunistically discuss vaccination and explain the importance of completing the full course of vaccinations. They also discussed that many gay, bisexual and other men who have sex with men still find it difficult to discuss their sexual health needs with healthcare professionals, so it was important for organisations to consider ways to make services more accessible. They agreed that the Department of Health and Social Care's 'You're welcome' quality criteria, although specifically aimed at young people, modelled good practice that could also be used for other groups (see also recommendation 1.1.3). They noted that in their view and experience, many men did not return for their follow-up vaccines. They agreed that it was important to highlight this, and the need to follow those men up, by making a recommendation.\n\nAlthough they did not see any evidence to support it, the committee agreed that in their experience, uptake might be increased by providing these vaccines during other routine health appointments for gay, bisexual and other men who have sex with men. However, they acknowledged that this will be limited by the availability of vaccines in alternative settings.\n\n## How the recommendations might affect practice\n\nThe committee agreed that these recommendations would not have a large impact on resource use. Sexual health services should already be providing information about vaccination to gay, bisexual and other men who have sex with men who are eligible for vaccination, and many primary care providers already offer these vaccines. Providing vaccinations alongside existing services should be a more efficient method of delivery, where this is possible.\n\nThe committee also noted that because these vaccines had already been assessed as being cost effective by the Joint Committee on Vaccination and Immunisation, an increase in the number of people being vaccinated should also be cost effective.\n\nReturn to recommendations\n\n# Raising awareness of pre-exposure prophylaxis for HIV\n\nRecommendations 1.5.1 to 1.5.6\n\n## Why the committee made the recommendations\n\nThe committee agreed that increasing uptake of pre-exposure prophylaxis for HIV (PrEP) among eligible populations was the highest priority. The evidence showed differing experiences and beliefs about PrEP for different populations, so they wanted to target populations that had negative experiences or are less engaged. With this in mind, they agreed that local groups with greater sexual health or access needs were an appropriate target for awareness raising, in line with NICE's guideline on community engagement and HIV Prevention England's PrEP health promotion campaign guidance. They agreed that particular attention needed to be paid to groups in which uptake of PrEP is lower, such as cisgender women with a Black African family background. They cautioned that it was also very important to make sure that people knew that PrEP was for HIV prevention specifically and that it did not protect against other STIs. The committee noted that the eligibility criteria for PrEP currently restricted it to people who reported recent condomless sex. They were therefore interested in whether providing PrEP to people who do not report recent condomless sex would also be cost effective, and made a recommendation for research on eligibility for PrEP.\n\nThe evidence showed that people are more likely to trust those from their own community or group when it came to information about PrEP. So the committee agreed that engaging with peers was a good way to normalise PrEP use and reduce both stigma and mistrust in services. They noted qualitative findings (from research predating more widespread use of PrEP) that stereotyped people who use PrEP as promiscuous or reckless. They also agreed that co-producing materials with those communities and groups could help to challenge stigma.\n\nThe committee noted that trans people in qualitative studies frequently expressed concerns about potential interactions between PrEP and gender-affirming hormones and the possibility of PrEP interfering with their transition. The committee reported information from the University of Liverpool's HIV drug interaction checker, which they agreed was robust based on communication with the University of Liverpool about the methodology underpinning the checker. This showed that there were no interactions expected, and thought that education was needed to raise awareness of the safety of PrEP for those undergoing medical transition. The committee agreed it was important to use this information to reassure potential PrEP users because participants with these concerns expressed that they would prioritise their transition above HIV prevention and may avoid PrEP because of this uncertainty.\n\nThe committee noted the importance of the Department of Health and Social Care's Towards zero: the HIV action plan for England (2022 to 2025), which was published after this guideline was drafted. They agreed that the action plan was consistent with this guideline and welcomed it.\n\n## How the recommendations might affect practice and services\n\nAdditional resources will be needed to train healthcare professionals on the needs of populations eligible for PrEP. If the total time allotted for training does not increase, this training will come at the expense of other training options.\n\nExisting appointments can be used to identify people eligible for PrEP and signpost them to appropriate services, but this might add to the time needed for each appointment to cover the additional conversations about PrEP.\n\nReturn to recommendations\n\n# Service design for PrEP services\n\nRecommendations 1.5.7 to 1.5.9\n\n## Why the committee made the recommendations\n\nThe committee were concerned that access to services is a barrier to PrEP uptake. The evidence suggested that this is because PrEP is only provided at sexual health clinics (in line with current NHS England commissioning policy) and that some groups are less likely to seek healthcare in this setting. Conversely, some committee members thought that PrEP should only be prescribed by healthcare professionals with knowledge of it and training in sexual health, which would generally mean only in a sexual health clinic.\n\nThe committee agreed that it is important that healthcare professionals in primary care, community settings and gender identity clinics are aware of who is eligible for PrEP, regardless of whether the setting provides it. This means that they will be better able to refer eligible people to services where PrEP can be provided. They agreed that healthcare professionals needed training about this. They acknowledged that some populations face particular barriers to accessing PrEP services in sexual health clinics.\n\nThe qualitative evidence indicated that some groups, particularly LGBT+ people, thought that healthcare professionals did not understand their sexual practices and individual risk factors. This led to them feeling uncomfortable discussing sexual health and being worried about feeling judged, therefore making it harder for them to start conversations about PrEP.\n\n## How the recommendations might affect practice and services\n\nAdditional resources will be needed to train healthcare professionals on the needs of populations eligible for PrEP. If the total time allotted for training does not increase, this training will come at the expense of other training options.\n\nIncreased uptake of PrEP is likely to have an impact on service capacity and allocation of resources in clinics that deliver PrEP and provide monitoring and testing for PrEP users. Clinics may need additional funding or expansion of services to meet increased demand. However, PrEP itself is a highly cost-effective intervention and therefore this should be a cost-effective use of resources.\n\nReturn to recommendations\n\n# Access to PrEP services\n\nRecommendations 1.5.10 to 1.5.12\n\n## Why the committee made the recommendations\n\nIn addition to making existing services more accessible, the committee were interested in the possibility of offering PrEP in other settings. However, they agreed that more evidence was needed on the effectiveness of doing this before they could recommend specific actions, therefore they made a recommendation for research\xa0on the availability of PrEP. They thought that, for now, increasing awareness of eligibility and enabling wider services to refer people to PrEP clinics was more important than prescribing PrEP in other settings. They agreed that there needs to be clear pathways for healthcare professionals who cannot or do not provide PrEP to support people in accessing services that prescribe it, and that the responsibility for this should lie with the healthcare professional. The committee agreed that this meant it was important for people to be able to access services outside of their local area or community.\n\n## How the recommendations might affect practice and services\n\nAdditional resources will be needed to train healthcare professionals on the needs of populations eligible for PrEP. If the total time allotted for training does not increase, this training will come at the expense of other training options.\n\nExisting appointments can be used to identify people eligible for PrEP and signpost them to appropriate services, but this might add to the time needed for each appointment to cover the additional conversations about PrEP.\n\nReturn to recommendations\n\n# Prescribing PrEP\n\nRecommendations 1.5.13 to 1.5.19\n\n## Why the committee made the recommendations\n\nThe committee recognised the evidence for the effectiveness of PrEP and thought that it was important for all groups outlined in the BASHH/BHIVA (British HIV Association) guidelines to be able to access it according to the risk criteria in these guidelines.\n\nThe committee agreed that the available economic evidence showed PrEP to be cost effective in a population of gay, bisexual and other men who have sex with men at higher risk of HIV (matching the criteria in the BASHH/BHIVA guidance). They also agreed that the findings should be generalisable to other populations at equivalent risk of HIV, as both the potential benefits and costs in those populations should be similar. The evidence also suggested that PrEP would remain cost effective in these populations regardless of potential unintended consequences (such as changes in condom use). Therefore, they were confident that these potential consequences did not need to result in any restrictions made to people eligible for PrEP.\n\nThe committee recognised from the evidence that the effectiveness of PrEP directly corresponded to adherence, so it is vital that people taking it are made aware of this and given support to take it as prescribed (see NICE's guideline on medicines adherence). They recognised that some people might experience barriers to adherence, so promoting knowledge and understanding about PrEP would be important for these people. The committee agreed that anyone taking PrEP needed knowledge of the risks involved (HIV, antiretroviral drug resistance) in not adhering to the treatment.\n\nThe committee recognised the importance of adherence to PrEP, the risk of adverse events and the potential relationship between these. So they agreed that clinical follow\xa0up of anyone taking PrEP was important and that the BASHH/BHIVA good practice points could be followed. The committee agreed that people who buy their own PrEP should also be able to access clinical follow\xa0up and monitoring via NHS services.\n\nThe committee were also interested in the potential adherence benefits of offering long-acting PrEP (for example, by injection) and noted that some people may prefer it to taking tablets on a daily or frequent basis (depending on the kind of PrEP they are using). However, they thought there was insufficient evidence to recommend long-acting PrEP and that research was needed to establish whether it is as effective as daily (or frequent) PrEP tablets. Therefore, they made a recommendation for research\xa0on mode of PrEP delivery.\n\nThe evidence also suggested some adverse effects associated with PrEP use (such as kidney or gastrointestinal symptoms). The committee recognised that people needed to be made aware of these so they could make an informed choice and manage their symptoms (see NICE's guideline on shared decision making). They noted that the evidence for increased risk of kidney problems corresponded to their own knowledge of how PrEP works pharmacologically. They therefore agreed that monitoring the renal health of those taking PrEP was important. Although the committee were aware of evidence showing that bone-mineral density will rebound after stopping PrEP, there was a lack of data on this for young people who have not yet reached their peak bone density (see the recommendation for research on mode of PrEP delivery).\n\nThe committee discussed the risk of antiretroviral therapy resistance in prescribing PrEP to people who were HIV positive and strongly supported current guidelines about the importance of regular HIV testing and the requirement for a negative HIV test before prescribing.\n\nThe committee noted that ongoing research seemed to be showing an association between people taking PrEP and an increase in STI rates, but they emphasised that it was not clear whether there was any causal link. They discussed several other plausible reasons for the association and agreed that it will be important to see how the evidence develops. They agreed on the value of providing condoms and behavioural support to this high-risk population, and that they should have regular screening for other STIs.\n\n## How the recommendations might affect practice and services\n\nIncreased uptake of PrEP is likely to have an impact on service capacity and allocation of resources in clinics that deliver PrEP and provide monitoring and testing for PrEP users. Clinics may need additional funding or expansion of services to meet increased demand. However, PrEP itself is a highly cost-effective intervention and therefore this should be a cost-effective use of resources.\n\nReturn to recommendations", 'Context': 'Sexually transmitted infections (STIs) can affect personal wellbeing, mental health and relationships. They can also lead to serious health problems including pelvic inflammatory disease, ectopic pregnancy and infertility. The rates of STIs are highest in young people aged\xa015 to\xa024; people from a Black family background; and gay, bisexual and other men who have sex with men.\n\nIn 2020, there were 3,482,700 consultations at sexual health services and\xa0317,901 diagnoses of new STIs in England. This was a decrease of\xa010% and\xa032%, respectively, compared with 2019, but this largely reflects the rapid reconfiguration of sexual health service delivery in response to the COVID‑19 pandemic. But the number of internet consultations doubled from 511,979 to 1,062,157 over the same period. Sexual health services carried out 1,649,429 sexual health screens (tests for chlamydia, gonorrhoea, syphilis or HIV) in 2020, a\xa025% decrease compared with 2019.\n\nNew HIV diagnoses have declined over the past decade, with a substantial decrease during 2019 (4,139 cases, a\xa010% fall from\xa04,580 in 2018). This recent reduction has been mostly driven by fewer HIV diagnoses among gay and bisexual men, which have decreased by 47% since 2014. There is also an ongoing human papillomavirus (HPV) vaccination programme for gay, bisexual and other men who have sex with men. The vaccine is recommended for all men up to and including the age of\xa045 who have sex with men.\n\nSocial and sexual networking apps have made it easier to buy recreational drugs. People who use drugs during sex are more likely to report unsafe sexual behaviours than those who do not.\n\nMycoplasma genitalium is being increasingly recognised as a public health concern because of its relatively high prevalence (1% to 2% of the general population) and high levels of antimicrobial resistance, along with already recognised drug-resistant gonorrhoea.\n\nSexually transmitted infections are a major public health concern and are costly to healthcare services. Although the COVID‑19 pandemic has reduced the diagnosis rates of STIs, this has coincided with a decrease in sexual health screening caused by the disruption to service provision. The overall trends continue to rise. Together with new evidence identified, this highlights the need for an updated guideline on this topic.'}	https://www.nice.org.uk/guidance/ng221	This guideline covers interventions to prevent sexually transmitted infections (STIs) in people aged 16 and over. It aims to reduce the transmission of all STIs, including HIV, and includes ways to help increase the uptake of STI testing and vaccines for human papillomavirus (HPV) and hepatitis A and B.
e62202baaa8cd2e52b9a20f78641a42675abae33	nice	Venetoclax for treating chronic lymphocytic leukaemia	Venetoclax for treating chronic lymphocytic leukaemia Evidence-based recommendations on venetoclax (Venclyxto) for chronic lymphocytic leukaemia in adults. # Recommendations Venetoclax monotherapy is recommended, within its marketing authorisation, for treating chronic lymphocytic leukaemia (CLL) in adults: with a 17p deletion or TP53 mutation and when a B‑cell receptor pathway inhibitor is unsuitable, or whose disease has progressed after a B‑cell receptor pathway inhibitor or without a 17p deletion or TP53 mutation, and whose disease has progressed after both chemo‑immunotherapy and a B‑cell receptor pathway inhibitor.It is recommended only if the company provides venetoclax according to the commercial arrangement. Why the committee made these recommendations This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for venetoclax for CLL. People with CLL for whom venetoclax monotherapy would be an option would otherwise usually have best supportive care. This includes rituximab and high-dose methylprednisolone. The new evidence is mainly data collected from the Systemic Anti-Cancer Therapy (SACT) database from people having treatment in the NHS, while venetoclax was available in the Cancer Drugs Fund in England. The benefit of venetoclax is uncertain because the original trials did not compare it with best supportive care, and no SACT data could be collected on best supportive care. Venetoclax meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost‑effectiveness estimates are around the range that NICE considers to be an acceptable use of NHS resources for end of life treatments. Venetoclax also fulfils an unmet need and is a valued treatment option. Therefore, it is recommended.# Information about venetoclax # Marketing authorisation indication Venetoclax (Venclyxto, AbbVie) is indicated for 'the treatment of CLL: in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B‑cell receptor pathway inhibitor, or in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B‑cell receptor pathway inhibitor'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for venetoclax. # Price The list price of venetoclax is £4,789.47 per 112‑tablet pack (100 mg; excluding VAT; BNF online accessed February 2022). The average cost for year 1 is £58,752.23 and for year 2 onwards is £41,126.56. The company has a commercial arrangement. This makes venetoclax available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. This review looks at data collected after time in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal can be found in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access agreement, data was collected on venetoclax for people with chronic lymphocytic leukaemia (CLL) in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset. # Clinical need and treatment pathway ## Chronic lymphocytic leukaemia has a substantial effect on quality of life CLL is the most common form of leukaemia and is associated with fatigue and recurrent infections. The patient experts explained that the disease is commonly relapsing–remitting and so patients are often thinking about the next treatment and the challenges this will bring. They described the significant physical, mental and financial effect on people with CLL and their families. The committee concluded that CLL has a substantial effect on quality of life. ## Venetoclax monotherapy is an important option for some people with relapsed chronic lymphocytic leukaemia Since the original appraisal of venetoclax for CLL, NICE has recommended venetoclax with obinutuzumab (see NICE's technology appraisal guidance on venetoclax with obinutuzumab for untreated chronic lymphocytic leukaemia) and with rituximab (see NICE's technology appraisal guidance on venetoclax with rituximab for previously treated chronic lymphocytic leukaemia). The B‑cell receptor pathway inhibitor acalabrutinib has also been recommended for untreated CLL (see NICE's technology appraisal guidance on acalabrutinib for treating chronic lymphocytic leukaemia). The clinical experts explained that most people with CLL have acalabrutinib or ibrutinib as first-line treatment and then venetoclax with rituximab as second line, or venetoclax with obinutuzumab as first-line treatment and acalabrutinib or ibrutinib as second line. Chemo‑immunotherapy is rarely used. Despite the changes to the treatment pathway since the original appraisal, clinical and patient experts considered that there was still an unmet need for people with relapsed CLL who have tried other treatments or who cannot have rituximab. The committee concluded that venetoclax monotherapy would be an important option for these people. ## The population should be considered as a whole The clinical experts explained that splitting the population by 17p deletion or TP53 mutation status is less relevant now than when venetoclax was originally appraised. This is because the split was largely based on the different effect of chemo‑immunotherapy depending on whether a 17p deletion or TP53 mutation was present, and now chemo‑immunotherapy is rarely used. The committee noted that the company's model results were presented separately for each population but that it would prefer to make the same recommendation for both groups. The committee noted there was not a large difference in the cost effectiveness between the groups. It concluded that the population should be considered as a whole. ## Best supportive care is an appropriate comparator In the original appraisal, the comparator was best supportive care, which the company defined as rituximab and high‑dose methylprednisolone. In the original appraisal, the committee concluded that best supportive care was an appropriate comparator. In line with NICE's guide to the processes of technology appraisal, the original scope was not changed for this Cancer Drugs Fund review. The clinical experts explained that best supportive care would include regular monitoring and transfusions and could include chemo‑immunotherapy in some cases. The committee concluded that best supportive care was the appropriate comparator for this Cancer Drugs Fund review. # Clinical effectiveness ## It is acceptable to use SACT data to represent venetoclax efficacy, but the costs of rituximab should be added to the venetoclax arm The company used data from the SACT dataset, which was collected while venetoclax was available through the Cancer Drugs Fund, for the clinical efficacy evidence for venetoclax. The company preferred to use this data, rather than data from the 3 venetoclax trials it had used in the original appraisal, because it considered the SACT Cancer Drugs Fund data was more generalisable to clinical practice in the NHS in England. The SACT Cancer Drugs Fund dataset comprised 406 people with CLL who had venetoclax. The data from the SACT Cancer Drugs Fund cohort showed that the median overall survival for the overall cohort was 43.1 months. For the subgroup with a 17p deletion or TP53 mutation, median overall survival was 33 months, and for the subgroup without a 17p deletion or TP53 mutation, median overall survival was not reached. The ERG highlighted that people in the SACT Cancer Drugs Fund cohort could switch from venetoclax monotherapy to venetoclax with rituximab and that 80 out of the 406 people had had rituximab on or after starting venetoclax. It explained that the benefit people got from adding rituximab was unknown, and that the company had not accounted for the costs of rituximab. The ERG also stated that in clinical practice, people for whom venetoclax monotherapy was suitable may have previously had venetoclax with rituximab or obinutuzumab. The ERG was concerned that the efficacy of venetoclax as retreatment may be lower than in the SACT Cancer Drugs Fund cohort, who were unlikely to have already had venetoclax. The clinical experts stated that evidence from the MURANO trial suggested that venetoclax was effective as a retreatment after previous venetoclax with rituximab. The committee acknowledged that there were limitations in using the SACT Cancer Drugs Fund data, but it agreed that this data was the best available data to represent venetoclax efficacy and was acceptable to use in this appraisal. The committee also concluded that, because some people in the SACT Cancer Drugs Fund cohort had rituximab on or after starting venetoclax, these costs should be accounted for in the modelling. ## Despite significant issues, the rituximab arm of trial 116 is the best available source to model best supportive care Because there were no trials that directly compared venetoclax with best supportive care, in the original appraisal the company used data from the placebo with rituximab arm of trial 116 to model best supportive care. Trial 116 was a randomised controlled trial which compared idelalisib plus rituximab with placebo plus rituximab. Further data on best supportive care had been expected from the Cancer Drugs Fund, but this could not be collected. Therefore, the company retained its approach of using the placebo plus rituximab arm from trial 116 to model best supportive care in the current Cancer Drugs Fund review. The company considered that the people in this dataset better aligned with the SACT Cancer Drugs Fund data than they had with the original venetoclax trials, because they had a more similar stage of disease. In the original appraisal, the committee had accepted using post‑progression survival from the idelalisib with rituximab arm of trial 116 to model overall survival for best supportive care. However, the company stated that this was now considered less appropriate than the placebo plus rituximab arm because of the high post‑progression survival of 4 years with idelalisib, which did not reflect clinical practice in the UK. The ERG also acknowledged that the idelalisib plus rituximab arm had limitations and was associated with implausible extrapolations for the subgroup with a 17p deletion or TP53 mutation. However, the ERG did not consider that the rituximab arm from trial 116 was a suitable comparator. This was because it was at an earlier point in the treatment pathway than venetoclax would be used, and people in trial 116 had other treatment options, which may have improved their survival after the study. There were also differences in the eligibility criteria between trial 116 and the SACT Cancer Drugs Fund. These included differences in previous treatments, whether people who had had a stem cell or solid organ transplant were included, and whether the time between previous treatment and progression was specified. The ERG identified some alternative potential sources of data for best supportive care, from studies by Aarup et al. (2020) and Rigolin et al. (2021). These gave comparable estimates of median overall survival to the company model. However, the company noted that neither of these studies included anyone from the UK. The committee noted that in the study by Aarup et al., 60% of people had further treatment, some of whom had venetoclax. People in the study by Rigolin et al. also had further treatments, although further details of these were not reported. For these reasons, the committee agreed that these 2 studies did not represent best supportive care. The clinical experts stated that there was a lack of evidence on best supportive care and agreed that trial 116 was a better source of comparator data than the 2 studies identified by the ERG. The clinical experts considered that the choice of arm from trial 116 may have a limited effect on overall survival for best supportive care because of treatment crossover within the trial. The committee concluded that, despite significant issues, the rituximab arm of trial 116 was the best evidence it had been presented with to model best supportive care. ## The ERG's statistical comparison of venetoclax with best supportive care is not appropriate for decision making The company did not present a statistical comparison of venetoclax with best supportive care, with matching for baseline characteristics or eligibility criteria. Instead, the relative benefit of venetoclax compared with best supportive care was based solely on survival models fitted to the clinical data. The ERG had concerns over this and considered that a statistical comparison would have value. It compared data from the SACT Cancer Drugs Fund cohort and additional data from people who had venetoclax as part of the early access to medicines scheme, with combined data from Rigolin et al. (2021) and Aarup et al. (2020; see section 3.6). From this analysis, the ERG calculated a hazard ratio of 0.57 for overall survival between venetoclax and best supportive care. It applied this hazard ratio to the company's survival extrapolations of best supportive care (see section 3.10) to derive survival extrapolations for venetoclax. The committee did not consider this analysis to be informative because of its concerns that the Rigolin et al. and Aarup et al. studies did not represent best supportive care (see section 3.6). It concluded that the ERG's statistical comparison of venetoclax with best supportive care was not appropriate for decision making. # Cost effectiveness ## The company's model structure is acceptable for decision making The company presented a partitioned survival model to assess the cost effectiveness of venetoclax. The model included 3 health states: progression-free disease, progressed disease and death. The committee noted that the model structure had not changed since the original appraisal, in which it had been considered acceptable. The committee concluded that the model structure was acceptable for decision making. ## The company's modelling of venetoclax overall survival is acceptable for decision making To extrapolate beyond the observed time period of data collected for venetoclax, the company fitted parametric survival models to data recreated from the SACT report. It selected a Weibull model for extrapolating overall survival. The ERG highlighted that the observed data showed the hazard rate increasing towards the end of follow up for the subgroup with a 17p deletion or TP53 mutation, and that the same would likely be seen in the longer term for the subgroup without a 17p deletion or TP53 mutation. In contrast, the Weibull model selected by the company had a continuously decreasing hazard rate. The ERG explained that this led to high estimates of post-progression survival for venetoclax in the company's model. It identified a paper by Eyre et al. (2019), which reported the post‑progression survival times of 22 people from the UK after having venetoclax. The ERG fitted parametric curves to the data from Eyre et al. to compare survival times with those from the company's model. Post‑progression survival for venetoclax in the company's model was much higher than in the ERG's estimates based on Eyre et al. The ERG presented a scenario analysis in which it reduced the post‑progression survival for venetoclax to be more in line with the estimates derived from Eyre et al. In response to technical engagement, the company updated its modelling, which decreased post‑progression survival times for venetoclax by increasing progression‑free survival (see section 3.11). However, the company continued using the Weibull model to extrapolate overall survival for venetoclax. The ERG considered that a model that captured an increasing hazard rate would have been preferable. The company highlighted that the increasing hazard rate seen by the ERG could have been because of small numbers of people remaining alive beyond 2 years. The company also noted that other more flexible models that it fitted during technical engagement were unable to capture the increasing hazard rate. This suggested that the increasing hazard rate could be an artefact of the small patient numbers remaining at risk. The clinical experts considered that the SACT Cancer Drugs Fund data was a more robust source of evidence for venetoclax than Eyre et al. The committee noted that the ERG's analysis involved pooling transition probabilities from venetoclax and best supportive care, which it considered added further uncertainty because of the uncertainty with the evidence for best supportive care (see section 3.6). The committee concluded that the company's modelling of venetoclax overall survival was acceptable for decision making. ## The company's more consistent updated survival modelling approach is acceptable For venetoclax, the company fitted independent parametric models to data from the SACT report for people with CLL with and without a 17p deletion or TP53 mutation. For best supportive care, it fitted 1 dependent survival model to data from the rituximab arm of trial 116 simultaneously for both populations. For the subgroup without a 17p deletion or TP53 mutation, it applied a hazard ratio (0.677 for progression‑free survival and 0.543 for overall survival) to the model for the subgroup without a 17p deletion or TP53 mutation. The company derived these hazard ratios from pooled data from the venetoclax trials. The ERG did not consider it appropriate to use a hazard ratio derived from venetoclax data to apply to the best supportive care model, or to model the 2 arms differently. In response to technical engagement, the company updated its modelling of venetoclax to fit a single dependent model, including a hazard ratio to model the relationship between the 2 populations. It also explored further extrapolation models beyond the Weibull model it had originally selected. It updated its base‑case model to include a dependent Weibull model for overall survival, and a dependent normal spline 2‑knot model for time on treatment. The committee concluded that the company's more consistent updated survival modelling approach was acceptable. ## It is plausible that progression-free survival is equivalent to time on treatment Progression‑free survival data was unavailable from the SACT Cancer Drugs Fund dataset, so the company used time-on-treatment data to approximate progression‑free survival for venetoclax. It also noted that using time‑on‑treatment data for venetoclax was inconsistent with the way the company had modelled best supportive care, where time‑on‑treatment data had not been used. In response to technical engagement, the company estimated the relationship between time on treatment and progression‑free survival from 2 of the venetoclax trials. It calculated 2 separate hazard ratios for people with CLL with and without a 17p deletion or TP53 mutation. It then applied these hazard ratios to its base case model, to estimate progression‑free survival curves for venetoclax, separate to the time‑on‑treatment curves. This reduced post‑progression survival for venetoclax compared with the company's original model. The ERG considered that the company's updated modelling of venetoclax was still inconsistent with the modelling of best supportive care because progression‑free survival and time on treatment were not modelled separately for best supportive care. The company highlighted that best supportive care was assumed to be rituximab (see section 3.6), which has a fixed duration of treatment, so it is more logical not to include time on treatment for the best supportive care arm. The clinical experts explained that few people having venetoclax stop treatment before progression. So, in practice there is likely to be little difference between time on treatment and progression‑free survival, although there is uncertainty because some people may progress early but keep having treatment. The committee concluded that it was plausible that progression‑free survival was equivalent to time on treatment for people having venetoclax. # End of life ## Venetoclax meets the criteria to be considered a life-extending treatment at the end of life The committee considered the advice about life‑extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the original appraisal, the data showed that venetoclax compared with best supportive care met both the end of life criteria for both populations. The committee did not hear any evidence to change this conclusion. Therefore, it concluded that venetoclax met the end of life criteria and could be considered a life‑extending treatment at the end of life. # Cost-effectiveness results ## Venetoclax is recommended for routine use The company's base‑case deterministic incremental cost‑effectiveness ratios (ICERs) for both the subgroups with and without a 17p deletion or TP53 mutation were around £50,000 per quality-adjusted life year (QALY) gained. These results included the patient access scheme discount for venetoclax and the confidential commercial discounts for other treatments. The ERG corrected an error in the company's model. It presented a scenario analysis in which the costs of rituximab were included in the venetoclax arm, which the committee had agreed was appropriate (see section 3.5). It presented a further scenario analysis in which progression‑free survival was equal to time on treatment for venetoclax, which the committee had agreed was appropriate (see section 3.11). These both increased the ICERs, and the ICER for the subgroup without a 17p deletion or TP53 mutation was above £50,000 per QALY gained. The committee recalled that it would prefer to consider the population as a whole, rather than split by 17p deletion or TP53 mutation status (see section 3.3). It considered that the ICERs for the whole population would likely be between those for the subgroups with and without a 17p deletion or TP53 mutation. The committee acknowledged that venetoclax monotherapy fulfilled an unmet need and was aware of its value to patients as another treatment option for CLL (see section 3.2). Because of changes in the treatment pathway since the original appraisal, it was also likely that a relatively small number of people would have venetoclax monotherapy in future. So, the consequences of decision error were low. The committee therefore recommended venetoclax for routine use. # Other factors ## There are no equality issues, and all relevant benefits are captured in the QALY A stakeholder highlighted that CLL is a disease that mainly affects older people. The committee agreed that its recommendations did not have a different impact on people protected by the equality legislation than on the wider population. It concluded that there were no equality issues, and all relevant benefits of the technology were captured in the QALY calculations.	{'Recommendations': "Venetoclax monotherapy is recommended, within its marketing authorisation, for treating chronic lymphocytic leukaemia (CLL) in adults:\n\nwith a 17p deletion or TP53 mutation and when a B‑cell receptor pathway inhibitor is unsuitable, or whose disease has progressed after a B‑cell receptor pathway inhibitor or\n\nwithout a 17p deletion or TP53 mutation, and whose disease has progressed after both chemo‑immunotherapy and a B‑cell receptor pathway inhibitor.It is recommended only if the company provides venetoclax according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for venetoclax for CLL.\n\nPeople with CLL for whom venetoclax monotherapy would be an option would otherwise usually have best supportive care. This includes rituximab and high-dose methylprednisolone.\n\nThe new evidence is mainly data collected from the Systemic Anti-Cancer Therapy (SACT) database from people having treatment in the NHS, while venetoclax was available in the Cancer Drugs Fund in England. The benefit of venetoclax is uncertain because the original trials did not compare it with best supportive care, and no SACT data could be collected on best supportive care.\n\nVenetoclax meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost‑effectiveness estimates are around the range that NICE considers to be an acceptable use of NHS resources for end of life treatments. Venetoclax also fulfils an unmet need and is a valued treatment option. Therefore, it is recommended.", 'Information about venetoclax': "# Marketing authorisation indication\n\nVenetoclax (Venclyxto, AbbVie) is indicated for 'the treatment of CLL:\n\nin the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B‑cell receptor pathway inhibitor, or\n\nin the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B‑cell receptor pathway inhibitor'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for venetoclax.\n\n# Price\n\nThe list price of venetoclax is £4,789.47 per 112‑tablet pack (100\xa0mg; excluding VAT; BNF online accessed February\xa02022). The average cost for year\xa01 is £58,752.23 and for year\xa02 onwards is £41,126.56.\n\nThe company has a commercial arrangement. This makes venetoclax available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThis review looks at data collected after time in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal can be found in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access agreement, data was collected on venetoclax for people with chronic lymphocytic leukaemia (CLL) in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset.\n\n# Clinical need and treatment pathway\n\n## Chronic lymphocytic leukaemia has a substantial effect on quality of life\n\nCLL is the most common form of leukaemia and is associated with fatigue and recurrent infections. The patient experts explained that the disease is commonly relapsing–remitting and so patients are often thinking about the next treatment and the challenges this will bring. They described the significant physical, mental and financial effect on people with CLL and their families. The committee concluded that CLL has a substantial effect on quality of life.\n\n## Venetoclax monotherapy is an important option for some people with relapsed chronic lymphocytic leukaemia\n\nSince the original appraisal of venetoclax for CLL, NICE has recommended venetoclax with obinutuzumab (see NICE's technology appraisal guidance on venetoclax with obinutuzumab for untreated chronic lymphocytic leukaemia) and with rituximab (see NICE's technology appraisal guidance on venetoclax with rituximab for previously treated chronic lymphocytic leukaemia). The B‑cell receptor pathway inhibitor acalabrutinib has also been recommended for untreated CLL (see NICE's technology appraisal guidance on acalabrutinib for treating chronic lymphocytic leukaemia). The clinical experts explained that most people with CLL have acalabrutinib or ibrutinib as first-line treatment and then venetoclax with rituximab as second line, or venetoclax with obinutuzumab as first-line treatment and acalabrutinib or ibrutinib as second line. Chemo‑immunotherapy is rarely used. Despite the changes to the treatment pathway since the original appraisal, clinical and patient experts considered that there was still an unmet need for people with relapsed CLL who have tried other treatments or who cannot have rituximab. The committee concluded that venetoclax monotherapy would be an important option for these people.\n\n## The population should be considered as a whole\n\nThe clinical experts explained that splitting the population by 17p deletion or TP53 mutation status is less relevant now than when venetoclax was originally appraised. This is because the split was largely based on the different effect of chemo‑immunotherapy depending on whether a 17p deletion or TP53 mutation was present, and now chemo‑immunotherapy is rarely used. The committee noted that the company's model results were presented separately for each population but that it would prefer to make the same recommendation for both groups. The committee noted there was not a large difference in the cost effectiveness between the groups. It concluded that the population should be considered as a whole.\n\n## Best supportive care is an appropriate comparator\n\nIn the original appraisal, the comparator was best supportive care, which the company defined as rituximab and high‑dose methylprednisolone. In the original appraisal, the committee concluded that best supportive care was an appropriate comparator. In line with NICE's guide to the processes of technology appraisal, the original scope was not changed for this Cancer Drugs Fund review. The clinical experts explained that best supportive care would include regular monitoring and transfusions and could include chemo‑immunotherapy in some cases. The committee concluded that best supportive care was the appropriate comparator for this Cancer Drugs Fund review.\n\n# Clinical effectiveness\n\n## It is acceptable to use SACT data to represent venetoclax efficacy, but the costs of rituximab should be added to the venetoclax arm\n\nThe company used data from the SACT dataset, which was collected while venetoclax was available through the Cancer Drugs Fund, for the clinical efficacy evidence for venetoclax. The company preferred to use this data, rather than data from the 3\xa0venetoclax trials it had used in the original appraisal, because it considered the SACT Cancer Drugs Fund data was more generalisable to clinical practice in the NHS in England. The SACT Cancer Drugs Fund dataset comprised 406\xa0people with CLL who had venetoclax. The data from the SACT Cancer Drugs Fund cohort showed that the median overall survival for the overall cohort was 43.1\xa0months. For the subgroup with a 17p deletion or TP53 mutation, median overall survival was 33\xa0months, and for the subgroup without a 17p deletion or TP53 mutation, median overall survival was not reached. The ERG highlighted that people in the SACT Cancer Drugs Fund cohort could switch from venetoclax monotherapy to venetoclax with rituximab and that 80 out of the 406\xa0people had had rituximab on or after starting venetoclax. It explained that the benefit people got from adding rituximab was unknown, and that the company had not accounted for the costs of rituximab. The ERG also stated that in clinical practice, people for whom venetoclax monotherapy was suitable may have previously had venetoclax with rituximab or obinutuzumab. The ERG was concerned that the efficacy of venetoclax as retreatment may be lower than in the SACT Cancer Drugs Fund cohort, who were unlikely to have already had venetoclax. The clinical experts stated that evidence from the MURANO trial suggested that venetoclax was effective as a retreatment after previous venetoclax with rituximab. The committee acknowledged that there were limitations in using the SACT Cancer Drugs Fund data, but it agreed that this data was the best available data to represent venetoclax efficacy and was acceptable to use in this appraisal. The committee also concluded that, because some people in the SACT Cancer Drugs Fund cohort had rituximab on or after starting venetoclax, these costs should be accounted for in the modelling.\n\n## Despite significant issues, the rituximab arm of trial\xa0116 is the best available source to model best supportive care\n\nBecause there were no trials that directly compared venetoclax with best supportive care, in the original appraisal the company used data from the placebo with rituximab arm of trial\xa0116 to model best supportive care. Trial\xa0116 was a randomised controlled trial which compared idelalisib plus rituximab with placebo plus rituximab. Further data on best supportive care had been expected from the Cancer Drugs Fund, but this could not be collected. Therefore, the company retained its approach of using the placebo plus rituximab arm from trial\xa0116 to model best supportive care in the current Cancer Drugs Fund review. The company considered that the people in this dataset better aligned with the SACT Cancer Drugs Fund data than they had with the original venetoclax trials, because they had a more similar stage of disease. In the original appraisal, the committee had accepted using post‑progression survival from the idelalisib with rituximab arm of trial\xa0116 to model overall survival for best supportive care. However, the company stated that this was now considered less appropriate than the placebo plus rituximab arm because of the high post‑progression survival of 4\xa0years with idelalisib, which did not reflect clinical practice in the UK. The ERG also acknowledged that the idelalisib plus rituximab arm had limitations and was associated with implausible extrapolations for the subgroup with a 17p deletion or TP53 mutation. However, the ERG did not consider that the rituximab arm from trial\xa0116 was a suitable comparator. This was because it was at an earlier point in the treatment pathway than venetoclax would be used, and people in trial\xa0116 had other treatment options, which may have improved their survival after the study. There were also differences in the eligibility criteria between trial\xa0116 and the SACT Cancer Drugs Fund. These included differences in previous treatments, whether people who had had a stem cell or solid organ transplant were included, and whether the time between previous treatment and progression was specified. The ERG identified some alternative potential sources of data for best supportive care, from studies by Aarup et al. (2020) and Rigolin et al. (2021). These gave comparable estimates of median overall survival to the company model. However, the company noted that neither of these studies included anyone from the UK. The committee noted that in the study by Aarup et al., 60% of people had further treatment, some of whom had venetoclax. People in the study by Rigolin et al. also had further treatments, although further details of these were not reported. For these reasons, the committee agreed that these 2\xa0studies did not represent best supportive care. The clinical experts stated that there was a lack of evidence on best supportive care and agreed that trial\xa0116 was a better source of comparator data than the 2\xa0studies identified by the ERG. The clinical experts considered that the choice of arm from trial\xa0116 may have a limited effect on overall survival for best supportive care because of treatment crossover within the trial. The committee concluded that, despite significant issues, the rituximab arm of trial\xa0116 was the best evidence it had been presented with to model best supportive care.\n\n## The ERG's statistical comparison of venetoclax with best supportive care is not appropriate for decision making\n\nThe company did not present a statistical comparison of venetoclax with best supportive care, with matching for baseline characteristics or eligibility criteria. Instead, the relative benefit of venetoclax compared with best supportive care was based solely on survival models fitted to the clinical data. The ERG had concerns over this and considered that a statistical comparison would have value. It compared data from the SACT Cancer Drugs Fund cohort and additional data from people who had venetoclax as part of the early access to medicines scheme, with combined data from Rigolin et al. (2021) and Aarup et al. (2020; see section\xa03.6). From this analysis, the ERG calculated a hazard ratio of 0.57 for overall survival between venetoclax and best supportive care. It applied this hazard ratio to the company's survival extrapolations of best supportive care (see section\xa03.10) to derive survival extrapolations for venetoclax. The committee did not consider this analysis to be informative because of its concerns that the Rigolin et al. and Aarup et al. studies did not represent best supportive care (see section\xa03.6). It concluded that the ERG's statistical comparison of venetoclax with best supportive care was not appropriate for decision making.\n\n# Cost effectiveness\n\n## The company's model structure is acceptable for decision making\n\nThe company presented a partitioned survival model to assess the cost effectiveness of venetoclax. The model included 3\xa0health states: progression-free disease, progressed disease and death. The committee noted that the model structure had not changed since the original appraisal, in which it had been considered acceptable. The committee concluded that the model structure was acceptable for decision making.\n\n## The company's modelling of venetoclax overall survival is acceptable for decision making\n\nTo extrapolate beyond the observed time period of data collected for venetoclax, the company fitted parametric survival models to data recreated from the SACT report. It selected a Weibull model for extrapolating overall survival. The ERG highlighted that the observed data showed the hazard rate increasing towards the end of follow up for the subgroup with a 17p deletion or TP53 mutation, and that the same would likely be seen in the longer term for the subgroup without a 17p deletion or TP53 mutation. In contrast, the Weibull model selected by the company had a continuously decreasing hazard rate. The ERG explained that this led to high estimates of post-progression survival for venetoclax in the company's model. It identified a paper by Eyre et al. (2019), which reported the post‑progression survival times of 22\xa0people from the UK after having venetoclax. The ERG fitted parametric curves to the data from Eyre et al. to compare survival times with those from the company's model. Post‑progression survival for venetoclax in the company's model was much higher than in the ERG's estimates based on Eyre et al. The ERG presented a scenario analysis in which it reduced the post‑progression survival for venetoclax to be more in line with the estimates derived from Eyre et al. In response to technical engagement, the company updated its modelling, which decreased post‑progression survival times for venetoclax by increasing progression‑free survival (see section\xa03.11). However, the company continued using the Weibull model to extrapolate overall survival for venetoclax. The ERG considered that a model that captured an increasing hazard rate would have been preferable. The company highlighted that the increasing hazard rate seen by the ERG could have been because of small numbers of people remaining alive beyond 2\xa0years. The company also noted that other more flexible models that it fitted during technical engagement were unable to capture the increasing hazard rate. This suggested that the increasing hazard rate could be an artefact of the small patient numbers remaining at risk. The clinical experts considered that the SACT Cancer Drugs Fund data was a more robust source of evidence for venetoclax than Eyre et al. The committee noted that the ERG's analysis involved pooling transition probabilities from venetoclax and best supportive care, which it considered added further uncertainty because of the uncertainty with the evidence for best supportive care (see section\xa03.6). The committee concluded that the company's modelling of venetoclax overall survival was acceptable for decision making.\n\n## The company's more consistent updated survival modelling approach is acceptable\n\nFor venetoclax, the company fitted independent parametric models to data from the SACT report for people with CLL with and without a 17p deletion or TP53 mutation. For best supportive care, it fitted 1\xa0dependent survival model to data from the rituximab arm of trial\xa0116 simultaneously for both populations. For the subgroup without a 17p deletion or TP53 mutation, it applied a hazard ratio (0.677 for progression‑free survival and 0.543 for overall survival) to the model for the subgroup without a 17p deletion or TP53 mutation. The company derived these hazard ratios from pooled data from the venetoclax trials. The ERG did not consider it appropriate to use a hazard ratio derived from venetoclax data to apply to the best supportive care model, or to model the 2\xa0arms differently. In response to technical engagement, the company updated its modelling of venetoclax to fit a single dependent model, including a hazard ratio to model the relationship between the 2\xa0populations. It also explored further extrapolation models beyond the Weibull model it had originally selected. It updated its base‑case model to include a dependent Weibull model for overall survival, and a dependent normal spline 2‑knot model for time on treatment. The committee concluded that the company's more consistent updated survival modelling approach was acceptable.\n\n## It is plausible that progression-free survival is equivalent to time on treatment\n\nProgression‑free survival data was unavailable from the SACT Cancer Drugs Fund dataset, so the company used time-on-treatment data to approximate progression‑free survival for venetoclax. It also noted that using time‑on‑treatment data for venetoclax was inconsistent with the way the company had modelled best supportive care, where time‑on‑treatment data had not been used. In response to technical engagement, the company estimated the relationship between time on treatment and progression‑free survival from 2 of the venetoclax trials. It calculated 2\xa0separate hazard ratios for people with CLL with and without a 17p deletion or TP53 mutation. It then applied these hazard ratios to its base case model, to estimate progression‑free survival curves for venetoclax, separate to the time‑on‑treatment curves. This reduced post‑progression survival for venetoclax compared with the company's original model. The ERG considered that the company's updated modelling of venetoclax was still inconsistent with the modelling of best supportive care because progression‑free survival and time on treatment were not modelled separately for best supportive care. The company highlighted that best supportive care was assumed to be rituximab (see section\xa03.6), which has a fixed duration of treatment, so it is more logical not to include time on treatment for the best supportive care arm. The clinical experts explained that few people having venetoclax stop treatment before progression. So, in practice there is likely to be little difference between time on treatment and progression‑free survival, although there is uncertainty because some people may progress early but keep having treatment. The committee concluded that it was plausible that progression‑free survival was equivalent to time on treatment for people having venetoclax.\n\n# End of life\n\n## Venetoclax meets the criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life‑extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the original appraisal, the data showed that venetoclax compared with best supportive care met both the end of life criteria for both populations. The committee did not hear any evidence to change this conclusion. Therefore, it concluded that venetoclax met the end of life criteria and could be considered a life‑extending treatment at the end of life.\n\n# Cost-effectiveness results\n\n## Venetoclax is recommended for routine use\n\nThe company's base‑case deterministic incremental cost‑effectiveness ratios (ICERs) for both the subgroups with and without a 17p deletion or TP53 mutation were around £50,000 per quality-adjusted life year (QALY) gained. These results included the patient access scheme discount for venetoclax and the confidential commercial discounts for other treatments. The ERG corrected an error in the company's model. It presented a scenario analysis in which the costs of rituximab were included in the venetoclax arm, which the committee had agreed was appropriate (see section\xa03.5). It presented a further scenario analysis in which progression‑free survival was equal to time on treatment for venetoclax, which the committee had agreed was appropriate (see section\xa03.11). These both increased the ICERs, and the ICER for the subgroup without a 17p deletion or TP53 mutation was above £50,000 per QALY gained. The committee recalled that it would prefer to consider the population as a whole, rather than split by 17p deletion or TP53 mutation status (see section\xa03.3). It considered that the ICERs for the whole population would likely be between those for the subgroups with and without a 17p deletion or TP53 mutation. The committee acknowledged that venetoclax monotherapy fulfilled an unmet need and was aware of its value to patients as another treatment option for CLL (see section\xa03.2). Because of changes in the treatment pathway since the original appraisal, it was also likely that a relatively small number of people would have venetoclax monotherapy in future. So, the consequences of decision error were low. The committee therefore recommended venetoclax for routine use.\n\n# Other factors\n\n## There are no equality issues, and all relevant benefits are captured in the QALY\n\nA stakeholder highlighted that CLL is a disease that mainly affects older people. The committee agreed that its recommendations did not have a different impact on people protected by the equality legislation than on the wider population. It concluded that there were no equality issues, and all relevant benefits of the technology were captured in the QALY calculations."}	https://www.nice.org.uk/guidance/ta796	Evidence-based recommendations on venetoclax (Venclyxto) for chronic lymphocytic leukaemia in adults.
a39a5f22557329a90dc4bf7d80c5c913a466054c	nice	Preterm labour and birth	Preterm labour and birth This guideline covers the care of women at increased risk of, or with symptoms and signs of, preterm labour (before 37 weeks), and women having a planned preterm birth. It aims to reduce the risks of preterm birth for the baby and describes treatments to prevent or delay early labour and birth. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Information and support When giving information and support to women at increased risk of preterm labour, or with suspected, diagnosed or established preterm labour, or having a planned preterm birth (and their family members or carers as appropriate): ensure this is given as early as possible, taking into account the likelihood of preterm birth and the status of labour follow the principles in NICE's guideline on patient experience in adult NHS services bear in mind that the woman (and their family members or carers) may be particularly anxious give both oral and written information describe the symptoms and signs of preterm labour explain about the care that may be offered. For women who are having a planned preterm birth or are offered treatment for preterm labour in line with the sections on tocolysis, maternal corticosteroids and magnesium sulfate for neuroprotection (and their family members or carers as appropriate), provide information and support that includes: information about the likelihood of the baby surviving and other outcomes (including long-term outcomes) and risks for the baby, giving values as natural frequencies (for example, 1 in 100) explanation of the neonatal care of preterm babies, including location of care explanation of the immediate problems that can arise when a baby is born preterm explanation of the possible long-term consequences of prematurity for the baby (how premature babies grow and develop) -ngoing opportunities to talk about and state their wishes about resuscitation of the baby an opportunity to tour the neonatal unit an opportunity to speak to a neonatologist or paediatrician. Be aware that, according to the 2021 Mothers and babies: reducing risk through audits and confidential enquiries across the UK (MBRRACE-UK) report on perinatal mortality, women from some minority ethnic backgrounds or who live in deprived areas have an increased risk of stillbirth and may need closer monitoring and additional support. The report showed that across all births (not just those which are preterm): compared with white babies (32 out of 10,000), the stillbirth rate is: more than twice as high in black babies (72 out of 10,000) around 50% higher in Asian babies (51 out of 10,000) compared with the least deprived areas (23 out of 10,000), the still birth rate is twice as high in the most deprived areas (47 out of 10,000). # Care of women at risk of preterm labour # Prophylactic vaginal progesterone and prophylactic cervical cerclage Offer a choice of prophylactic vaginal progesterone or prophylactic cervical cerclage to women who have both: a history of spontaneous preterm birth (up to 34+0 weeks of pregnancy) or loss (from 16+0 weeks of pregnancy onwards), and results from a transvaginal ultrasound scan carried out between 16+0 and 24+0 weeks of pregnancy that show a cervical length of 25 mm or less. Discuss the risks and benefits of both options with the woman, and make a shared decision on which treatment is most suitable.In August 2019, this was an off-label use of vaginal progesterone. See NICE's information on prescribing medicines. Consider prophylactic vaginal progesterone for women who have either: a history of spontaneous preterm birth (up to 34+0 weeks of pregnancy) or loss (from 16+0 weeks of pregnancy onwards), or results from a transvaginal ultrasound scan carried out between 16+0 and 24+0 weeks of pregnancy that show a cervical length of 25 mm or less.In August 2019, this was an off-label use of vaginal progesterone. See NICE's information on prescribing medicines. When using vaginal progesterone, start treatment between 16+0 and 24+0 weeks of pregnancy and continue until at least 34 weeks. Consider prophylactic cervical cerclage for women when results of a transvaginal ultrasound scan carried out between 16+0 and 24+0 weeks of pregnancy show a cervical length of 25 mm or less, who have had either: preterm prelabour rupture of membranes (P‑PROM) in a previous pregnancy or a history of cervical trauma. If prophylactic cervical cerclage is used, ensure a plan is made and documented for removal of the suture. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prophylactic vaginal progesterone . Full details of the evidence and the committee's discussion are in evidence review A: clinical effectiveness of prophylactic progesterone in preventing preterm labour. Loading. Please wait. # Diagnosing preterm prelabour rupture of membranes (P-PROM) In a woman reporting symptoms suggestive of P‑PROM, offer a speculum examination to look for pooling of amniotic fluid and: if pooling of amniotic fluid is observed, do not perform any diagnostic test but offer care consistent with the woman having P‑PROM (see the sections on antenatal prophylactic antibiotics for women with P-PROM, identifying infection in women with P-PROM and maternal corticosteroids) if pooling of amniotic fluid is not observed, perform an insulin-like growth factor binding protein‑1 test or placental alpha-microglobulin‑1 test of vaginal fluid. If the results of the insulin-like growth factor binding protein‑1 or placental alpha-microglobulin‑1 test are positive, do not use the test results alone to decide what care to offer the woman, but also take into account her clinical condition, medical and pregnancy history and gestational age, and either: -ffer care consistent with the woman having P‑PROM (see the sections on antenatal prophylactic antibiotics for women with P-PROM, identifying infection in women with P-PROM and maternal corticosteroids or re-evaluate the woman's diagnostic status at a later time point. If the results of the insulin-like growth factor binding protein‑1 or placental alpha-microglobulin‑1 test are negative and no amniotic fluid is observed: do not offer antenatal prophylactic antibiotics explain to the woman that it is unlikely she has P‑PROM, but that she should return for reassessment if there are any further symptoms suggestive of P‑PROM or preterm labour. Do not use nitrazine to diagnose P‑PROM. Do not perform diagnostic tests for P‑PROM if labour becomes established in a woman reporting symptoms suggestive of P‑PROM. # Antenatal prophylactic antibiotics for women with P-PROM As prophylaxis for intrauterine infection, offer women with P-PROM oral erythromycin 250 mg 4 times a day for a maximum of 10 days or until the woman is in established labour (whichever is sooner). For women with P‑PROM who cannot tolerate erythromycin or in whom erythromycin is contraindicated, consider an oral penicillin for a maximum of 10 days or until the woman is in established labour (whichever is sooner). Do not offer women with P‑PROM co‑amoxiclav as prophylaxis for intrauterine infection. For guidance on the use of intrapartum antibiotics, see the section on intrapartum antibiotics in NICE's guideline on neonatal infection, and when applicable also see the section on treatment for women with prolonged prelabour rupture of membranes who have group B streptococcal colonisation, bacteriuria or infection. # Identifying infection in women with P-PROM Use a combination of clinical assessment and tests (C‑reactive protein, white blood cell count and measurement of fetal heart rate using cardiotocography) to diagnose intrauterine infection in women with P‑PROM. Do not use any one of the following in isolation to confirm or exclude intrauterine infection in women with P‑PROM: a single test of C‑reactive protein white blood cell count measurement of fetal heart rate using cardiotocography. If the results of the clinical assessment or any of the tests are not consistent with each other, continue to observe the woman and consider repeating the tests. # Emergency cervical cerclage Do not offer emergency cervical cerclage to women with: signs of infection, or active vaginal bleeding, or uterine contractions. Consider emergency cervical cerclage for women between 16+0 and 27+6 weeks of pregnancy with a dilated cervix and exposed, unruptured fetal membranes. Also: take into account gestational age (being aware that the benefits are likely to be greater for earlier gestations) and the extent of cervical dilatation discuss with a consultant obstetrician and consultant paediatrician. If emergency cervical cerclage is being considered, explain to the woman (and their family members or carers, as appropriate): about the risks of the procedure that it aims to delay the birth, and so increase the likelihood of the baby surviving and of reducing serious neonatal morbidity If emergency cervical cerclage is used, ensure that a plan is made and documented for removal of the suture. For a short explanation of why the committee made the 2019 recommendation and how it might affect practice, see the rationale and impact section on emergency cervical cerclage . Loading. Please wait. # Care of women with suspected or established preterm labour # Diagnosing preterm labour for women with intact membranes Explain to women reporting symptoms of preterm labour who have intact membranes (and their family members or carers, as appropriate): about the clinical assessment and diagnostic tests that are available how the clinical assessment and diagnostic tests are carried out what the benefits, risks and possible consequences of the clinical assessment and diagnostic tests are, including the consequences of false-positive and false-negative test results and taking into account gestational age. Offer a clinical assessment to women reporting symptoms of preterm labour who have intact membranes. This should include: clinical history taking the observations described for the initial assessment of labour in NICE's guideline on intrapartum care a speculum examination (followed by a digital vaginal examination if the extent of cervical dilatation cannot be assessed; be aware that if a swab for fetal fibronectin testing is anticipated the swab should be taken before any digital vaginal examination). If the clinical assessment suggests that the woman is in suspected preterm labour and she is 29+6 weeks pregnant or less, advise treatment for preterm labour as described in the sections on tocolysis and maternal corticosteroids. If the clinical assessment suggests that the woman is in suspected preterm labour and she is 30+0 weeks pregnant or more, consider transvaginal ultrasound measurement of cervical length as a diagnostic test to determine likelihood of birth within 48 hours. Act on the results as follows: if cervical length is more than 15 mm, explain to the woman that it is unlikely to be preterm labour and: think about alternative diagnoses discuss with her the benefits and risks of going home compared with continued monitoring and treatment in hospital advise her that if she does decide to go home, she should return if symptoms suggestive of preterm labour persist or recur if cervical length is 15 mm or less, view the woman as being in diagnosed preterm labour and offer treatment as described in the sections on tocolysis and maternal corticosteroids. Consider fetal fibronectin testing as a diagnostic test to determine likelihood of birth within 48 hours for women who are 30+0 weeks pregnant or more if transvaginal ultrasound measurement of cervical length is indicated, but is not available or not acceptable. Act on the results as follows: if fetal fibronectin testing is negative (concentration 50 ng/ml or less), explain to the woman that it is unlikely she is in preterm labour and: think about alternative diagnoses discuss with her the benefits and risks of going home compared with continued monitoring and treatment in hospital advise her that if she decides to go home, she should return if symptoms suggestive of preterm labour persist or recur if fetal fibronectin testing is positive (concentration more than 50 ng/ml), view the woman as being in diagnosed preterm labour and offer treatment as described in the sections on tocolysis and maternal corticosteroids. If a woman in suspected preterm labour who is 30+0 weeks pregnant or more does not have transvaginal ultrasound measurement of cervical length or fetal fibronectin testing to exclude preterm labour, offer treatment consistent with her being in diagnosed preterm labour (see the sections on tocolysis and maternal corticosteroids). Do not use transvaginal ultrasound measurement of cervical length and fetal fibronectin testing in combination to diagnose preterm labour. Ultrasound scans should be performed by healthcare professionals with training in, and experience of, transvaginal ultrasound measurement of cervical length. For guidance on the use of other biomarker tests used for the diagnosis of preterm labour, see NICE's diagnostics guidance on biomarker tests to help diagnose preterm labour in women with intact membranes. # Tocolysis Take the following factors into account when making a decision about whether to start tocolysis: whether the woman is in suspected or diagnosed preterm labour -ther clinical features (for example, bleeding or infection) that may suggest that stopping labour is contraindicated gestational age at presentation likely benefit of maternal corticosteroids (see the section on maternal corticosteroids) availability of an appropriate level of neonatal care (if there is need for transfer to another unit). See also NHS England's guidance on saving babies' lives care bundle version 2 (recommendation 5.9). the preference of the woman. Consider nifedipine for tocolysis for women between 24+0 and 25+6 weeks of pregnancy who have intact membranes and are in suspected preterm labour.In November 2015, this was an off-label use of nifedipine. See NICE's information on prescribing medicines. Offer nifedipine for tocolysis to women between 26+0 and 33+6 weeks of pregnancy who have intact membranes and are in suspected or diagnosed preterm labour. In November 2015, this was an off-label use of nifedipine. See NICE's information on prescribing medicines. If nifedipine is contraindicated, offer oxytocin receptor antagonists for tocolysis. Do not offer betamimetics for tocolysis. # Maternal corticosteroids In June 2022 this was an off-label use of betamethasone and dexamethasone. See NICE's information on prescribing medicines. For women between 22+0 and 23+6 weeks of pregnancy who are in suspected or established preterm labour, are having a planned preterm birth or have P‑PROM (see the section on diagnosing P-PROM), discuss with the woman (and her family members or carers, as appropriate) and the multidisciplinary team the use of maternal corticosteroids in the context of her individual circumstances. Offer maternal corticosteroids to women between 24+0 and 33+6 weeks of pregnancy who are in suspected, diagnosed or established preterm labour, are having a planned preterm birth or have P‑PROM. Consider maternal corticosteroids for women between 34+0 and 35+6 weeks of pregnancy who are in suspected, diagnosed or established preterm labour, are having a planned preterm birth or have P‑PROM. Consider a single repeat course of maternal corticosteroids for women less than 34+0 weeks of pregnancy who: have already had a course of corticosteroids when this was more than 7 days ago, and are at very high risk of giving birth in the next 48 hours.Where the woman is less than 30+0 weeks pregnant or if there is suspected growth restriction, take into account the possible impact on fetal growth of a repeat course of maternal corticosteroids. Do not give more than 2 courses of maternal corticosteroids for preterm birth. When offering or considering maternal corticosteroids, discuss the benefits and risks with the woman (and her family members or carers, as appropriate). For guidance on the use of corticosteroids in people with diabetes, see NICE's guideline on diabetes in pregnancy. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on repeat courses of maternal corticosteroids . Full details of the evidence and the committee's discussion are in evidence review B: effectiveness of repeat courses of maternal corticosteroids for fetal lung maturation. Loading. Please wait. # Magnesium sulfate for neuroprotection In August 2019, the use of intravenous magnesium sulfate in recommendations 1.10.1 to 1.10.3 was off label. See NICE's information on prescribing medicines. This guideline does not recommend using magnesium sulfate beyond 24 hours. But if uncertainty around exact timing of delivery results in repeat administration, follow the MHRA safety advice on the prolonged or repeated use of magnesium sulfate in pregnancy. For women between 23+0 and 23+6 weeks of pregnancy who are in established preterm labour or having a planned preterm birth within 24 hours, discuss with the woman (and her family members or carers, as appropriate) the use of intravenous magnesium sulfate for neuroprotection of the baby, in the context of her individual circumstances. Offer intravenous magnesium sulfate for neuroprotection of the baby to women between 24+0 and 29+6 weeks of pregnancy who are: in established preterm labour, or having a planned preterm birth within 24 hours. Consider intravenous magnesium sulfate for neuroprotection of the baby for women between 30+0 and 33+6 weeks of pregnancy who are: in established preterm labour, or having a planned preterm birth within 24 hours. Give a 4 g intravenous bolus of magnesium sulfate over 15 minutes, followed by an intravenous infusion of 1 g per hour until the birth or for 24 hours (whichever is sooner). For women on magnesium sulfate, monitor for clinical signs of magnesium toxicity at least every 4 hours by recording pulse, blood pressure, respiratory rate and deep tendon (for example, patellar) reflexes. If a woman has or develops oliguria or other evidence of renal failure: monitor more frequently for magnesium toxicity reduce or stop the dose of magnesium sulfate. # Intrapartum antibiotics For guidance on the use of intrapartum antibiotics in established preterm labour, see NICE's guideline on neonatal infection. # Fetal monitoring ## Monitoring options: cardiotocography and intermittent auscultation Discuss with women in suspected, diagnosed or established preterm labour (and their family members or carers, as appropriate): the purpose of fetal monitoring and what it involves the clinical decisions it informs at different gestational ages if appropriate, the option not to monitor the fetal heart rate (for example, at the threshold of viability). Involve a senior obstetrician in discussions about whether and how to monitor the fetal heart rate for women who are between 23+0 and 25+6 weeks pregnant. Explain the different fetal monitoring options to the woman (and her family members or carers, as appropriate), being aware that: there is limited evidence about the usefulness of specific features to suggest hypoxia or acidosis in preterm babies the available evidence is broadly consistent with that for babies born at term (see the NICE guideline on fetal monitoring in labour) a normal cardiotocography trace is reassuring and indicates that the baby is coping well with labour, but an abnormal trace does not necessarily indicate that fetal hypoxia or acidosis is present. Explain that there is an absence of evidence that using cardiotocography improves the outcomes of preterm labour for the parent or the baby compared with intermittent auscultation. Include family members or carers in the discussion, as appropriate. In established preterm labour with no other risk factors (see the NICE guideline on fetal monitoring in labour), offer a choice of fetal heart rate monitoring using either: cardiotocography using external ultrasound or intermittent auscultation. For guidance on using intermittent auscultation for fetal heart rate monitoring, see the NICE guideline on fetal monitoring in labour. ## Fetal scalp electrode Do not use a fetal scalp electrode for fetal heart rate monitoring if the woman is less than 34+0 weeks pregnant unless all of the following apply: it is not possible to monitor the fetal heart rate using either external cardiotocography or intermittent auscultation it has been discussed with a senior obstetrician the benefits are likely to outweigh the potential risks the alternatives (immediate birth, intermittent ultrasound and no monitoring) have been discussed with the woman and are unacceptable to her. Discuss with the woman (and her family members or carers, as appropriate) the possible use of a fetal scalp electrode between 34+0 and 36+6 weeks of pregnancy if it is not possible to monitor the fetal heart rate using either external cardiotocography or intermittent auscultation. ## Fetal blood sampling Do not carry out fetal blood sampling if the woman is less than 34+0 weeks pregnant. Discuss with the woman the possible use of fetal blood sampling between 34+0 and 36+6 weeks of pregnancy if the benefits are likely to outweigh the potential risks. When offering fetal blood sampling, advise the woman that if a blood sample cannot be obtained a caesarean section is likely. Also see the advice on fetal blood sampling in the NICE guidelines on intrapartum care for women with existing medical conditions or obstetric complications and their babies and intrapartum care for healthy women and babies. # Mode of birth Discuss the general benefits and risks of caesarean birth and vaginal birth with women in suspected, diagnosed or established preterm labour and in P‑PROM (and their family members or carers, as appropriate). See the section on planning mode of birth in NICE's guideline caesarean birth. Explain to women in suspected, diagnosed or established preterm labour and women with P‑PROM about the benefits and risks of caesarean birth that are specific to gestational age. In particular, highlight the difficulties associated with performing a caesarean birth for a preterm birth, especially the increased likelihood of a vertical uterine (classical) incision and the implications of this for future pregnancies. Explain to women in suspected, diagnosed or established preterm labour that there are no known benefits or harms for the baby from caesarean birth, but the evidence is very limited. Consider caesarean birth for women presenting in suspected, diagnosed or established preterm labour between 26+0 and 36+6 weeks of pregnancy with breech presentation. # Timing of cord clamping for preterm babies (born vaginally or by caesarean birth) Wait at least 60 seconds before clamping the cord of preterm babies unless there are specific maternal or fetal conditions that need earlier clamping. Position the baby at or below the level of the placenta before clamping the cord. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster. ## Cervical trauma Physical injury to the cervix including surgery; for example, previous cone biopsy (cold knife or laser), large loop excision of the transformation zone (LLETZ; any number) or radical diathermy. ## Diagnosed preterm labour A woman is in diagnosed preterm labour if she is in suspected preterm labour and has had a positive diagnostic test for preterm labour. ## Emergency cervical cerclage (previously known as 'rescue') Cervical cerclage performed as an emergency procedure for premature cervical dilatation, often with exposed fetal membranes. ## Established preterm labour A woman is in established preterm labour if she has progressive cervical dilatation from 4 cm with regular contractions (see the definition of the established first stage of labour in NICE's guideline on intrapartum care). ## MBRRACE-UK Mothers and babies: reducing risk through audits and confidential enquiries across the UK (MBRRACE-UK) is a series of audits carried out with the aim of identifying causes of maternal and perinatal death and morbidity and making recommendations to inform maternity care and so reduce these poor outcomes. ## Preterm prelabour rupture of membranes (P‑PROM) A woman is described as having P‑PROM if she has ruptured membranes before 37+0 weeks of pregnancy but is not in established labour. ## Suspected preterm labour A woman is in suspected preterm labour if she has reported symptoms of preterm labour and has had a clinical assessment (including a speculum or digital vaginal examination) that confirms the possibility of preterm labour, but rules out established labour. ## Symptoms of preterm labour A woman has presented before 37+0 weeks of pregnancy reporting symptoms that might be indicative of preterm labour (such as abdominal pain), but no clinical assessment (including speculum or digital vaginal examination) has taken place.# Recommendations for research The guideline committee has made the following recommendations for research. As part of the 2019 update, the guideline committee made 3 additional recommendations for research on prophylactic progesterone. As part of the 2022 update, the guideline committee made an additional recommendation for research on repeating maternal corticosteroids. # Key recommendations for research ## Repeating maternal corticosteroids Is a single repeat dose or a single repeat course (2 doses) of maternal corticosteroids more effective than a single course for preterm neonatal outcomes and longer-term outcomes for babies and children, and what is the optimal time interval between completing the initial course (2 doses) and the repeat dose or course? For a short explanation of why the committee made the recommendation for research, see the rationale section on repeat courses of maternal corticosteroids . Full details of the evidence and the committee's discussion are in evidence review B: effectiveness of repeat courses of maternal corticosteroids for fetal lung maturation. Loading. Please wait. ## Prophylactic vaginal progesterone Does progesterone reduce the risk of preterm birth in women who have risk factors for preterm birth, but do not have a short cervix (cervical length of more than 25 mm)? ## Why this is important Preterm birth is a cause of significant morbidity for women and babies, and impacts negatively on women and their families, as well as being costly to the NHS. There is good evidence for the use of progesterone to reduce preterm birth, however studies include women with a combination of risk factors for preterm birth, such as a history of preterm birth and a shortened cervix. There is no evidence for the effectiveness of progesterone in women who do not have a short cervix, but who do have other risk factors for preterm birth. It is therefore difficult to decide if progesterone should be recommended for women, and also whether measuring the cervical length to guide treatment is necessary. ## Prophylactic vaginal progesterone Does progesterone reduce the risk of preterm birth in women who have a short cervix (cervical length of 25 mm or less), but do not have other risk factors for preterm birth? ## Why this is important Preterm birth is a cause of significant morbidity for women and babies, and impacts negatively on women and their families, as well as being costly to the NHS. There is good evidence for the use of progesterone to reduce preterm birth, however studies include people with a combination of risk factors for preterm birth, such as a history of preterm birth and a shortened cervix. There is a lack of evidence for the effectiveness of progesterone in women with a cervical length of 25 mm or less, but without other risk factors for preterm birth. It is therefore difficult to decide if progesterone should be recommended for women, and consequently whether measuring the cervix to guide treatment is necessary for women with no other risk factors. ## Prophylactic vaginal progesterone At what gestation should treatment with prophylactic vaginal progesterone for the prevention of preterm birth be started and stopped? ## Why this is important Preterm birth is a cause of significant morbidity for women and babies, and impacts negatively on women and their families, as well as being costly to the NHS. There is good evidence for the use of progesterone to reduce preterm birth, however studies do not define the optimal gestational age that this treatment should be started and stopped, and it is therefore difficult to recommend when it should start and the optimal duration of treatment. ## Prophylactic vaginal progesterone and prophylactic cervical cerclage What is the clinical effectiveness of prophylactic cervical cerclage alone compared with prophylactic vaginal progesterone alone and with both strategies together for preventing preterm birth in women with a short cervix and a history of spontaneous preterm birth? ## Why this is important Preterm birth causes significant neonatal morbidity and mortality, as well as long-term disability. Therefore strategies for preventing preterm birth are important. There are recognised risk factors for preterm birth, and so interventions can be offered to women with these risk factors. Both prophylactic cervical cerclage and prophylactic vaginal progesterone are effective in preventing preterm birth in women with a short cervix and a history of preterm birth, but there is limited evidence on which is more effective, and the relative risks and benefits (including costs) of each. More randomised research is needed to compare the relative effectiveness of prophylactic cervical cerclage and prophylactic vaginal progesterone in improving both neonatal and maternal outcomes. This will help women and healthcare professionals to make an informed decision about which is the most effective prophylactic option. ## Identifying infection in women with preterm prelabour rupture of membranes (P‑PROM) What is the diagnostic accuracy of serial C‑reactive protein testing to identify chorioamnionitis in women with P‑PROM? ## Why this is important Identifying infection in women with P‑PROM is needed to provide best practice care. Early diagnosis of infection allows consideration of therapeutic strategies (including antibiotics and/or early birth). Effective treatment of infection is particularly important given that sepsis is a common direct cause of maternal death. There is currently limited evidence that serial C‑reactive protein testing might be useful, but the committee is aware that this strategy is in common practice. Evidence from diagnostic studies is needed about the accuracy of serial C‑reactive protein testing for identifying chorioamnionitis, which is one of the most common and serious infective complications of P‑PROM. ## Emergency cervical cerclage What is the clinical effectiveness of emergency cerclage in improving outcomes for women at risk of preterm birth? ## Why this is important There is some evidence from randomised studies that emergency cerclage might be effective in improving neonatal outcomes in women with a dilated cervix and exposed, intact fetal membranes. However, there is uncertainty about the magnitude of this effect. The full consequences of this strategy and the subgroups of women at risk of preterm labour who might particularly benefit are not known. A randomised controlled trial would best address this question, but a national registry of the most critical outcomes (neonatal mortality and morbidity, maternal morbidity) could also be considered for women who did not want to participate in a randomised trial but who opt for 'rescue' cerclage. ## Magnesium sulfate for neuroprotection What is the clinical effectiveness of a bolus plus infusion of magnesium sulfate compared with a bolus alone for preventing neurodevelopmental injury in babies born preterm? ## Why this is important There is evidence from randomised studies that magnesium sulfate has neuroprotective properties for the baby when given to women who will deliver preterm up to 34+0 weeks of pregnancy. However, there is uncertainty about the best method of administering magnesium sulfate for this purpose, with different studies using different strategies. There are significant advantages for the woman and for reducing healthcare costs if a bolus is as effective as a bolus plus infusion, because magnesium sulfate has side effects for the woman, and more monitoring is needed for infusion, with additional associated healthcare costs. A randomised controlled trial would best address this question by assessing the effects of each method on neonatal and maternal outcomes.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Prophylactic vaginal progesterone Recommendations 1.2.1 to 1.2.5 ## Why the committee made the recommendations There was good evidence that vaginal progesterone reduced the risk of preterm birth before 34 weeks in women with a previous history of preterm birth, and in women with a short cervix (25 mm or less). The committee were aware that these groups overlapped, as some women with a previous history of preterm birth will also have a short cervix. Therefore, they adopted the recommendation from the previous guideline to offer vaginal progesterone to women with a previous history of preterm birth and a short cervix. The committee concluded that, as in the previous guideline, progesterone should be offered as an equal option with cervical cerclage (for which no new evidence review had been done), as there is no evidence to determine which of these options is more effective. As the treatment options are very different (regular use of vaginal progesterone pessaries throughout pregnancy, compared with a single operative procedure), the committee highlighted that the choice of treatment should be made after discussion of the risks and benefits of the 2 treatments. The committee were aware that there is uncertainty about which risk factors should be used to identify women at risk of preterm birth (cervical length measurements, previous history of preterm birth, previous cervical surgery). There is also variation in practice across the country about which women are offered cervical length scanning. Cervical scanning is currently offered when there is clinical concern about the risk of preterm birth, rather than as a routine part of antenatal care. Also, vaginal progesterone may be effective at reducing preterm birth for women with some risk factors, but not others. Identifying specific groups of women who would benefit from treatment with progesterone was difficult because of the overlap in risk factors for an individual woman: some women with a previous history of preterm birth also have a cervical length of 25 mm or less, and some women with a cervical length of 25 mm or less also have a previous history of preterm birth. Therefore, it was hard to determine which of these 2 factors could identify women at high risk of preterm birth who would definitely benefit from treatment with vaginal progesterone. Consequently, the committee agreed that treatment with progesterone should be considered for women with either of these risk factors (cervical length of 25 mm or less, or a previous history of preterm birth). Because of the uncertainty over the benefits of progesterone in women who have risk factors for a preterm birth but do not have a cervical length of 25 mm or less, and women who have a cervical length of 25 mm or less but do not have a history of preterm birth, the committee made recommendations for research on this topic. The timing of progesterone administration varied between the studies. However, most trials started treatment between 16+0 and 24+0 weeks. This was in keeping with the experience of the committee members, therefore they made a recommendation to start treatment at any suitable time during that range of gestational age. There was no evidence on when progesterone should be stopped, but the committee's experience was that it should be continued until at least 34 weeks. As there was uncertainty about these timings, the committee also made a recommendation for research on the optimal timing of treatment. The recommendation on ensuring a plan is in place for removal of the suture when prophylactic cervical cerclage is used was made in response to an NHS England safety report, which highlighted some instances when removal did not happen. ## How the recommendations might affect practice Vaginal progesterone is a relatively inexpensive and commonly used treatment for women at risk of preterm birth, so the recommendations are unlikely to significantly alter practice. As vaginal progesterone should now be considered for women with a history of preterm birth (with an unknown cervical length or a cervical length greater than 25 mm on scan), this might increase the use of progesterone, but the benefits of reduced numbers of preterm births are likely to lead to cost savings overall. The recommendation on planning for removal of the suture when prophylactic cervical cerclage is used is not expected to affect practice. Return to recommendations # Emergency cervical cerclage Recommendation 1.6.4 ## Why the committee made the recommendation The recommendation on ensuring a plan is in place for removal of the suture when emergency cervical cerclage is used was made in response to an NHS England safety report, which highlighted some instances when removal did not happen. ## How the recommendation might affect practice The recommendation is not expected to affect practice. Return to recommendation # Repeat courses of maternal corticosteroids Recommendations 1.9.4 to 1.9.6 ## Why the committee made the recommendations There was some evidence that repeat doses of maternal corticosteroids reduce birthweight, but the absolute reductions in birthweight were small, with a mean difference in birthweight of 114 g between women receiving repeat courses and women receiving a single course. Subgroup analyses showed reductions were seen when corticosteroids were administered at lower gestational ages (below 30 weeks), when administered at intervals of less than 7 days, and when higher doses of more than 24 mg (total dose of repeat course) were administered. There was also a significant trend for reducing birthweight as the number of repeat courses increased. There was no evidence of benefit of maternal corticosteroids on chronic lung disease, but the committee were aware of a benefit seen with the need for respiratory support in neonates, although this outcome had not been prioritised for inclusion in the review. There was good evidence that repeat courses of maternal corticosteroids had no effect or beneficial effects on perinatal mortality, neonatal admission, intraventricular haemorrhage, growth at 2 years and neurodevelopmental delay. The committee agreed that a single repeat course may be beneficial in certain circumstances, when the previous course had been given more than 7 days previously and preterm birth was imminent, but that with multiple repeat courses the effects on birthweight may outweigh the benefits. However, the committee agreed that corticosteroids administered for other reasons during pregnancy would not count towards this total of 2 courses, and so clarified in their recommendation that only courses administered for preterm labour should be counted. The committee were concerned with the lack of evidence for longer-term neurodevelopmental and growth outcomes beyond 2 years and lack of evidence on the optimal dose and interval for the repeat corticosteroids and so made a recommendation for research. ## How the recommendations might affect practice The recommendations provide guidance on when a single repeat course of maternal corticosteroids may be used, and so may reduce variation in practice. This may increase the number of women who receive a single repeat course, and may reduce the number of multiple (more than 2) courses of maternal corticosteroids given. The cost impact is therefore likely to be minimal considering the low cost of a course of maternal corticosteroids and the relatively small population of women for whom this will be considered. Return to recommendations# Context Preterm birth is the single biggest cause of neonatal mortality and morbidity in the UK. Over 52,000 babies (around 7.3% of live births) in England and Wales in 2012 were born preterm (that is, before 37+0 weeks of pregnancy). There has been no decline in the preterm birth rate in the UK over the last 10 years. Babies born preterm have high rates of neonatal and infant mortality, and the risk of mortality increases as gestational age at birth decreases. Babies who survive preterm birth have increased rates of disability. Recent UK studies comparing cohorts born in 1995 and 2006 have shown improved rates of survival (from 40% to 53%) for extreme preterm births (born between 22 and 26 weeks). Rates of disability in survivors were largely unchanged over this time period. The major long-term consequence of prematurity is neurodevelopmental disability. Although the risk for the individual child is greatest for those born at the earliest gestational ages, the global burden of neurodevelopmental disabilities depends on the number of babies born at each of these gestations, and so is greatest for babies born between 32 and 36 weeks, less for those born between 28 and 31 weeks, and least for those born at less than 28 weeks gestation. Around 75% of preterm births occur after preterm labour, which may or may not be preceded by preterm prelabour rupture of membranes. The remaining women giving birth preterm have an elective preterm birth when this is thought to be in the fetal or maternal interest (for example, because of extreme growth retardation in the baby or maternal conditions such as pre-eclampsia). This guideline reviews the evidence for the best way to provide treatment for women who present with symptoms and signs of preterm labour, and women who are scheduled to have an early planned birth. It also reviews how preterm birth can be optimally diagnosed when symptoms are present, given that many women thought to be in preterm labour on a clinical assessment will not give birth preterm. The guideline does not cover who should and should not have medically indicated preterm birth, or diagnostic or predictive tests in asymptomatic women.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Information and support\n\nWhen giving information and support to women at increased risk of preterm labour, or with suspected, diagnosed or established preterm labour, or having a planned preterm birth (and their family members or carers as appropriate):\n\nensure this is given as early as possible, taking into account the likelihood of preterm birth and the status of labour\n\nfollow the principles in NICE's guideline on patient experience in adult NHS services\n\nbear in mind that the woman (and their family members or carers) may be particularly anxious\n\ngive both oral and written information\n\ndescribe the symptoms and signs of preterm labour\n\nexplain about the care that may be offered. \n\nFor women who are having a planned preterm birth or are offered treatment for preterm labour in line with the sections on tocolysis, maternal corticosteroids and magnesium sulfate for neuroprotection (and their family members or carers as appropriate), provide information and support that includes:\n\ninformation about the likelihood of the baby surviving and other outcomes (including long-term outcomes) and risks for the baby, giving values as natural frequencies (for example, 1\xa0in\xa0100)\n\nexplanation of the neonatal care of preterm babies, including location of care\n\nexplanation of the immediate problems that can arise when a baby is born preterm\n\nexplanation of the possible long-term consequences of prematurity for the baby (how premature babies grow and develop)\n\nongoing opportunities to talk about and state their wishes about resuscitation of the baby\n\nan opportunity to tour the neonatal unit\n\nan opportunity to speak to a neonatologist or paediatrician. \n\nBe aware that, according to the 2021 Mothers and babies: reducing risk through audits and confidential enquiries across the UK (MBRRACE-UK) report on perinatal mortality, women from some minority ethnic backgrounds or who live in deprived areas have an increased risk of stillbirth and may need closer monitoring and additional support. The report showed that across all births (not just those which are preterm):\n\ncompared with white babies (32 out of 10,000), the stillbirth rate is:\n\n\n\nmore than twice as high in black babies (72 out of 10,000)\n\naround 50% higher in Asian babies (51 out of 10,000)\n\n\n\ncompared with the least deprived areas (23 out of 10,000), the still birth rate is twice as high in the most deprived areas (47 out of 10,000). \n\n# Care of women at risk of preterm labour\n\n# Prophylactic vaginal progesterone and prophylactic cervical cerclage\n\nOffer a choice of prophylactic vaginal progesterone or prophylactic cervical cerclage to women who have both:\n\na history of spontaneous preterm birth (up to 34+0\xa0weeks of pregnancy) or loss (from 16+0\xa0weeks of pregnancy onwards), and\n\nresults from a transvaginal ultrasound scan carried out between 16+0\xa0and 24+0\xa0weeks of pregnancy that show a cervical length of 25\xa0mm or less. Discuss the risks and benefits of both options with the woman, and make a shared decision on which treatment is most suitable.In August\xa02019, this was an off-label use of vaginal progesterone. See NICE's information on prescribing medicines. [2019, amended 2022]\n\nConsider prophylactic vaginal progesterone for women who have either:\n\na history of spontaneous preterm birth (up to 34+0\xa0weeks of pregnancy) or loss (from 16+0\xa0weeks of pregnancy onwards), or\n\nresults from a transvaginal ultrasound scan carried out between 16+0\xa0and 24+0\xa0weeks of pregnancy that show a cervical length of 25\xa0mm or less.In August\xa02019, this was an off-label use of vaginal progesterone. See NICE's information on prescribing medicines. [2019, amended 2022]\n\nWhen using vaginal progesterone, start treatment between 16+0\xa0and\xa024+0\xa0weeks of pregnancy and continue until at least 34\xa0weeks. \n\nConsider prophylactic cervical cerclage for women when results of a transvaginal ultrasound scan carried out between 16+0\xa0and\xa024+0\xa0weeks of pregnancy show a cervical length of 25\xa0mm or less, who have had either:\n\npreterm prelabour rupture of membranes (P‑PROM) in a previous pregnancy or\n\na history of cervical trauma. [2015, amended 2019]\n\nIf prophylactic cervical cerclage is used, ensure a plan is made and documented for removal of the suture. [2019, amended 2022]\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prophylactic vaginal progesterone\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: clinical effectiveness of prophylactic progesterone in preventing preterm labour.\n\nLoading. Please wait.\n\n# Diagnosing preterm prelabour rupture of membranes (P-PROM)\n\nIn a woman reporting symptoms suggestive of P‑PROM, offer a speculum examination to look for pooling of amniotic fluid and:\n\nif pooling of amniotic fluid is observed, do not perform any diagnostic test but offer care consistent with the woman having P‑PROM (see the sections on antenatal prophylactic antibiotics for women with P-PROM, identifying infection in women with P-PROM and maternal corticosteroids)\n\nif pooling of amniotic fluid is not observed, perform an insulin-like growth factor binding protein‑1 test or placental alpha-microglobulin‑1 test of vaginal fluid. [2015, amended 2019]\n\nIf the results of the insulin-like growth factor binding protein‑1 or placental alpha-microglobulin‑1 test are positive, do not use the test results alone to decide what care to offer the woman, but also take into account her clinical condition, medical and pregnancy history and gestational age, and either:\n\noffer care consistent with the woman having P‑PROM (see the sections on antenatal prophylactic antibiotics for women with P-PROM, identifying infection in women with P-PROM and maternal corticosteroids\xa0or\n\nre-evaluate the woman's diagnostic status at a later time point. \n\nIf the results of the insulin-like growth factor binding protein‑1 or placental alpha-microglobulin‑1 test are negative and no amniotic fluid is observed:\n\ndo not offer antenatal prophylactic antibiotics\n\nexplain to the woman that it is unlikely she has P‑PROM, but that she should return for reassessment if there are any further symptoms suggestive of P‑PROM or preterm labour. [2015, amended 2022]\n\nDo not use nitrazine to diagnose P‑PROM. \n\nDo not perform diagnostic tests for P‑PROM if labour becomes established in a woman reporting symptoms suggestive of P‑PROM. \n\n# Antenatal prophylactic antibiotics for women with P-PROM\n\nAs prophylaxis for intrauterine infection, offer women with P-PROM oral erythromycin 250\xa0mg 4\xa0times a day for a maximum of 10\xa0days or until the woman is in established labour (whichever is sooner). [2015, amended 2022]\n\nFor women with P‑PROM who cannot tolerate erythromycin or in whom erythromycin is contraindicated, consider an oral penicillin for a maximum of 10\xa0days or until the woman is in established labour (whichever is sooner). [2015, amended 2019]\n\nDo not offer women with P‑PROM co‑amoxiclav as prophylaxis for intrauterine infection. \n\nFor guidance on the use of intrapartum antibiotics, see the section on intrapartum antibiotics in NICE's guideline on neonatal infection, and when applicable also see the section on treatment for women with prolonged prelabour rupture of membranes who have group B streptococcal colonisation, bacteriuria or infection. \n\n# Identifying infection in women with P-PROM\n\nUse a combination of clinical assessment and tests (C‑reactive protein, white blood cell count and measurement of fetal heart rate using cardiotocography) to diagnose intrauterine infection in women with P‑PROM. \n\nDo not use any one of the following in isolation to confirm or exclude intrauterine infection in women with P‑PROM:\n\na single test of C‑reactive protein\n\nwhite blood cell count\n\nmeasurement of fetal heart rate using cardiotocography. \n\nIf the results of the clinical assessment or any of the tests are not consistent with each other, continue to observe the woman and consider repeating the tests. \n\n# Emergency cervical cerclage\n\nDo not offer emergency cervical cerclage to women with:\n\nsigns of infection, or\n\nactive vaginal bleeding, or\n\nuterine contractions. [2015, amended 2022]\n\nConsider emergency cervical cerclage for women between 16+0\xa0and\xa027+6\xa0weeks of pregnancy with a dilated cervix and exposed, unruptured fetal membranes. Also:\n\ntake into account gestational age (being aware that the benefits are likely to be greater for earlier gestations) and the extent of cervical dilatation\n\ndiscuss with a consultant obstetrician and consultant paediatrician. [2015, amended 2022]\n\nIf emergency cervical cerclage is being considered, explain to the woman (and their family members or carers, as appropriate):\n\nabout the risks of the procedure\n\nthat it aims to delay the birth, and so increase the likelihood of the baby surviving and of reducing serious neonatal morbidity [2015, amended 2022]\n\nIf emergency cervical cerclage is used, ensure that a plan is made and documented for removal of the suture. [2019, amended 2022]\n\nFor a short explanation of why the committee made the 2019 recommendation and how it might affect practice, see the rationale and impact section on emergency cervical cerclage\xa0.\n\nLoading. Please wait.\n\n# Care of women with suspected or established preterm labour\n\n# Diagnosing preterm labour for women with intact membranes\n\nExplain to women reporting symptoms of preterm labour who have intact membranes (and their family members or carers, as appropriate):\n\nabout the clinical assessment and diagnostic tests that are available\n\nhow the clinical assessment and diagnostic tests are carried out\n\nwhat the benefits, risks and possible consequences of the clinical assessment and diagnostic tests are, including the consequences of false-positive and false-negative test results and taking into account gestational age. \n\nOffer a clinical assessment to women reporting symptoms of preterm labour who have intact membranes. This should include:\n\nclinical history taking\n\nthe observations described for the initial assessment of labour in NICE's guideline on intrapartum care\n\na speculum examination (followed by a digital vaginal examination if the extent of cervical dilatation cannot be assessed; be aware that if a swab for fetal fibronectin testing is anticipated [see recommendation\xa01.7.5] the swab should be taken before any digital vaginal examination). \n\nIf the clinical assessment suggests that the woman is in suspected preterm labour and she is 29+6\xa0weeks pregnant or less, advise treatment for preterm labour as described in the sections on tocolysis and maternal corticosteroids. \n\nIf the clinical assessment suggests that the woman is in suspected preterm labour and she is 30+0\xa0weeks pregnant or more, consider transvaginal ultrasound measurement of cervical length as a diagnostic test to determine likelihood of birth within 48\xa0hours. Act on the results as follows:\n\nif cervical length is more than 15\xa0mm, explain to the woman that it is unlikely to be preterm labour and:\n\n\n\nthink about alternative diagnoses\n\ndiscuss with her the benefits and risks of going home compared with continued monitoring and treatment in hospital\n\nadvise her that if she does decide to go home, she should return if symptoms suggestive of preterm labour persist or recur\n\n\n\nif cervical length is 15\xa0mm or less, view the woman as being in diagnosed preterm labour and offer treatment as described in the sections on tocolysis and maternal corticosteroids. \n\nConsider fetal fibronectin testing as a diagnostic test to determine likelihood of birth within 48\xa0hours for women who are 30+0\xa0weeks pregnant or more if transvaginal ultrasound measurement of cervical length is indicated, but is not available or not acceptable. Act on the results as follows:\n\nif fetal fibronectin testing is negative (concentration 50\xa0ng/ml or less), explain to the woman that it is unlikely she is in preterm labour and:\n\n\n\nthink about alternative diagnoses\n\ndiscuss with her the benefits and risks of going home compared with continued monitoring and treatment in hospital\n\nadvise her that if she decides to go home, she should return if symptoms suggestive of preterm labour persist or recur\n\n\n\nif fetal fibronectin testing is positive (concentration more than 50\xa0ng/ml), view the woman as being in diagnosed preterm labour and offer treatment as described in the sections on tocolysis and maternal corticosteroids. \n\nIf a woman in suspected preterm labour who is 30+0\xa0weeks pregnant or more does not have transvaginal ultrasound measurement of cervical length or fetal fibronectin testing to exclude preterm labour, offer treatment consistent with her being in diagnosed preterm labour (see the sections on tocolysis and maternal corticosteroids). \n\nDo not use transvaginal ultrasound measurement of cervical length and fetal fibronectin testing in combination to diagnose preterm labour. \n\nUltrasound scans should be performed by healthcare professionals with training in, and experience of, transvaginal ultrasound measurement of cervical length. \n\nFor guidance on the use of other biomarker tests used for the diagnosis of preterm labour, see NICE's diagnostics guidance on biomarker tests to help diagnose preterm labour in women with intact membranes. \n\n# Tocolysis\n\nTake the following factors into account when making a decision about whether to start tocolysis:\n\nwhether the woman is in suspected or diagnosed preterm labour\n\nother clinical features (for example, bleeding or infection) that may suggest that stopping labour is contraindicated\n\ngestational age at presentation\n\nlikely benefit of maternal corticosteroids (see the section on maternal corticosteroids)\n\navailability of an appropriate level of neonatal care (if there is need for transfer to another unit). See also NHS England's guidance on saving babies' lives care bundle version 2 (recommendation 5.9).\n\nthe preference of the woman. [2015, amended 2022]\n\nConsider nifedipine for tocolysis for women between 24+0\xa0and\xa025+6\xa0weeks of pregnancy who have intact membranes and are in suspected preterm labour.In November\xa02015, this was an off-label use of nifedipine. See NICE's information on prescribing medicines. \n\nOffer nifedipine for tocolysis to women between 26+0 and 33+6\xa0weeks of pregnancy who have intact membranes and are in suspected or diagnosed preterm labour. In November\xa02015, this was an off-label use of nifedipine. See NICE's information on prescribing medicines. \n\nIf nifedipine is contraindicated, offer oxytocin receptor antagonists for tocolysis. \n\nDo not offer betamimetics for tocolysis. \n\n# Maternal corticosteroids\n\nIn June\xa02022 this was an off-label use of betamethasone and dexamethasone. See NICE's information on prescribing medicines.\n\nFor women between 22+0\xa0and 23+6\xa0weeks of pregnancy who are in suspected or established preterm labour, are having a planned preterm birth or have P‑PROM (see the section on diagnosing P-PROM), discuss with the woman (and her family members or carers, as appropriate) and the multidisciplinary team the use of maternal corticosteroids in the context of her individual circumstances. [2015, amended 2022]\n\nOffer maternal corticosteroids to women between 24+0 and 33+6\xa0weeks of pregnancy who are in suspected, diagnosed or established preterm labour, are having a planned preterm birth or have P‑PROM. [2015, amended 2019]\n\nConsider maternal corticosteroids for women between 34+0 and 35+6\xa0weeks of pregnancy who are in suspected, diagnosed or established preterm labour, are having a planned preterm birth or have P‑PROM. \n\nConsider a single repeat course of maternal corticosteroids for women less than 34+0\xa0weeks of pregnancy who:\n\nhave already had a course of corticosteroids when this was more than 7\xa0days ago, and\n\nare at very high risk of giving birth in the next 48\xa0hours.Where the woman is less than 30+0\xa0weeks pregnant or if there is suspected growth restriction, take into account the possible impact on fetal growth of a repeat course of maternal corticosteroids. \n\nDo not give more than 2\xa0courses of maternal corticosteroids for preterm birth. \n\nWhen offering or considering maternal corticosteroids, discuss the benefits and risks with the woman (and her family members or carers, as appropriate). [2015, amended 2022]\n\nFor guidance on the use of corticosteroids in people with diabetes, see NICE's guideline on diabetes in pregnancy. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on repeat courses of maternal corticosteroids\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: effectiveness of repeat courses of maternal corticosteroids for fetal lung maturation.\n\nLoading. Please wait.\n\n# Magnesium sulfate for neuroprotection\n\nIn August 2019, the use of intravenous magnesium sulfate in recommendations 1.10.1 to 1.10.3 was off label. See NICE's information on prescribing medicines.\n\nThis guideline does not recommend using magnesium sulfate beyond 24\xa0hours. But if uncertainty around exact timing of delivery results in repeat administration, follow the MHRA safety advice on the prolonged or repeated use of magnesium sulfate in pregnancy.\n\nFor women between 23+0 and 23+6\xa0weeks of pregnancy who are in established preterm labour or having a planned preterm birth within 24\xa0hours, discuss with the woman (and her family members or carers, as appropriate) the use of intravenous magnesium sulfate for neuroprotection of the baby, in the context of her individual circumstances. \n\nOffer intravenous magnesium sulfate for neuroprotection of the baby to women between 24+0 and 29+6\xa0weeks of pregnancy who are:\n\nin established preterm labour, or\n\nhaving a planned preterm birth within 24\xa0hours. \n\nConsider intravenous magnesium sulfate for neuroprotection of the baby for women between 30+0 and 33+6\xa0weeks of pregnancy who are:\n\nin established preterm labour, or\n\nhaving a planned preterm birth within 24\xa0hours. \n\nGive a 4\xa0g intravenous bolus of magnesium sulfate over 15\xa0minutes, followed by an intravenous infusion of 1\xa0g per hour until the birth or for 24\xa0hours (whichever is sooner). \n\nFor women on magnesium sulfate, monitor for clinical signs of magnesium toxicity at least every 4\xa0hours by recording pulse, blood pressure, respiratory rate and deep tendon (for example, patellar) reflexes. \n\nIf a woman has or develops oliguria or other evidence of renal failure:\n\nmonitor more frequently for magnesium toxicity\n\nreduce or stop the dose of magnesium sulfate. [2015, amended 2022]\n\n# Intrapartum antibiotics\n\nFor guidance on the use of intrapartum antibiotics in established preterm labour, see NICE's guideline on neonatal infection. \n\n# Fetal monitoring\n\n## Monitoring options: cardiotocography and intermittent auscultation\n\nDiscuss with women in suspected, diagnosed or established preterm labour (and their family members or carers, as appropriate):\n\nthe purpose of fetal monitoring and what it involves\n\nthe clinical decisions it informs at different gestational ages\n\nif appropriate, the option not to monitor the fetal heart rate (for example, at the threshold of viability). \n\nInvolve a senior obstetrician in discussions about whether and how to monitor the fetal heart rate for women who are between 23+0 and 25+6\xa0weeks pregnant. \n\nExplain the different fetal monitoring options to the woman (and her family members or carers, as appropriate), being aware that:\n\nthere is limited evidence about the usefulness of specific features to suggest hypoxia or acidosis in preterm babies\n\nthe available evidence is broadly consistent with that for babies born at term (see the NICE guideline on fetal monitoring in labour)\n\na normal cardiotocography trace is reassuring and indicates that the baby is coping well with labour, but an abnormal trace does not necessarily indicate that fetal hypoxia or acidosis is present. \n\nExplain that there is an absence of evidence that using cardiotocography improves the outcomes of preterm labour for the parent or the baby compared with intermittent auscultation. Include family members or carers in the discussion, as appropriate. \n\nIn established preterm labour with no other risk factors (see the NICE guideline on fetal monitoring in labour), offer a choice of fetal heart rate monitoring using either:\n\ncardiotocography using external ultrasound or\n\nintermittent auscultation. \n\nFor guidance on using intermittent auscultation for fetal heart rate monitoring, see the NICE guideline on fetal monitoring in labour. \n\n## Fetal scalp electrode\n\nDo not use a fetal scalp electrode for fetal heart rate monitoring if the woman is less than 34+0\xa0weeks pregnant unless all of the following apply:\n\nit is not possible to monitor the fetal heart rate using either external cardiotocography or intermittent auscultation\n\nit has been discussed with a senior obstetrician\n\nthe benefits are likely to outweigh the potential risks\n\nthe alternatives (immediate birth, intermittent ultrasound and no monitoring) have been discussed with the woman and are unacceptable to her. \n\nDiscuss with the woman (and her family members or carers, as appropriate) the possible use of a fetal scalp electrode between 34+0 and 36+6\xa0weeks of pregnancy if it is not possible to monitor the fetal heart rate using either external cardiotocography or intermittent auscultation. \n\n## Fetal blood sampling\n\nDo not carry out fetal blood sampling if the woman is less than 34+0\xa0weeks pregnant. \n\nDiscuss with the woman the possible use of fetal blood sampling between 34+0 and 36+6\xa0weeks of pregnancy if the benefits are likely to outweigh the potential risks. \n\nWhen offering fetal blood sampling, advise the woman that if a blood sample cannot be obtained a caesarean section is likely. Also see the advice on fetal blood sampling in the NICE guidelines on intrapartum care for women with existing medical conditions or obstetric complications and their babies and intrapartum care for healthy women and babies. [2015, amended 2020]\n\n# Mode of birth\n\nDiscuss the general benefits and risks of caesarean birth and vaginal birth with women in suspected, diagnosed or established preterm labour and in P‑PROM (and their family members or carers, as appropriate). See the section on planning mode of birth in NICE's guideline caesarean birth. \n\nExplain to women in suspected, diagnosed or established preterm labour and women with P‑PROM about the benefits and risks of caesarean birth that are specific to gestational age. In particular, highlight the difficulties associated with performing a caesarean birth for a preterm birth, especially the increased likelihood of a vertical uterine (classical) incision and the implications of this for future pregnancies. [2015, amended 2022]\n\nExplain to women in suspected, diagnosed or established preterm labour that there are no known benefits or harms for the baby from caesarean birth, but the evidence is very limited. \n\nConsider caesarean birth for women presenting in suspected, diagnosed or established preterm labour between 26+0 and 36+6\xa0weeks of pregnancy with breech presentation. \n\n# Timing of cord clamping for preterm babies (born vaginally or by caesarean birth)\n\nWait at least 60\xa0seconds before clamping the cord of preterm babies unless there are specific maternal or fetal conditions that need earlier clamping. [2015, amended 2022]\n\nPosition the baby at or below the level of the placenta before clamping the cord. \n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Cervical trauma\n\nPhysical injury to the cervix including surgery; for example, previous cone biopsy (cold knife or laser), large loop excision of the transformation zone (LLETZ; any number) or radical diathermy.\n\n## Diagnosed preterm labour\n\nA woman is in diagnosed preterm labour if she is in suspected preterm labour and has had a positive diagnostic test for preterm labour.\n\n## Emergency cervical cerclage (previously known as 'rescue')\n\nCervical cerclage performed as an emergency procedure for premature cervical dilatation, often with exposed fetal membranes.\n\n## Established preterm labour\n\nA woman is in established preterm labour if she has progressive cervical dilatation from 4\xa0cm with regular contractions (see the definition of the established first stage of labour in NICE's guideline on intrapartum care).\n\n## MBRRACE-UK\n\nMothers and babies: reducing risk through audits and confidential enquiries across the UK (MBRRACE-UK) is a series of audits carried out with the aim of identifying causes of maternal and perinatal death and morbidity and making recommendations to inform maternity care and so reduce these poor outcomes.\n\n## Preterm prelabour rupture of membranes (P‑PROM)\n\nA woman is described as having P‑PROM if she has ruptured membranes before 37+0\xa0weeks of pregnancy but is not in established labour.\n\n## Suspected preterm labour\n\nA woman is in suspected preterm labour if she has reported symptoms of preterm labour and has had a clinical assessment (including a speculum or digital vaginal examination) that confirms the possibility of preterm labour, but rules out established labour.\n\n## Symptoms of preterm labour\n\nA woman has presented before 37+0\xa0weeks of pregnancy reporting symptoms that might be indicative of preterm labour (such as abdominal pain), but no clinical assessment (including speculum or digital vaginal examination) has taken place.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\nAs part of the 2019 update, the guideline committee made 3 additional recommendations for research on prophylactic progesterone. As part of the 2022 update, the guideline committee made an additional recommendation for research on repeating maternal corticosteroids.\n\n# Key recommendations for research\n\n## Repeating maternal corticosteroids\n\nIs a single repeat dose or a single repeat course (2\xa0doses) of maternal corticosteroids more effective than a single course for preterm neonatal outcomes and longer-term outcomes for babies and children, and what is the optimal time interval between completing the initial course (2\xa0doses) and the repeat dose or course? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on repeat courses of maternal corticosteroids\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: effectiveness of repeat courses of maternal corticosteroids for fetal lung maturation.\n\nLoading. Please wait.\n\n## Prophylactic vaginal progesterone\n\nDoes progesterone reduce the risk of preterm birth in women who have risk factors for preterm birth, but do not have a short cervix (cervical length of more than 25\xa0mm)? \n\n## Why this is important\n\nPreterm birth is a cause of significant morbidity for women and babies, and impacts negatively on women and their families, as well as being costly to the NHS. There is good evidence for the use of progesterone to reduce preterm birth, however studies include women with a combination of risk factors for preterm birth, such as a history of preterm birth and a shortened cervix.\n\nThere is no evidence for the effectiveness of progesterone in women who do not have a short cervix, but who do have other risk factors for preterm birth. It is therefore difficult to decide if progesterone should be recommended for women, and also whether measuring the cervical length to guide treatment is necessary.\n\n## Prophylactic vaginal progesterone\n\nDoes progesterone reduce the risk of preterm birth in women who have a short cervix (cervical length of 25\xa0mm or less), but do not have other risk factors for preterm birth? \n\n## Why this is important\n\nPreterm birth is a cause of significant morbidity for women and babies, and impacts negatively on women and their families, as well as being costly to the NHS. There is good evidence for the use of progesterone to reduce preterm birth, however studies include people with a combination of risk factors for preterm birth, such as a history of preterm birth and a shortened cervix.\n\nThere is a lack of evidence for the effectiveness of progesterone in women with a cervical length of 25\xa0mm or less, but without other risk factors for preterm birth. It is therefore difficult to decide if progesterone should be recommended for women, and consequently whether measuring the cervix to guide treatment is necessary for women with no other risk factors.\n\n## Prophylactic vaginal progesterone\n\nAt what gestation should treatment with prophylactic vaginal progesterone for the prevention of preterm birth be started and stopped? \n\n## Why this is important\n\nPreterm birth is a cause of significant morbidity for women and babies, and impacts negatively on women and their families, as well as being costly to the NHS. There is good evidence for the use of progesterone to reduce preterm birth, however studies do not define the optimal gestational age that this treatment should be started and stopped, and it is therefore difficult to recommend when it should start and the optimal duration of treatment.\n\n## Prophylactic vaginal progesterone and prophylactic cervical cerclage\n\nWhat is the clinical effectiveness of prophylactic cervical cerclage alone compared with prophylactic vaginal progesterone alone and with both strategies together for preventing preterm birth in women with a short cervix and a history of spontaneous preterm birth? \n\n## Why this is important\n\nPreterm birth causes significant neonatal morbidity and mortality, as well as long-term disability. Therefore strategies for preventing preterm birth are important. There are recognised risk factors for preterm birth, and so interventions can be offered to women with these risk factors. Both prophylactic cervical cerclage and prophylactic vaginal progesterone are effective in preventing preterm birth in women with a short cervix and a history of preterm birth, but there is limited evidence on which is more effective, and the relative risks and benefits (including costs) of each. More randomised research is needed to compare the relative effectiveness of prophylactic cervical cerclage and prophylactic vaginal progesterone in improving both neonatal and maternal outcomes. This will help women and healthcare professionals to make an informed decision about which is the most effective prophylactic option.\n\n## Identifying infection in women with preterm prelabour rupture of membranes (P‑PROM)\n\nWhat is the diagnostic accuracy of serial C‑reactive protein testing to identify chorioamnionitis in women with P‑PROM? \n\n## Why this is important\n\nIdentifying infection in women with P‑PROM is needed to provide best practice care. Early diagnosis of infection allows consideration of therapeutic strategies (including antibiotics and/or early birth). Effective treatment of infection is particularly important given that sepsis is a common direct cause of maternal death. There is currently limited evidence that serial C‑reactive protein testing might be useful, but the committee is aware that this strategy is in common practice.\n\nEvidence from diagnostic studies is needed about the accuracy of serial C‑reactive protein testing for identifying chorioamnionitis, which is one of the most common and serious infective complications of P‑PROM.\n\n## Emergency cervical cerclage\n\nWhat is the clinical effectiveness of emergency cerclage in improving outcomes for women at risk of preterm birth? \n\n## Why this is important\n\nThere is some evidence from randomised studies that emergency cerclage might be effective in improving neonatal outcomes in women with a dilated cervix and exposed, intact fetal membranes. However, there is uncertainty about the magnitude of this effect. The full consequences of this strategy and the subgroups of women at risk of preterm labour who might particularly benefit are not known. A randomised controlled trial would best address this question, but a national registry of the most critical outcomes (neonatal mortality and morbidity, maternal morbidity) could also be considered for women who did not want to participate in a randomised trial but who opt for 'rescue' cerclage.\n\n## Magnesium sulfate for neuroprotection\n\nWhat is the clinical effectiveness of a bolus plus infusion of magnesium sulfate compared with a bolus alone for preventing neurodevelopmental injury in babies born preterm? \n\n## Why this is important\n\nThere is evidence from randomised studies that magnesium sulfate has neuroprotective properties for the baby when given to women who will deliver preterm up to 34+0\xa0weeks of pregnancy. However, there is uncertainty about the best method of administering magnesium sulfate for this purpose, with different studies using different strategies. There are significant advantages for the woman and for reducing healthcare costs if a bolus is as effective as a bolus plus infusion, because magnesium sulfate has side effects for the woman, and more monitoring is needed for infusion, with additional associated healthcare costs. A randomised controlled trial would best address this question by assessing the effects of each method on neonatal and maternal outcomes.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Prophylactic vaginal progesterone\n\nRecommendations 1.2.1 to 1.2.5\n\n## Why the committee made the recommendations\n\nThere was good evidence that vaginal progesterone reduced the risk of preterm birth before 34\xa0weeks in women with a previous history of preterm birth, and in women with a short cervix (25\xa0mm or less). The committee were aware that these groups overlapped, as some women with a previous history of preterm birth will also have a short cervix. Therefore, they adopted the recommendation from the previous guideline to offer vaginal progesterone to women with a previous history of preterm birth and a short cervix. The committee concluded that, as in the previous guideline, progesterone should be offered as an equal option with cervical cerclage (for which no new evidence review had been done), as there is no evidence to determine which of these options is more effective.\n\nAs the treatment options are very different (regular use of vaginal progesterone pessaries throughout pregnancy, compared with a single operative procedure), the committee highlighted that the choice of treatment should be made after discussion of the risks and benefits of the 2\xa0treatments.\n\nThe committee were aware that there is uncertainty about which risk factors should be used to identify women at risk of preterm birth (cervical length measurements, previous history of preterm birth, previous cervical surgery). There is also variation in practice across the country about which women are offered cervical length scanning. Cervical scanning is currently offered when there is clinical concern about the risk of preterm birth, rather than as a routine part of antenatal care. Also, vaginal progesterone may be effective at reducing preterm birth for women with some risk factors, but not others.\n\nIdentifying specific groups of women who would benefit from treatment with progesterone was difficult because of the overlap in risk factors for an individual woman: some women with a previous history of preterm birth also have a cervical length of 25\xa0mm or less, and some women with a cervical length of 25\xa0mm or less also have a previous history of preterm birth. Therefore, it was hard to determine which of these 2\xa0factors could identify women at high risk of preterm birth who would definitely benefit from treatment with vaginal progesterone. Consequently, the committee agreed that treatment with progesterone should be considered for women with either of these risk factors (cervical length of 25\xa0mm or less, or a previous history of preterm birth). Because of the uncertainty over the benefits of progesterone in women who have risk factors for a preterm birth but do not have a cervical length of 25\xa0mm or less, and women who have a cervical length of 25\xa0mm or less but do not have a history of preterm birth, the committee made recommendations for research on this topic.\n\nThe timing of progesterone administration varied between the studies. However, most trials started treatment between 16+0 and 24+0\xa0weeks. This was in keeping with the experience of the committee members, therefore they made a recommendation to start treatment at any suitable time during that range of gestational age. There was no evidence on when progesterone should be stopped, but the committee's experience was that it should be continued until at least 34\xa0weeks. As there was uncertainty about these timings, the committee also made a recommendation for research on the optimal timing of treatment.\n\nThe recommendation on ensuring a plan is in place for removal of the suture when prophylactic cervical cerclage is used was made in response to an NHS England safety report, which highlighted some instances when removal did not happen.\n\n## How the recommendations might affect practice\n\nVaginal progesterone is a relatively inexpensive and commonly used treatment for women at risk of preterm birth, so the recommendations are unlikely to significantly alter practice. As vaginal progesterone should now be considered for women with a history of preterm birth (with an unknown cervical length or a cervical length greater than 25\xa0mm on scan), this might increase the use of progesterone, but the benefits of reduced numbers of preterm births are likely to lead to cost savings overall.\n\nThe recommendation on planning for removal of the suture when prophylactic cervical cerclage is used is not expected to affect practice.\n\nReturn to recommendations\n\n# Emergency cervical cerclage\n\nRecommendation 1.6.4\n\n## Why the committee made the recommendation\n\nThe recommendation on ensuring a plan is in place for removal of the suture when emergency cervical cerclage is used was made in response to an NHS England safety report, which highlighted some instances when removal did not happen.\n\n## How the recommendation might affect practice\n\nThe recommendation is not expected to affect practice.\n\nReturn to recommendation\n\n# Repeat courses of maternal corticosteroids\n\nRecommendations 1.9.4 to 1.9.6\n\n## Why the committee made the recommendations\n\nThere was some evidence that repeat doses of maternal corticosteroids reduce birthweight, but the absolute reductions in birthweight were small, with a mean difference in birthweight of 114\xa0g between women receiving repeat courses and women receiving a single course. Subgroup analyses showed reductions were seen when corticosteroids were administered at lower gestational ages (below 30\xa0weeks), when administered at intervals of less than 7\xa0days, and when higher doses of more than 24\xa0mg (total dose of repeat course) were administered. There was also a significant trend for reducing birthweight as the number of repeat courses increased. There was no evidence of benefit of maternal corticosteroids on chronic lung disease, but the committee were aware of a benefit seen with the need for respiratory support in neonates, although this outcome had not been prioritised for inclusion in the review. There was good evidence that repeat courses of maternal corticosteroids had no effect or beneficial effects on perinatal mortality, neonatal admission, intraventricular haemorrhage, growth at 2\xa0years and neurodevelopmental delay. The committee agreed that a single repeat course may be beneficial in certain circumstances, when the previous course had been given more than 7\xa0days previously and preterm birth was imminent, but that with multiple repeat courses the effects on birthweight may outweigh the benefits. However, the committee agreed that corticosteroids administered for other reasons during pregnancy would not count towards this total of 2\xa0courses, and so clarified in their recommendation that only courses administered for preterm labour should be counted.\n\nThe committee were concerned with the lack of evidence for longer-term neurodevelopmental and growth outcomes beyond 2\xa0years and lack of evidence on the optimal dose and interval for the repeat corticosteroids and so made a recommendation for research.\n\n## How the recommendations might affect practice\n\nThe recommendations provide guidance on when a single repeat course of maternal corticosteroids may be used, and so may reduce variation in practice. This may increase the number of women who receive a single repeat course, and may reduce the number of multiple (more than 2) courses of maternal corticosteroids given. The cost impact is therefore likely to be minimal considering the low cost of a course of maternal corticosteroids and the relatively small population of women for whom this will be considered.\n\nReturn to recommendations", 'Context': 'Preterm birth is the single biggest cause of neonatal mortality and morbidity in the UK. Over 52,000\xa0babies (around 7.3% of live births) in England and Wales in 2012 were born preterm (that is, before 37+0\xa0weeks of pregnancy). There has been no decline in the preterm birth rate in the UK over the last 10\xa0years.\n\nBabies born preterm have high rates of neonatal and infant mortality, and the risk of mortality increases as gestational age at birth decreases. Babies who survive preterm birth have increased rates of disability. Recent UK studies comparing cohorts born in 1995 and 2006 have shown improved rates of survival (from 40% to 53%) for extreme preterm births (born between 22\xa0and 26\xa0weeks). Rates of disability in survivors were largely unchanged over this time period.\n\nThe major long-term consequence of prematurity is neurodevelopmental disability. Although the risk for the individual child is greatest for those born at the earliest gestational ages, the global burden of neurodevelopmental disabilities depends on the number of babies born at each of these gestations, and so is greatest for babies born between 32\xa0and 36\xa0weeks, less for those born between 28\xa0and 31\xa0weeks, and least for those born at less than 28\xa0weeks gestation.\n\nAround 75% of preterm births occur after preterm labour, which may or may not be preceded by preterm prelabour rupture of membranes. The remaining women giving birth preterm have an elective preterm birth when this is thought to be in the fetal or maternal interest (for example, because of extreme growth retardation in the baby or maternal conditions such as pre-eclampsia).\n\nThis guideline reviews the evidence for the best way to provide treatment for women who present with symptoms and signs of preterm labour, and women who are scheduled to have an early planned birth. It also reviews how preterm birth can be optimally diagnosed when symptoms are present, given that many women thought to be in preterm labour on a clinical assessment will not give birth preterm.\n\nThe guideline does not cover who should and should not have medically indicated preterm birth, or diagnostic or predictive tests in asymptomatic women.'}	https://www.nice.org.uk/guidance/ng25	This guideline covers the care of women at increased risk of, or with symptoms and signs of, preterm labour (before 37 weeks), and women having a planned preterm birth. It aims to reduce the risks of preterm birth for the baby and describes treatments to prevent or delay early labour and birth.
b3f485d532277b5d28bcf932dfee05ec5031a73a	nice	Gout: diagnosis and management	Gout: diagnosis and management This guideline covers the diagnosis and management of gout. It includes recommendations on diagnosing gout, managing flares, long-term management of gout and referral to specialist services. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Diagnosis and assessment ## Symptoms and signs Suspect gout in people presenting with any of the following: rapid onset (often overnight) of severe pain together with redness and swelling, in 1 or both first metatarsophalangeal (MTP) joints tophi. Consider gout in people presenting with rapid onset (often overnight) of severe pain, redness or swelling in joints other than the first MTP joints (for example, midfoot, ankle, knee, hand, wrist, elbow). Assess the possibility of septic arthritis, calcium pyrophosphate crystal deposition and inflammatory arthritis in people presenting with a painful, red, swollen joint. If septic arthritis is suspected, refer immediately according to the local care pathway. Consider chronic gouty arthritis in people presenting with chronic inflammatory joint pain. In people with suspected gout, take a detailed history and carry out a physical examination to assess the symptoms and signs (see recommendations 1.1.1 and 1.1.2). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on symptoms and signs of gout . Full details of the evidence and the committee's discussion are in evidence review B: what signs and symptoms indicate gout as a possible diagnosis? Loading. Please wait. ## Diagnosis Measure the serum urate level in people with symptoms and signs of gout (see recommendations 1.1.1 and 1.1.2) to confirm the clinical diagnosis (serum urate level of 360 micromol/litre or more). If serum urate level is below 360 micromol/litre (6 mg/dl) during a flare and gout is strongly suspected, repeat the serum urate level measurement at least 2 weeks after the flare has settled. Consider joint aspiration and microscopy of synovial fluid if a diagnosis of gout remains uncertain or unconfirmed. If joint aspiration cannot be carried out or the diagnosis of gout remains uncertain, consider imaging the affected joints with X-ray, ultrasound or dual-energy CT. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnosis . Full details of the evidence and the committee's discussion are in evidence review C: what are the most accurate and cost-effective approaches to diagnosing gout, in particular serum urate level compared with joint aspiration? Loading. Please wait. # Information and support Provide tailored information to people with gout and their family members or carers (as appropriate) at the time of diagnosis and during subsequent follow-up appointments. Explain: the symptoms and signs of gout the causes of gout that the disease progresses without intervention because high levels of urate in the blood lead to the formation of new urate crystals any risk factors for gout they have, including genetics, excess body weight or obesity, medicines they are taking, and comorbidities such as chronic kidney disease (CKD) or hypertension how to manage gout flares and the treatment options available that gout is a lifelong condition that benefits from long-term urate-lowering therapy (ULT) to eliminate urate crystals and prevent flares, shrink tophi and prevent long-term joint damage where to find other sources of information and support such as local support groups, online forums and national charities.See also the recommendations on diet and lifestyle. Follow the recommendations in NICE's guidelines on patient experience in adult NHS services and shared decision making. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support . Full details of the evidence and the committee's discussion are in evidence review A: patient information. Loading. Please wait. # Managing gout flares ## Treatment for gout flares Offer a non-steroidal anti-inflammatory drug (NSAID), colchicine or a short course of an oral corticosteroid for first-line treatment of a gout flare, taking into account the person's comorbidities, co-prescriptions and preferences.In June 2022, this was an off-label use of oral corticosteroids. See NICE's information on prescribing medicines. Consider adding a proton pump inhibitor for people with gout who are taking an NSAID to treat a gout flare. Consider an intra-articular or intramuscular corticosteroid injection to treat a gout flare if NSAIDs and colchicine are contraindicated, not tolerated or ineffective.In June 2022, this was an off-label use of corticosteroid injections. See NICE's information on prescribing medicines. Do not offer an interleukin-1 (IL-1) inhibitor to treat a gout flare unless NSAIDs, colchicine and corticosteroids are contraindicated, not tolerated or ineffective. Refer the person to a rheumatology service before prescribing an IL-1 inhibitor. Advise people with gout that applying ice packs to the affected joint (cold therapy) in addition to taking prescribed medicine may help alleviate pain. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing gout flares . Full details of the evidence and the committee's discussion are in evidence review D: pharmacological and non-pharmacological interventions for managing gout flares. Loading. Please wait. ## Follow-up after a gout flare Consider a follow-up appointment after a gout flare has settled to: measure the serum urate level provide information about gout and how to self-manage and reduce the risk of future flares (see the section on information and support) assess lifestyle and comorbidities (including cardiovascular risk factors and CKD) review medications and discuss the risks and benefits of long-term ULT. For guidance on adherence to medicines, see NICE's guideline on medicines adherence. For guidance on investigations for CKD, see NICE's guideline on chronic kidney disease. For guidance on cardiovascular risk factors, see NICE's guideline on cardiovascular disease. For guidance on shared decision making, see NICE's guideline on shared decision making. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on follow-up after a gout flare . Full details of the evidence and the committee's discussion are in evidence review M: follow-up for people with gout after a gout flare. Loading. Please wait. # Diet and lifestyle Explain to people with gout that there is not enough evidence to show that any specific diet prevents flares or lowers serum urate levels. Advise them to follow a healthy, balanced diet. Advise people with gout that excess body weight or obesity, or excessive alcohol consumption, may exacerbate gout flares and symptoms.For guidance on maintaining a healthy weight see NICE's guidelines on preventing excess weight gain and obesity: identification, assessment and management. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diet and lifestyle . Full details of the evidence and the committee's discussion are in evidence review I: diet and lifestyle modifications for managing gout. Loading. Please wait. # Long-term management of gout ## Management of gout with urate-lowering therapies Offer ULT, using a treat-to-target strategy, to people with gout who have: multiple or troublesome flares CKD stages 3 to 5 (glomerular filtration rate categories G3 to G5) diuretic therapy tophi chronic gouty arthritis. Discuss the option of ULT, using a treat-to-target strategy, with people who have had a first or subsequent gout flare who are not within the groups listed in recommendation 1.5.1 (see recommendation 1.5.4 on when to start ULT). Ensure people understand that ULT is usually continued after the target serum urate level is reached, and is typically a lifelong treatment. Start ULT at least 2 to 4 weeks after a gout flare has settled. If flares are more frequent, ULT can be started during a flare (see the section on preventing flares when starting or titrating ULT). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on management of gout with urate-lowering therapies . Full details of the evidence and the committee's discussion are in: evidence review E: which people with gout should be offered a urate-lowering therapy? evidence review F: timing of urate-lowering therapy in relation to a flare in people with gout. Loading. Please wait. ## Treat-to-target strategy Start with a low dose of ULT and use monthly serum urate levels to guide dose increases, as tolerated, until the target serum urate level is reached. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on treat-to-target strategy . Full details of the evidence and the committee's discussion are in evidence review J: treat-to-target management. Loading. Please wait. ## Target serum urate level Aim for a target serum urate level below 360 micromol/litre (6 mg/dl). Consider a lower target serum urate level below 300 micromol/litre (5 mg/dl) for people with gout who: have tophi or chronic gouty arthritis continue to have ongoing frequent flares despite having a serum urate level below 360 micromol/litre (6 mg/dl). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on target serum urate level . Full details of the evidence and the committee's discussion are in evidence review K: best serum urate level target to use when treating-to-target in gout?. Loading. Please wait. ## Urate-lowering therapies Offer either allopurinol or febuxostat as first-line treatment when starting treat-to-target ULT, taking into account the person's comorbidities and preferences. Offer allopurinol as first-line treatment to people with gout who have major cardiovascular disease (for example, previous myocardial infarction or stroke, or unstable angina). Consider switching to second-line treatment with allopurinol or febuxostat if the target serum urate level is not reached or first-line treatment is not tolerated, taking into account the person's comorbidities and preferences. See recommendation 1.5.5 for guidance on treat-to-target strategy. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on urate-lowering therapies . Full details of the evidence and the committee's discussion are in evidence review G: urate-lowering therapies for the long-term management of gout. Loading. Please wait. ## Preventing gout flares when starting or titrating urate-lowering therapy Discuss with the person the benefits and risks of taking medicines to prevent gout flares when starting or titrating ULT. For people who choose to have treatment to prevent gout flares when starting or titrating ULT, offer colchicine while the target serum urate level is being reached. If colchicine is contraindicated, not tolerated or ineffective, consider a low-dose NSAID or low-dose oral corticosteroid.In June 2022, this was an off-label use of NSAIDs and oral corticosteroids. See NICE's information on prescribing medicines. Consider adding a proton pump inhibitor for people with gout who are taking an NSAID or a corticosteroid to prevent gout flares when starting or titrating ULT. Take into account the person's individual risk factors for adverse events.In June 2022, this was an off-label use of NSAIDs and corticosteroids. See NICE's information on prescribing medicines. Do not offer an IL-1 inhibitor when starting or titrating ULT to prevent gout flares unless colchicine, NSAIDs and corticosteroids are contraindicated, not tolerated or ineffective. Refer the person to a rheumatology service before prescribing an IL-1 inhibitor. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preventing gout flares when starting or titrating ULT . Full details of the evidence and the committee's discussion are in evidence review H: colchicine, NSAIDs, corticosteroids and IL-1 inhibitors for the prevention of gout flares during the initiation or titration of urate-lowering therapy. Loading. Please wait. ## Monitoring serum urate level Consider annual monitoring of serum urate level in people with gout who are continuing ULT after reaching their target serum urate level. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on monitoring serum urate level . Full details of the evidence and the committee's discussion are in evidence review L: optimum frequency of monitoring. Loading. Please wait. # Referral to specialist services Consider referring a person with gout to a rheumatology service if: the diagnosis of gout is uncertain treatment is contraindicated, not tolerated or ineffective they have CKD stages 3b to 5 (GFR categories G3b to G5) they have had an organ transplant. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on referral to specialist services. Full details of the evidence and the committee's discussion are in: evidence review N: referral to specialist services evidence review O: surgical excision of tophi. Loading. Please wait.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Pharmacological management of gout flares In people with gout (including people with gout and chronic kidney disease ), what is the clinical and cost effectiveness of colchicine compared with corticosteroids for managing gout flares? For a short explanation of why the committee made the recommendation for research, see the rationale section on managing gout flares . Full details of the evidence and the committee's discussion are in evidence review D: pharmacological and non-pharmacological interventions for managing gout flares. Loading. Please wait. ## Preventing gout flares In people with gout (including people with gout and CKD), what is the clinical and cost effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids for preventing gout flares when starting or titrating urate-lowering therapy (ULT)? For a short explanation of why the committee made the recommendation for research, see the rationale section on preventing gout flares when starting or titrating ULT . Full details of the evidence and the committee's discussion are in evidence review H: colchicine, NSAIDs, corticosteroids and IL-1 inhibitors for the prevention of gout flares during the initiation or titration of urate-lowering therapy. Loading. Please wait. ## Target serum urate level What is the best and most cost-effective target serum urate level when using a treat‑to‑target strategy to treat gout, including in people with CKD? For a short explanation of why the committee made the recommendation for research, see the rationale section on target serum urate level . Full details of the evidence and the committee's discussion are in evidence review K: best serum urate level target to use when treating-to-target in gout?. Loading. Please wait. ## Follow-up after a gout flare What is the clinical and cost effectiveness and patient acceptability of different approaches to follow-up, including provision of patient information and managing gout flares? For a short explanation of why the committee made the recommendation for research, see the rationale section on follow-up after a gout flare . Full details of the evidence and the committee's discussion are in evidence review M: follow-up for people with gout after a gout flare. Loading. Please wait. ## Monitoring gout In people with gout (including people with gout and CKD), what is the most clinically and cost-effective frequency of serum urate level monitoring when target serum urate level is reached? For a short explanation of why the committee made the recommendation for research, see the rationale section on monitoring serum urate level . Full details of the evidence and the committee's discussion are in evidence review L: optimum frequency of monitoring. Loading. Please wait. # Other recommendations for research ## When to start urate-lowering therapy What is the clinical and cost effectiveness of starting ULT during a flare compared with starting ULT once a flare has settled? For a short explanation of why the committee made the recommendation for research, see the rationale section on management of gout with urate-lowering therapies . Full details of the evidence and the committee's discussion are in evidence review F: timing of urate-lowering therapy in relation to a flare in people with gout. Loading. Please wait.# Rationale and impact # Symptoms and signs of gout Recommendations 1.1.1 to 1.1.6 ## Why the committee made the recommendations Although evidence is limited, the symptoms and signs of gout reported in studies are generally in line with the committee's clinical experience. The committee agreed that if a person has only 1 symptom or sign this is not enough to diagnose gout, but gout should be suspected if they have a combination of symptoms and signs. The committee agreed that gout should be strongly suspected if a person presents with rapid onset pain together with redness and swelling in 1 or both first metatarsophalangeal (MTP) joints, especially if symptom onset occurs overnight. The presence of tophi suggests longstanding, untreated gout. Symptoms and signs in other joints (such as the knee, wrist, ankle, midfoot joints, finger interphalangeal joints or elbow) may be caused by gout. The committee noted that the possibility of other diagnoses should also be assessed when people present with red, swollen and painful joints. ## How the recommendations might affect practice The recommendations may be useful for non-specialist clinicians, but are not expected to lead to significant changes in practice. Return to recommendations # Diagnosis Recommendations 1.1.7 to 1.1.9 ## Why the committee made the recommendations There is no clinical evidence on diagnosing gout by taking a history, doing a physical examination or measuring serum urate level. There is evidence on imaging techniques, including ultrasonography, dual-energy CT (DECT) and plain radiography. The committee based their recommendations on the available evidence for diagnosing gout and their experience of current practice. In clinical practice, gout is typically diagnosed by a GP taking a detailed history, doing a physical examination and measuring serum urate levels with a blood test. Most people with gout have hyperuricaemia (serum urate level of 360 micromol/litre or more) but many people with hyperuricaemia do not have gout. If the serum urate level is below 360 micromol/litre but gout is strongly suspected, an additional serum urate level measurement should be done at least 2 weeks after the acute flare has settled. This is because serum urate levels can be lower when a person is experiencing a gout flare. When diagnosis is uncertain, joint aspiration and microscopy of synovial fluid can be used to diagnose gout. This is usually done in secondary care. The committee noted that joint aspiration is the 'gold standard' test to diagnose gout when the diagnosis remains uncertain. If the affected joint is small, it may be difficult or impossible to aspirate the joint. When joint aspiration cannot be done or diagnosis of gout remains uncertain, plain X-ray imaging can be used to detect any long-term damage to the affected joints. The committee noted that ultrasound or DECT may also be used to diagnose gout, although DECT is not widely available in the UK. Evidence on plain X-ray and DECT is limited. There is evidence on ultrasonography for diagnosing gout, but the committee found it difficult to interpret its overall accuracy because so many different signs associated with gout were reported. However, the committee agreed ultrasound is more sensitive than plain X-ray and is commonly used to confirm or refute the diagnosis. ## How the recommendations might affect practice The recommendations generally reflect current practice and are not likely to result in changes. Return to recommendations # Information and support Recommendations 1.2.1 and 1.2.2 ## Why the committee made the recommendations There was moderate- to high-quality evidence for this topic, which included findings on: patient knowledge of the causes of gout and of dietary advice long-term impact of gout tailored information for women -nline sources of information information or education preferences. The committee agreed that the evidence represents the information that people with gout need. They thought that information provided at the time of diagnosis and at follow-up appointments should be tailored to the needs of the person with gout and the stage of their care pathway. However, there are many incorrect beliefs about the causes and treatment of gout, and people who have gout. The committee therefore included information on symptoms and signs and the risk factors for gout in the recommendations. They also made it clear that people should know that diet and lifestyle changes are not enough, and that long-term urate-lowering therapy (ULT) is usually needed for this lifelong condition. ## How the recommendations might affect practice The recommendations should improve the information provided by healthcare practitioners to people with gout. They are unlikely to impact on the current services provided because information can be given at the time of diagnosis or at follow-up appointments already scheduled. Return to recommendations # Managing gout flares Recommendations 1.3.1 to 1.3.5 ## Why the committee made the recommendations The evidence shows no difference between non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids for most outcomes, including pain and joint tenderness or swelling. The committee noted that in current practice an NSAID or colchicine would usually be prescribed first before corticosteroids and agreed that there is no strong evidence showing that any 1 treatment is more effective when used before any other. They concluded that the current practice of offering either an NSAID, colchicine or a corticosteroid, based on comorbidities, other medications being taken and the person's preferences, should be continued. The committee noted many people have contraindications to NSAIDs, for example, people with chronic kidney disease (CKD) or cardiovascular disease. There is no evidence on whether a corticosteroid or colchicine is more effective or better tolerated in these groups. The committee therefore decided to make a recommendation for research on pharmacological management of gout flares. The committee agreed that intra-articular and intramuscular corticosteroids are sometimes used in practice and agreed they should be considered if NSAIDs and colchicine are contraindicated, not tolerated or ineffective. There is no evidence supporting 1 route of administration over the other. Interleukin-1 (IL-1) inhibitors show a clinical benefit compared with corticosteroids for pain and quality of life outcomes. However, IL-1 inhibitors are very expensive and other medicines are adequate alternatives. The committee concluded that IL-1 inhibitors would not be a cost-effective use of NHS resources for most people with gout flares. If response to treatment has been inadequate, or NSAIDs, colchicine and corticosteroids are contraindicated or not tolerated, the person should be referred to rheumatology services before prescribing an IL-1 inhibitor. Evidence from 1 small study shows that cold therapy reduces pain. Although the evidence is limited, the committee recommended using ice alongside pharmacological treatments because in their experience this helps ease pain and inflammation. ## How the recommendations might affect practice The recommendations generally reflect current practice and are not likely to result in changes. Return to recommendations # Follow-up after a gout flare Recommendation 1.3.6 ## Why the committee made the recommendation In current practice, little or no follow-up is offered to people after a gout flare. The committee noted that a follow-up appointment after a gout flare provides an opportunity to review medication and discuss the option of long-term ULT. The healthcare practitioner can also provide information about gout and how to reduce the risk of future flares, and assess any comorbidities and lifestyle factors that may impact how the person self-manages their gout. Based on their clinical experience, the committee agreed that follow-up appointments after a gout flare would allow people to have a better health-related quality of life in the long term. This is because they will likely have fewer subsequent gout flares as a result of starting ULT sooner. People will also be better equipped to manage their gout flares and have more information on how to minimise their risk of recurrent flares. The committee thought that the benefits of follow-up appointments would outweigh the costs and that it is likely to be a cost-effective strategy, but there is not enough evidence to confirm this. There is no evidence on which follow-up strategies are most effective, including the frequency and duration of follow-up, and which healthcare professionals should lead the follow-up and in what settings. The committee made a recommendation for research on follow-up after a gout flare. ## How the recommendation might affect practice This recommendation is likely to be a change in practice for many and will affect a large proportion of people with gout. Follow-up appointments after a gout flare provide an opportunity for people to start ULT and reduce gout flares. Therefore, this recommendation is expected to be cost saving or at least cost neutral. Return to recommendation # Diet and lifestyle Recommendations 1.4.1 and 1.4.2 ## Why the committee made the recommendations The committee discussed the diverse dietary interventions for gout, which included dietary advice, cherry extract and vitamin C. They noted that all studies had small numbers of participants and short follow-up periods. The committee agreed it would be difficult to implement dietary interventions in practice and concluded that there is not enough strong evidence to support any specific diet. They also wanted to avoid giving conflicting advice because many people with gout have comorbidities and may have already had dietary advice for these conditions. The committee acknowledged that people with gout often seek dietary advice because they believe there is a link between diet and gout. They noted that in current practice the healthcare professional and the person with gout often discuss diet and lifestyle. The committee agreed that people with gout should be advised that there is not enough evidence to support any specific diet to manage gout and they should follow a healthy, balanced diet. People should also be advised that excess weight, obesity or excessive alcohol consumption may exacerbate gout flares. ## How the recommendations might affect practice The recommendations generally reflect current practice and are not likely to result in changes. Return to recommendations # Management of gout with urate-lowering therapies Recommendations 1.5.1 to 1.5.4 ## Why the committee made the recommendations The committee agreed that evidence on which people should be selected for long‑term management of gout with ULT is limited because there are only 3 studies of moderate to high quality. The evidence shows that people with chronic renal failure and people using diuretics are more likely to have gout flares, and that people with tophi and swollen or tender joints have more disability through damage to joints. Gout is characterised by severe pain, therefore pain reduction is an important outcome of treatment. People with gout experience the most pain during flares. Reducing the frequency of flares along with reducing joint swelling, inflammation, and joint tenderness, can reduce pain and improve the person's comfort. The committee reinforced the benefits of ULT for reducing serum urate levels and reducing gout flares in the long term. The committee noted that opportunities to offer ULTs to people with gout early in their disease may be missed, but acknowledged that there was a lack of evidence for this. Therefore, the committee recommended discussing and considering the option of ULT with all people having a first or subsequent gout flare. Once the target serum urate level is reached people with gout will usually remain on ULT. The committee agreed that the importance of long-term treatment should be discussed with the patient. The committee highlighted that ULT use in current practice varies and there is low uptake of ULTs. The recommendations are likely to result in an increased number of people having ULT. A costing analysis in evidence review E assessed the costs of current and future practice. This included increased uptake of ULT, a greater proportion of people having ULT with febuxostat, and using a treat-to-target strategy. The analysis showed that future practice is less costly than current practice. The committee acknowledged that a costing analysis is not as robust as a health economic model. They noted additional supporting evidence in evidence review G showing that treatment with ULTs is cost effective compared with no treatment. They also noted additional supporting evidence in evidence review J showing that a treat-to-target strategy is cost effective. The committee were confident that treatment with ULTs will be less costly and more effective than no treatment. The committee agreed that evidence on when to start ULT is very limited because there are only 2 small studies and both included people with a current gout flare. The committee noted that in current practice ULTs are started 2 to 4 weeks after a flare has settled to prevent exacerbating the flare. This is because in previous practice people started treatment with 300 mg allopurinol, which can exacerbate a flare more than starting treatment with 100 mg and up-titrating. The committee suggested that exacerbation of flares may be less of a concern when starting ULT at a low dose and increasing the dose gradually. The committee discussed that starting ULT at least 2 to 4 weeks after a flare has settled means that people who have very frequent flares may not have a sufficiently long flare-free period in which to start ULT. However, the committee also noted that the person may be in too much pain during a gout flare to understand information about ULTs and the importance of treatment adherence. Based on their experience, the committee recommended that people with gout who choose ULT should ideally start treatment after a flare, but people who have frequent flares can start during a gout flare. Because the evidence is very limited the committee decided to make a recommendation for research on when to start ULT. ## How the recommendations might affect practice The recommendations for ULT are likely to result in a change in clinical practice and have a significant resource impact given the prevalence of gout and the current limited uptake of ULTs. A lower incidence of flares resulting from more people starting ULT will likely result in long-term cost savings. The recommendation on when to start ULT generally reflects current practice and is unlikely to result in change. Return to recommendations # Treat-to-target strategy Recommendation 1.5.5 ## Why the committee made the recommendation Two randomised controlled trials evaluated treat-to-target strategies using ULTs. Both studies compared ULT with usual care, which was any available option chosen by the healthcare provider, such as continuing the current dose of allopurinol or febuxostat, or no treatment. The evidence shows that a treat-to-target strategy increases the frequency of flares at 1 year compared with usual care, but reduces frequency of flares at 2 years. The committee agreed that starting ULT and increasing the dose could set off a flare, so the number of flares might initially increase in the first year but decrease by the second year when the dose is stabilised. The high use of febuxostat in 1 study was also noted and was thought to not reflect current practice. Health economic analysis shows that a treat-to-target management strategy is cost effective and therefore the committee recommended it. Overall, the committee agreed that the evidence supports a treat-to-target strategy based on the benefits shown for quality of life outcomes, frequency of flares in the longer term, and the cost-effectiveness results. ## How the recommendation might affect practice The number of people with gout who have a treat-to-target strategy varies in current practice. The committee acknowledged that care is sub-optimal and people with gout are more likely to have usual care. The recommendation will likely increase the number of people using a treat-to-target strategy and therefore change practice. Return to recommendation # Target serum urate level Recommendations 1.5.6 and 1.5.7 ## Why the committee made the recommendations There is no evidence on the best target serum urate level when using a treat-to-target strategy. The committee discussed the clinical benefits and costs associated with target serum urate levels below 300 micromol/litre (5 mg/dl) and 360 micromol/litre (6 mg/dl). They agreed that reaching a serum urate level below 360 micromol/litre is more achievable for people with gout. They also agreed that it is unknown whether a lower target is more beneficial, although clinical improvement may be seen more quickly after achieving a lower target. The committee agreed a target of below 360 micromol/litre reflected current practice within primary care. Achieving a target serum urate level below 360 micromol/litre would also have a lower cost than achieving a target serum urate level below 300 micromol/litre because reaching a lower target is likely to need more appointments and higher doses. The committee noted that a target serum urate level of below 300 micromol/litre would be more appropriate for people with more severe gout because they have a higher level of crystal deposition, and response to treatment takes longer. A lower target level will help crystals dissolve more quickly and support clinical improvement. This includes people still having gout flares despite reaching a target serum urate level below 360 micromol/litre or people who have tophi or chronic gouty arthritis. The committee discussed that gout is frequently undertreated and this may be because of uncertainty about the optimum target serum urate level. They noted the different levels recommended by the British Society for Rheumatology and European League Against Rheumatism. The committee agreed further research in this area is needed and made a recommendation for research on target serum urate level. ## How the recommendations might affect practice For people having ULT, usual practice is to reach a target serum urate level below 360 micromol/litre, therefore the recommendations are not likely to result in changes. Return to recommendations # Urate-lowering therapies Recommendations 1.5.8 to 1.5.10 ## Why the committee made the recommendations There is evidence on ULTs from 17 randomised controlled trials, including on first- and second-line treatment, CKD status, and allopurinol or febuxostat dosage. The evidence mainly shows that febuxostat and allopurinol reduce serum urate levels to target compared with placebo. For first-line treatment, febuxostat reduces the frequency of flares compared with allopurinol and reduces serum urate levels compared with allopurinol and placebo. The committee noted that important outcomes are frequency of flares and cardiovascular adverse events, however not all trials report these. Allopurinol has fewer adverse events such as withdrawal and gastrointestinal issues compared with placebo. A costing analysis comparing allopurinol and febuxostat for 1 year of treatment with a treat-to-target strategy shows that there are minimal cost differences between allopurinol and febuxostat. The committee thought the evidence showed little difference between allopurinol and febuxostat as first-line treatments for gout so they recommended both drugs. The committee thought that shared decision making is important when choosing treatment and that people with gout should be made aware of the differences between drugs. Febuxostat is easier to titrate than allopurinol because there are only two available doses and it is only taken once a day. The evidence shows that the target serum urate level is more frequently achieved with febuxostat than allopurinol, however, it also causes more flares and therefore more people would also need treatment to prevent flares. Most of the trials compared febuxostat with sub-optimal doses of allopurinol (up to 300 mg). Allopurinol doses up to 300 mg are often too low to achieve the target serum urate level and many people with gout would need higher doses to manage their condition. The committee recommended that people with major cardiovascular disease should have allopurinol as first-line treatment because of the 2019 Medicines and Healthcare products Regulatory Agency (MHRA) advice on febuxostat within this population. They noted that this recommendation may change in the future. There were only 2 studies on second-line treatment. The evidence does not strongly favour 1 treatment, so the committee recommended that both allopurinol and febuxostat could be considered as second-line treatments. This recommendation is dependent on target serum urate level not being reached or when first-line treatment is not tolerated. The committee also noted the importance of taking into account comorbidities and patient preferences when switching to a second-line treatment. An increase in the number of people taking ULT is likely to lead to an increase in monitoring serum urate levels, using prophylaxis and treating flares. However, a treat-to-target ULT strategy has been shown to be cost effective, so offering people ULT is clinically effective and highly likely to be cost effective compared with offering no treatment. ## How the recommendations might affect practice The recommendations are a change in practice because currently people have allopurinol as first-line ULT. These recommendations are not expected to result in a substantial resource impact because the cost of allopurinol and febuxostat are similar. Return to recommendations # Preventing gout flares when starting or titrating ULT Recommendations 1.5.11 to 1.5.14 ## Why the committee made the recommendations The committee noted that the evidence is limited as there are only 3 studies and they all compared colchicine with an IL-1 inhibitor, placebo and no treatment. The evidence shows that colchicine reduces the frequency of gout flares when starting ULT compared with placebo and no treatment, but has some gastrointestinal adverse events compared with placebo. The committee discussed that in current practice, colchicine and NSAIDs are most frequently offered to people with gout to prevent flares. There is no evidence supporting the use of NSAIDs, so the committee agreed colchicine should be offered to people with gout during the start and titration of ULT to prevent gout flares. Although there is no evidence on preventing flares during the titration of ULT, the committee agreed that colchicine can also be used to reduce the risk of flares after up-titration of ULT. The committee noted that colchicine may not be appropriate for some people with gout because of tolerability, comorbidities such as CKD or prescriptions such as statins. The committee agreed that an NSAID or corticosteroid should be considered for people when colchicine is contraindicated, not tolerated or ineffective. Although no evidence was found for either NSAIDs or corticosteroids, the committee agreed an alternative treatment is needed to prevent flares, which can cause severe pain. The committee noted their experience that NSAIDs are well tolerated by people with gout. Because no evidence was found for NSAIDs or corticosteroids the committee also decided to make a recommendation for research on preventing gout flares. Evidence from 1 study shows that canakinumab reduces the frequency of flares, however the committee noted that IL-1 inhibitors are rarely prescribed to people with gout. Use of IL-1 inhibitors requires close monitoring and they are currently only prescribed in secondary care. The committee concluded there was insufficient evidence to recommend IL-1 inhibitors over other routine treatments currently used within clinical practice unless colchicine, NSAIDs and corticosteroids are contraindicated, not tolerated or ineffective. ## How the recommendations might affect practice The recommendations generally reflect current practice and are not likely to result in changes. Return to recommendations # Monitoring serum urate level Recommendation 1.5.15 ## Why the committee made the recommendation There was no evidence on the optimum frequency of monitoring serum urate level in people having ULT. The committee agreed that one reason to continue monitoring a person's serum urate level when the target serum urate level has been reached is to prevent it increasing, which can occur with age or because of changes in lifestyle, comorbidities or medications. The committee noted that people may stop treatment if they feel better, but continuing ULT as prescribed is important because serum urate levels can increase quickly once ULT is stopped. The committee discussed that in current practice the frequency of serum urate level monitoring is highly variable. Patients usually make appointments with their GP in response to gout flares and a health professional would measure their serum urate level in that appointment. However, the committee agreed this was not sufficient as the goal of monitoring is to prevent gout flares rather than manage them. Patient support and monitoring is usually based on individual factors after discussion with the patient. The committee highlighted the importance of monitoring and noted that without monitoring, people may have poor medication adherence which increases serum urate levels. This can lead to poorer long-term outcomes for people and impact their health-related quality of life, and may also be associated with additional costs to the NHS. There was no available evidence to estimate how many flares would be avoided with annual monitoring. The committee noted that there may be better medication adherence with annual monitoring and that more people might remain at their target serum urate level. Overall, the committee agreed that annual monitoring is likely to be a cost-effective strategy and therefore they made a recommendation to consider it. The committee also made a recommendation for research on monitoring gout. ## How the recommendation might affect practice In people with gout who are having ULT, annual monitoring once target serum urate levels are reached may result in a change in clinical practice. Return to recommendation # Referral to specialist services Recommendation 1.6.1 ## Why the committee made the recommendation No relevant evidence on referral to specialist gout services was identified. The committee were not aware of any published referral criteria for gout. They acknowledged that referral to a specialist was likely based on the complexity of care needed by the patient, and the gout knowledge and skillset of the GP caring for them. The committee noted that the diagnosis and treatment of people with gout is mainly managed within primary care. The committee discussed when referral to a rheumatologist would be considered and made recommendations based on their experience. This included: when diagnosis is uncertain and joint aspiration or imaging is needed, because this would usually be done in secondary care if the person cannot tolerate medication, or has any allergic reaction or difficulty taking allopurinol or febuxostat when response to treatment has been inadequate, including difficulty in controlling gout symptoms with ULT. The committee acknowledged that a specialist would prefer to examine people with gout who have comorbidities and complex needs and have a face-to-face consultation instead of relying on their history and test results. Treating gout in people with CKD can be challenging, particularly in people with severe CKD (stages 4 to 5 or glomerular filtration rate categories G4 to G5). However, the committee also recognised that stage 3 (GFR category G3) CKD comprises a wide clinical spectrum and that some people with stage 3 (GFR category G3) CKD and gout may also need referral, often because of difficulties in treating gout in this population. The committee discussed that including people with stage 3 (GFR category G3) CKD within the recommendation could increase the numbers of people being referred, because this represents a large population. They agreed that people with CKD stage 3b (GFR category G3b) are more likely to need specialist input to achieve optimal management of their gout. People with gout who have had an organ transplant will usually be referred to a specialist because treatments for transplant rejection may exacerbate hyperuricaemia and may interact with treatments for gout and renal dysfunction. There is no relevant evidence on surgical removal of tophi. The committee discussed that tophi develop very slowly over years and typically occur in the toes, fingers, elbows or attachment of the Achilles tendon to the heel bone. The committee agreed that surgical removal of tophi is an uncommon procedure, and surgery is only offered to people whose gout is impacting their quality of life because of pain or restriction in movement. The committee discussed that tophi are seen in people with uncontrolled gout and persistent high urate levels, and they tend to develop in older people. They agreed that with targeted treatment to reduce serum urate levels, tophi will dissolve or reduce over time, and in their experience referral to orthopaedic surgery would rarely be needed. The committee agreed not to make a recommendation because any decision to refer for consideration for surgery would be made on an individual basis. Doing research in this area would be difficult because of the limited number of people that have tophi removed. The committee concluded that research is not feasible and is also low priority given the few people who have this surgical procedure. ## How the recommendation might affect practice Referral to rheumatology services is variable within current practice. The recommendation may lead to an increase in referrals to specialist services. Return to recommendation# Context Gout is a type of arthritis caused by monosodium urate crystals forming inside and around joints, resulting in sudden flares of severe pain, heat and swelling. Any joint can be affected but gout is most common in distal joints, such as big toes, knees and ankles, and fingers. Between 2 and 3 in every 100 people in the UK have gout. It usually occurs in men over 30 and women after menopause, and is more common in men than women. Long-term complications of gout include joint damage and renal stones. Almost 25% of people with gout have chronic kidney disease (CKD) stages 3 to 5 (glomerular filtration rate categories G3 to G5). Gout is most often managed in primary care without specialist rheumatological input. Flares are usually treated with non-steroidal anti-inflammatory drugs, colchicine or corticosteroids. However, most people have further flares. They can be prevented by taking medicines to reduce serum urate levels (such as allopurinol or febuxostat). However, only one-third of people with gout have these medicines and they are used effectively (lowering serum urate level to the target) by only one-third of people who take them. People with CKD also often have contraindications to medicines used to manage gout. Diagnosing gout and differentiating gout from other types of arthritis is not always straightforward and the best method of diagnosis is often unclear. There is a need to improve the diagnosis and management of gout and the quality of life for people with gout.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Diagnosis and assessment\n\n## Symptoms and signs\n\nSuspect gout in people presenting with any of the following:\n\nrapid onset (often overnight) of severe pain together with redness and swelling, in 1 or both first metatarsophalangeal (MTP) joints\n\ntophi.\n\nConsider gout in people presenting with rapid onset (often overnight) of severe pain, redness or swelling in joints other than the first MTP joints (for example, midfoot, ankle, knee, hand, wrist, elbow).\n\nAssess the possibility of septic arthritis, calcium pyrophosphate crystal deposition and inflammatory arthritis in people presenting with a painful, red, swollen joint.\n\nIf septic arthritis is suspected, refer immediately according to the local care pathway.\n\nConsider chronic gouty arthritis in people presenting with chronic inflammatory joint pain.\n\nIn people with suspected gout, take a detailed history and carry out a physical examination to assess the symptoms and signs (see recommendations\xa01.1.1 and 1.1.2).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on symptoms and signs of gout\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: what signs and symptoms indicate gout as a possible diagnosis?\n\nLoading. Please wait.\n\n## Diagnosis\n\nMeasure the serum urate level in people with symptoms and signs of gout (see recommendations\xa01.1.1 and 1.1.2) to confirm the clinical diagnosis (serum urate level of 360\xa0micromol/litre [6\xa0mg/dl] or more). If serum urate level is below 360\xa0micromol/litre (6\xa0mg/dl) during a flare and gout is strongly suspected, repeat the serum urate level measurement at least 2\xa0weeks after the flare has settled.\n\nConsider joint aspiration and microscopy of synovial fluid if a diagnosis of gout remains uncertain or unconfirmed.\n\nIf joint aspiration cannot be carried out or the diagnosis of gout remains uncertain, consider imaging the affected joints with X-ray, ultrasound or dual-energy CT.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: what are the most accurate and cost-effective approaches to diagnosing gout, in particular serum urate level compared with joint aspiration?\n\nLoading. Please wait.\n\n# Information and support\n\nProvide tailored information to people with gout and their family members or carers (as appropriate) at the time of diagnosis and during subsequent follow-up appointments. Explain:\n\nthe symptoms and signs of gout\n\nthe causes of gout\n\nthat the disease progresses without intervention because high levels of urate in the blood lead to the formation of new urate crystals\n\nany risk factors for gout they have, including genetics, excess body weight or obesity, medicines they are taking, and comorbidities such as chronic kidney disease (CKD) or hypertension\n\nhow to manage gout flares and the treatment options available\n\nthat gout is a lifelong condition that benefits from long-term urate-lowering therapy (ULT) to eliminate urate crystals and prevent flares, shrink tophi and prevent long-term joint damage\n\nwhere to find other sources of information and support such as local support groups, online forums and national charities.See also the recommendations on diet and lifestyle.\n\nFollow the recommendations in NICE's guidelines on patient experience in adult NHS services and shared decision making.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: patient information.\n\nLoading. Please wait.\n\n# Managing gout flares\n\n## Treatment for gout flares\n\nOffer a non-steroidal anti-inflammatory drug (NSAID), colchicine or a short course of an oral corticosteroid for first-line treatment of a gout flare, taking into account the person's comorbidities, co-prescriptions and preferences.In June 2022, this was an off-label use of oral corticosteroids. See NICE's information on prescribing medicines.\n\nConsider adding a proton pump inhibitor for people with gout who are taking an NSAID to treat a gout flare.\n\nConsider an intra-articular or intramuscular corticosteroid injection to treat a gout flare if NSAIDs and colchicine are contraindicated, not tolerated or ineffective.In June 2022, this was an off-label use of corticosteroid injections. See NICE's information on prescribing medicines.\n\nDo not offer an interleukin-1 (IL-1) inhibitor to treat a gout flare unless NSAIDs, colchicine and corticosteroids are contraindicated, not tolerated or ineffective. Refer the person to a rheumatology service before prescribing an IL-1 inhibitor.\n\nAdvise people with gout that applying ice packs to the affected joint (cold therapy) in addition to taking prescribed medicine may help alleviate pain.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing gout flares\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: pharmacological and non-pharmacological interventions for managing gout flares.\n\nLoading. Please wait.\n\n## Follow-up after a gout flare\n\nConsider a follow-up appointment after a gout flare has settled to:\n\nmeasure the serum urate level\n\nprovide information about gout and how to self-manage and reduce the risk of future flares (see the section on information and support)\n\nassess lifestyle and comorbidities (including cardiovascular risk factors and CKD)\n\nreview medications and discuss the risks and benefits of long-term ULT. For guidance on adherence to medicines, see NICE's guideline on medicines adherence. For guidance on investigations for CKD, see NICE's guideline on chronic kidney disease. For guidance on cardiovascular risk factors, see NICE's guideline on cardiovascular disease. For guidance on shared decision making, see NICE's guideline on shared decision making.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on follow-up after a gout flare\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: follow-up for people with gout after a gout flare.\n\nLoading. Please wait.\n\n# Diet and lifestyle\n\nExplain to people with gout that there is not enough evidence to show that any specific diet prevents flares or lowers serum urate levels. Advise them to follow a healthy, balanced diet.\n\nAdvise people with gout that excess body weight or obesity, or excessive alcohol consumption, may exacerbate gout flares and symptoms.For guidance on maintaining a healthy weight see NICE's guidelines on preventing excess weight gain and obesity: identification, assessment and management.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diet and lifestyle\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: diet and lifestyle modifications for managing gout.\n\nLoading. Please wait.\n\n# Long-term management of gout\n\n## Management of gout with urate-lowering therapies\n\nOffer ULT, using a treat-to-target strategy, to people with gout who have:\n\nmultiple or troublesome flares\n\nCKD stages 3 to 5 (glomerular filtration rate [GFR] categories G3 to G5)\n\ndiuretic therapy\n\ntophi\n\nchronic gouty arthritis.\n\nDiscuss the option of ULT, using a treat-to-target strategy, with people who have had a first or subsequent gout flare who are not within the groups listed in recommendation\xa01.5.1 (see recommendation\xa01.5.4 on when to start ULT).\n\nEnsure people understand that ULT is usually continued after the target serum urate level is reached, and is typically a lifelong treatment.\n\nStart ULT at least 2\xa0to 4\xa0weeks after a gout flare has settled. If flares are more frequent, ULT can be started during a flare (see the section on preventing flares when starting or titrating ULT).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on management of gout with urate-lowering therapies\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0E: which people with gout should be offered a urate-lowering therapy?\n\nevidence review\xa0F: timing of urate-lowering therapy in relation to a flare in people with gout.\n\nLoading. Please wait.\n\n## Treat-to-target strategy\n\nStart with a low dose of ULT and use monthly serum urate levels to guide dose increases, as tolerated, until the target serum urate level is reached.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on treat-to-target strategy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: treat-to-target management.\n\nLoading. Please wait.\n\n## Target serum urate level\n\nAim for a target serum urate level below 360\xa0micromol/litre (6\xa0mg/dl).\n\nConsider a lower target serum urate level below 300\xa0micromol/litre (5\xa0mg/dl) for people with gout who:\n\nhave tophi or chronic gouty arthritis\n\ncontinue to have ongoing frequent flares despite having a serum urate level below 360\xa0micromol/litre (6\xa0mg/dl).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on target serum urate level\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: best serum urate level target to use when treating-to-target in gout?.\n\nLoading. Please wait.\n\n## Urate-lowering therapies\n\nOffer either allopurinol or febuxostat as first-line treatment when starting treat-to-target ULT, taking into account the person's comorbidities and preferences.\n\nOffer allopurinol as first-line treatment to people with gout who have major cardiovascular disease (for example, previous myocardial infarction or stroke, or unstable angina).\n\nConsider switching to second-line treatment with allopurinol or febuxostat if the target serum urate level is not reached or first-line treatment is not tolerated, taking into account the person's comorbidities and preferences. See recommendation\xa01.5.5 for guidance on treat-to-target strategy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on urate-lowering therapies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: urate-lowering therapies for the long-term management of gout.\n\nLoading. Please wait.\n\n## Preventing gout flares when starting or titrating urate-lowering therapy\n\nDiscuss with the person the benefits and risks of taking medicines to prevent gout flares when starting or titrating ULT.\n\nFor people who choose to have treatment to prevent gout flares when starting or titrating ULT, offer colchicine while the target serum urate level is being reached. If colchicine is contraindicated, not tolerated or ineffective, consider a low-dose NSAID or low-dose oral corticosteroid.In June 2022, this was an off-label use of NSAIDs and oral corticosteroids. See NICE's information on prescribing medicines.\n\nConsider adding a proton pump inhibitor for people with gout who are taking an NSAID or a corticosteroid to prevent gout flares when starting or titrating ULT. Take into account the person's individual risk factors for adverse events.In June 2022, this was an off-label use of NSAIDs and corticosteroids. See NICE's information on prescribing medicines.\n\nDo not offer an IL-1 inhibitor when starting or titrating ULT to prevent gout flares unless colchicine, NSAIDs and corticosteroids are contraindicated, not tolerated or ineffective. Refer the person to a rheumatology service before prescribing an IL-1 inhibitor.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preventing gout flares when starting or titrating ULT\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: colchicine, NSAIDs, corticosteroids and IL-1 inhibitors for the prevention of gout flares during the initiation or titration of urate-lowering therapy.\n\nLoading. Please wait.\n\n## Monitoring serum urate level\n\nConsider annual monitoring of serum urate level in people with gout who are continuing ULT after reaching their target serum urate level.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on monitoring serum urate level\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: optimum frequency of monitoring.\n\nLoading. Please wait.\n\n# Referral to specialist services\n\nConsider referring a person with gout to a rheumatology service if:\n\nthe diagnosis of gout is uncertain\n\ntreatment is contraindicated, not tolerated or ineffective\n\nthey have CKD stages 3b to 5 (GFR categories G3b to G5)\n\nthey have had an organ transplant.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on referral to specialist services.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0N: referral to specialist services\n\nevidence review\xa0O: surgical excision of tophi.\n\nLoading. Please wait.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Pharmacological management of gout flares\n\nIn people with gout (including people with gout and chronic kidney disease [CKD]), what is the clinical and cost effectiveness of colchicine compared with corticosteroids for managing gout flares?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on managing gout flares\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: pharmacological and non-pharmacological interventions for managing gout flares.\n\nLoading. Please wait.\n\n## Preventing gout flares\n\nIn people with gout (including people with gout and CKD), what is the clinical and cost effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids for preventing gout flares when starting or titrating urate-lowering therapy (ULT)?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on preventing gout flares when starting or titrating ULT\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: colchicine, NSAIDs, corticosteroids and IL-1 inhibitors for the prevention of gout flares during the initiation or titration of urate-lowering therapy.\n\nLoading. Please wait.\n\n## Target serum urate level\n\nWhat is the best and most cost-effective target serum urate level when using a treat‑to‑target strategy to treat gout, including in people with CKD?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on target serum urate level\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: best serum urate level target to use when treating-to-target in gout?.\n\nLoading. Please wait.\n\n## Follow-up after a gout flare\n\nWhat is the clinical and cost effectiveness and patient acceptability of different approaches to follow-up, including provision of patient information and managing gout flares?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on follow-up after a gout flare\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: follow-up for people with gout after a gout flare.\n\nLoading. Please wait.\n\n## Monitoring gout\n\nIn people with gout (including people with gout and CKD), what is the most clinically and cost-effective frequency of serum urate level monitoring when target serum urate level is reached?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on monitoring serum urate level\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: optimum frequency of monitoring.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## When to start urate-lowering therapy\n\nWhat is the clinical and cost effectiveness of starting ULT during a flare compared with starting ULT once a flare has settled?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on management of gout with urate-lowering therapies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: timing of urate-lowering therapy in relation to a flare in people with gout.\n\nLoading. Please wait.", 'Rationale and impact': "# Symptoms and signs of gout\n\nRecommendations\xa01.1.1 to 1.1.6\n\n## Why the committee made the recommendations\n\nAlthough evidence is limited, the symptoms and signs of gout reported in studies are generally in line with the committee's clinical experience. The committee agreed that if a person has only 1 symptom or sign this is not enough to diagnose gout, but gout should be suspected if they have a combination of symptoms and signs.\n\nThe committee agreed that gout should be strongly suspected if a person presents with rapid onset pain together with redness and swelling in 1 or both first metatarsophalangeal (MTP) joints, especially if symptom onset occurs overnight. The presence of tophi suggests longstanding, untreated gout.\n\nSymptoms and signs in other joints (such as the knee, wrist, ankle, midfoot joints, finger interphalangeal joints or elbow) may be caused by gout. The committee noted that the possibility of other diagnoses should also be assessed when people present with red, swollen and painful joints.\n\n## How the recommendations might affect practice\n\nThe recommendations may be useful for non-specialist clinicians, but are not expected to lead to significant changes in practice.\n\nReturn to recommendations\n\n# Diagnosis\n\nRecommendations\xa01.1.7 to 1.1.9\n\n## Why the committee made the recommendations\n\nThere is no clinical evidence on diagnosing gout by taking a history, doing a physical examination or measuring serum urate level. There is evidence on imaging techniques, including ultrasonography, dual-energy CT (DECT) and plain radiography. The committee based their recommendations on the available evidence for diagnosing gout and their experience of current practice.\n\nIn clinical practice, gout is typically diagnosed by a GP taking a detailed history, doing a physical examination and measuring serum urate levels with a blood test. Most people with gout have hyperuricaemia (serum urate level of 360\xa0micromol/litre [6\xa0mg/dl] or more) but many people with hyperuricaemia do not have gout. If the serum urate level is below 360\xa0micromol/litre but gout is strongly suspected, an additional serum urate level measurement should be done at least 2\xa0weeks after the acute flare has settled. This is because serum urate levels can be lower when a person is experiencing a gout flare.\n\nWhen diagnosis is uncertain, joint aspiration and microscopy of synovial fluid can be used to diagnose gout. This is usually done in secondary care. The committee noted that joint aspiration is the 'gold standard' test to diagnose gout when the diagnosis remains uncertain. If the affected joint is small, it may be difficult or impossible to aspirate the joint. When joint aspiration cannot be done or diagnosis of gout remains uncertain, plain X-ray imaging can be used to detect any long-term damage to the affected joints. The committee noted that ultrasound or DECT may also be used to diagnose gout, although DECT is not widely available in the UK. Evidence on plain X-ray and DECT is limited. There is evidence on ultrasonography for diagnosing gout, but the committee found it difficult to interpret its overall accuracy because so many different signs associated with gout were reported. However, the committee agreed ultrasound is more sensitive than plain X-ray and is commonly used to confirm or refute the diagnosis.\n\n## How the recommendations might affect practice\n\nThe recommendations generally reflect current practice and are not likely to result in changes.\n\nReturn to recommendations\n\n# Information and support\n\nRecommendations 1.2.1 and 1.2.2\n\n## Why the committee made the recommendations\n\nThere was moderate- to high-quality evidence for this topic, which included findings on:\n\npatient knowledge of the causes of gout and of dietary advice\n\nlong-term impact of gout\n\ntailored information for women\n\nonline sources of information\n\ninformation or education preferences.\n\nThe committee agreed that the evidence represents the information that people with gout need. They thought that information provided at the time of diagnosis and at follow-up appointments should be tailored to the needs of the person with gout and the stage of their care pathway. However, there are many incorrect beliefs about the causes and treatment of gout, and people who have gout. The committee therefore included information on symptoms and signs and the risk factors for gout in the recommendations. They also made it clear that people should know that diet and lifestyle changes are not enough, and that long-term urate-lowering therapy (ULT) is usually needed for this lifelong condition.\n\n## How the recommendations might affect practice\n\nThe recommendations should improve the information provided by healthcare practitioners to people with gout. They are unlikely to impact on the current services provided because information can be given at the time of diagnosis or at follow-up appointments already scheduled.\n\nReturn to recommendations\n\n# Managing gout flares\n\nRecommendations 1.3.1 to 1.3.5\n\n## Why the committee made the recommendations\n\nThe evidence shows no difference between non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids for most outcomes, including pain and joint tenderness or swelling. The committee noted that in current practice an NSAID or colchicine would usually be prescribed first before corticosteroids and agreed that there is no strong evidence showing that any 1\xa0treatment is more effective when used before any other. They concluded that the current practice of offering either an NSAID, colchicine or a corticosteroid, based on comorbidities, other medications being taken and the person's preferences, should be continued. The committee noted many people have contraindications to NSAIDs, for example, people with chronic kidney disease (CKD) or cardiovascular disease. There is no evidence on whether a corticosteroid or colchicine is more effective or better tolerated in these groups. The committee therefore decided to make a recommendation for research on pharmacological management of gout flares.\n\nThe committee agreed that intra-articular and intramuscular corticosteroids are sometimes used in practice and agreed they should be considered if NSAIDs and colchicine are contraindicated, not tolerated or ineffective. There is no evidence supporting 1 route of administration over the other.\n\nInterleukin-1 (IL-1) inhibitors show a clinical benefit compared with corticosteroids for pain and quality of life outcomes. However, IL-1 inhibitors are very expensive and other medicines are adequate alternatives. The committee concluded that IL-1 inhibitors would not be a cost-effective use of NHS resources for most people with gout flares. If response to treatment has been inadequate, or NSAIDs, colchicine and corticosteroids are contraindicated or not tolerated, the person should be referred to rheumatology services before prescribing an IL-1 inhibitor.\n\nEvidence from\xa01 small study shows that cold therapy reduces pain. Although the evidence is limited, the committee recommended using ice alongside pharmacological treatments because in their experience this helps ease pain and inflammation.\n\n## How the recommendations might affect practice\n\nThe recommendations generally reflect current practice and are not likely to result in changes.\n\nReturn to recommendations\n\n# Follow-up after a gout flare\n\nRecommendation\xa01.3.6\n\n## Why the committee made the recommendation\n\nIn current practice, little or no follow-up is offered to people after a gout flare. The committee noted that a follow-up appointment after a gout flare provides an opportunity to review medication and discuss the option of long-term ULT. The healthcare practitioner can also provide information about gout and how to reduce the risk of future flares, and assess any comorbidities and lifestyle factors that may impact how the person self-manages their gout. Based on their clinical experience, the committee agreed that follow-up appointments after a gout flare would allow people to have a better health-related quality of life in the long term. This is because they will likely have fewer subsequent gout flares as a result of starting ULT sooner. People will also be better equipped to manage their gout flares and have more information on how to minimise their risk of recurrent flares. The committee thought that the benefits of follow-up appointments would outweigh the costs and that it is likely to be a cost-effective strategy, but there is not enough evidence to confirm this.\n\nThere is no evidence on which follow-up strategies are most effective, including the frequency and duration of follow-up, and which healthcare professionals should lead the follow-up and in what settings. The committee made a recommendation for research on follow-up after a gout flare.\n\n## How the recommendation might affect practice\n\nThis recommendation is likely to be a change in practice for many and will affect a large proportion of people with gout. Follow-up appointments after a gout flare provide an opportunity for people to start ULT and reduce gout flares. Therefore, this recommendation is expected to be cost saving or at least cost neutral.\n\nReturn to recommendation\n\n# Diet and lifestyle\n\nRecommendations\xa01.4.1 and 1.4.2\n\n## Why the committee made the recommendations\n\nThe committee discussed the diverse dietary interventions for gout, which included dietary advice, cherry extract and vitamin C. They noted that all studies had small numbers of participants and short follow-up periods. The committee agreed it would be difficult to implement dietary interventions in practice and concluded that there is not enough strong evidence to support any specific diet. They also wanted to avoid giving conflicting advice because many people with gout have comorbidities and may have already had dietary advice for these conditions.\n\nThe committee acknowledged that people with gout often seek dietary advice because they believe there is a link between diet and gout. They noted that in current practice the healthcare professional and the person with gout often discuss diet and lifestyle. The committee agreed that people with gout should be advised that there is not enough evidence to support any specific diet to manage gout and they should follow a healthy, balanced diet. People should also be advised that excess weight, obesity or excessive alcohol consumption may exacerbate gout flares.\n\n## How the recommendations might affect practice\n\nThe recommendations generally reflect current practice and are not likely to result in changes.\n\nReturn to recommendations\n\n# Management of gout with urate-lowering therapies\n\nRecommendations\xa01.5.1 to 1.5.4\n\n## Why the committee made the recommendations\n\nThe committee agreed that evidence on which people should be selected for long‑term management of gout with ULT is limited because there are only 3\xa0studies of moderate to high quality. The evidence shows that people with chronic renal failure and people using diuretics are more likely to have gout flares, and that people with tophi and swollen or tender joints have more disability through damage to joints.\n\nGout is characterised by severe pain, therefore pain reduction is an important outcome of treatment. People with gout experience the most pain during flares. Reducing the frequency of flares along with reducing joint swelling, inflammation, and joint tenderness, can reduce pain and improve the person's comfort. The committee reinforced the benefits of ULT for reducing serum urate levels and reducing gout flares in the long term. The committee noted that opportunities to offer ULTs to people with gout early in their disease may be missed, but acknowledged that there was a lack of evidence for this. Therefore, the committee recommended discussing and considering the option of ULT with all people having a first or subsequent gout flare. Once the target serum urate level is reached people with gout will usually remain on ULT. The committee agreed that the importance of long-term treatment should be discussed with the patient. The committee highlighted that ULT use in current practice varies and there is low uptake of ULTs.\n\nThe recommendations are likely to result in an increased number of people having ULT. A costing analysis in evidence review\xa0E assessed the costs of current and future practice. This included increased uptake of ULT, a greater proportion of people having ULT with febuxostat, and using a treat-to-target strategy. The analysis showed that future practice is less costly than current practice. The committee acknowledged that a costing analysis is not as robust as a health economic model. They noted additional supporting evidence in evidence review\xa0G showing that treatment with ULTs is cost effective compared with no treatment. They also noted additional supporting evidence in evidence review\xa0J showing that a treat-to-target strategy is cost effective. The committee were confident that treatment with ULTs will be less costly and more effective than no treatment.\n\nThe committee agreed that evidence on when to start ULT is very limited because there are only 2 small studies and both included people with a current gout flare. The committee noted that in current practice ULTs are started 2\xa0to 4\xa0weeks after a flare has settled to prevent exacerbating the flare. This is because in previous practice people started treatment with 300\xa0mg allopurinol, which can exacerbate a flare more than starting treatment with 100\xa0mg and up-titrating. The committee suggested that exacerbation of flares may be less of a concern when starting ULT at a low dose and increasing the dose gradually. The committee discussed that starting ULT at least 2\xa0to 4\xa0weeks after a flare has settled means that people who have very frequent flares may not have a sufficiently long flare-free period in which to start ULT. However, the committee also noted that the person may be in too much pain during a gout flare to understand information about ULTs and the importance of treatment adherence.\n\nBased on their experience, the committee recommended that people with gout who choose ULT should ideally start treatment after a flare, but people who have frequent flares can start during a gout flare. Because the evidence is very limited the committee decided to make a recommendation for research on when to start ULT.\n\n## How the recommendations might affect practice\n\nThe recommendations for ULT are likely to result in a change in clinical practice and have a significant resource impact given the prevalence of gout and the current limited uptake of ULTs. A lower incidence of flares resulting from more people starting ULT will likely result in long-term cost savings. The recommendation on when to start ULT generally reflects current practice and is unlikely to result in change.\n\nReturn to recommendations\n\n# Treat-to-target strategy\n\nRecommendation\xa01.5.5\n\n## Why the committee made the recommendation\n\nTwo randomised controlled trials evaluated treat-to-target strategies using ULTs. Both studies compared ULT with usual care, which was any available option chosen by the healthcare provider, such as continuing the current dose of allopurinol or febuxostat, or no treatment.\n\nThe evidence shows that a treat-to-target strategy increases the frequency of flares at 1\xa0year compared with usual care, but reduces frequency of flares at 2\xa0years. The committee agreed that starting ULT and increasing the dose could set off a flare, so the number of flares might initially increase in the first year but decrease by the second year when the dose is stabilised. The high use of febuxostat in 1\xa0study was also noted and was thought to not reflect current practice.\n\nHealth economic analysis shows that a treat-to-target management strategy is cost effective and therefore the committee recommended it.\n\nOverall, the committee agreed that the evidence supports a treat-to-target strategy based on the benefits shown for quality of life outcomes, frequency of flares in the longer term, and the cost-effectiveness results.\n\n## How the recommendation might affect practice\n\nThe number of people with gout who have a treat-to-target strategy varies in current practice. The committee acknowledged that care is sub-optimal and people with gout are more likely to have usual care. The recommendation will likely increase the number of people using a treat-to-target strategy and therefore change practice.\n\nReturn to recommendation\n\n# Target serum urate level\n\nRecommendations\xa01.5.6 and 1.5.7\n\n## Why the committee made the recommendations\n\nThere is no evidence on the best target serum urate level when using a treat-to-target strategy.\n\nThe committee discussed the clinical benefits and costs associated with target serum urate levels below 300\xa0micromol/litre (5\xa0mg/dl) and 360\xa0micromol/litre (6\xa0mg/dl). They agreed that reaching a serum urate level below 360\xa0micromol/litre is more achievable for people with gout. They also agreed that it is unknown whether a lower target is more beneficial, although clinical improvement may be seen more quickly after achieving a lower target. The committee agreed a target of below 360\xa0micromol/litre reflected current practice within primary care. Achieving a target serum urate level below 360\xa0micromol/litre would also have a lower cost than achieving a target serum urate level below 300\xa0micromol/litre because reaching a lower target is likely to need more appointments and higher doses.\n\nThe committee noted that a target serum urate level of below 300\xa0micromol/litre would be more appropriate for people with more severe gout because they have a higher level of crystal deposition, and response to treatment takes longer. A lower target level will help crystals dissolve more quickly and support clinical improvement. This includes people still having gout flares despite reaching a target serum urate level below 360\xa0micromol/litre or people who have tophi or chronic gouty arthritis.\n\nThe committee discussed that gout is frequently undertreated and this may be because of uncertainty about the optimum target serum urate level. They noted the different levels recommended by the British Society for Rheumatology and European League Against Rheumatism. The committee agreed further research in this area is needed and made a recommendation for research on target serum urate level.\n\n## How the recommendations might affect practice\n\nFor people having ULT, usual practice is to reach a target serum urate level below 360\xa0micromol/litre, therefore the recommendations are not likely to result in changes.\n\nReturn to recommendations\n\n# Urate-lowering therapies\n\nRecommendations\xa01.5.8 to 1.5.10\n\n## Why the committee made the recommendations\n\nThere is evidence on ULTs from 17\xa0randomised controlled trials, including on first- and second-line treatment, CKD status, and allopurinol or febuxostat dosage. The evidence mainly shows that febuxostat and allopurinol reduce serum urate levels to target compared with placebo. For first-line treatment, febuxostat reduces the frequency of flares compared with allopurinol and reduces serum urate levels compared with allopurinol and placebo. The committee noted that important outcomes are frequency of flares and cardiovascular adverse events, however not all trials report these. Allopurinol has fewer adverse events such as withdrawal and gastrointestinal issues compared with placebo.\n\nA costing analysis comparing allopurinol and febuxostat for 1\xa0year of treatment with a treat-to-target strategy shows that there are minimal cost differences between allopurinol and febuxostat. The committee thought the evidence showed little difference between allopurinol and febuxostat as first-line treatments for gout so they recommended both drugs. The committee thought that shared decision making is important when choosing treatment and that people with gout should be made aware of the differences between drugs. Febuxostat is easier to titrate than allopurinol because there are only two available doses and it is only taken once a day. The evidence shows that the target serum urate level is more frequently achieved with febuxostat than allopurinol, however, it also causes more flares and therefore more people would also need treatment to prevent flares. Most of the trials compared febuxostat with sub-optimal doses of allopurinol (up to 300\xa0mg). Allopurinol doses up to 300\xa0mg are often too low to achieve the target serum urate level and many people with gout would need higher doses to manage their condition.\n\nThe committee recommended that people with major cardiovascular disease should have allopurinol as first-line treatment because of the 2019 Medicines and Healthcare products Regulatory Agency (MHRA) advice on febuxostat within this population. They noted that this recommendation may change in the future.\n\nThere were only 2\xa0studies on second-line treatment. The evidence does not strongly favour 1\xa0treatment, so the committee recommended that both allopurinol and febuxostat could be considered as second-line treatments. This recommendation is dependent on target serum urate level not being reached or when first-line treatment is not tolerated. The committee also noted the importance of taking into account comorbidities and patient preferences when switching to a second-line treatment.\n\nAn increase in the number of people taking ULT is likely to lead to an increase in monitoring serum urate levels, using prophylaxis and treating flares. However, a treat-to-target ULT strategy has been shown to be cost effective, so offering people ULT is clinically effective and highly likely to be cost effective compared with offering no treatment.\n\n## How the recommendations might affect practice\n\nThe recommendations are a change in practice because currently people have allopurinol as first-line ULT. These recommendations are not expected to result in a substantial resource impact because the cost of allopurinol and febuxostat are similar.\n\nReturn to recommendations\n\n# Preventing gout flares when starting or titrating ULT\n\nRecommendations\xa01.5.11 to 1.5.14\n\n## Why the committee made the recommendations\n\nThe committee noted that the evidence is limited as there are only 3\xa0studies and they all compared colchicine with an IL-1 inhibitor, placebo and no treatment. The evidence shows that colchicine reduces the frequency of gout flares when starting ULT compared with placebo and no treatment, but has some gastrointestinal adverse events compared with placebo. The committee discussed that in current practice, colchicine and NSAIDs are most frequently offered to people with gout to prevent flares. There is no evidence supporting the use of NSAIDs, so the committee agreed colchicine should be offered to people with gout during the start and titration of ULT to prevent gout flares. Although there is no evidence on preventing flares during the titration of ULT, the committee agreed that colchicine can also be used to reduce the risk of flares after up-titration of ULT.\n\nThe committee noted that colchicine may not be appropriate for some people with gout because of tolerability, comorbidities such as CKD or prescriptions such as statins. The committee agreed that an NSAID or corticosteroid should be considered for people when colchicine is contraindicated, not tolerated or ineffective. Although no evidence was found for either NSAIDs or corticosteroids, the committee agreed an alternative treatment is needed to prevent flares, which can cause severe pain. The committee noted their experience that NSAIDs are well tolerated by people with gout. Because no evidence was found for NSAIDs or corticosteroids the committee also decided to make a recommendation for research on preventing gout flares. Evidence from 1\xa0study shows that canakinumab reduces the frequency of flares, however the committee noted that IL-1 inhibitors are rarely prescribed to people with gout. Use of IL-1 inhibitors requires close monitoring and they are currently only prescribed in secondary care. The committee concluded there was insufficient evidence to recommend IL-1 inhibitors over other routine treatments currently used within clinical practice unless colchicine, NSAIDs and corticosteroids are contraindicated, not tolerated or ineffective.\n\n## How the recommendations might affect practice\n\nThe recommendations generally reflect current practice and are not likely to result in changes.\n\nReturn to recommendations\n\n# Monitoring serum urate level\n\nRecommendation\xa01.5.15\n\n## Why the committee made the recommendation\n\nThere was no evidence on the optimum frequency of monitoring serum urate level in people having ULT.\n\nThe committee agreed that one reason to continue monitoring a person's serum urate level when the target serum urate level has been reached is to prevent it increasing, which can occur with age or because of changes in lifestyle, comorbidities or medications. The committee noted that people may stop treatment if they feel better, but continuing ULT as prescribed is important because serum urate levels can increase quickly once ULT is stopped. The committee discussed that in current practice the frequency of serum urate level monitoring is highly variable. Patients usually make appointments with their GP in response to gout flares and a health professional would measure their serum urate level in that appointment. However, the committee agreed this was not sufficient as the goal of monitoring is to prevent gout flares rather than manage them. Patient support and monitoring is usually based on individual factors after discussion with the patient.\n\nThe committee highlighted the importance of monitoring and noted that without monitoring, people may have poor medication adherence which increases serum urate levels. This can lead to poorer long-term outcomes for people and impact their health-related quality of life, and may also be associated with additional costs to the NHS.\n\nThere was no available evidence to estimate how many flares would be avoided with annual monitoring. The committee noted that there may be better medication adherence with annual monitoring and that more people might remain at their target serum urate level.\n\nOverall, the committee agreed that annual monitoring is likely to be a cost-effective strategy and therefore they made a recommendation to consider it. The committee also made a recommendation for research on monitoring gout.\n\n## How the recommendation might affect practice\n\nIn people with gout who are having ULT, annual monitoring once target serum urate levels are reached may result in a change in clinical practice.\n\nReturn to recommendation\n\n# Referral to specialist services\n\nRecommendation\xa01.6.1\n\n## Why the committee made the recommendation\n\nNo relevant evidence on referral to specialist gout services was identified. The committee were not aware of any published referral criteria for gout. They acknowledged that referral to a specialist was likely based on the complexity of care needed by the patient, and the gout knowledge and skillset of the GP caring for them. The committee noted that the diagnosis and treatment of people with gout is mainly managed within primary care.\n\nThe committee discussed when referral to a rheumatologist would be considered and made recommendations based on their experience. This included:\n\nwhen diagnosis is uncertain and joint aspiration or imaging is needed, because this would usually be done in secondary care\n\nif the person cannot tolerate medication, or has any allergic reaction or difficulty taking allopurinol or febuxostat\n\nwhen response to treatment has been inadequate, including difficulty in controlling gout symptoms with ULT.\n\nThe committee acknowledged that a specialist would prefer to examine people with gout who have comorbidities and complex needs and have a face-to-face consultation instead of relying on their history and test results. Treating gout in people with CKD can be challenging, particularly in people with severe CKD (stages\xa04 to 5 or glomerular filtration rate [GFR] categories G4 to G5). However, the committee also recognised that stage\xa03 (GFR category G3) CKD comprises a wide clinical spectrum and that some people with stage\xa03 (GFR category G3) CKD and gout may also need referral, often because of difficulties in treating gout in this population. The committee discussed that including people with stage\xa03 (GFR category G3) CKD within the recommendation could increase the numbers of people being referred, because this represents a large population. They agreed that people with CKD stage\xa03b (GFR category G3b) are more likely to need specialist input to achieve optimal management of their gout.\n\nPeople with gout who have had an organ transplant will usually be referred to a specialist because treatments for transplant rejection may exacerbate hyperuricaemia and may interact with treatments for gout and renal dysfunction.\n\nThere is no relevant evidence on surgical removal of tophi. The committee discussed that tophi develop very slowly over years and typically occur in the toes, fingers, elbows or attachment of the Achilles tendon to the heel bone. The committee agreed that surgical removal of tophi is an uncommon procedure, and surgery is only offered to people whose gout is impacting their quality of life because of pain or restriction in movement.\n\nThe committee discussed that tophi are seen in people with uncontrolled gout and persistent high urate levels, and they tend to develop in older people. They agreed that with targeted treatment to reduce serum urate levels, tophi will dissolve or reduce over time, and in their experience referral to orthopaedic surgery would rarely be needed.\n\nThe committee agreed not to make a recommendation because any decision to refer for consideration for surgery would be made on an individual basis.\n\nDoing research in this area would be difficult because of the limited number of people that have tophi removed. The committee concluded that research is not feasible and is also low priority given the few people who have this surgical procedure.\n\n## How the recommendation might affect practice\n\nReferral to rheumatology services is variable within current practice. The recommendation may lead to an increase in referrals to specialist services.\n\nReturn to recommendation", 'Context': 'Gout is a type of arthritis caused by monosodium urate crystals forming inside and around joints, resulting in sudden flares of severe pain, heat and swelling. Any joint can be affected but gout is most common in distal joints, such as big toes, knees and ankles, and fingers.\n\nBetween 2 and 3 in every 100\xa0people in the UK have gout. It usually occurs in men over\xa030 and women after menopause, and is more common in men than women. Long-term complications of gout include joint damage and renal stones. Almost\xa025% of people with gout have chronic kidney disease (CKD) stages\xa03 to 5 (glomerular filtration rate [GFR] categories G3 to G5).\n\nGout is most often managed in primary care without specialist rheumatological input. Flares are usually treated with non-steroidal anti-inflammatory drugs, colchicine or corticosteroids. However, most people have further flares. They can be prevented by taking medicines to reduce serum urate levels (such as allopurinol or febuxostat).\n\nHowever, only one-third of people with gout have these medicines and they are used effectively (lowering serum urate level to the target) by only one-third of people who take them. People with CKD also often have contraindications to medicines used to manage gout.\n\nDiagnosing gout and differentiating gout from other types of arthritis is not always straightforward and the best method of diagnosis is often unclear. There is a need to improve the diagnosis and management of gout and the quality of life for people with gout.'}	https://www.nice.org.uk/guidance/ng219	This guideline covers the diagnosis and management of gout. It includes recommendations on diagnosing gout, managing flares, long-term management of gout and referral to specialist services.
ef9fb4e0f5ecf33cf000358da45f72ab27389d5d	nice	Diroximel fumarate for treating relapsing–remitting multiple sclerosis	Diroximel fumarate for treating relapsing–remitting multiple sclerosis Evidence-based recommendations on diroximel fumarate (Vumerity) for active relapsing–remitting multiple sclerosis in adults. # Recommendations Diroximel fumarate is recommended as an option for treating active relapsing–remitting multiple sclerosis (normally defined as 2 clinically significant relapses in the previous 2 years) in adults, only if: they do not have highly active or rapidly evolving severe relapsing–remitting multiple sclerosis and the company provides diroximel fumarate according to the commercial arrangement. If patients and their clinicians consider diroximel fumarate to be one of a range of suitable treatments (including dimethyl fumarate), choose the least expensive treatment, taking into account administration costs, dosage, price per dose and commercial arrangements. These recommendations are not intended to affect treatment with diroximel fumarate that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations The summary of product characteristics states that diroximel fumarate is expected to be as clinically effective as dimethyl fumarate, which NICE already recommends for active relapsing–remitting multiple sclerosis. Clinical trial evidence suggests that diroximel fumarate causes fewer gastrointestinal side effects than dimethyl fumarate. Comparing the costs of diroximel fumarate and dimethyl fumarate is appropriate because the 2 treatments work in the same way and are likely be used in the same population. The total costs associated with diroximel fumarate are similar to or lower than those associated with dimethyl fumarate. So, diroximel fumarate is recommended.# Information about diroximel fumarate # Marketing authorisation indication Diroximel fumarate (Vumerity, Biogen) has a marketing authorisation 'for the treatment of adult patients with relapsing–remitting multiple sclerosis'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for diroximel fumarate. # Price The list price of diroximel fumarate is £1,471.07 per pack (231 mg, 120 capsules; excluding VAT; price as quoted in the company's submission). The company has a commercial arrangement. This makes diroximel fumarate available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Biogen, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## People with relapsing–remitting multiple sclerosis would welcome an additional oral treatment Multiple sclerosis is a chronic, lifelong disease with no cure, resulting in progressive, irreversible disability. It has a wide range of distressing and debilitating symptoms including loss of balance, stiffness, spasms, speech problems, fatigue, pain, incontinence and vision problems. Most people have the relapsing–remitting form of the disease, characterised by periods of new or worsened symptoms. Recovery is often incomplete, leading to accumulation of disability with each successive relapse. Statements from patient experts highlighted that multiple sclerosis has a significant impact on all aspects of life. Current treatments are associated with side effects, and people commonly switch treatments multiple times to balance effectiveness and safety risks. Oral treatments for relapsing–remitting multiple sclerosis are limited, but people generally prefer them because they are easier to use. The committee agreed that a range of treatments provides options for different responses and personal preferences and that there was an unmet need for oral treatments with fewer side effects. It concluded that people would welcome additional oral treatment options for relapsing–remitting multiple sclerosis. # Decision problem ## The company's proposed population is consistent with NICE's recommendations for active relapsing–remitting multiple sclerosis The company proposed that diroximel fumarate should be considered as an alternative to other first-line disease-modifying treatments for active relapsing–remitting multiple sclerosis, and for the population in the NICE technology appraisal guidance on dimethyl fumarate for treating relapsing–remitting multiple sclerosis (TA320). The committee noted that in TA320, dimethyl fumarate was not recommended for people with highly active or rapidly evolving severe multiple sclerosis because of a lack of evidence. It also noted that active relapsing–remitting multiple sclerosis was normally defined as 2 clinically significant relapses in the previous 2 years when dimethyl fumarate was recommended in 2014. The committee was aware that in current practice, clinicians sometimes offer disease-modifying treatments to people considered to have 'active' disease with a single recent relapse or the presence of radiological activity, such as new MRI lesions, without a clinical relapse. The committee concluded that the company's proposed population was consistent with previous NICE recommendations for active relapsing–remitting multiple sclerosis. ## Dimethyl fumarate is an appropriate comparator for cost comparison The company presented a comparison with a NICE-recommended treatment, dimethyl fumarate (TA320). The company, which is the marketing authorisation holder for both treatments, chose dimethyl fumarate as the comparator because it is one of the most widely prescribed disease-modifying treatments for active relapsing–remitting multiple sclerosis in England. The committee recalled that TA320 recommended dimethyl fumarate for active relapsing–remitting multiple sclerosis and excluded highly active or rapidly evolving severe multiple sclerosis, aligned with the relevant population for diroximel fumarate. So, if recommended, diroximel fumarate would likely be used as an alternative treatment for people who would currently have dimethyl fumarate. The committee concluded that dimethyl fumarate is a relevant comparator for diroximel fumarate and a cost comparison is appropriate. # Clinical effectiveness ## Diroximel fumarate and dimethyl fumarate are expected to be equally effective Regulatory approval for diroximel fumarate was granted because it has the same active metabolite as dimethyl fumarate and pharmacokinetic analyses have demonstrated bioequivalence. This meant that evidence on the clinical efficacy of dimethyl fumarate was accepted by the regulators to reflect the clinical efficacy of diroximel fumarate. The ERG also considered the clinical effectiveness of diroximel fumarate and dimethyl fumarate to be similar because of the established bioequivalence. The committee concluded that diroximel fumarate and dimethyl fumarate are expected to be equally effective. ## Diroximel fumarate has fewer gastrointestinal side effects and overall has a similar safety profile to dimethyl fumarate The safety of diroximel fumarate was compared with that of dimethyl fumarate in a phase‑3, randomised, double-blind trial, EVOLVE‑MS‑2. This trial included 504 patients with relapsing–remitting multiple sclerosis who were neurologically stable and had 5 weeks of treatment with diroximel fumarate or dimethyl fumarate. Gastrointestinal side effects were assessed using 2 patient self-reported scales developed by the company, ranging from 0 (no gastrointestinal side effects) to 10 (extreme gastrointestinal side effects). The results suggested that diroximel fumarate was associated with fewer gastrointestinal side effects than dimethyl fumarate, regardless of the severity scale threshold used to define the presence of side effects. The patient expert submissions stated that gastrointestinal side effects are less likely to interfere with regular daily activities and work productivity with diroximel fumarate than with dimethyl fumarate. The ERG also noted that other non-gastrointestinal side effects assessed in EVOLVE‑MS‑2 for diroximel fumarate were aligned with those of dimethyl fumarate, and overall the safety profile of diroximel fumarate was better. The committee noted that some side effects, for example flushing, which the patient experts' submission described as bothersome, continued with diroximel fumarate. However, the patient expert submissions suggested that flushing is mostly mild to moderate, reduces after the first month of treatment, and is less likely to result in treatment discontinuation than gastrointestinal side effects. The committee concluded that treatment with diroximel fumarate has fewer gastrointestinal side effects and overall may be associated with a better safety profile than dimethyl fumarate. # Cost comparison ## The total costs associated with diroximel fumarate are similar to or lower than those associated with dimethyl fumarate The company presented a cost-comparison analysis that compared the acquisition costs of diroximel fumarate and dimethyl fumarate. The company stated that, because diroximel fumarate is an oral treatment and can be self-administered at home, similar to other oral disease-modifying treatments, no changes in service provision or management will be needed. The base case assumed equal treatment effect, monitoring, safety profile and subsequent therapies for diroximel fumarate and dimethyl fumarate. The ERG considered the cost comparison appropriate. Considering the confidential patient access schemes for diroximel fumarate and dimethyl fumarate, the committee concluded that the total costs associated with diroximel fumarate were similar to or lower than those associated with dimethyl fumarate (the exact results cannot be reported here because the discounts are confidential). # Conclusion ## Diroximel fumarate is recommended as an option for treating relapsing–remitting multiple sclerosis in adults The committee concluded that the criteria for a positive cost comparison were met because: diroximel fumarate is expected to provide similar or greater overall health benefits compared with dimethyl fumarate the total costs associated with diroximel fumarate were similar to or lower than the total costs associated with dimethyl fumarate.The committee noted that the ERG had no concerns with the company submission. The committee therefore recommended diroximel fumarate as an option for treating relapsing–remitting multiple sclerosis in adults. It concluded that the population included in the recommendation for diroximel fumarate should be consistent with that in the company's proposal and in TA320, that is, people who: have active relapsing–remitting multiple sclerosis (normally defined as 2 clinically significant relapses in the previous 2 years) do not have highly active or rapidly evolving severe relapsing–remitting multiple sclerosis.If patients and their clinicians consider diroximel fumarate to be one of a range of suitable treatments, including dimethyl fumarate, the least expensive should be chosen (taking into account administration costs, dosage, price per dose and commercial arrangements).	{'Recommendations': 'Diroximel fumarate is recommended as an option for treating active relapsing–remitting multiple sclerosis (normally defined as 2\xa0clinically significant relapses in the previous 2\xa0years) in adults, only if:\n\nthey do not have highly active or rapidly evolving severe relapsing–remitting multiple sclerosis and\n\nthe company provides diroximel fumarate according to the commercial arrangement.\n\nIf patients and their clinicians consider diroximel fumarate to be one of a range of suitable treatments (including dimethyl fumarate), choose the least expensive treatment, taking into account administration costs, dosage, price per dose and commercial arrangements.\n\nThese recommendations are not intended to affect treatment with diroximel fumarate that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThe summary of product characteristics states that diroximel fumarate is expected to be as clinically effective as dimethyl fumarate, which NICE already recommends for active relapsing–remitting multiple sclerosis. Clinical trial evidence suggests that diroximel fumarate causes fewer gastrointestinal side effects than dimethyl fumarate.\n\nComparing the costs of diroximel fumarate and dimethyl fumarate is appropriate because the 2\xa0treatments work in the same way and are likely be used in the same population. The total costs associated with diroximel fumarate are similar to or lower than those associated with dimethyl fumarate. So, diroximel fumarate is recommended.', 'Information about diroximel fumarate': "# Marketing authorisation indication\n\nDiroximel fumarate (Vumerity, Biogen) has a marketing authorisation 'for the treatment of adult patients with relapsing–remitting multiple sclerosis'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for diroximel fumarate.\n\n# Price\n\nThe list price of diroximel fumarate is £1,471.07 per pack (231\xa0mg, 120\xa0capsules; excluding VAT; price as quoted in the company's submission).\n\nThe company has a commercial arrangement. This makes diroximel fumarate available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Biogen, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## People with relapsing–remitting multiple sclerosis would welcome an additional oral treatment\n\nMultiple sclerosis is a chronic, lifelong disease with no cure, resulting in progressive, irreversible disability. It has a wide range of distressing and debilitating symptoms including loss of balance, stiffness, spasms, speech problems, fatigue, pain, incontinence and vision problems. Most people have the relapsing–remitting form of the disease, characterised by periods of new or worsened symptoms. Recovery is often incomplete, leading to accumulation of disability with each successive relapse. Statements from patient experts highlighted that multiple sclerosis has a significant impact on all aspects of life. Current treatments are associated with side effects, and people commonly switch treatments multiple times to balance effectiveness and safety risks. Oral treatments for relapsing–remitting multiple sclerosis are limited, but people generally prefer them because they are easier to use. The committee agreed that a range of treatments provides options for different responses and personal preferences and that there was an unmet need for oral treatments with fewer side effects. It concluded that people would welcome additional oral treatment options for relapsing–remitting multiple sclerosis.\n\n# Decision problem\n\n## The company's proposed population is consistent with NICE's recommendations for active relapsing–remitting multiple sclerosis\n\nThe company proposed that diroximel fumarate should be considered as an alternative to other first-line disease-modifying treatments for active relapsing–remitting multiple sclerosis, and for the population in the NICE technology appraisal guidance on dimethyl fumarate for treating relapsing–remitting multiple sclerosis (TA320). The committee noted that in TA320, dimethyl fumarate was not recommended for people with highly active or rapidly evolving severe multiple sclerosis because of a lack of evidence. It also noted that active relapsing–remitting multiple sclerosis was normally defined as 2\xa0clinically significant relapses in the previous 2\xa0years when dimethyl fumarate was recommended in 2014. The committee was aware that in current practice, clinicians sometimes offer disease-modifying treatments to people considered to have 'active' disease with a single recent relapse or the presence of radiological activity, such as new MRI lesions, without a clinical relapse. The committee concluded that the company's proposed population was consistent with previous NICE recommendations for active relapsing–remitting multiple sclerosis.\n\n## Dimethyl fumarate is an appropriate comparator for cost comparison\n\nThe company presented a comparison with a NICE-recommended treatment, dimethyl fumarate (TA320). The company, which is the marketing authorisation holder for both treatments, chose dimethyl fumarate as the comparator because it is one of the most widely prescribed disease-modifying treatments for active relapsing–remitting multiple sclerosis in England. The committee recalled that TA320 recommended dimethyl fumarate for active relapsing–remitting multiple sclerosis and excluded highly active or rapidly evolving severe multiple sclerosis, aligned with the relevant population for diroximel fumarate. So, if recommended, diroximel fumarate would likely be used as an alternative treatment for people who would currently have dimethyl fumarate. The committee concluded that dimethyl fumarate is a relevant comparator for diroximel fumarate and a cost comparison is appropriate.\n\n# Clinical effectiveness\n\n## Diroximel fumarate and dimethyl fumarate are expected to be equally effective\n\nRegulatory approval for diroximel fumarate was granted because it has the same active metabolite as dimethyl fumarate and pharmacokinetic analyses have demonstrated bioequivalence. This meant that evidence on the clinical efficacy of dimethyl fumarate was accepted by the regulators to reflect the clinical efficacy of diroximel fumarate. The ERG also considered the clinical effectiveness of diroximel fumarate and dimethyl fumarate to be similar because of the established bioequivalence. The committee concluded that diroximel fumarate and dimethyl fumarate are expected to be equally effective.\n\n## Diroximel fumarate has fewer gastrointestinal side effects and overall has a similar safety profile to dimethyl fumarate\n\nThe safety of diroximel fumarate was compared with that of dimethyl fumarate in a phase‑3, randomised, double-blind trial, EVOLVE‑MS‑2. This trial included 504\xa0patients with relapsing–remitting multiple sclerosis who were neurologically stable and had 5\xa0weeks of treatment with diroximel fumarate or dimethyl fumarate. Gastrointestinal side effects were assessed using 2\xa0patient self-reported scales developed by the company, ranging from 0 (no gastrointestinal side effects) to 10 (extreme gastrointestinal side effects). The results suggested that diroximel fumarate was associated with fewer gastrointestinal side effects than dimethyl fumarate, regardless of the severity scale threshold used to define the presence of side effects. The patient expert submissions stated that gastrointestinal side effects are less likely to interfere with regular daily activities and work productivity with diroximel fumarate than with dimethyl fumarate. The ERG also noted that other non-gastrointestinal side effects assessed in EVOLVE‑MS‑2 for diroximel fumarate were aligned with those of dimethyl fumarate, and overall the safety profile of diroximel fumarate was better. The committee noted that some side effects, for example flushing, which the patient experts' submission described as bothersome, continued with diroximel fumarate. However, the patient expert submissions suggested that flushing is mostly mild to moderate, reduces after the first month of treatment, and is less likely to result in treatment discontinuation than gastrointestinal side effects. The committee concluded that treatment with diroximel fumarate has fewer gastrointestinal side effects and overall may be associated with a better safety profile than dimethyl fumarate.\n\n# Cost comparison\n\n## The total costs associated with diroximel fumarate are similar to or lower than those associated with dimethyl fumarate\n\nThe company presented a cost-comparison analysis that compared the acquisition costs of diroximel fumarate and dimethyl fumarate. The company stated that, because diroximel fumarate is an oral treatment and can be self-administered at home, similar to other oral disease-modifying treatments, no changes in service provision or management will be needed. The base case assumed equal treatment effect, monitoring, safety profile and subsequent therapies for diroximel fumarate and dimethyl fumarate. The ERG considered the cost comparison appropriate. Considering the confidential patient access schemes for diroximel fumarate and dimethyl fumarate, the committee concluded that the total costs associated with diroximel fumarate were similar to or lower than those associated with dimethyl fumarate (the exact results cannot be reported here because the discounts are confidential).\n\n# Conclusion\n\n## Diroximel fumarate is recommended as an option for treating relapsing–remitting multiple sclerosis in adults\n\nThe committee concluded that the criteria for a positive cost comparison were met because:\n\ndiroximel fumarate is expected to provide similar or greater overall health benefits compared with dimethyl fumarate\n\nthe total costs associated with diroximel fumarate were similar to or lower than the total costs associated with dimethyl fumarate.The committee noted that the ERG had no concerns with the company submission. The committee therefore recommended diroximel fumarate as an option for treating relapsing–remitting multiple sclerosis in adults. It concluded that the population included in the recommendation for diroximel fumarate should be consistent with that in the company's proposal and in TA320, that is, people who:\n\nhave active relapsing–remitting multiple sclerosis (normally defined as 2\xa0clinically significant relapses in the previous 2\xa0years)\n\ndo not have highly active or rapidly evolving severe relapsing–remitting multiple sclerosis.If patients and their clinicians consider diroximel fumarate to be one of a range of suitable treatments, including dimethyl fumarate, the least expensive should be chosen (taking into account administration costs, dosage, price per dose and commercial arrangements)."}	https://www.nice.org.uk/guidance/ta794	Evidence-based recommendations on diroximel fumarate (Vumerity) for active relapsing–remitting multiple sclerosis in adults.
2ac464dc7958efcf4e5d3396e5e3c2e385f65bc2	nice	Ibrutinib for treating Waldenstrom's macroglobulinaemia	Ibrutinib for treating Waldenstrom's macroglobulinaemia Evidence-based recommendations on ibrutinib (Imbruvica) for Waldenstrom’s macroglobulinaemia in adults who have had at least 1 previous therapy. # Recommendations Ibrutinib is not recommended, within its marketing authorisation, for treating Waldenstrom's macroglobulinaemia in adults who have had at least 1 previous therapy. This recommendation is not intended to affect treatment with ibrutinib that was funded by the Cancer Drugs Fund before final guidance was published. If this applies, when that funding ends ibrutinib will be funded by the company until the patient and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for ibrutinib for treating Waldenstrom's macroglobulinaemia in adults who have had at least 1 previous therapy (NICE technology appraisal guidance 491). The new evidence includes data for ibrutinib from clinical trials and from people having treatment with ibrutinib in the NHS in the Cancer Drugs Fund. It shows that ibrutinib improves how long people live before their condition gets worse and how long they live for. But it is uncertain by how much it does this compared with chemoimmunotherapy. The cost-effectiveness estimates for ibrutinib are higher than what NICE usually considers a cost-effective use of NHS resources. So, it is not recommended.# Information about ibrutinib # Marketing authorisation indication Ibrutinib (Imbruvica, Janssen) has a marketing authorisation for treating 'adult patients with Waldenstrom's macroglobulinaemia who have received at least one prior therapy, or in first-line treatment for patients unsuitable for chemo-immunotherapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for ibrutinib. # Price The list price for ibrutinib is £1,430.80 for a 28‑tablet pack of 140 mg tablets (excluding VAT; BNF online accessed December 2021). The company has a commercial arrangement. This makes ibrutinib available to the NHS with a discount and it would have also applied to this indication if the technology had been recommended. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Janssen, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. This review looks at data collected as part of the Cancer Drugs Fund to address uncertainties identified during the original appraisal for ibrutinib. Further information about the original appraisal can be found in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from study 1118E. In addition, data was collected on ibrutinib for people with Waldenstrom's macroglobulinaemia who had had at least 1 previous therapy in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset. The managed access arrangement for ibrutinib to be used in the Cancer Drugs Fund did not cover the whole population included in the marketing authorisation for ibrutinib and was limited to people who had had at least 1 previous therapy. # Treatment pathway and clinical need ## There is high clinical need for alternative treatments to rituximab and chemotherapy Waldenstrom's macroglobulinaemia is an incurable, rare type of non-Hodgkin lymphoma with limited treatment options. There is no established standard care. Treatment options include chemoimmunotherapy, such as rituximab combined with a range of chemotherapy regimens including alkylating agents (such as cyclophosphamide) or nucleoside analogues (cladribine or fludarabine). When chemoimmunotherapy is unsuitable, treatment options include monotherapy with rituximab or chlorambucil. The marketing authorisation for ibrutinib includes people for whom chemoimmunotherapy is unsuitable but this population was not included in the managed access arrangement for use of ibrutinib in the Cancer Drugs Fund. The clinical experts explained that generally, the disease responds well to chemotherapy but there are a restricted number of lines of chemotherapy that can be used because of cumulative toxicity. Chemotherapy options can rapidly become exhausted, leaving no effective therapies available. Some people may also have intolerance to rituximab. The patient expert highlighted that the constant risk of relapse has a significant effect on the mental wellbeing of patients and families. The committee noted that Waldenstrom's macroglobulinaemia is associated with major disease-related symptoms such as neutropenia which can cause infections, weakness, extreme fatigue and breathlessness. The patient expert explained that symptoms like fatigue can be intense, disabling and significantly impair day-to-day life. The committee concluded that there is no standard care for treating Waldenstrom's macroglobulinaemia and there is high unmet clinical need for new and effective therapies. ## Ibrutinib is a step-change in managing Waldenstrom's macroglobulinaemia The clinical experts explained that ibrutinib is a novel and effective non-chemoimmunotherapy treatment option for disease that is refractory to first-line treatment or that has relapsed after successful first-line therapy. Both the patient and clinical experts emphasised that ibrutinib is highly effective compared with existing treatments, and very well tolerated. The convenience of an oral therapy is also greatly valued by patients because it allows them to take the treatment at home, with no need for hospital visits for infusions. The patient expert explained that he had been having ibrutinib for several years. He found it to be a life-transforming drug that had dramatically improved his quality of life, allowing him to take part in general day-to-day activities and very quickly return to normal life. The clinical experts noted that although the condition often responds to chemoimmunotherapy, the speed and durability of response is better with ibrutinib, meaning that people having ibrutinib "feel better" a lot more quickly than with chemoimmunotherapy. The clinical experts attributed the highly effective, immediate, and durable disease control with ibrutinib to be a step-change in the management of Waldenstrom's macroglobulinaemia. The committee agreed and concluded that the availability of an effective and well-tolerated oral treatment option as an alternative to chemoimmunotherapy is highly valued by both patients and clinicians and ibrutinib is a step-change in managing Waldenstrom's macroglobulinaemia. # Clinical evidence ## SACT data is generalisable to NHS clinical practice and more relevant than updated trial data from study 1118E and iNNOVATE arm C In the original appraisal, clinical-effectiveness evidence for ibrutinib came from 2 sources: a single-arm, open-label study without a control group (study 1118E) for 63 adults with Waldenstrom's macroglobulinaemia who had had at least 1 previous therapy an open-label sub-study of 1 arm of a randomised controlled trial (iNNOVATE arm C) with no comparator data for 31 people with Waldenstrom's macroglobulinaemia whose disease relapsed within 12 months of having treatment containing rituximab.The committee noted that the original appraisal concluded that further data collection on progression and overall survival was needed in the Cancer Drugs Fund because of uncertainties about long-term survival. The updated data submitted by the company included: additional 22 months clinical trial evidence from study 1118E (median age 63 years) additional 40.9 months clinical trial evidence from iNNOVATE arm C (median age 67 years) new observational data for people in the Cancer Drugs Fund obtained from the SACT dataset for 823 people with Waldenstrom's macroglobulinaemia that had at least 1 previous therapy before ibrutinib (median age 75 years) new observational data from a UK clinical registry (Rory Morrison Registry) for 112 people with Waldenstrom's macroglobulinaemia that had ibrutinib as second or subsequent-line treatment; the company and clinical experts noted that this data was a subset of people from the SACT dataset; the committee noted that the company considered the SACT data the most generalisable to how ibrutinib would be used in clinical practice.The committee understood that the SACT database did not collect data on disease progression. It also noted that the cost-effectiveness estimates are dependent on the progression-free survival of people having ibrutinib compared with standard care. The committee noted that the proportion of patients alive at 24 months in study 1118E and the SACT was 95% and 73% respectively. People who had ibrutinib through the Cancer Drugs Fund (and who were included in the SACT dataset) were on average older than people in the trials. So, it acknowledged that real world evidence could be associated with lower overall survival rates than trial evidence because of potential differences in patient baseline characteristics. The committee also noted that people having ibrutinib in the SACT dataset may have had multiple previous treatments before ibrutinib, and that it was expected to be used primarily as a second- or third-line treatment in the future. The Cancer Drugs Fund clinical lead explained that real world evidence from 823 patients for a rare disease like Waldenstrom's macroglobulinaemia offers best available data and noted that 84% of people in the SACT cohort had only 1 or 2 lines of previous therapies in keeping with expected use. The clinical experts also agreed that the SACT cohort was reflective of current and future use of ibrutinib in the NHS. The committee concluded that SACT data is generalisable to NHS clinical practice and is more relevant than updated trial data from study 1118E and iNNOVATE arm C. ## The agreed approach for estimating ibrutinib progression-free survival indirectly from SACT data is reasonable but uncertain Because progression-free survival data was not collected in SACT, the company indirectly estimated progression-free survival for ibrutinib using time to treatment discontinuation data from SACT. In the original appraisal for ibrutinib, time to treatment discontinuation had been assumed to be equal to progression-free survival. For the current appraisal, the company did not consider time to treatment discontinuation a good proxy for progression-free survival because 67% of people stopped treatment before disease progression in the SACT dataset. At technical engagement, the company accepted the ERG preferred approach of estimating progression-free survival for the ibrutinib group by assuming a proportional relationship between time to treatment discontinuation and progression-free survival in the Rory Morrison Registry, based on a comparison of exponential survival models fitted to this data. The hazard ratio between time to treatment discontinuation and progression-free survival was then applied to the time to treatment discontinuation SACT data. The ERG noted that this approach assumes that the hazards for time to treatment discontinuation compared with progression-free survival in the Rory Morrison Registry are proportional and that the same relationship is found in other populations such as people in the whole SACT cohort. The clinical experts stated that people generally stay on treatment until disease progression and may even stay on treatment after disease progression because ibrutinib may slow subsequent disease progression. However, some people will stop treatment before progression, and progression happens soon after treatment discontinuation. The committee noted that time to treatment discontinuation in SACT was lower than in the Rory Morrison Registry. A clinical expert considered this may have been because of variation in clinical practice. They explained that some people would stay on treatment with ibrutinib because of clinical benefit despite clinical assessment of disease progression. The committee concluded that in the absence of progression-free survival data from the SACT database, the agreed approach to indirectly estimate it was reasonable but subject to uncertainty. ## Based on an indirect comparison the extent to which ibrutinib improves progression-free survival compared with standard therapies is uncertain The company did not update its estimate of the hazard ratio for progression-free survival on ibrutinib compared with standard therapies from the original appraisal of ibrutinib. But it updated its estimate of progression-free survival on ibrutinib to be applicable to the SACT cohort. In the original appraisal for ibrutinib, the company presented an indirect comparison of progression-free survival with ibrutinib compared with existing treatments for Waldenstrom's macroglobulinaemia. This was referred to as 'physician's choice of standard therapies' (a blend of alternative second-line or more rituximab plus chemotherapy options) and will be referred to as standard therapies going forward in this document. The data for standard therapies came from a European chart review; a retrospective observational study that generated data on epidemiology, treatment and efficacy outcomes for untreated and relapsed Waldenstrom's macroglobulinaemia over 10 years. The committee recalled that in the original appraisal, the company created a matched cohort to the study 1118E population by selecting a subset of the European chart review cohort who had had similar lines of therapy to the people in study 1118E. The indirect comparison estimated a hazard ratio for progression-free survival for ibrutinib compared with standard therapies of 0.25 (95% confidence interval 0.11 to 0.57, p=0.001). This suggested a substantial reduction in the risk of disease progression with ibrutinib compared with standard therapies. The committee noted that the indirect comparison was of trial data for ibrutinib compared with data from a non-trial setting (real world evidence) for standard therapies which made the hazard ratio highly uncertain. The ERG explained it had concerns about methods used to select people in the matched cohort. In the submission for the current appraisal, the company stated that it considered its original estimate, based on 24 months data from study 1118E to be relevant and best available estimate of the hazard ratio for progression-free survival with ibrutinib compared with standard therapies. On the ERG's request, the company updated the indirect treatment comparison with additional study 1118E long-term data using an unanchored matching-adjusted indirect comparison (MAIC) with the full dataset from the European chart review after technical engagement. The hazard ratio from this analysis is 0.28 (95% CI 0.10 to 0.49). The ERG explained that the MAIC is useful in providing supporting evidence of the relative treatment effect on progression-free survival for ibrutinib compared with standard therapies but is an unanchored comparison meaning that data from single-arm studies, rather than studies with a common comparator, had been included. This approach assumes that prognostic variables and effect modifiers have been accounted for. Given limited data on prognostic variables available with most trial data needing to be imputed, the results from the MAIC based on this assumption are highly uncertain. The committee discussed the size of the estimated treatment effect of ibrutinib compared with standard care which showed a large benefit of ibrutinib in delaying disease progression. The clinical experts and Cancer Drugs Fund clinical lead stated that a large benefit was plausible, and the committee noted the statements from the clinical and patient experts that ibrutinib was a step-change in managing Waldenstrom's macroglobulinaemia (see section 3.2). The committee recalled its conclusion in the original appraisal that the hazard ratio was highly uncertain. The committee accepted, based on the results of the indirect comparison and the testimonies from patients and clinical experts, that ibrutinib appears to be more clinically effective than existing treatments but concluded that there remains significant uncertainty around the extent to which ibrutinib improves progression-free survival. # Cost effectiveness ## The company's updated model is suitable for decision making The company used the same modelling approach as in its original appraisal for ibrutinib, that is a Markov state transition model comparing ibrutinib with standard therapies. The health states included progression-free survival and having up to 4 follow-on treatments after progression. It also modelled the chance of dying in each health state. The modelled cohort was updated to reflect the population for whom data was collected in the SACT database rather than study 1118E, that is a population with an average age of 70. Updated data and assumptions used in the model included: adverse event frequencies from additional long-term clinical outcomes data from study 1118E time to treatment discontinuation for ibrutinib from the SACT dataset an updated approach to modelling pre-progression mortality with ibrutinib based on SACT data, with a calibration so that overall modelled survival with ibrutinib reflected overall survival observed in the SACT dataset progression-free survival for ibrutinib was based on the indirect estimates of progression-free survival in the SACT database based on the time to treatment discontinuation seen in this cohort.To model progression-free survival on standard therapies, the updated model applied the hazard ratio from the original appraisal for progression-free survival with ibrutinib compared with standard therapies. However, because the modelled progression-free survival was updated for ibrutinib in the current appraisal, this resulted in a different modelled progression-free survival for standard therapies than the original appraisal. The modelled time on treatment for standard therapies was assumed to be the same as progression-free survival. This meant that the modelled time on treatment for standard therapies was also different to that in the original appraisal. The committee noted that the company had aligned its modelling with the ERG's preferred assumptions for estimating progression-free survival for the SACT dataset (see section 3.4) and the ERG's approach for modelling pre-progression mortality with ibrutinib and calibrating modelled overall survival for ibrutinib to reflect the observed data from the SACT dataset. The committee considered the company's approach to use the SACT data is reasonable but noted that the evidence available to estimate progression-free survival for ibrutinib and any outcome in the standard therapies group, which is dependent on the progression-free survival hazard ratio for ibrutinib compared with standard therapies, is subject to considerable uncertainty. The committee concluded that the company's updated model is suitable for decision making, but the modelling uncertainties should be considered. ## The model predicted survival outcomes from the company's revised base-case model do not correlate with clinical experience and are highly uncertain The committee discussed the modelled clinical outcomes from the company's revised base case. There were 3 modelled outcomes which did not reflect outcomes seen in clinical practice: The modelled delay between stopping treatment and disease progression. The revised model predicted a 6‑month delay before disease progression after stopping treatment with ibrutinib. This was not considered reflective of clinical practice in the NHS by the clinical experts. They explained that most people would still be on treatment when their disease progressed, or if they had stopped treatment before progression would be expected to have disease progression soon after stopping (see section 3.4). The company stated at the second meeting that its analysis of the time between disease progression and stopping treatment for people in the SACT database supported what it had modelled. The modelled post-progression survival, that is the time between a person's disease progressing and their death. The revised model predicted that post-progression survival for people in both the ibrutinib and standard therapies was about 1 year. The clinical experts explained that at least two thirds of patients whose disease progresses while on ibrutinib treatment achieve good response to further lines of chemotherapy and that the median time between disease progression and death in clinical practice is much more than a year. The modelled overall survival in the standard therapies treatment arm. The committee noted that the modelled overall survival in the original appraisal for ibrutinib was longer for both ibrutinib and comparators than in the revised model although the life year gain in both was predicted to be around 3 years. It noted that the modelled overall survival estimates for ibrutinib reflected those seen in the SACT data were lower than the original appraisal which had used data from an older population (with an average age of 75) than study 1118E. The revised model for the current appraisal also predicted that nearly all patients in the standard therapies arm would have died by 6 years after starting treatment for relapsed or refractory Waldenstrom's macroglobulinaemia, and that the mean modelled survival on standard therapies was less than 2 years, which the clinical experts explained is unrealistic and clinically implausible. The clinical experts considered that the longer survival estimate (3 years more in each arm) predicted by the model used in the original appraisal for ibrutinib based on study 1118E data was more reliable and clinically plausible than outcomes predicted by the revised company model. The committee recalled that the company submission for the original appraisal noted that Waldenstrom's macroglobulinaemia is an indolent disease and provided estimates of median life expectancy ranging from 4 to 12 years.The committee considered that although the key finding of a 3‑year overall survival gain for ibrutinib compared with standard therapies as predicted by the model for the original appraisal and the revised model for the Cancer Drugs Fund review could be plausible, there remained considerable concern about the validity of the modelled overall survival in the standard therapies arm. Furthermore, the modelled time between stopping ibrutinib and disease progression, and time between disease progression on a person's first treatment for relapsed or refractory Waldenstrom's macroglobulinaemia did not reflect what is seen in clinical practice. The committee agreed that these 3 modelled outcomes were dependent on the hazard ratio for progression-free survival for ibrutinib compared with standard therapies (see section 3.5) and updated estimates of progression-free survival for ibrutinib (see section 3.4). However, it agreed that although these were the most reasonable given the available data, these were uncertain because of the limitation of not having progression-free survival data from SACT and data directly comparing progression-free survival for ibrutinib compared with standard therapies. The committee concluded that although the model gave some implausible outputs, given the limitations in the available data, there was no alternative analysis that could be done to address these concerns. Therefore, it should take into account the considerable uncertainty when considering the estimates of cost effectiveness. # Cost-effectiveness results ## The cost-effectiveness estimates were over £30,000 per QALY gained The committee noted that there is a confidential patient access scheme for ibrutinib and that some of the standard care therapies included in the standard therapies arm are available to the NHS at a confidential discount. Incremental life years gained with ibrutinib were 2.88 in the revised company base case using a hazard ratio for progression-free survival of 0.25. When higher hazard ratios (ranging from 0.28 to 0.75) were explored, the life years gained with ibrutinib decreased (ranging from 2.80 to 1.78 respectively). The exact incremental costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) associated with these analyses are confidential and cannot be reported here, but the cost-effectiveness estimate in the company base case, and all alternative analyses explored, were considerably higher than £30,000 per QALY gained. ## Innovation ## Additional health-related benefits not captured in QALY were not identified The committee recalled its discussions about the innovative aspect of ibrutinib in the original appraisal. It accepted that the treatment has several benefits including oral administration, manageable adverse reactions and low toxicity. It further noted the particular importance to people of being able to have treatment at home, reducing hospital visits, and the company's statement in response to the appraisal consultation document that the modelling did not capture the psychological benefit of having an effective treatment. The committee concluded that ibrutinib could be considered a step-change in managing Waldenstrom's macroglobulinaemia. But it considered it likely that all the clinical benefits had already been included in the modelling, and did not consider that any additional health-related benefits, that had not been captured fully in the QALY calculation (if present), would be enough to lower the ICER to within the range normally considered cost effective. ## Because of the uncertainty, an acceptable ICER would be comfortably below £30,000 per QALY gained NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented.The committee noted the high level of uncertainty, specifically: The hazard ratio for progression-free survival for ibrutinib compared with standard therapies estimated from an indirect comparison is uncertain. The revised approach for estimating ibrutinib progression-free survival indirectly from SACT data is highly uncertain.The committee recalled statements by clinical and patient experts that ibrutinib is an effective treatment option for Waldenstrom's macroglobulinaemia (see section 3.5). It acknowledged the difficulty in obtaining further evidence for a rare condition like Waldenstrom's macroglobulinaemia and the absence of any further analyses that could resolve the uncertainty in the evidence base, or an alternative approach to modelling. The committee concluded that although there was major uncertainty about the exact extent of the benefit of ibrutinib, it was satisfied that ibrutinib is a highly effective technology. Therefore, it agreed that an acceptable ICER could be over £20,000 per QALY gained. However, it would have to be comfortably below £30,000 per QALY gained, not at the upper limit, to reduce the risk of approving a cost-ineffective treatment for use in the NHS, and the potential opportunity costs, when the true cost effectiveness was uncertain. # Cancer Drugs Fund ## Ibrutinib cannot be recommended in the Cancer Drugs Fund The aim of a Cancer Drugs Fund guidance review is to decide if the drug can be recommended for routine use. Ibrutinib for treating Waldenstrom's macroglobulinaemia may not remain in the Cancer Drugs Fund once the guidance review has been completed (see section 6.19 of the NICE guide to the processes of technology appraisal). # Conclusion ## Ibrutinib is not recommended Ibrutinib is a clinically effective technology compared with chemoimmunotherapy but there is uncertainty about the exact size of its clinical benefits. Ibrutinib could be considered cost effective if the ICER was comfortably below £30,000 per QALY gained. However, the company base case was considerably above this so ibrutinib is not recommended for treating Waldenstrom's macroglobulinaemia in adults who have had at least 1 previous therapy.	{'Recommendations': "Ibrutinib is not recommended, within its marketing authorisation, for treating Waldenstrom's macroglobulinaemia in adults who have had at least 1\xa0previous therapy.\n\nThis recommendation is not intended to affect treatment with ibrutinib that was funded by the Cancer Drugs Fund before final guidance was published. If this applies, when that funding ends ibrutinib will be funded by the company until the patient and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for ibrutinib for treating Waldenstrom's macroglobulinaemia in adults who have had at least 1\xa0previous therapy (NICE technology appraisal guidance 491).\n\nThe new evidence includes data for ibrutinib from clinical trials and from people having treatment with ibrutinib in the NHS in the Cancer Drugs Fund. It shows that ibrutinib improves how long people live before their condition gets worse and how long they live for. But it is uncertain by how much it does this compared with chemoimmunotherapy.\n\nThe cost-effectiveness estimates for ibrutinib are higher than what NICE usually considers a cost-effective use of NHS resources. So, it is not recommended.", 'Information about ibrutinib': "# Marketing authorisation indication\n\nIbrutinib (Imbruvica, Janssen) has a marketing authorisation for treating 'adult patients with Waldenstrom's macroglobulinaemia who have received at least one prior therapy, or in first-line treatment for patients unsuitable for chemo-immunotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for ibrutinib.\n\n# Price\n\nThe list price for ibrutinib is £1,430.80 for a 28‑tablet pack of 140\xa0mg tablets (excluding VAT; BNF online accessed December\xa02021).\n\nThe company has a commercial arrangement. This makes ibrutinib available to the NHS with a discount and it would have also applied to this indication if the technology had been recommended. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': 'The appraisal committee considered evidence submitted by Janssen, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThis review looks at data collected as part of the Cancer Drugs Fund to address uncertainties identified during the original appraisal for ibrutinib. Further information about the original appraisal can be found in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from study\xa01118E. In addition, data was collected on ibrutinib for people with Waldenstrom\'s macroglobulinaemia who had had at least 1\xa0previous therapy in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset.\n\nThe managed access arrangement for ibrutinib to be used in the Cancer Drugs Fund did not cover the whole population included in the marketing authorisation for ibrutinib and was limited to people who had had at least 1\xa0previous therapy.\n\n# Treatment pathway and clinical need\n\n## There is high clinical need for alternative treatments to rituximab and chemotherapy\n\nWaldenstrom\'s macroglobulinaemia is an incurable, rare type of non-Hodgkin lymphoma with limited treatment options. There is no established standard care. Treatment options include chemoimmunotherapy, such as rituximab combined with a range of chemotherapy regimens including alkylating agents (such as cyclophosphamide) or nucleoside analogues (cladribine or fludarabine). When chemoimmunotherapy is unsuitable, treatment options include monotherapy with rituximab or chlorambucil. The marketing authorisation for ibrutinib includes people for whom chemoimmunotherapy is unsuitable but this population was not included in the managed access arrangement for use of ibrutinib in the Cancer Drugs Fund. The clinical experts explained that generally, the disease responds well to chemotherapy but there are a restricted number of lines of chemotherapy that can be used because of cumulative toxicity. Chemotherapy options can rapidly become exhausted, leaving no effective therapies available. Some people may also have intolerance to rituximab. The patient expert highlighted that the constant risk of relapse has a significant effect on the mental wellbeing of patients and families. The committee noted that Waldenstrom\'s macroglobulinaemia is associated with major disease-related symptoms such as neutropenia which can cause infections, weakness, extreme fatigue and breathlessness. The patient expert explained that symptoms like fatigue can be intense, disabling and significantly impair day-to-day life. The committee concluded that there is no standard care for treating Waldenstrom\'s macroglobulinaemia and there is high unmet clinical need for new and effective therapies.\n\n## Ibrutinib is a step-change in managing Waldenstrom\'s macroglobulinaemia\n\nThe clinical experts explained that ibrutinib is a novel and effective non-chemoimmunotherapy treatment option for disease that is refractory to first-line treatment or that has relapsed after successful first-line therapy. Both the patient and clinical experts emphasised that ibrutinib is highly effective compared with existing treatments, and very well tolerated. The convenience of an oral therapy is also greatly valued by patients because it allows them to take the treatment at home, with no need for hospital visits for infusions. The patient expert explained that he had been having ibrutinib for several years. He found it to be a life-transforming drug that had dramatically improved his quality of life, allowing him to take part in general day-to-day activities and very quickly return to normal life. The clinical experts noted that although the condition often responds to chemoimmunotherapy, the speed and durability of response is better with ibrutinib, meaning that people having ibrutinib "feel better" a lot more quickly than with chemoimmunotherapy. The clinical experts attributed the highly effective, immediate, and durable disease control with ibrutinib to be a step-change in the management of Waldenstrom\'s macroglobulinaemia. The committee agreed and concluded that the availability of an effective and well-tolerated oral treatment option as an alternative to chemoimmunotherapy is highly valued by both patients and clinicians and ibrutinib is a step-change in managing Waldenstrom\'s macroglobulinaemia.\n\n# Clinical evidence\n\n## SACT data is generalisable to NHS clinical practice and more relevant than updated trial data from study\xa01118E and iNNOVATE arm\xa0C\n\nIn the original appraisal, clinical-effectiveness evidence for ibrutinib came from 2\xa0sources:\n\na single-arm, open-label study without a control group (study\xa01118E) for 63\xa0adults with Waldenstrom\'s macroglobulinaemia who had had at least 1\xa0previous therapy\n\nan open-label sub-study of 1\xa0arm of a randomised controlled trial (iNNOVATE arm\xa0C) with no comparator data for 31\xa0people with Waldenstrom\'s macroglobulinaemia whose disease relapsed within 12\xa0months of having treatment containing rituximab.The committee noted that the original appraisal concluded that further data collection on progression and overall survival was needed in the Cancer Drugs Fund because of uncertainties about long-term survival. The updated data submitted by the company included:\n\nadditional 22\xa0months clinical trial evidence from study\xa01118E (median age 63\xa0years)\n\nadditional 40.9\xa0months clinical trial evidence from iNNOVATE arm\xa0C (median age 67\xa0years)\n\nnew observational data for people in the Cancer Drugs Fund obtained from the SACT dataset for 823\xa0people with Waldenstrom\'s macroglobulinaemia that had at least 1\xa0previous therapy before ibrutinib (median age 75\xa0years)\n\nnew observational data from a UK clinical registry (Rory Morrison Registry) for 112\xa0people with Waldenstrom\'s macroglobulinaemia that had ibrutinib as second or subsequent-line treatment; the company and clinical experts noted that this data was a subset of people from the SACT dataset; the committee noted that the company considered the SACT data the most generalisable to how ibrutinib would be used in clinical practice.The committee understood that the SACT database did not collect data on disease progression. It also noted that the cost-effectiveness estimates are dependent on the progression-free survival of people having ibrutinib compared with standard care. The committee noted that the proportion of patients alive at 24\xa0months in study\xa01118E and the SACT was 95% and 73% respectively. People who had ibrutinib through the Cancer Drugs Fund (and who were included in the SACT dataset) were on average older than people in the trials. So, it acknowledged that real world evidence could be associated with lower overall survival rates than trial evidence because of potential differences in patient baseline characteristics. The committee also noted that people having ibrutinib in the SACT dataset may have had multiple previous treatments before ibrutinib, and that it was expected to be used primarily as a second- or third-line treatment in the future. The Cancer Drugs Fund clinical lead explained that real world evidence from 823\xa0patients for a rare disease like Waldenstrom\'s macroglobulinaemia offers best available data and noted that 84% of people in the SACT cohort had only 1 or 2\xa0lines of previous therapies in keeping with expected use. The clinical experts also agreed that the SACT cohort was reflective of current and future use of ibrutinib in the NHS. The committee concluded that SACT data is generalisable to NHS clinical practice and is more relevant than updated trial data from study\xa01118E and iNNOVATE arm\xa0C.\n\n## The agreed approach for estimating ibrutinib progression-free survival indirectly from SACT data is reasonable but uncertain\n\nBecause progression-free survival data was not collected in SACT, the company indirectly estimated progression-free survival for ibrutinib using time to treatment discontinuation data from SACT. In the original appraisal for ibrutinib, time to treatment discontinuation had been assumed to be equal to progression-free survival. For the current appraisal, the company did not consider time to treatment discontinuation a good proxy for progression-free survival because 67% of people stopped treatment before disease progression in the SACT dataset. At technical engagement, the company accepted the ERG preferred approach of estimating progression-free survival for the ibrutinib group by assuming a proportional relationship between time to treatment discontinuation and progression-free survival in the Rory Morrison Registry, based on a comparison of exponential survival models fitted to this data. The hazard ratio between time to treatment discontinuation and progression-free survival was then applied to the time to treatment discontinuation SACT data. The ERG noted that this approach assumes that the hazards for time to treatment discontinuation compared with progression-free survival in the Rory Morrison Registry are proportional and that the same relationship is found in other populations such as people in the whole SACT cohort. The clinical experts stated that people generally stay on treatment until disease progression and may even stay on treatment after disease progression because ibrutinib may slow subsequent disease progression. However, some people will stop treatment before progression, and progression happens soon after treatment discontinuation. The committee noted that time to treatment discontinuation in SACT was lower than in the Rory Morrison Registry. A clinical expert considered this may have been because of variation in clinical practice. They explained that some people would stay on treatment with ibrutinib because of clinical benefit despite clinical assessment of disease progression. The committee concluded that in the absence of progression-free survival data from the SACT database, the agreed approach to indirectly estimate it was reasonable but subject to uncertainty.\n\n## Based on an indirect comparison the extent to which ibrutinib improves progression-free survival compared with standard therapies is uncertain\n\nThe company did not update its estimate of the hazard ratio for progression-free survival on ibrutinib compared with standard therapies from the original appraisal of ibrutinib. But it updated its estimate of progression-free survival on ibrutinib to be applicable to the SACT cohort. In the original appraisal for ibrutinib, the company presented an indirect comparison of progression-free survival with ibrutinib compared with existing treatments for Waldenstrom\'s macroglobulinaemia. This was referred to as \'physician\'s choice of standard therapies\' (a blend of alternative second-line or more rituximab plus chemotherapy options) and will be referred to as standard therapies going forward in this document. The data for standard therapies came from a European chart review; a retrospective observational study that generated data on epidemiology, treatment and efficacy outcomes for untreated and relapsed Waldenstrom\'s macroglobulinaemia over 10\xa0years. The committee recalled that in the original appraisal, the company created a matched cohort to the study\xa01118E population by selecting a subset of the European chart review cohort who had had similar lines of therapy to the people in study\xa01118E. The indirect comparison estimated a hazard ratio for progression-free survival for ibrutinib compared with standard therapies of 0.25 (95% confidence interval [CI] 0.11 to 0.57, p=0.001). This suggested a substantial reduction in the risk of disease progression with ibrutinib compared with standard therapies. The committee noted that the indirect comparison was of trial data for ibrutinib compared with data from a non-trial setting (real world evidence) for standard therapies which made the hazard ratio highly uncertain. The ERG explained it had concerns about methods used to select people in the matched cohort. In the submission for the current appraisal, the company stated that it considered its original estimate, based on 24\xa0months data from study\xa01118E to be relevant and best available estimate of the hazard ratio for progression-free survival with ibrutinib compared with standard therapies. On the ERG\'s request, the company updated the indirect treatment comparison with additional study\xa01118E long-term data using an unanchored matching-adjusted indirect comparison (MAIC) with the full dataset from the European chart review after technical engagement. The hazard ratio from this analysis is 0.28 (95% CI 0.10 to 0.49). The ERG explained that the MAIC is useful in providing supporting evidence of the relative treatment effect on progression-free survival for ibrutinib compared with standard therapies but is an unanchored comparison meaning that data from single-arm studies, rather than studies with a common comparator, had been included. This approach assumes that prognostic variables and effect modifiers have been accounted for. Given limited data on prognostic variables available with most trial data needing to be imputed, the results from the MAIC based on this assumption are highly uncertain. The committee discussed the size of the estimated treatment effect of ibrutinib compared with standard care which showed a large benefit of ibrutinib in delaying disease progression. The clinical experts and Cancer Drugs Fund clinical lead stated that a large benefit was plausible, and the committee noted the statements from the clinical and patient experts that ibrutinib was a step-change in managing Waldenstrom\'s macroglobulinaemia (see section\xa03.2). The committee recalled its conclusion in the original appraisal that the hazard ratio was highly uncertain. The committee accepted, based on the results of the indirect comparison and the testimonies from patients and clinical experts, that ibrutinib appears to be more clinically effective than existing treatments but concluded that there remains significant uncertainty around the extent to which ibrutinib improves progression-free survival.\n\n# Cost effectiveness\n\n## The company\'s updated model is suitable for decision making\n\nThe company used the same modelling approach as in its original appraisal for ibrutinib, that is a Markov state transition model comparing ibrutinib with standard therapies. The health states included progression-free survival and having up to 4\xa0follow-on treatments after progression. It also modelled the chance of dying in each health state. The modelled cohort was updated to reflect the population for whom data was collected in the SACT database rather than study\xa01118E, that is a population with an average age of 70. Updated data and assumptions used in the model included:\n\nadverse event frequencies from additional long-term clinical outcomes data from study\xa01118E\n\ntime to treatment discontinuation for ibrutinib from the SACT dataset\n\nan updated approach to modelling pre-progression mortality with ibrutinib based on SACT data, with a calibration so that overall modelled survival with ibrutinib reflected overall survival observed in the SACT dataset\n\nprogression-free survival for ibrutinib was based on the indirect estimates of progression-free survival in the SACT database based on the time to treatment discontinuation seen in this cohort.To model progression-free survival on standard therapies, the updated model applied the hazard ratio from the original appraisal for progression-free survival with ibrutinib compared with standard therapies. However, because the modelled progression-free survival was updated for ibrutinib in the current appraisal, this resulted in a different modelled progression-free survival for standard therapies than the original appraisal. The modelled time on treatment for standard therapies was assumed to be the same as progression-free survival. This meant that the modelled time on treatment for standard therapies was also different to that in the original appraisal. The committee noted that the company had aligned its modelling with the ERG\'s preferred assumptions for estimating progression-free survival for the SACT dataset (see section\xa03.4) and the ERG\'s approach for modelling pre-progression mortality with ibrutinib and calibrating modelled overall survival for ibrutinib to reflect the observed data from the SACT dataset. The committee considered the company\'s approach to use the SACT data is reasonable but noted that the evidence available to estimate progression-free survival for ibrutinib and any outcome in the standard therapies group, which is dependent on the progression-free survival hazard ratio for ibrutinib compared with standard therapies, is subject to considerable uncertainty. The committee concluded that the company\'s updated model is suitable for decision making, but the modelling uncertainties should be considered.\n\n## The model predicted survival outcomes from the company\'s revised base-case model do not correlate with clinical experience and are highly uncertain\n\nThe committee discussed the modelled clinical outcomes from the company\'s revised base case. There were 3\xa0modelled outcomes which did not reflect outcomes seen in clinical practice:\n\nThe modelled delay between stopping treatment and disease progression. The revised model predicted a 6‑month delay before disease progression after stopping treatment with ibrutinib. This was not considered reflective of clinical practice in the NHS by the clinical experts. They explained that most people would still be on treatment when their disease progressed, or if they had stopped treatment before progression would be expected to have disease progression soon after stopping (see section\xa03.4). The company stated at the second meeting that its analysis of the time between disease progression and stopping treatment for people in the SACT database supported what it had modelled.\n\nThe modelled post-progression survival, that is the time between a person\'s disease progressing and their death. The revised model predicted that post-progression survival for people in both the ibrutinib and standard therapies was about 1\xa0year. The clinical experts explained that at least two thirds of patients whose disease progresses while on ibrutinib treatment achieve good response to further lines of chemotherapy and that the median time between disease progression and death in clinical practice is much more than a year.\n\nThe modelled overall survival in the standard therapies treatment arm. The committee noted that the modelled overall survival in the original appraisal for ibrutinib was longer for both ibrutinib and comparators than in the revised model although the life year gain in both was predicted to be around 3\xa0years. It noted that the modelled overall survival estimates for ibrutinib reflected those seen in the SACT data were lower than the original appraisal which had used data from an older population (with an average age of 75) than study\xa01118E. The revised model for the current appraisal also predicted that nearly all patients in the standard therapies arm would have died by 6\xa0years after starting treatment for relapsed or refractory Waldenstrom\'s macroglobulinaemia, and that the mean modelled survival on standard therapies was less than 2\xa0years, which the clinical experts explained is unrealistic and clinically implausible. The clinical experts considered that the longer survival estimate (3\xa0years more in each arm) predicted by the model used in the original appraisal for ibrutinib based on study\xa01118E data was more reliable and clinically plausible than outcomes predicted by the revised company model. The committee recalled that the company submission for the original appraisal noted that Waldenstrom\'s macroglobulinaemia is an indolent disease and provided estimates of median life expectancy ranging from 4 to 12\xa0years.The committee considered that although the key finding of a 3‑year overall survival gain for ibrutinib compared with standard therapies as predicted by the model for the original appraisal and the revised model for the Cancer Drugs Fund review could be plausible, there remained considerable concern about the validity of the modelled overall survival in the standard therapies arm. Furthermore, the modelled time between stopping ibrutinib and disease progression, and time between disease progression on a person\'s first treatment for relapsed or refractory Waldenstrom\'s macroglobulinaemia did not reflect what is seen in clinical practice. The committee agreed that these 3\xa0modelled outcomes were dependent on the hazard ratio for progression-free survival for ibrutinib compared with standard therapies (see section\xa03.5) and updated estimates of progression-free survival for ibrutinib (see section\xa03.4). However, it agreed that although these were the most reasonable given the available data, these were uncertain because of the limitation of not having progression-free survival data from SACT and data directly comparing progression-free survival for ibrutinib compared with standard therapies. The committee concluded that although the model gave some implausible outputs, given the limitations in the available data, there was no alternative analysis that could be done to address these concerns. Therefore, it should take into account the considerable uncertainty when considering the estimates of cost effectiveness.\n\n# Cost-effectiveness results\n\n## The cost-effectiveness estimates were over £30,000 per QALY gained\n\nThe committee noted that there is a confidential patient access scheme for ibrutinib and that some of the standard care therapies included in the standard therapies arm are available to the NHS at a confidential discount. Incremental life years gained with ibrutinib were 2.88 in the revised company base case using a hazard ratio for progression-free survival of 0.25. When higher hazard ratios (ranging from 0.28 to 0.75) were explored, the life years gained with ibrutinib decreased (ranging from 2.80 to 1.78 respectively). The exact incremental costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) associated with these analyses are confidential and cannot be reported here, but the cost-effectiveness estimate in the company base case, and all alternative analyses explored, were considerably higher than £30,000 per QALY gained.\n\n## Innovation\n\n## Additional health-related benefits not captured in QALY were not identified\n\nThe committee recalled its discussions about the innovative aspect of ibrutinib in the original appraisal. It accepted that the treatment has several benefits including oral administration, manageable adverse reactions and low toxicity. It further noted the particular importance to people of being able to have treatment at home, reducing hospital visits, and the company\'s statement in response to the appraisal consultation document that the modelling did not capture the psychological benefit of having an effective treatment. The committee concluded that ibrutinib could be considered a step-change in managing Waldenstrom\'s macroglobulinaemia. But it considered it likely that all the clinical benefits had already been included in the modelling, and did not consider that any additional health-related benefits, that had not been captured fully in the QALY calculation (if present), would be enough to lower the ICER to within the range normally considered cost effective.\n\n## Because of the uncertainty, an acceptable ICER would be comfortably below £30,000 per QALY gained\n\nNICE\'s guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented.The committee noted the high level of uncertainty, specifically:\n\nThe hazard ratio for progression-free survival for ibrutinib compared with standard therapies estimated from an indirect comparison is uncertain.\n\nThe revised approach for estimating ibrutinib progression-free survival indirectly from SACT data is highly uncertain.The committee recalled statements by clinical and patient experts that ibrutinib is an effective treatment option for Waldenstrom\'s macroglobulinaemia (see section\xa03.5). It acknowledged the difficulty in obtaining further evidence for a rare condition like Waldenstrom\'s macroglobulinaemia and the absence of any further analyses that could resolve the uncertainty in the evidence base, or an alternative approach to modelling. The committee concluded that although there was major uncertainty about the exact extent of the benefit of ibrutinib, it was satisfied that ibrutinib is a highly effective technology. Therefore, it agreed that an acceptable ICER could be over £20,000 per QALY gained. However, it would have to be comfortably below £30,000 per QALY gained, not at the upper limit, to reduce the risk of approving a cost-ineffective treatment for use in the NHS, and the potential opportunity costs, when the true cost effectiveness was uncertain.\n\n# Cancer Drugs Fund\n\n## Ibrutinib cannot be recommended in the Cancer Drugs Fund\n\nThe aim of a Cancer Drugs Fund guidance review is to decide if the drug can be recommended for routine use. Ibrutinib for treating Waldenstrom\'s macroglobulinaemia may not remain in the Cancer Drugs Fund once the guidance review has been completed (see section\xa06.19 of the NICE guide to the processes of technology appraisal).\n\n# Conclusion\n\n## Ibrutinib is not recommended\n\nIbrutinib is a clinically effective technology compared with chemoimmunotherapy but there is uncertainty about the exact size of its clinical benefits. Ibrutinib could be considered cost effective if the ICER was comfortably below £30,000 per QALY gained. However, the company base case was considerably above this so ibrutinib is not recommended for treating Waldenstrom\'s macroglobulinaemia in adults who have had at least 1\xa0previous therapy.'}	https://www.nice.org.uk/guidance/ta795	Evidence-based recommendations on ibrutinib (Imbruvica) for Waldenstrom’s macroglobulinaemia in adults who have had at least 1 previous therapy.
13065cbe8cca46e2413fec075fcc70e6d50d15ec	nice	Peristeen Plus transanal irrigation system for managing bowel dysfunction	Peristeen Plus transanal irrigation system for managing bowel dysfunction Evidence-based recommendations on Peristeen Plus transanal irrigation system for managing bowel dysfunction. # Recommendations The case for adopting Peristeen Plus for transanal irrigation in people with bowel dysfunction is supported by the evidence. Peristeen Plus can reduce the severity of constipation and incontinence, improve quality of life and promote dignity and independence. Peristeen Plus may not be suitable for all people with bowel dysfunction. It may take several weeks before a person is comfortable with using Peristeen Plus, and some people may choose to stop using it. Peristeen Plus is therefore most effective when it is offered with specialist training for users, carers and NHS staff, and structured patient support. Cost modelling for Peristeen Plus is uncertain, but it is likely that Peristeen Plus provides additional clinical benefits without costing more than standard bowel care. # The technology # Description of the technology Peristeen Plus (Coloplast) is a transanal irrigation system for managing bowel dysfunction. The company's instructions for use in this indication recommend that it should be used every other day to empty the rectum and distal sigmoid colon, in order to prevent uncontrolled bowel movements (faecal incontinence) or to relieve and prevent constipation. Peristeen Plus is usually self-administered while sitting on a toilet, commode or shower chair. It comprises a rectal catheter with inflatable balloon or a cone catheter, a manual control unit with pump, leg straps and a bag with temperature gauge to hold water. Peristeen Plus uses a constant-flow pump which does not rely on gravity so that the user does not need to hang the bag up for the water to flow. Peristeen Plus needs a new catheter each time it is used.There is no published evidence on Peristeen Plus with the cone catheter. This guidance therefore focuses on Peristeen Plus with the balloon catheter. The cost of Peristeen Plus with the balloon catheter is £79.45 per system (comprising a Peristeen pump, 2 catheters, 2 straps and a water bag) and £138.47 per consumable pack of 15 catheters and replacement water bag (excluding VAT). The claimed benefits of Peristeen Plus in the case for adoption presented by the company are that it: improves symptoms and reduces the severity of chronic constipation reduces the severity and frequency of faecal incontinence improves quality of life for people with bowel dysfunction reduces the incidence, frequency and costs associated with urinary tract infections reduces the rate of stoma surgery reduces the cost of treating neurogenic bowel dysfunction in people who have already had unsuccessful standard care reduces the rate of hospitalisation in people with neurogenic bowel dysfunction. # Current management Bowel dysfunction may be caused by a neurogenic disorder (such as spinal cord injury, spina bifida, multiple sclerosis or Parkinson's disease), or by a non-neurogenic disorder (such as injury to the rectum or bowel, slow transit constipation or obstructed defaecation symptoms). Current treatment options for bowel dysfunction include medication (oral drugs, suppositories and enemas), changes to diet, physiotherapy and surgery. People with bowel dysfunction may also be offered training to help manage their symptoms at home, using biofeedback, bowel washouts and manual removal of faeces. The NICE guideline on managing faecal incontinence in adults states that a combination of management strategies is likely to be needed. People with faecal incontinence should therefore be offered advice on a range of coping strategies and treatment options and are encouraged to find the methods that work best for them. There is currently no NICE guidance on managing bowel dysfunction in children. If bowel continence cannot be achieved by medication, changes to diet and physiotherapy and long-term management strategies such as transanal irrigation should be considered. A number of different transanal irrigation systems, including Peristeen Plus, are available. Clinicians and patients should discuss the options available and may try a number of devices before settling on a preferred system. Some patients may need or prefer surgery, most often a colostomy, ileostomy or a procedure to allow treatment with anterograde continence enemas (ACE procedure).# Evidence # Summary of clinical evidence All studies evaluated the original Peristeen system, which is assumed to be equivalent to Peristeen Plus with the balloon catheter. The evidence for Peristeen assessed by the external assessment centre (EAC) comprises 13 studies in adults and 11 studies in children, plus 2 studies and 1 audit that were included specifically to provide information on adverse events. Only 1 study was a randomised controlled trial (Christensen et al. 2006); all others were observational studies. For full details of the clinical evidence, see section 3 of the assessment report. # EAC's analysis of the clinical evidence Christensen et al. (2006) was a randomised controlled trial in adults (n=87) that showed statistically significant improvements in bowel-related patient-reported outcomes for Peristeen compared with standard bowel care over 10 weeks' follow up. The EAC considered this to be the best quality evidence to support the use of Peristeen. The other 12 studies in adults were observational case series (9 prospective and 3 retrospective). The EAC acknowledged that these studies have a high risk of bias because they included a broad patient population (including people with neurogenic and non-neurogenic bowel dysfunction) and often used inconsistent and non-validated outcome measures and questionnaires. Furthermore, there were high initial drop-out rates in all studies. The EAC stated that despite these uncertainties, the evidence showed that adults who choose to continue using Peristeen report improved clinical outcomes. All the studies in children were non-comparative, observational case series (6 observational and 5 retrospective). The studies were done in a very broad patient population with a wide range of ages, types of bowel dysfunction and concurrent conditions. The studies showed improvements in some outcomes for children using Peristeen but the EAC considered the overall published evidence in children to be of low quality. Many of the patient-reported outcomes in the studies were not adapted or validated specifically for use in children, and it was often unclear if the questionnaires had been completed by the child themselves or by a carer or guardian. The EAC and clinical experts commented that these limitations are to be expected, considering that Peristeen is used in a community environment with patient or carer support, and is associated with subjective as well as objective clinical benefits that children may find difficult to describe themselves. Bowel perforation is a serious adverse event that is potentially linked to the use of Peristeen. It was a rare complication (2 in 1 million irrigations) reported in the global audit by Christensen et al. (2016). It may be even rarer in children (1 in 1 million irrigations) as reported in a review of best practice by Mosiello et al. (2017). Other, less serious adverse events such as abdominal pain, rectal bleeding and nausea were more common. For full details of the adverse events, see section 3.7 of the assessment report. # Summary of economic evidence The cost model submitted by the company includes only adults with neurogenic bowel dysfunction as a result of a spinal cord injury. It is based on the economic methodology used in Emmanuel et al. (2016), a paper that describes a cost-effectiveness model based on an audit database from 3 UK hospitals that was set up in 2006. It is a Markov model with a 6‑month cycle and 37‑year time horizon, and assumes that patients entering the model are the same in terms of spinal injury and constant transition probabilities. It also assumes that Peristeen is used every other day (as recommended by the company), and that the comparator is standard bowel care. For full details of the economic evidence see section 3 of the assessment report. # EAC's analysis of the economic evidence The company did not include the audit data (on which the model was based) as part of its clinical evidence submission, and these data are not published elsewhere. However, the company provided the EAC with an extract from the data that was used for quality-of-life calculations and also provided information on length of use, and whether patients had stopped using Peristeen. The EAC considered that the audit data seemed to be taken from an appropriate NHS setting, with suitable patient pathways and an appropriate, if heterogeneous, population (227 patients aged 17 to 70 years with neurogenic bowel disease and different neurological diagnoses). However, the EAC concluded that it had not seen enough information to fully critique the audit data or its suitability for the model. The company's base-case results showed that using Peristeen could lead to cost savings of £21,768 per patient over 37 years. However, the EAC identified limitations in the company's base case. It made a number of changes and corrections to the model, including: incorporating the costs of standard care for people who stop using Peristeen within the Peristeen arm adjusting transition probabilities changing the costs of pressure ulcers and urinary tract infections adding background mortality.These changes decreased the cost savings associated with Peristeen to £5,267 per patient over the same period. For full details of these changes, see section 4.5 of the assessment report. The main factors affecting these cost savings are the number of catheters used (driven by frequency of use), carer time to help with irrigation, frequency of faecal incontinence and hospitalisations (particularly for pressure ulcers). # Additional evidence submitted during consultation During consultation, a healthcare professional submitted a retrospective service review that described the use of transanal irrigation and ACE procedures to treat bowel dysfunction in children (n=111) at 1 UK centre in the UK between 2007 and 2016. The review included children with a wide range of neurological and non-neurological bowel dysfunctions between 2007 and 2016. Children in the study were offered 1 of 3 devices: Peristeen (which 90% of children had) or either of 2 cone-based systems. Although 18 of the 111 children discontinued transanal irrigation during the study, 75 (68%) had restored continence or symptom resolution. The review also noted that 13 of the 68 children with constipation and soiling (19%) had been weaned off transanal irrigation and discharged from the centre. The review reported highly positive comments from parents and carers, who stated that transanal irrigation had significantly improved their child's quality of life. The EAC noted that this study would have been excluded from the literature search, because it included results from 3 devices.# Committee discussion The committee discussion was on the original Peristeen system, which is assumed to be equivalent to Peristeen Plus with the balloon catheter. # Clinical effectiveness Christensen et al. (2006) and the observational studies reported significant improvements in patient-reported outcome measures. The committee noted some uncertainty in the quality of this evidence including because Peristeen is self-administered, so there are limitations with patient-reported outcome measures. The clinical and patient experts explained that for people with bowel dysfunction, even small improvements in these patient-reported outcome measures can translate into significant quality-of-life benefits and could mean the difference between adequate bowel control and incontinence. The committee concluded that the evidence with which it had been presented may underestimate the quality-of-life benefits of Peristeen. The patient experts emphasised that using Peristeen has vastly improved their lives, allowing them a degree of functional independence (such as going on holiday and maintaining a permanent job) that was not possible with the standard bowel care they had previously received. The committee also heard from the clinical experts that using Peristeen may lead to improved attendance and participation in school and social life for some children with bowel dysfunction. # Drop-out rates in the trials The committee discussed the high initial drop-out rates in the clinical trials, and was advised by the experts that this accurately reflected their own clinical practice experience. People who try Peristeen are likely to know within the first 1 or 2 months if it is going to be suitable for them. The patient experts explained that it takes up to 2 months to become confident with using Peristeen and that people wishing to use Peristeen must be motivated and determined to succeed with the technology. # Peristeen's use in children The committee noted that the evidence for Peristeen in children is less robust than in adults. However, it recognised that clinical studies are difficult in children with a wide range of underlying conditions, particularly because of challenges with communicating patient-reported outcome measures. One clinical expert had experience of using Peristeen in teenagers with megarectum. This group used the device on average once a week and were able to maintain bowel control that allowed them to attend school. Several comments were received during consultation about the successful use of Peristeen in children at centres across the NHS, including a report from the UK Paediatric Colorectal Group of the British Association of Paediatric Surgeons. The committee acknowledged that Peristeen is successfully used in children in the NHS and that there is anecdotal evidence describing its long-term use. The committee noted observations that the drop-out rate for children using Peristeen was not as high as for adults. The expert advisers considered that this is likely to be because of ongoing encouragement and support from parents and carers for children using Peristeen. Despite limitations in the published evidence, the committee concluded that Peristeen may offer significant benefits for children with bowel dysfunction. The committee was aware that the economic modelling only considered adults, but it judged that using Peristeen in children is unlikely to cost any more than standard bowel care. # Comparators The patient experts explained that, before trying Peristeen, their symptoms were severe enough for them to have considered more invasive treatments such as colostomy. The clinical experts stated that stoma surgery may represent an improvement in quality of life for some people with bowel dysfunction who are severely disabled by their symptoms and find a colostomy easier to manage. ACE procedures may also be offered to patients and are often an option in children. The experts advised, however, that stoma surgery is associated with a risk of subsequent hernias and the need for revision surgery. # NHS and system impact considerations The committee was aware that there are other transanal irrigation devices available in the NHS. It considered that clinicians should discuss the different options with the patient to help identify the device which is most appropriate. The clinical and patient experts explained that the high initial drop-out rates associated with using Peristeen may be reduced by ensuring good quality training and support for both patients and staff. The company has a team of nurses in the UK that provide training for patients and for bowel care specialists, with additional non-clinical resources including a patient support phone programme. The committee was advised that Peristeen is usually first prescribed by specialist bowel care teams with ongoing prescription in primary care. It considered that there is a need for improved awareness of transanal irrigation in the NHS as a treatment option for bowel dysfunction. The clinical and patient experts explained that Peristeen should be offered as part of a supportive bowel care programme. People using Peristeen should have training from a specialist healthcare professional. The committee heard that most people will have 1 face-to-face appointment to learn how to use Peristeen, and then have further follow-up support in the community (usually over the phone). The experts noted that it takes most people a few months to get used to Peristeen. Even once someone is confident with using the device, they still need access to a professional support system (such as easily accessible contact details of a specialist nurse) to provide advice as needed. The patient experts commented that the support of dedicated specialists was essential to their being able to use Peristeen effectively. They added that they would have found a patient support group helpful. # Cost modelling The committee accepted the external assessment centre's (EAC) suggested changes to the company's model, and concluded that its results were more plausible than the company's base case. The EAC's updated model showed that using Peristeen could result in cost savings of £5,627 per patient over 37 years. These savings mainly come from fewer healthcare professional visits and less carer time, reduced incidence of faecal incontinence needing incontinence pads, reduced incidence of urinary tract infections and fewer hospitalisations. The committee considered that there was considerable uncertainty in the cost modelling for Peristeen. The audit data used in the model was not available for scrutiny and a number of assumptions used in the model were not sourced. Although the EAC was unable to source more robust assumptions, it identified that the hospitalisation rates for pressure ulcers and urinary tract infections were higher than expected so included these in its changes to the model. The committee discussed the frequency of administration because the cost of each catheter is an important factor influencing the overall cost of treatment. The instructions for use recommend that it should be used every other day after an initial few weeks of using it every day. The clinical experts confirmed that this was the average frequency of use for most people with neurogenic bowel dysfunction using Peristeen. The committee noted the EAC's sensitivity analysis which showed that Peristeen would become cost incurring if it were used more than 4 times per week. The patient experts stated that although they normally use the device every other day, there are times when they need to irrigate more frequently (such as when travelling or after a change in diet). The committee considered that Peristeen can provide important clinical benefits in most people with bowel dysfunction, including improving quality of life and promoting independence. It acknowledged that it may take several weeks before a person is comfortable with using Peristeen, so the device is most effective when offered with specialist training and structured patient support. The committee concluded that although the cost modelling is uncertain, it is likely that using Peristeen in people with bowel dysfunction does not cost any more than standard care. For the guidance review, the EAC revised the model to reflect 2021 costs. Costs were revised for Peristeen Plus with the balloon catheter, standard bowel care, third-line treatment and adverse events. Details of the parameter changes are in the costing update report. Base-case results for the 2021 revised model show the cost saving associated with Peristeen Plus was £5,144 (corrected original guidance value was £5,627) per person over a 37‑year time horizon. Cost modelling was not done for Peristeen Plus with cone catheters because of a lack of evidence on the cone catheter.	{'Recommendations': 'The case for adopting Peristeen Plus for transanal irrigation in people with bowel dysfunction is supported by the evidence. Peristeen Plus can reduce the severity of constipation and incontinence, improve quality of life and promote dignity and independence.\n\nPeristeen Plus may not be suitable for all people with bowel dysfunction. It may take several weeks before a person is comfortable with using Peristeen Plus, and some people may choose to stop using it. Peristeen Plus is therefore most effective when it is offered with specialist training for users, carers and NHS staff, and structured patient support.\n\nCost modelling for Peristeen Plus is uncertain, but it is likely that Peristeen Plus provides additional clinical benefits without costing more than standard bowel care. ', 'The technology': "# Description of the technology\n\nPeristeen Plus (Coloplast) is a transanal irrigation system for managing bowel dysfunction. The company's instructions for use in this indication recommend that it should be used every other day to empty the rectum and distal sigmoid colon, in order to prevent uncontrolled bowel movements (faecal incontinence) or to relieve and prevent constipation. Peristeen Plus is usually self-administered while sitting on a toilet, commode or shower chair. It comprises a rectal catheter with inflatable balloon or a cone catheter, a manual control unit with pump, leg straps and a bag with temperature gauge to hold water. Peristeen Plus uses a constant-flow pump which does not rely on gravity so that the user does not need to hang the bag up for the water to flow. Peristeen Plus needs a new catheter each time it is used.There is no published evidence on Peristeen Plus with the cone catheter. This guidance therefore focuses on Peristeen Plus with the balloon catheter. \n\nThe cost of Peristeen Plus with the balloon catheter is £79.45 per system (comprising a Peristeen pump, 2 catheters, 2 straps and a water bag) and £138.47 per consumable pack of 15 catheters and replacement water bag (excluding VAT). \n\nThe claimed benefits of Peristeen Plus in the case for adoption presented by the company are that it:\n\nimproves symptoms and reduces the severity of chronic constipation\n\nreduces the severity and frequency of faecal incontinence\n\nimproves quality of life for people with bowel dysfunction\n\nreduces the incidence, frequency and costs associated with urinary tract infections\n\nreduces the rate of stoma surgery\n\nreduces the cost of treating neurogenic bowel dysfunction in people who have already had unsuccessful standard care\n\nreduces the rate of hospitalisation in people with neurogenic bowel dysfunction.\n\n# Current management\n\nBowel dysfunction may be caused by a neurogenic disorder (such as spinal cord injury, spina bifida, multiple sclerosis or Parkinson's disease), or by a non-neurogenic disorder (such as injury to the rectum or bowel, slow transit constipation or obstructed defaecation symptoms).\n\nCurrent treatment options for bowel dysfunction include medication (oral drugs, suppositories and enemas), changes to diet, physiotherapy and surgery. People with bowel dysfunction may also be offered training to help manage their symptoms at home, using biofeedback, bowel washouts and manual removal of faeces.\n\nThe NICE guideline on managing faecal incontinence in adults states that a combination of management strategies is likely to be needed. People with faecal incontinence should therefore be offered advice on a range of coping strategies and treatment options and are encouraged to find the methods that work best for them. There is currently no NICE guidance on managing bowel dysfunction in children.\n\nIf bowel continence cannot be achieved by medication, changes to diet and physiotherapy and long-term management strategies such as transanal irrigation should be considered. A number of different transanal irrigation systems, including Peristeen Plus, are available. Clinicians and patients should discuss the options available and may try a number of devices before settling on a preferred system. Some patients may need or prefer surgery, most often a colostomy, ileostomy or a procedure to allow treatment with anterograde continence enemas (ACE procedure).", 'Evidence': "# Summary of clinical evidence\n\nAll studies evaluated the original Peristeen system, which is assumed to be equivalent to Peristeen Plus with the balloon catheter. The evidence for Peristeen assessed by the external assessment centre (EAC) comprises 13 studies in adults and 11 studies in children, plus 2 studies and 1 audit that were included specifically to provide information on adverse events. Only 1 study was a randomised controlled trial (Christensen et al. 2006); all others were observational studies. For full details of the clinical evidence, see section\xa03 of the assessment report. \n\n# EAC's analysis of the clinical evidence\n\nChristensen et al. (2006) was a randomised controlled trial in adults (n=87) that showed statistically significant improvements in bowel-related patient-reported outcomes for Peristeen compared with standard bowel care over 10\xa0weeks' follow up. The EAC considered this to be the best quality evidence to support the use of Peristeen.\n\nThe other 12 studies in adults were observational case series (9 prospective and 3 retrospective). The EAC acknowledged that these studies have a high risk of bias because they included a broad patient population (including people with neurogenic and non-neurogenic bowel dysfunction) and often used inconsistent and non-validated outcome measures and questionnaires. Furthermore, there were high initial drop-out rates in all studies. The EAC stated that despite these uncertainties, the evidence showed that adults who choose to continue using Peristeen report improved clinical outcomes.\n\nAll the studies in children were non-comparative, observational case series (6 observational and 5 retrospective). The studies were done in a very broad patient population with a wide range of ages, types of bowel dysfunction and concurrent conditions. The studies showed improvements in some outcomes for children using Peristeen but the EAC considered the overall published evidence in children to be of low quality. Many of the patient-reported outcomes in the studies were not adapted or validated specifically for use in children, and it was often unclear if the questionnaires had been completed by the child themselves or by a carer or guardian. The EAC and clinical experts commented that these limitations are to be expected, considering that Peristeen is used in a community environment with patient or carer support, and is associated with subjective as well as objective clinical benefits that children may find difficult to describe themselves.\n\nBowel perforation is a serious adverse event that is potentially linked to the use of Peristeen. It was a rare complication (2 in 1 million irrigations) reported in the global audit by Christensen et al. (2016). It may be even rarer in children (1 in 1 million irrigations) as reported in a review of best practice by Mosiello et al. (2017). Other, less serious adverse events such as abdominal pain, rectal bleeding and nausea were more common. For full details of the adverse events, see section\xa03.7 of the assessment report. \n\n# Summary of economic evidence\n\nThe cost model submitted by the company includes only adults with neurogenic bowel dysfunction as a result of a spinal cord injury. It is based on the economic methodology used in Emmanuel et al. (2016), a paper that describes a cost-effectiveness model based on an audit database from 3 UK hospitals that was set up in 2006. It is a Markov model with a 6‑month cycle and 37‑year time horizon, and assumes that patients entering the model are the same in terms of spinal injury and constant transition probabilities. It also assumes that Peristeen is used every other day (as recommended by the company), and that the comparator is standard bowel care. For full details of the economic evidence see section\xa03 of the assessment report.\n\n# EAC's analysis of the economic evidence\n\nThe company did not include the audit data (on which the model was based) as part of its clinical evidence submission, and these data are not published elsewhere. However, the company provided the EAC with an extract from the data that was used for quality-of-life calculations and also provided information on length of use, and whether patients had stopped using Peristeen. The EAC considered that the audit data seemed to be taken from an appropriate NHS setting, with suitable patient pathways and an appropriate, if heterogeneous, population (227 patients aged 17 to 70\xa0years with neurogenic bowel disease and different neurological diagnoses). However, the EAC concluded that it had not seen enough information to fully critique the audit data or its suitability for the model.\n\nThe company's base-case results showed that using Peristeen could lead to cost savings of £21,768 per patient over 37\xa0years. However, the EAC identified limitations in the company's base case. It made a number of changes and corrections to the model, including:\n\nincorporating the costs of standard care for people who stop using Peristeen within the Peristeen arm\n\nadjusting transition probabilities\n\nchanging the costs of pressure ulcers and urinary tract infections\n\nadding background mortality.These changes decreased the cost savings associated with Peristeen to £5,267 per patient over the same period. For full details of these changes, see section\xa04.5 of the assessment report. [corrected 2022]\n\nThe main factors affecting these cost savings are the number of catheters used (driven by frequency of use), carer time to help with irrigation, frequency of faecal incontinence and hospitalisations (particularly for pressure ulcers).\n\n# Additional evidence submitted during consultation\n\nDuring consultation, a healthcare professional submitted a retrospective service review that described the use of transanal irrigation and ACE procedures to treat bowel dysfunction in children (n=111) at 1 UK centre in the UK between 2007 and 2016. The review included children with a wide range of neurological and non-neurological bowel dysfunctions between 2007 and 2016. Children in the study were offered 1 of 3 devices: Peristeen (which 90% of children had) or either of 2 cone-based systems. Although 18 of the 111 children discontinued transanal irrigation during the study, 75 (68%) had restored continence or symptom resolution. The review also noted that 13 of the 68 children with constipation and soiling (19%) had been weaned off transanal irrigation and discharged from the centre. The review reported highly positive comments from parents and carers, who stated that transanal irrigation had significantly improved their child's quality of life. The EAC noted that this study would have been excluded from the literature search, because it included results from 3\xa0devices.", 'Committee discussion': "The committee discussion was on the original Peristeen system, which is assumed to be equivalent to Peristeen Plus with the balloon catheter. \n\n# Clinical effectiveness\n\nChristensen et al. (2006) and the observational studies reported significant improvements in patient-reported outcome measures. The committee noted some uncertainty in the quality of this evidence including because Peristeen is self-administered, so there are limitations with patient-reported outcome measures.\n\nThe clinical and patient experts explained that for people with bowel dysfunction, even small improvements in these patient-reported outcome measures can translate into significant quality-of-life benefits and could mean the difference between adequate bowel control and incontinence. The committee concluded that the evidence with which it had been presented may underestimate the quality-of-life benefits of Peristeen.\n\nThe patient experts emphasised that using Peristeen has vastly improved their lives, allowing them a degree of functional independence (such as going on holiday and maintaining a permanent job) that was not possible with the standard bowel care they had previously received. The committee also heard from the clinical experts that using Peristeen may lead to improved attendance and participation in school and social life for some children with bowel dysfunction.\n\n# Drop-out rates in the trials\n\nThe committee discussed the high initial drop-out rates in the clinical trials, and was advised by the experts that this accurately reflected their own clinical practice experience. People who try Peristeen are likely to know within the first 1 or 2\xa0months if it is going to be suitable for them. The patient experts explained that it takes up to 2\xa0months to become confident with using Peristeen and that people wishing to use Peristeen must be motivated and determined to succeed with the technology.\n\n# Peristeen's use in children\n\nThe committee noted that the evidence for Peristeen in children is less robust than in adults. However, it recognised that clinical studies are difficult in children with a wide range of underlying conditions, particularly because of challenges with communicating patient-reported outcome measures. One clinical expert had experience of using Peristeen in teenagers with megarectum. This group used the device on average once a week and were able to maintain bowel control that allowed them to attend school. Several comments were received during consultation about the successful use of Peristeen in children at centres across the NHS, including a report from the UK Paediatric Colorectal Group of the British Association of Paediatric Surgeons.\n\nThe committee acknowledged that Peristeen is successfully used in children in the NHS and that there is anecdotal evidence describing its long-term use. The committee noted observations that the drop-out rate for children using Peristeen was not as high as for adults. The expert advisers considered that this is likely to be because of ongoing encouragement and support from parents and carers for children using Peristeen. Despite limitations in the published evidence, the committee concluded that Peristeen may offer significant benefits for children with bowel dysfunction. The committee was aware that the economic modelling only considered adults, but it judged that using Peristeen in children is unlikely to cost any more than standard bowel care.\n\n# Comparators\n\nThe patient experts explained that, before trying Peristeen, their symptoms were severe enough for them to have considered more invasive treatments such as colostomy.\n\nThe clinical experts stated that stoma surgery may represent an improvement in quality of life for some people with bowel dysfunction who are severely disabled by their symptoms and find a colostomy easier to manage. ACE procedures may also be offered to patients and are often an option in children. The experts advised, however, that stoma surgery is associated with a risk of subsequent hernias and the need for revision surgery.\n\n# NHS and system impact considerations\n\nThe committee was aware that there are other transanal irrigation devices available in the NHS. It considered that clinicians should discuss the different options with the patient to help identify the device which is most appropriate.\n\nThe clinical and patient experts explained that the high initial drop-out rates associated with using Peristeen may be reduced by ensuring good quality training and support for both patients and staff. The company has a team of nurses in the UK that provide training for patients and for bowel care specialists, with additional non-clinical resources including a patient support phone programme.\n\nThe committee was advised that Peristeen is usually first prescribed by specialist bowel care teams with ongoing prescription in primary care. It considered that there is a need for improved awareness of transanal irrigation in the NHS as a treatment option for bowel dysfunction.\n\nThe clinical and patient experts explained that Peristeen should be offered as part of a supportive bowel care programme. People using Peristeen should have training from a specialist healthcare professional. The committee heard that most people will have 1 face-to-face appointment to learn how to use Peristeen, and then have further follow-up support in the community (usually over the phone). The experts noted that it takes most people a few months to get used to Peristeen. Even once someone is confident with using the device, they still need access to a professional support system (such as easily accessible contact details of a specialist nurse) to provide advice as needed.\n\nThe patient experts commented that the support of dedicated specialists was essential to their being able to use Peristeen effectively. They added that they would have found a patient support group helpful.\n\n# Cost modelling\n\nThe committee accepted the external assessment centre's (EAC) suggested changes to the company's model, and concluded that its results were more plausible than the company's base case. The EAC's updated model showed that using Peristeen could result in cost savings of £5,627 per patient over 37\xa0years. These savings mainly come from fewer healthcare professional visits and less carer time, reduced incidence of faecal incontinence needing incontinence pads, reduced incidence of urinary tract infections and fewer hospitalisations. [corrected 2022]\n\nThe committee considered that there was considerable uncertainty in the cost modelling for Peristeen. The audit data used in the model was not available for scrutiny and a number of assumptions used in the model were not sourced. Although the EAC was unable to source more robust assumptions, it identified that the hospitalisation rates for pressure ulcers and urinary tract infections were higher than expected so included these in its changes to the model.\n\nThe committee discussed the frequency of administration because the cost of each catheter is an important factor influencing the overall cost of treatment. The instructions for use recommend that it should be used every other day after an initial few weeks of using it every day. The clinical experts confirmed that this was the average frequency of use for most people with neurogenic bowel dysfunction using Peristeen.\n\nThe committee noted the EAC's sensitivity analysis which showed that Peristeen would become cost incurring if it were used more than 4 times per week. The patient experts stated that although they normally use the device every other day, there are times when they need to irrigate more frequently (such as when travelling or after a change in diet).\n\nThe committee considered that Peristeen can provide important clinical benefits in most people with bowel dysfunction, including improving quality of life and promoting independence. It acknowledged that it may take several weeks before a person is comfortable with using Peristeen, so the device is most effective when offered with specialist training and structured patient support. The committee concluded that although the cost modelling is uncertain, it is likely that using Peristeen in people with bowel dysfunction does not cost any more than standard care.\n\nFor the guidance review, the EAC revised the model to reflect 2021 costs. Costs were revised for Peristeen Plus with the balloon catheter, standard bowel care, third-line treatment and adverse events. Details of the parameter changes are in the costing update report. Base-case results for the 2021 revised model show the cost saving associated with Peristeen Plus was £5,144 (corrected original guidance value was £5,627) per person over a 37‑year time horizon. Cost modelling was not done for Peristeen Plus with cone catheters because of a lack of evidence on the cone catheter. "}	https://www.nice.org.uk/guidance/mtg36	Evidence-based recommendations on Peristeen Plus transanal irrigation system for managing bowel dysfunction.
e90c741782f9e51cdf31fbf5478193787a3d521f	nice	Thopaz+ portable digital system for managing chest drains	Thopaz+ portable digital system for managing chest drains Evidence-based recommendations on Thopaz+ for managing chest drains. # Recommendations The case for adopting Thopaz+ for managing chest drains is supported by the evidence. Thopaz+ can reduce drainage time and length of stay in hospital, and improves safety for people with chest drains. Its use may also improve clinical decision-making through continuous, objective monitoring of air leaks and fluid loss. Thopaz+ should be considered for people who need chest drainage after pulmonary resection or because of a pneumothorax. The system can increase patient mobility because it is portable. Staff find it more convenient and easier to use than conventional chest drains. Cost modelling indicates that Thopaz+ is cost saving compared with conventional chest drains in people after pulmonary resection. The estimated saving is £108 per patient per hospital stay, with savings mainly achieved through reduced length of stay . The resource impact assessment for this guidance shows that, at a national level, adopting Thopaz+ is expected to save around £8.5 million per year in England.# The technology # Description of the technology Thopaz+ (Medela UK) is a portable digital chest drain system that provides regulated negative pressure close to the patient's chest and continuously monitors and records air leak and fluid drainage. The system comprises an in-built, regulated suction pump with a digital display, rechargeable battery, tubing that connects to any standard chest drain catheter and a Thopaz+ disposable fluid collection canister. Sensors in the system turn the pump on and off to ensure the pressure level set by the healthcare professional is precisely maintained. The rental cost of each Thopaz+ unit, as stated in the company's submission, is £115 per month. It can also be purchased for £3,570 . The claimed benefits of Thopaz+ in the case for adoption presented by the company are: reduced chest tube duration shorter length of hospital stay reduced rates of patient complications higher patient satisfaction reduced hospital costs increased convenience for doctors and nursing staff improved chest drain management better prediction of patient outcomes less plastic consumable waste. # Current management Conventional chest drains use an underwater seal to help drain air and fluid from the pleural space, allowing the lung to re-inflate. This can be done with or without additional wall suction. NICE's guideline on major trauma recommends chest drains for managing chest trauma in pre-hospital and hospital settings, but chest drain management is not specifically covered by NICE guidance. The British Thoracic Society guidelines on pleural disease state that chest drains should include a valve mechanism to prevent fluid or air entering the pleural cavity. This may be an underwater seal, flutter valve or other recognised mechanism. Chest drains with underwater seals appear to be standard care in the NHS and consist of a water seal, optional suction control and drainage collection bottle. These drains collect fluid and prevent backflow into the pleural cavity, while at the same time allowing a subjective assessment of air leaks and fluid loss. The drainage bottle must be placed below chest level and kept upright. Suction may sometimes be needed, depending on the patient's condition, and can usually be provided using a wall suction unit.# Clinical evidence # Summary of clinical evidence The evidence for Thopaz+ assessed by the external assessment centre (EAC) comprises 13 studies (n=1,632), including 9 comparative studies. Six of the studies were randomised controlled trials (n=826), although no blinding was possible because the devices used look very different. There was 1 non-comparative study in children (Costa et al. 2016) and the remaining studies were in adults. Only 1 study centre in 1 multicentre trial (Pompili et al. 2014) was in the UK: the 12 other studies were done in Europe, Asia and North America. For full details of the clinical evidence, see section 3 of the assessment report. # Main points from the EAC's analysis of the clinical evidence The EAC considered that of the 6 randomised controlled trials: Pompili et al. (2014) was well designed and reported, and of excellent quality were of good quality with clear protocols and results (Gilbert et al. 2015, Lijkendijk et al. 2015, Jablonski et al. 2013 and Marjanski et al. 2013) Mier et al. (2010) was of lower quality with no clear hypothesis but had well-matched comparative groups of patients.The EAC also noted that 3 observational comparative studies (Pompili et al. 2011, Miller et al. 2016 and Shoji et al. 2016) were of high quality using propensity-matched control cohorts. The EAC considered that all of the sites in the studies were likely to have different local protocols for inserting and removing chest drains, which may make the results more reflective of the likely variation in chest tube drainage protocols across the NHS. All but 1 of the comparative studies (Jablonski et al. 2013) were on the use of Thopaz+ after pulmonary resection. All of the comparators were conventional analogue drainage units using wall suction. The results showed that Thopaz+ was associated with shorter drainage times (7 of 8 studies) and a shorter length of stay (4 of 6 studies) compared with conventional chest drainage. Two studies that included patients with pneumothorax (air in the pleural space around the lung) were identified, 1 of which was comparative (n=60; Jablonski et al. 2013). Results from the comparative study showed that both drainage time and length of hospital stay are statistically significantly shorter with Thopaz+. Chest drains needed to be reinserted in 4 of the comparative trials. Rates of reinsertion were lower for Thopaz+ than for conventional chest drainage, but the difference was not statistically significant. The EAC found no published quantitative, comparative evidence for staff time spent on chest drainage when using Thopaz+ or for fluid loss measurement. # Summary of economic evidence The company's economic submission was a simple decision tree with 1 decision node for the use of Thopaz+ or conventional chest drainage with wall suction, based on inputs from Pompili et al. (2011). The time horizon was the length of hospital stay. For full details of the economic evidence, see section 3 of the assessment report. # EAC's analysis of the economic evidence The EAC agreed that the company's simple model structure was appropriate, but it made some changes to better reflect the evidence and current NHS practice. These changes comprised: adding costs for consumables and training associated with standard drainage using a length of hospital stay of 5.4 days for Thopaz+ (based on a weighted average from 6 studies) and 5.8 days for conventional chest drainage (based on 3 studies) using a drainage time of 3.5 days for Thopaz+ (based on 8 studies) adding the cost of chest drain reinsertion and complications (reinsertion prevalence was calculated as 0.017 from 4 studies) revising the consumer and training costs for Thopaz+.For full details of these changes, see section 4.4 of the assessment report. The company's base case resulted in a cost saving per patient of £35.56 for Thopaz+ compared with conventional chest drainage over the length of hospital stay. After the EAC's changes, this cost saving increased to £107.99 per patient . The main driver of the cost savings for Thopaz+ is shorter length of hospital stay. The device remained cost saving throughout all realistic one-way sensitivity analyses.# Committee discussion # Clinical effectiveness The committee noted that the evidence presented for Thopaz+ was mainly for its use in patients after pulmonary resection. The clinical experts confirmed that this reflected their experience in the NHS. The committee considered that Thopaz+ has clear clinical advantages compared with conventional chest drainage using wall suction in patients after pulmonary resection, including a shorter drainage time and a shorter length of stay in hospital. The committee recognised that the evidence to support the use of Thopaz+ for chest drains inserted after a pneumothorax was relatively limited. Nonetheless, the committee noted that the studies available appeared to demonstrate clinical benefits that were comparable with those observed after pulmonary resection. One clinical expert noted that audit data from their NHS hospital had indicated that Thopaz+ showed similar clinical advantages in both patient populations. The committee therefore concluded that the clinical benefits of the technology are likely to be generalisable to patients with pneumothorax. The committee considered the use of Thopaz+ in other patients who need chest drainage. None of the experts had experience of using the technology in children, but they did report the use of Thopaz+ in other patients needing chest drainage (such as after cardiac surgery and trauma). The clinical experts explained that if devices are available on wards they may be used safely for a broad range of patients who need chest drainage, but evidence to support clinical or system benefits in these circumstances is currently lacking. The clinical experts stated that there are other potential benefits that may not be reflected in the published evidence. They described improved decision-making because Thopaz+ can objectively measure the rate of air leakage and total fluid drainage. The clinical experts also advised that Thopaz+ is portable and easy to manage, allowing increased mobility which aids recovery and patient satisfaction. The committee concluded that there may be additional advantages for patients not captured in the published studies. # NHS and system impact considerations The clinical experts explained that using Thopaz+ allows treatment across wards to be standardised, because it provides objective measurements of air leakage and fluid loss. These data make it easier to assess and record patients' progress. This, in turn, may help clinicians determine when is best to remove the chest drain. One clinical expert explained how the use of Thopaz+ had helped them redesign the logging system for chest drain management. The committee heard that managing chest drains with Thopaz+ is easier than with conventional chest drainage and this may release nurse time. Patients may also need fewer chest X-rays with the use of Thopaz+. The clinical experts explained that using Thopaz+ improves patient safety. The system has in-built alarms that warn users of potential problems such as a blocked tube, full canister or low battery. When visiting the X-ray department, people may be safely accompanied by non-nursing staff because of the alarm. If the device is accidentally switched off, it changes to a normal, single-way valve chest drain. The committee concluded that the safety features of the technology increase staff confidence in managing chest drains. # Cost savings The committee noted that the estimated cost savings with Thopaz+ of £107.99 per patient in people after pulmonary resection was largely attributable to a reduced length in hospital of up to 1.5 days (average 0.4 days) per patient compared with conventional chest drainage . The committee considered the implications of this reduced length of stay and whether it was realisable in practice. The clinical experts explained that the continuous, objective monitoring possible with Thopaz+ helps reliable decision-making and encourages earlier chest drain removal and discharge. The committee noted that Thopaz+ remained cost saving even with a difference in length of stay of only 0.071 days. The EAC explored device utilisation in a sensitivity analysis. In its base case, the company assumed 50% device utilisation. The committee heard from 2 clinical experts who use Thopaz+ that device utilisation in their own units was closer to 100%, and that once introduced Thopaz+ rapidly became the standard of care for patients with chest drains. The committee concluded, therefore, that the device utilisation in the company's base case was conservative. The committee considered the different options through which Thopaz+ is available (that is, purchase or rental). It noted that the EAC scenario analysis based on a £3,570 purchase price resulted in increased savings of £120.74 per patient. However, including the purchase of 5-year warranties reduced the cost savings by £1.96 per patient . The company stated that leasing arrangements are available and that volume purchasing discounts are available; for example, buying over 25 devices would reduce the individual purchase price to £3,000 . The committee concluded that cost savings are also likely in people with pneumothorax. It noted that the EAC's scenario analysis, which produced a cost saving of £653.82 per patient, was based on a single comparative study . This reported a larger difference in length of hospital stay between Thopaz+ and conventional chest drain use in people with pneumothorax compared with people after pulmonary resection (1.9 days compared with 0.4 days). The clinical experts clarified that shorter drainage times and lengths of stay were plausible in this patient group. The committee concluded that Thopaz+ is likely to be cost saving in people with pneumothorax, but that the evidence is more uncertain than in people after pulmonary resection. The committee concluded that cost savings are also likely in people with pneumothorax. It noted that the EAC's scenario analysis, which produced a cost saving of £550.90 per patient, was based on a single comparative study. This reported a larger difference in length of hospital stay between Thopaz+ and conventional chest drain use in people with pneumothorax compared with people after pulmonary resection (1.9 days compared with 0.4 days). The clinical experts clarified that shorter drainage times and lengths of stay were plausible in this patient group. The committee concluded that Thopaz+ is likely to be cost saving in people with pneumothorax, but that the evidence is more uncertain than in people after pulmonary resection. The committee concluded that using Thopaz+ is likely to lead to significant clinical and system benefits compared with conventional chest drainage in people who need chest drainage after pulmonary resection or pneumothorax. For the guidance review, the EAC revised the model to reflect 2021 costs (original guidance values given in brackets). The main parameter change was the cost of Thopaz+ at £3,570 (£3,400). Other parameter changes were associated with staff costs, bed days and complications. Further details of the 2021 revised model are in the revised model summary .	{'Recommendations': 'The case for adopting Thopaz+ for managing chest drains is supported by the evidence. Thopaz+ can reduce drainage time and length of stay in hospital, and improves safety for people with chest drains. Its use may also improve clinical decision-making through continuous, objective monitoring of air leaks and fluid loss.\n\nThopaz+ should be considered for people who need chest drainage after pulmonary resection or because of a pneumothorax. The system can increase patient mobility because it is portable. Staff find it more convenient and easier to use than conventional chest drains.\n\nCost modelling indicates that Thopaz+ is cost saving compared with conventional chest drains in people after pulmonary resection. The estimated saving is £108\xa0per patient per hospital stay, with savings mainly achieved through reduced length of stay . The resource impact assessment for this guidance shows that, at a national level, adopting Thopaz+ is expected to save around £8.5\xa0million per year in England.', 'The technology': "# Description of the technology\n\nThopaz+ (Medela UK) is a portable digital chest drain system that provides regulated negative pressure close to the patient's chest and continuously monitors and records air leak and fluid drainage. The system comprises an in-built, regulated suction pump with a digital display, rechargeable battery, tubing that connects to any standard chest drain catheter and a Thopaz+ disposable fluid collection canister. Sensors in the system turn the pump on and off to ensure the pressure level set by the healthcare professional is precisely maintained.\n\nThe rental cost of each Thopaz+ unit, as stated in the company's submission, is £115 per month. It can also be purchased for £3,570 .\n\nThe claimed benefits of Thopaz+ in the case for adoption presented by the company are:\n\nreduced chest tube duration\n\nshorter length of hospital stay\n\nreduced rates of patient complications\n\nhigher patient satisfaction\n\nreduced hospital costs\n\nincreased convenience for doctors and nursing staff\n\nimproved chest drain management\n\nbetter prediction of patient outcomes\n\nless plastic consumable waste.\n\n# Current management\n\nConventional chest drains use an underwater seal to help drain air and fluid from the pleural space, allowing the lung to re-inflate. This can be done with or without additional wall suction. NICE's guideline on major trauma recommends chest drains for managing chest trauma in pre-hospital and hospital settings, but chest drain management is not specifically covered by NICE guidance.\n\nThe British Thoracic Society guidelines on pleural disease state that chest drains should include a valve mechanism to prevent fluid or air entering the pleural cavity. This may be an underwater seal, flutter valve or other recognised mechanism. Chest drains with underwater seals appear to be standard care in the NHS and consist of a water seal, optional suction control and drainage collection bottle. These drains collect fluid and prevent backflow into the pleural cavity, while at the same time allowing a subjective assessment of air leaks and fluid loss. The drainage bottle must be placed below chest level and kept upright. Suction may sometimes be needed, depending on the patient's condition, and can usually be provided using a wall suction unit.", 'Clinical evidence': "# Summary of clinical evidence\n\nThe evidence for Thopaz+ assessed by the external assessment centre (EAC) comprises 13\xa0studies (n=1,632), including 9 comparative studies. Six of the\xa0studies were randomised controlled trials (n=826), although no blinding was possible because the devices used look very different. There was 1 non-comparative study in children (Costa et al. 2016) and the remaining studies were in adults. Only 1 study centre in 1 multicentre trial (Pompili et al. 2014) was in the UK: the 12 other studies were done in Europe, Asia and North America. For full details of the clinical evidence, see section 3 of the assessment report.\n\n# Main points from the EAC's analysis of the clinical evidence\n\nThe EAC considered that of the 6 randomised controlled trials:\n\nPompili\xa0et\xa0al. (2014) was well designed and reported, and of excellent quality\n\nwere of good quality with clear protocols and results (Gilbert\xa0et\xa0al. 2015, Lijkendijk\xa0et\xa0al. 2015, Jablonski\xa0et\xa0al. 2013 and Marjanski\xa0et\xa0al. 2013)\n\nMier\xa0et\xa0al. (2010) was of lower quality with no clear hypothesis but had well-matched comparative groups of patients.The EAC also noted that 3 observational comparative\xa0studies (Pompili\xa0et\xa0al. 2011, Miller\xa0et\xa0al. 2016 and Shoji\xa0et\xa0al. 2016) were of high quality using propensity-matched control cohorts.\n\nThe EAC considered that all of the sites in the\xa0studies were likely to have different local protocols for inserting and removing chest drains, which may make the results more reflective of the likely variation in chest tube drainage protocols across the NHS.\n\nAll but 1 of the comparative\xa0studies (Jablonski\xa0et\xa0al. 2013) were on the use of Thopaz+ after pulmonary resection. All of the comparators were conventional analogue drainage units using wall suction. The results showed that Thopaz+ was associated with shorter drainage times (7 of 8\xa0studies) and a shorter length of stay (4 of 6\xa0studies) compared with conventional chest drainage.\n\nTwo\xa0studies that included patients with pneumothorax (air in the pleural space around the lung) were identified, 1 of which was comparative (n=60; Jablonski\xa0et\xa0al. 2013). Results from the comparative study showed that both drainage time and length of hospital stay are statistically significantly shorter with Thopaz+.\n\nChest drains needed to be reinserted in 4 of the comparative trials. Rates of reinsertion were lower for Thopaz+ than for conventional chest drainage, but the difference was not statistically significant.\n\nThe EAC found no published quantitative, comparative evidence for staff time spent on chest drainage when using Thopaz+ or for fluid loss measurement.\n\n# Summary of economic evidence\n\nThe company's economic submission was a simple decision tree with 1 decision node for the use of Thopaz+ or conventional chest drainage with wall suction, based on inputs from Pompili\xa0et\xa0al. (2011). The time horizon was the length of hospital stay. For full details of the economic evidence, see section 3 of the assessment report.\n\n# EAC's analysis of the economic evidence\n\nThe EAC agreed that the company's simple model structure was appropriate, but it made some changes to better reflect the evidence and current NHS practice. These changes comprised:\n\nadding costs for consumables and training associated with standard drainage\n\nusing a length of hospital stay of 5.4\xa0days for Thopaz+ (based on a weighted average from 6\xa0studies) and 5.8\xa0days for conventional chest drainage (based on 3\xa0studies)\n\nusing a drainage time of 3.5\xa0days for Thopaz+ (based on 8\xa0studies)\n\nadding the cost of chest drain reinsertion and complications (reinsertion prevalence was calculated as 0.017 from 4\xa0studies)\n\nrevising the consumer and training costs for Thopaz+.For full details of these changes, see section 4.4 of the assessment report.\n\nThe company's base case resulted in a cost saving\xa0per\xa0patient of £35.56 for Thopaz+ compared with conventional chest drainage over the length of hospital stay. After the EAC's changes, this cost saving increased to £107.99\xa0per\xa0patient .\n\nThe main driver of the cost savings for Thopaz+ is shorter length of hospital stay. The device remained cost saving throughout all realistic one-way sensitivity analyses.", 'Committee discussion': "# Clinical effectiveness\n\nThe committee noted that the evidence presented for Thopaz+ was mainly for its use in patients after pulmonary resection. The clinical experts confirmed that this reflected their experience in the NHS. The committee considered that Thopaz+ has clear clinical advantages compared with conventional chest drainage using wall suction in patients after pulmonary resection, including a shorter drainage time and a shorter length of stay in hospital.\n\nThe committee recognised that the evidence to support the use of Thopaz+ for chest drains inserted after a pneumothorax was relatively limited. Nonetheless, the committee noted that the\xa0studies available appeared to demonstrate clinical benefits that were comparable with those observed after pulmonary resection. One clinical expert noted that audit data from their NHS hospital had indicated that Thopaz+ showed similar clinical advantages in both patient populations. The committee therefore concluded that the clinical benefits of the technology are likely to be generalisable to patients with pneumothorax.\n\nThe committee considered the use of Thopaz+ in other patients who need chest drainage. None of the experts had experience of using the technology in children, but they did report the use of Thopaz+ in other patients needing chest drainage (such as after cardiac surgery and trauma). The clinical experts explained that if devices are available on wards they may be used safely for a broad range of patients who need chest drainage, but evidence to support clinical or system benefits in these circumstances is currently lacking.\n\nThe clinical experts stated that there are other potential benefits that may not be reflected in the published evidence. They described improved decision-making because Thopaz+ can objectively measure the rate of air leakage and total fluid drainage. The clinical experts also advised that Thopaz+ is portable and easy to manage, allowing increased mobility which aids recovery and patient satisfaction. The committee concluded that there may be additional advantages for patients not captured in the published\xa0studies.\n\n# NHS and system impact considerations\n\nThe clinical experts explained that using Thopaz+ allows treatment across wards to be standardised, because it provides objective measurements of air leakage and fluid loss. These data make it easier to assess and record patients' progress. This, in turn, may help clinicians determine when is best to remove the chest drain. One clinical expert explained how the use of Thopaz+ had helped them redesign the logging system for chest drain management.\n\nThe committee heard that managing chest drains with Thopaz+ is easier than with conventional chest drainage and this may release nurse time. Patients may also need fewer chest X-rays with the use of Thopaz+.\n\nThe clinical experts explained that using Thopaz+ improves patient safety. The system has in-built alarms that warn users of potential problems such as a blocked tube, full canister or low battery. When visiting the X-ray department, people may be safely accompanied by non-nursing staff because of the alarm. If the device is accidentally switched off, it changes to a normal, single-way valve chest drain. The committee concluded that the safety features of the technology increase staff confidence in managing chest drains.\n\n# Cost savings\n\nThe committee noted that the estimated cost savings with Thopaz+ of £107.99\xa0per\xa0patient in people after pulmonary resection was largely attributable to a reduced length in hospital of up to 1.5\xa0days (average 0.4\xa0days)\xa0per\xa0patient compared with conventional chest drainage . The committee considered the implications of this reduced length of stay and whether it was realisable in practice. The clinical experts explained that the continuous, objective monitoring possible with Thopaz+ helps reliable decision-making and encourages earlier chest drain removal and discharge. The committee noted that Thopaz+ remained cost saving even with a difference in length of stay of only 0.071\xa0days.\n\nThe EAC explored device utilisation in a sensitivity analysis. In its base case, the company assumed 50% device utilisation. The committee heard from 2 clinical experts who use Thopaz+ that device utilisation in their own units was closer to 100%, and that once introduced Thopaz+ rapidly became the standard of care for patients with chest drains. The committee concluded, therefore, that the device utilisation in the company's base case was conservative.\n\nThe committee considered the different options through which Thopaz+ is available (that is, purchase or rental). It noted that the EAC scenario analysis based on a £3,570 purchase price resulted in increased savings of £120.74 per patient. However, including the purchase of 5-year warranties reduced the cost savings by £1.96 per patient . The company stated that leasing arrangements are available and that volume purchasing discounts are available; for example, buying over 25 devices would reduce the individual purchase price to £3,000 .\n\nThe committee concluded that cost savings are also likely in people with pneumothorax. It noted that the EAC's scenario analysis, which produced a cost saving of £653.82 per patient, was based on a single comparative study . This reported a larger difference in length of hospital stay between Thopaz+ and conventional chest drain use in people with pneumothorax compared with people after pulmonary resection (1.9\xa0days compared with 0.4\xa0days). The clinical experts clarified that shorter drainage times and lengths of stay were plausible in this patient group. The committee concluded that Thopaz+ is likely to be cost saving in people with pneumothorax, but that the evidence is more uncertain than in people after pulmonary resection.\n\nThe committee concluded that cost savings are also likely in people with pneumothorax. It noted that the EAC's scenario analysis, which produced a cost saving of £550.90\xa0per\xa0patient, was based on a single comparative study. This reported a larger difference in length of hospital stay between Thopaz+ and conventional chest drain use in people with pneumothorax compared with people after pulmonary resection (1.9\xa0days compared with 0.4\xa0days). The clinical experts clarified that shorter drainage times and lengths of stay were plausible in this patient group. The committee concluded that Thopaz+ is likely to be cost saving in people with pneumothorax, but that the evidence is more uncertain than in people after pulmonary resection.\n\nThe committee concluded that using Thopaz+ is likely to lead to significant clinical and system benefits compared with conventional chest drainage in people who need chest drainage after pulmonary resection or pneumothorax.\n\nFor the guidance review, the EAC revised the model to reflect 2021 costs (original guidance values given in brackets). The main parameter change was the cost of Thopaz+ at £3,570 (£3,400). Other parameter changes were associated with staff costs, bed days and complications. Further details of the 2021 revised model are in the revised model summary ."}	https://www.nice.org.uk/guidance/mtg37	Evidence-based recommendations on Thopaz+ for managing chest drains.
5250d639a71ff55aa19dbf36f3d946f6d0e4e983	nice	Filgotinib for treating moderately to severely active ulcerative colitis	Filgotinib for treating moderately to severely active ulcerative colitis Evidence-based recommendations on filgotinib (Jyseleca) for moderately to severely active ulcerative colitis in adults when conventional or biological treatment cannot be tolerated, or the disease has responded inadequately or lost response to treatment. # Recommendations Filgotinib is recommended, within its marketing authorisation, as an option for treating moderately to severely active ulcerative colitis in adults: when conventional or biological treatment cannot be tolerated, or if the disease has not responded well enough or has stopped responding to these treatments, and if the company provides filgotinib according to the commercial arrangement. Why the committee made these recommendations Standard treatments for moderately to severely active ulcerative colitis after conventional treatment are tumour necrosis factor (TNF)‑alpha inhibitors (adalimumab, golimumab or infliximab), tofacitinib, ustekinumab or vedolizumab. Clinical trial evidence shows that filgotinib is more effective than placebo for treating moderately to severely active ulcerative colitis. There is no direct evidence comparing filgotinib with treatments that are offered after conventional treatment. Indirect comparison suggests that filgotinib is likely to be as effective as most of them. The most likely cost-effectiveness estimates for filgotinib compared with other treatments are within the range NICE normally considers an acceptable use of NHS resources. So filgotinib is recommended.# Information about filgotinib # Marketing authorisation indication Filgotinib (Jyseleca, Galapagos) is indicated for treating moderately to severely active ulcerative colitis in adults when conventional or biological treatment cannot be tolerated, or the disease has responded inadequately or lost response to treatment. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for filgotinib. # Price The price for filgotinib is £863.10 per bottle for thirty 200‑mg tablets (BNF online, accessed March 2022). The average cost for each patient per year is estimated at £10,508 based on the list price. The company has a commercial arrangement. This makes filgotinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Galapagos, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Living with moderately to severely active ulcerative disease is physically and emotionally challenging The patient experts explained that the experience of living with ulcerative colitis varies on an individual level, but when the disease is active it is extremely challenging. They explained that the symptoms and unpredictable nature of the disease have a profound and devastating impact on all aspects of a person's life. People have abdominal pain and fatigue, frequent diarrhoea and extra-intestinal manifestations such as joint, skin and eye problems. These can lead to an inability to sleep, work, socialise, have a relationship, or look after children. They explained that feeling out of control is an important and common issue for many people with moderately to severely active ulcerative colitis. The committee understood that people with the disease often have difficulty doing day-to-day tasks, have side effects from treatments, fear of having surgery, and difficulties having relationships, and that it affects their self-esteem. The committee concluded that living with moderately to severely active disease is physically and emotionally challenging, and that if medical treatment fails, surgery may be needed. ## There is an unmet need for new treatments that induce and maintain remission The clinical and patient experts explained that there is an unmet need for new treatments that induce and maintain remission. This is because for many people their disease does not respond well to current treatments, or they stop working. The only option for them, other than surgery, is long-term corticosteroids. This may be associated with extreme side effects including mood changes such as irritability and depression, osteoporosis, cataracts, and risk of steroid dependency and withdrawal. The patient experts explained that if multiple treatments are available early on in the treatment pathway, it allows them to identify the best option as quickly as possible. The clinical experts explained that surgery can be effective for some people, but is left until it is unavoidable. Surgery outcomes vary: there can be a psychological impact both from the surgery and having a stoma, even if it is temporary. Pelvic surgery can also significantly affect sexual and reproductive function. The clinical and patient experts agreed that, because filgotinib is an oral treatment, it may be more convenient than other treatment options. The committee concluded that people with the condition and clinicians would welcome a new treatment option for moderately to severely active ulcerative colitis. # The treatment pathway ## Current standard care for people with moderate to severely active disease varies The clinical experts explained that most people are offered a tumour necrosis factor (TNF)‑alpha inhibitor first if conventional treatments (aminosalicylates, corticosteroids or thiopurines) cannot be tolerated, or if the disease has not responded well enough or stopped responding to treatment. This is because cheaper biosimilars are available in this class. But they said that TNF‑alpha inhibitors are not appropriate for everyone, for example, people with a high risk of heart failure or who are prone to infection. The clinical experts explained that they would usually be offered vedolizumab or ustekinumab instead. If someone has had a TNF‑alpha inhibitor and their disease does not respond well enough or stops responding, they are offered a different TNF‑alpha inhibitor, or vedolizumab, tofacitinib or ustekinumab. The clinical experts said that treatment is chosen based on factors such as what the person has already tried and the disease's response to these, the safety profile of the drug, and the person's preference. The committee concluded that the most appropriate comparators are TNF‑alpha inhibitors, tofacitinib, ustekinumab and vedolizumab, and that in practice the order in which these are given varies. ## Filgotinib could be used at 3 different positions in the treatment pathway Filgotinib has a marketing authorisation for treating moderately to severely active ulcerative colitis when conventional or biological treatment cannot be tolerated, or if the disease has not responded well enough or stopped responding to treatment. The company's submission presented filgotinib at 3 positions in the treatment pathway: A first-line treatment for the 'biologic-naive' – people who have never had a biological treatment (a TNF‑alpha inhibitor or vedolizumab) or tofacitinib (a Janus-associated kinase inhibitor), but have had conventional treatment and their disease has likely not responded to it or lost response to it. A second-line treatment for 'biologic-experienced' – people who have had 1 biological treatment or tofacitinib and either their disease did not respond to it, lost response to it, or they could not tolerate it. A third-line treatment for biologic-experienced – people who have had 2 or more biological treatments or tofacitinib and either their disease did not respond or lost an initial response, or they could not tolerate it.The company clarified that in the biologic-experienced subgroup it assumed the same efficacy for filgotinib as a second or third-line treatment because of the lack of evidence. The ERG noted that efficacy reduces when moving from the first biologic to a second or third biologic when the disease does not respond adequately or loses response. It explained that in the SELECTION trial (see section 3.6) remission at 10 weeks reduced from 16.3% in people taking their second biologic to 7.4% in people taking their third biologic. The clinical experts explained that they would expect efficacy to reduce when moving from second to third-line treatment because of previous drug exposure or because people needing further treatments have disease that is more difficult to treat. The clinical and patient experts agreed with the company's positioning of filgotinib because it would offer an additional choice at each line of treatment. The committee noted it was not presented with evidence of filgotinib's effectiveness specifically as a third-line treatment. The committee considered that the company's assumption that filgotinib would have the same efficacy, regardless of how many biologics treatments people had previously, was unlikely and optimistic. But it noted that this applies to all treatments and not just filgotinib. The committee considered that having another option at each of the 3 positions in the pathway offers people more choice, and agreed with the company's positioning. ## Conventional treatment is not an appropriate comparator for filgotinib The NICE scope included conventional treatment, infliximab, adalimumab, golimumab, tofacitinib, ustekinumab and vedolizumab as comparators. The company explained that it considered conventional treatment as a relevant comparator in line with the NICE scope and NICE's technology appraisal guidance on tofacitinib and ustekinumab. The ERG noted that the population under consideration was: people with moderately to severely active ulcerative colitis whose disease has not responded well enough, or has stopped responding to, or could not tolerate conventional or biologic treatment – that is, people who had already had conventional treatment. Therefore, the ERG did not consider conventional treatment a relevant comparator. The clinical experts agreed that filgotinib will only be used after conventional treatment. The committee concluded that conventional treatment is not an appropriate comparator for filgotinib. # Clinical evidence ## The SELECTION trial is broadly generalisable to UK clinical practice SELECTION was a phase 2b/3 randomised, double-blind, multicentre trial comparing filgotinib 200 mg, filgotinib 100 mg and placebo. It included adults with moderately to severely active ulcerative colitis, defined by a Mayo clinic score of between 6 and 12, and component subscores of at least 1 for stool frequency and rectal bleeding and at least 2 for endoscopic findings and physicians' global assessment. It had an induction and a maintenance phase: Induction phase: included 2 cohorts, biologic-naive (n=659) and biologic-experienced (n=689). Participants were randomised to filgotinib 200 mg or 100 mg, or placebo. The primary outcome was the proportion of people who had remission from endoscopy, bleeding or stool frequency (EBS). The main secondary outcomes were the Mayo clinic score for remission and response, mucosal healing, an endoscopic subscore of 0, and histologic remission. All outcomes were measured at the end of week 10. Maintenance phase: the 664 participants whose disease responded after 10 weeks of induction treatment were re-randomised to maintenance treatment of filgotinib 200 mg or 100 mg, or placebo. Participants having filgotinib during the induction phase could be randomised to the dose of filgotinib they had during induction, or placebo. Participants whose disease responded to placebo during the induction phase continued on placebo. The primary outcome was the proportion of people with EBS remission. The main secondary outcomes were the Mayo clinic score for remission and response, mucosal healing, an endoscopic subscore of 0, histologic remission, sustained EBS remission and 6‑month corticosteroid-free remission. All outcomes were measured up to week 58. The clinical experts explained that the population in SELECTION was broadly generalisable to the people who would have filgotinib in clinical practice. However, they noted that the biologic-naive subgroup of the induction phase included more women and non-US people having filgotinib than placebo. The committee considered that a greater proportion of US people could have a minor influence on disease severity and concomitant treatment use. It concluded that SELECTION is broadly generalisable to NHS practice and is suitable for decision making. ## Filgotinib is more effective than placebo at inducing and maintaining remission In the induction phase of the SELECTION trial, the rate of EBS remission in biologic-naive participants was statistically significantly higher in the filgotinib arm at 26.1% (95% confidence interval 20.4% to 31.8%) than the placebo arm at 15.3% (95% CI 8.9% to 21.7%). Similarly, rates of EBS remission were also statistically significantly higher in the filgotinib arm at 11.5% (95% CI 7.4% to 15.5%) than the placebo arm at 4.2% (95% CI 0.6 to 7.9%) for the biologic-experienced subgroup in the induction phase. At week 58 of the maintenance phase, a statistically significantly higher proportion of people who had filgotinib were in EBS remission at 37.2% (95% CI 30.2% to 44.2%) than people who had placebo at 11.2% (95% CI 4.5% to 18.0%). The committee concluded that filgotinib is more effective than placebo for inducing and maintaining remission for people with moderately to severely active ulcerative colitis. ## Filgotinib is likely to be as effective as most comparators in the induction phase There was no head-to-head evidence comparing filgotinib against the comparators in the NICE scope (see section 3.5). Therefore, the company did network meta-analyses (NMAs) to allow for indirect treatment comparisons with them. It presented NMAs according to previous biologic use for induction and for maintenance treatment with filgotinib. Analyses were of clinical response, clinical remission and mucosal healing: The biologic-naive subgroup included people who had not had a biologic. The analysis estimated the relative efficacy of filgotinib compared with adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab. The biologic-experienced subgroup included people who had had a biologic. The analysis estimated the relative efficacy of filgotinib with adalimumab, tofacitinib, ustekinumab and vedolizumab. The results of the company's induction NMAs showed that filgotinib is likely to be as effective as the comparators in the biologic-naive and biologic-experienced subgroups. The results are academic in confidence and cannot be presented here. The ERG considered that the company's induction phase NMAs were methodologically robust and were a suitable source of clinical data for its model. The committee noted that the trials included in the NMAs had different designs, but concluded that the company's induction phase NMAs were appropriate. ## Filgotinib's effectiveness in the maintenance phase is uncertain The company's maintenance phase NMAs estimated values to populate the longer-term effectiveness of each treatment for the cost-effectiveness model. They estimated that filgotinib is likely to be as effective as most comparators in biologic-naive and biologic-experienced subgroups. The results are academic in confidence and cannot be presented here. The ERG noted that the results of the maintenance phase NMAs were invalid because people in the maintenance phase represent the population whose disease has responded to the different induction treatments, which varied between trials. The ERG explained that the company's NMAs used placebo as a common comparator, but what constituted the 'placebo group' varied between trials. The company's NMAs included participants whose disease responded to filgotinib who were then re-randomised to placebo. Other studies included participants whose disease responded to comparator treatments who were then re-randomised to placebo, thus disconnecting the network and making the results invalid. The ERG explained that in clinical practice people entering the maintenance phase either continue the induction treatment that their disease responded to or stop it. At this point there is no option to switch to another treatment without first being inducted onto that treatment. Therefore, the ERG preferred to calculate 50‑week probabilities of no response, response without remission and remission conditional on having the response at 10 weeks at the end of induction. It used these values to replace the values from the maintenance phase NMAs in its base case. The committee noted that the re-randomisation of people in trials at the start of the maintenance phase made judging the relative effectiveness of treatments beyond the induction period difficult. It also noted that neither the company nor the ERG had explored adjusting for differences in baseline risks in the maintenance part of the NMAs. It would have preferred to see a maintenance phase NMA that included only trial participants who remained on active treatment or placebo for the duration of the trial or participants randomised to active treatment or placebo for both the induction and maintenance phase. However, the committee noted that, because of the trial's design, this would still only include people whose disease responded during the induction phase. The committee considered that both the company's and ERG's approaches were biased. However, the committee noted that using either approach had a minimal effect on the cost-effectiveness results. The committee concluded that it had concerns about the methodology of the maintenance NMAs and that the effectiveness of filgotinib in the maintenance phase was uncertain. # Economic model ## The company's economic model is appropriate for decision making The company used a Markov model to estimate the cost effectiveness of filgotinib compared with adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab. The company's model structure was similar to those used in previous ulcerative colitis technology appraisals. It included health states defined by the type of treatment (advanced treatment, conventional treatment, surgery, post-surgery), as well as degree of disease control (remission or response without remission) to replicate the relapsing and remitting nature of ulcerative colitis. The Markov model had a lifetime horizon and a cycle length of 10 weeks and included clinical response, clinical remission and serious infections. The ERG agreed that the company captured all relevant health states and that its approach was appropriate. The committee concluded that the company's model was appropriate for its decision making. ## Cardiovascular adverse events should have been included in the model The company's model only included serious infections. It excluded all other adverse events associated with filgotinib. The ERG considered that the company's approach was appropriate and in line with NICE's technology appraisal guidance on tofacitinib and ustekinumab. However, the committee was aware of the association between the JAK inhibitor tofacitinib and incidence of cardiovascular events and malignancies shown in a safety study of people over 50 with rheumatoid arthritis and at least 1 additional cardiovascular risk factor. It was also aware of broader ongoing investigations of JAK inhibitors. The committee questioned if filgotinib would also be associated with increased cardiovascular risk in people with ulcerative colitis. The clinical experts pointed out that people with ulcerative colitis are much younger and may have a different risk profile than people with rheumatoid arthritis. The committee concluded that it was concerned that people having filgotinib were likely to have an increased risk of cardiovascular events, and that balancing the benefit and risks before starting filgotinib was essential. It also agreed that cardiovascular adverse events should have been included in the model. ## Long-term loss of response in the model should have been different in people in the 'response without remission' and 'remission' health states Ulcerative colitis is not always active. Many people with the disease have periods of response and loss of response. In its model, the company estimated long-term loss of response from its NMAs and used the same value for the 'response without remission' and 'remission' health states. The company explained that, if the disease responded to treatment, it would not expect this response to wane over time. So, it considered that using the same loss of response for both health states was appropriate. The ERG explained that remission is harder to achieve than response without remission. But once it is achieved it is more stable. It said that the company's approach is inconsistent with this and favours filgotinib. The ERG noted that it could not adjust the model for differential loss of response. The clinical experts agreed with the ERG, saying loss of response was less likely in people whose disease is in remission than in people whose disease has only responded. The committee concluded that it would have been more appropriate to use a differential loss of response for each health state. ## Loss of response is unlikely to be constant over time In its model, the company assumed a constant loss of response for the 'remission' and 'response without remission' health states. The company considered that its assumption that loss of response is constant over time was likely to be an overestimate. The company also explained that the constant loss of response rates would likely underestimate the average duration of treatment. It provided a scenario analysis assuming a 25% reduction in the loss of response rate after the first year of maintenance. The clinical experts considered this scenario to be appropriate. However, the ERG explained that a 25% reduction refers to the reduction in loss of response rate not to the loss of response rate. The committee was aware that NICE's technology appraisal guidance on ustekinumab used a 25% reduction after the first 2 years of treatment. It noted that the company's scenario had a minimal effect on cost-effectiveness results. The committee concluded that, because of the lack of long-term efficacy data, it was not clear if loss of response would be constant over time, and it considered the company's scenario in its decision making. ## The health state utility values for people with active ulcerative colitis are uncertain The company and the ERG used health state utility values based on the SELECTION trial in their base cases. The company used utility values collected at baseline for the 'active ulcerative colitis' health state and utility values collected at 10 weeks for the 'response without remission' and 'remission' health states. It applied the same values for the full duration of the model. The utility values are academic in confidence and cannot be presented here. The ERG agreed with the company's utility values, except for the 'active ulcerative colitis' health state. The ERG preferred to use the utility values collected at 10 weeks, which were specific to non-responders, and for consistency with the other health states. The ERG asked the company to provide scenarios exploring utility values specific to biologic-naive and experienced people, and specific to people in the induction and maintenance phase. The committee was disappointed that the company did not provide these scenarios. It was also aware that considerably lower utility values for active ulcerative colitis were used in NICE's technology appraisal guidance on tofacitinib and ustekinumab. In the absence of additional scenarios, the committee concluded that the ERG's approach was reasonable, but recognised that the quality of life of people with active ulcerative colitis in the analysis was uncertain. ## Comparator treatment sequences used in the NHS vary The ERG noted that the company's model included relevant comparators and some treatment sequences used in NHS clinical practice. However, it also noted that the company could have explored additional treatment sequences. The clinical experts explained that in clinical practice if people with the disease have a loss of response and have produced antibodies on 1 TNF‑alpha inhibitor, they would often be offered another TNF‑alpha inhibitor. Therefore, a treatment sequence of infliximab followed by another TNF‑alpha inhibitor (for example, adalimumab) and other combinations of anti-TNFs should be considered. The clinical experts said that the company's modelled treatment sequences did not fully reflect clinical practice, and some were less plausible (for example, using tofacitinib after vedolizumab). The committee was aware that ulcerative colitis is a heterogeneous disease and treatment choices are influenced by many factors. It was pleased that the company attempted to model treatment sequences and recognised that, because of the large number of possible treatment sequences, it was not practical to model them all. The committee noted that the company's choice of treatment sequences had a minimal effect on cost-effectiveness results. It concluded that a range of treatment sequences for moderately to severely active ulcerative colitis are plausible, and the company's modelled treatment sequences do not fully reflect clinical practice. ## The cost of dose escalation for comparators should only be included if the clinical benefit is also included In its model, the company used dose escalation for some comparators but not filgotinib. It clarified that dose escalation for filgotinib is not appropriate because there are only 2 approved doses, 200 mg and 100 mg, and filgotinib 100 mg is only approved for ulcerative colitis with moderate to severe renal impairment. The company explained that the dose of comparators is commonly escalated in NHS clinical practice, if allowed by the marketing authorisation. The ERG explained that the proportion of people who have dose escalation and the time to escalation is not certain. It noted that the company's approach was inconsistent because it applied additional costs for escalated doses, but not the additional clinical benefits associated with dose escalation. This favoured filgotinib. Therefore, the ERG considered that it was not appropriate to include the cost of dose escalation in its base case. The clinical experts explained that dose escalation is common to try to achieve remission or regain partially lost response. The committee recalled that it was not appropriate to include dose escalation for filgotinib and that it was not used in clinical trials of comparator treatments. The committee considered the ERG's approach more appropriate for decision making. It considered that, if the cost of dose escalation is included, its clinical benefit should also be included. ## The ERG's approach of a consistent probability and quality of life impact of chronic pouchitis is appropriate The company estimated the rates of long-term complications after surgery from Ferrante et al. (2012), in line with the approach in NICE's technology appraisal guidance on tofacitinib. Ferrante et al. reported that 46% of people developed at least 1 episode of acute pouchitis and 19% developed chronic pouchitis. The company used the 46% figure to calculate the 10‑weekly constant probability of developing post-surgery complications for the 'post-surgery complications' health state, and assigned a lower utility score for the remainder of their lifetime in its model. The ERG explained that most people do not develop chronic pouchitis, and that acute pouchitis can be treated. Therefore, the ERG considered that 46% was not a correct estimate of the probability of developing chronic complications. Instead it used the value of 19%, which was consistent with the impact on quality of life applied in the model. The committee concluded that the ERG's approach of using the probability of chronic pouchitis was more appropriate for decision making. # Cost-effectiveness estimates ## The most likely cost-effectiveness estimates are lower than those normally considered an acceptable use of NHS resources Cost effectiveness was assessed by calculating net health benefit, because there were multiple comparators for each subgroup. The incremental net health benefit of filgotinib was compared with each comparator at a threshold of £20,000 and £30,000 per quality-adjusted life year (QALY) gained for each subgroup. The company's and ERG's base case results included the confidential commercial discounts, which means they cannot be reported here. However, the committee recalled that there were several uncertainties in the company's approach, specifically: no evidence was presented for efficacy estimates for filgotinib at third-line for the biologic-experienced subgroup (see section 3.4) the results of the maintenance phase NMAs (see section 3.9) equal loss of response for the 'remission' and 'response without remission' health states (see section 3.12) uncertainty in quality-of-life estimates (see section 3.14) the comparator treatment sequences did not fully reflect clinical practice (see section 3.15) the application of dose escalation (see section 3.16).The committee noted that most of the uncertainties had minimal effect on cost-effectiveness results. It considered the biologic-naive and biologic-experienced subgroups separately. It concluded that, taking into account the uncertainty, the cost-effectiveness estimates for filgotinib compared with other treatments for moderately to severely active ulcerative colitis were below what NICE normally considers an acceptable use of NHS resources. # Innovation ## The benefits of filgotinib are adequately captured in the cost-effectiveness analysis The company considered filgotinib to be innovative because it is a second-generation JAK inhibitor that is a preferential and reversible inhibitor of JAK1. It explained that targeted inhibition of JAK1 could reduce inflammatory cytokine signalling in ulcerative colitis. Filgotinib is administered orally so there will be no additional costs associated with its use. The clinical experts noted that other treatments with similar class and efficacy are available. The committee acknowledged the benefits offered by filgotinib and that people value an oral treatment, but it noted that it had not been presented with evidence of any additional benefits that were not captured in the QALY measurements. The committee concluded that the benefits of filgotinib were adequately captured in the model. # Equalities consideration ## There are no equalities issues relevant to the recommendations The patient experts explained that for certain faith groups the impact of active disease and the effects of surgery may interfere with religious practices and cause distress. The committee did not consider this an equality issue that could be resolved by this appraisal. No other equality or social value judgement issues were identified.	{'Recommendations': 'Filgotinib is recommended, within its marketing authorisation, as an option for treating moderately to severely active ulcerative colitis in adults:\n\nwhen conventional or biological treatment cannot be tolerated, or\n\nif the disease has not responded well enough or has stopped responding to these treatments, and\n\nif the company provides filgotinib according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nStandard treatments for moderately to severely active ulcerative colitis after conventional treatment are tumour necrosis factor (TNF)‑alpha inhibitors (adalimumab, golimumab or infliximab), tofacitinib, ustekinumab or vedolizumab.\n\nClinical trial evidence shows that filgotinib is more effective than placebo for treating moderately to severely active ulcerative colitis. There is no direct evidence comparing filgotinib with treatments that are offered after conventional treatment. Indirect comparison suggests that filgotinib is likely to be as effective as most of them.\n\nThe most likely cost-effectiveness estimates for filgotinib compared with other treatments are within the range NICE normally considers an acceptable use of NHS resources. So filgotinib is recommended.', 'Information about filgotinib': "# Marketing authorisation indication\n\nFilgotinib (Jyseleca, Galapagos) is indicated for treating moderately to severely active ulcerative colitis in adults when conventional or biological treatment cannot be tolerated, or the disease has responded inadequately or lost response to treatment.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for filgotinib.\n\n# Price\n\nThe price for filgotinib is £863.10 per bottle for thirty 200‑mg tablets (BNF online, accessed March\xa02022). The average cost for each patient per year is estimated at £10,508 based on the list price.\n\nThe company has a commercial arrangement. This makes filgotinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Galapagos, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Living with moderately to severely active ulcerative disease is physically and emotionally challenging\n\nThe patient experts explained that the experience of living with ulcerative colitis varies on an individual level, but when the disease is active it is extremely challenging. They explained that the symptoms and unpredictable nature of the disease have a profound and devastating impact on all aspects of a person's life. People have abdominal pain and fatigue, frequent diarrhoea and extra-intestinal manifestations such as joint, skin and eye problems. These can lead to an inability to sleep, work, socialise, have a relationship, or look after children. They explained that feeling out of control is an important and common issue for many people with moderately to severely active ulcerative colitis. The committee understood that people with the disease often have difficulty doing day-to-day tasks, have side effects from treatments, fear of having surgery, and difficulties having relationships, and that it affects their self-esteem. The committee concluded that living with moderately to severely active disease is physically and emotionally challenging, and that if medical treatment fails, surgery may be needed.\n\n## There is an unmet need for new treatments that induce and maintain remission\n\nThe clinical and patient experts explained that there is an unmet need for new treatments that induce and maintain remission. This is because for many people their disease does not respond well to current treatments, or they stop working. The only option for them, other than surgery, is long-term corticosteroids. This may be associated with extreme side effects including mood changes such as irritability and depression, osteoporosis, cataracts, and risk of steroid dependency and withdrawal. The patient experts explained that if multiple treatments are available early on in the treatment pathway, it allows them to identify the best option as quickly as possible. The clinical experts explained that surgery can be effective for some people, but is left until it is unavoidable. Surgery outcomes vary: there can be a psychological impact both from the surgery and having a stoma, even if it is temporary. Pelvic surgery can also significantly affect sexual and reproductive function. The clinical and patient experts agreed that, because filgotinib is an oral treatment, it may be more convenient than other treatment options. The committee concluded that people with the condition and clinicians would welcome a new treatment option for moderately to severely active ulcerative colitis.\n\n# The treatment pathway\n\n## Current standard care for people with moderate to severely active disease varies\n\nThe clinical experts explained that most people are offered a tumour necrosis factor (TNF)‑alpha inhibitor first if conventional treatments (aminosalicylates, corticosteroids or thiopurines) cannot be tolerated, or if the disease has not responded well enough or stopped responding to treatment. This is because cheaper biosimilars are available in this class. But they said that TNF‑alpha inhibitors are not appropriate for everyone, for example, people with a high risk of heart failure or who are prone to infection. The clinical experts explained that they would usually be offered vedolizumab or ustekinumab instead. If someone has had a TNF‑alpha inhibitor and their disease does not respond well enough or stops responding, they are offered a different TNF‑alpha inhibitor, or vedolizumab, tofacitinib or ustekinumab. The clinical experts said that treatment is chosen based on factors such as what the person has already tried and the disease's response to these, the safety profile of the drug, and the person's preference. The committee concluded that the most appropriate comparators are TNF‑alpha inhibitors, tofacitinib, ustekinumab and vedolizumab, and that in practice the order in which these are given varies.\n\n## Filgotinib could be used at 3\xa0different positions in the treatment pathway\n\nFilgotinib has a marketing authorisation for treating moderately to severely active ulcerative colitis when conventional or biological treatment cannot be tolerated, or if the disease has not responded well enough or stopped responding to treatment. The company's submission presented filgotinib at 3\xa0positions in the treatment pathway:\n\nA first-line treatment for the 'biologic-naive' – people who have never had a biological treatment (a TNF‑alpha inhibitor or vedolizumab) or tofacitinib (a Janus-associated kinase [JAK] inhibitor), but have had conventional treatment and their disease has likely not responded to it or lost response to it.\n\nA second-line treatment for 'biologic-experienced' – people who have had 1 biological treatment or tofacitinib and either their disease did not respond to it, lost response to it, or they could not tolerate it.\n\nA third-line treatment for biologic-experienced – people who have had 2 or more biological treatments or tofacitinib and either their disease did not respond or lost an initial response, or they could not tolerate it.The company clarified that in the biologic-experienced subgroup it assumed the same efficacy for filgotinib as a second or third-line treatment because of the lack of evidence. The ERG noted that efficacy reduces when moving from the first biologic to a second or third biologic when the disease does not respond adequately or loses response. It explained that in the SELECTION trial (see section\xa03.6) remission at 10\xa0weeks reduced from 16.3% in people taking their second biologic to 7.4% in people taking their third biologic. The clinical experts explained that they would expect efficacy to reduce when moving from second to third-line treatment because of previous drug exposure or because people needing further treatments have disease that is more difficult to treat. The clinical and patient experts agreed with the company's positioning of filgotinib because it would offer an additional choice at each line of treatment. The committee noted it was not presented with evidence of filgotinib's effectiveness specifically as a third-line treatment. The committee considered that the company's assumption that filgotinib would have the same efficacy, regardless of how many biologics treatments people had previously, was unlikely and optimistic. But it noted that this applies to all treatments and not just filgotinib. The committee considered that having another option at each of the 3\xa0positions in the pathway offers people more choice, and agreed with the company's positioning.\n\n## Conventional treatment is not an appropriate comparator for filgotinib\n\nThe NICE scope included conventional treatment, infliximab, adalimumab, golimumab, tofacitinib, ustekinumab and vedolizumab as comparators. The company explained that it considered conventional treatment as a relevant comparator in line with the NICE scope and\xa0NICE's technology appraisal guidance on tofacitinib and ustekinumab. The ERG noted that the population under consideration was: people with moderately to severely active ulcerative colitis whose disease has not responded well enough, or has stopped responding to, or could not tolerate conventional or biologic treatment – that is, people who had already had conventional treatment. Therefore, the ERG did not consider conventional treatment a relevant comparator. The clinical experts agreed that filgotinib will only be used after conventional treatment. The committee concluded that conventional treatment is not an appropriate comparator for filgotinib.\n\n# Clinical evidence\n\n## The SELECTION trial is broadly generalisable to UK clinical practice\n\nSELECTION was a phase\xa02b/3 randomised, double-blind, multicentre trial comparing filgotinib 200\xa0mg, filgotinib 100\xa0mg and placebo. It included adults with moderately to severely active ulcerative colitis, defined by a Mayo clinic score of between 6 and 12, and component subscores of at least 1 for stool frequency and rectal bleeding and at least 2 for endoscopic findings and physicians' global assessment. It had an induction and a maintenance phase:\n\nInduction phase: included 2\xa0cohorts, biologic-naive (n=659) and biologic-experienced (n=689). Participants were randomised to filgotinib 200\xa0mg or 100\xa0mg, or placebo. The primary outcome was the proportion of people who had remission from endoscopy, bleeding or stool frequency (EBS). The main secondary outcomes were the Mayo clinic score for remission and response, mucosal healing, an endoscopic subscore of 0, and histologic remission. All outcomes were measured at the end of week\xa010.\n\nMaintenance phase: the 664\xa0participants whose disease responded after 10\xa0weeks of induction treatment were re-randomised to maintenance treatment of filgotinib 200\xa0mg or 100\xa0mg, or placebo. Participants having filgotinib during the induction phase could be randomised to the dose of filgotinib they had during induction, or placebo. Participants whose disease responded to placebo during the induction phase continued on placebo. The primary outcome was the proportion of people with EBS remission. The main secondary outcomes were the Mayo clinic score for remission and response, mucosal healing, an endoscopic subscore of 0, histologic remission, sustained EBS remission and 6‑month corticosteroid-free remission. All outcomes were measured up to week\xa058. The clinical experts explained that the population in SELECTION was broadly generalisable to the people who would have filgotinib in clinical practice. However, they noted that the biologic-naive subgroup of the induction phase included more women and non-US people having filgotinib than placebo. The committee considered that a greater proportion of US people could have a minor influence on disease severity and concomitant treatment use. It concluded that SELECTION is broadly generalisable to NHS practice and is suitable for decision making.\n\n## Filgotinib is more effective than placebo at inducing and maintaining remission\n\nIn the induction phase of the SELECTION trial, the rate of EBS remission in biologic-naive participants was statistically significantly higher in the filgotinib arm at 26.1% (95% confidence interval [CI] 20.4% to 31.8%) than the placebo arm at 15.3% (95% CI 8.9% to 21.7%). Similarly, rates of EBS remission were also statistically significantly higher in the filgotinib arm at 11.5% (95% CI 7.4% to 15.5%) than the placebo arm at 4.2% (95% CI 0.6 to 7.9%) for the biologic-experienced subgroup in the induction phase. At week\xa058 of the maintenance phase, a statistically significantly higher proportion of people who had filgotinib were in EBS remission at 37.2% (95% CI 30.2% to 44.2%) than people who had placebo at 11.2% (95% CI 4.5% to 18.0%). The committee concluded that filgotinib is more effective than placebo for inducing and maintaining remission for people with moderately to severely active ulcerative colitis.\n\n## Filgotinib is likely to be as effective as most comparators in the induction phase\n\nThere was no head-to-head evidence comparing filgotinib against the comparators in the NICE scope (see section\xa03.5). Therefore, the company did network meta-analyses (NMAs) to allow for indirect treatment comparisons with them. It presented NMAs according to previous biologic use for induction and for maintenance treatment with filgotinib. Analyses were of clinical response, clinical remission and mucosal healing:\n\nThe biologic-naive subgroup included people who had not had a biologic. The analysis estimated the relative efficacy of filgotinib compared with adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab.\n\nThe biologic-experienced subgroup included people who had had a biologic. The analysis estimated the relative efficacy of filgotinib with adalimumab, tofacitinib, ustekinumab and vedolizumab. The results of the company's induction NMAs showed that filgotinib is likely to be as effective as the comparators in the biologic-naive and biologic-experienced subgroups. The results are academic in confidence and cannot be presented here. The ERG considered that the company's induction phase NMAs were methodologically robust and were a suitable source of clinical data for its model. The committee noted that the trials included in the NMAs had different designs, but concluded that the company's induction phase NMAs were appropriate.\n\n## Filgotinib's effectiveness in the maintenance phase is uncertain\n\nThe company's maintenance phase NMAs estimated values to populate the longer-term effectiveness of each treatment for the cost-effectiveness model. They estimated that filgotinib is likely to be as effective as most comparators in biologic-naive and biologic-experienced subgroups. The results are academic in confidence and cannot be presented here. The ERG noted that the results of the maintenance phase NMAs were invalid because people in the maintenance phase represent the population whose disease has responded to the different induction treatments, which varied between trials. The ERG explained that the company's NMAs used placebo as a common comparator, but what constituted the 'placebo group' varied between trials. The company's NMAs included participants whose disease responded to filgotinib who were then re-randomised to placebo. Other studies included participants whose disease responded to comparator treatments who were then re-randomised to placebo, thus disconnecting the network and making the results invalid. The ERG explained that in clinical practice people entering the maintenance phase either continue the induction treatment that their disease responded to or stop it. At this point there is no option to switch to another treatment without first being inducted onto that treatment. Therefore, the ERG preferred to calculate 50‑week probabilities of no response, response without remission and remission conditional on having the response at 10\xa0weeks at the end of induction. It used these values to replace the values from the maintenance phase NMAs in its base case. The committee noted that the re-randomisation of people in trials at the start of the maintenance phase made judging the relative effectiveness of treatments beyond the induction period difficult. It also noted that neither the company nor the ERG had explored adjusting for differences in baseline risks in the maintenance part of the NMAs. It would have preferred to see a maintenance phase NMA that included only trial participants who remained on active treatment or placebo for the duration of the trial or participants randomised to active treatment or placebo for both the induction and maintenance phase. However, the committee noted that, because of the trial's design, this would still only include people whose disease responded during the induction phase. The committee considered that both the company's and ERG's approaches were biased. However, the committee noted that using either approach had a minimal effect on the cost-effectiveness results. The committee concluded that it had concerns about the methodology of the maintenance NMAs and that the effectiveness of filgotinib in the maintenance phase was uncertain.\n\n# Economic model\n\n## The company's economic model is appropriate for decision making\n\nThe company used a Markov model to estimate the cost effectiveness of filgotinib compared with adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab. The company's model structure was similar to those used in previous ulcerative colitis technology appraisals. It included health states defined by the type of treatment (advanced treatment, conventional treatment, surgery, post-surgery), as well as degree of disease control (remission or response without remission) to replicate the relapsing and remitting nature of ulcerative colitis. The Markov model had a lifetime horizon and a cycle length of 10\xa0weeks and included clinical response, clinical remission and serious infections. The ERG agreed that the company captured all relevant health states and that its approach was appropriate. The committee concluded that the company's model was appropriate for its decision making.\n\n## Cardiovascular adverse events should have been included in the model\n\nThe company's model only included serious infections. It excluded all other adverse events associated with filgotinib. The ERG considered that the company's approach was appropriate and in line with NICE's technology appraisal guidance on tofacitinib and ustekinumab. However, the committee was aware of the association between the JAK inhibitor tofacitinib and incidence of cardiovascular events and malignancies shown in a safety study of people over\xa050 with rheumatoid arthritis and at least 1\xa0additional cardiovascular risk factor. It was also aware of broader ongoing investigations of JAK inhibitors. The committee questioned if filgotinib would also be associated with increased cardiovascular risk in people with ulcerative colitis. The clinical experts pointed out that people with ulcerative colitis are much younger and may have a different risk profile than people with rheumatoid arthritis. The committee concluded that it was concerned that people having filgotinib were likely to have an increased risk of cardiovascular events, and that balancing the benefit and risks before starting filgotinib was essential. It also agreed that cardiovascular adverse events should have been included in the model.\n\n## Long-term loss of response in the model should have been different in people in the 'response without remission' and 'remission' health states\n\nUlcerative colitis is not always active. Many people with the disease have periods of response and loss of response. In its model, the company estimated long-term loss of response from its NMAs and used the same value for the 'response without remission' and 'remission' health states. The company explained that, if the disease responded to treatment, it would not expect this response to wane over time. So, it considered that using the same loss of response for both health states was appropriate. The ERG explained that remission is harder to achieve than response without remission. But once it is achieved it is more stable. It said that the company's approach is inconsistent with this and favours filgotinib. The ERG noted that it could not adjust the model for differential loss of response. The clinical experts agreed with the ERG, saying loss of response was less likely in people whose disease is in remission than in people whose disease has only responded. The committee concluded that it would have been more appropriate to use a differential loss of response for each health state.\n\n## Loss of response is unlikely to be constant over time\n\nIn its model, the company assumed a constant loss of response for the 'remission' and 'response without remission' health states. The company considered that its assumption that loss of response is constant over time was likely to be an overestimate. The company also explained that the constant loss of response rates would likely underestimate the average duration of treatment. It provided a scenario analysis assuming a 25% reduction in the loss of response rate after the first year of maintenance. The clinical experts considered this scenario to be appropriate. However, the ERG explained that a 25% reduction refers to the reduction in loss of response rate not to the loss of response rate. The committee was aware that NICE's technology appraisal guidance on ustekinumab used a 25% reduction after the first 2\xa0years of treatment. It noted that the company's scenario had a minimal effect on cost-effectiveness results. The committee concluded that, because of the lack of long-term efficacy data, it was not clear if loss of response would be constant over time, and it considered the company's scenario in its decision making.\n\n## The health state utility values for people with active ulcerative colitis are uncertain\n\nThe company and the ERG used health state utility values based on the SELECTION trial in their base cases. The company used utility values collected at baseline for the 'active ulcerative colitis' health state and utility values collected at 10\xa0weeks for the 'response without remission' and 'remission' health states. It applied the same values for the full duration of the model. The utility values are academic in confidence and cannot be presented here. The ERG agreed with the company's utility values, except for the 'active ulcerative colitis' health state. The ERG preferred to use the utility values collected at 10\xa0weeks, which were specific to non-responders, and for consistency with the other health states. The ERG asked the company to provide scenarios exploring utility values specific to biologic-naive and experienced people, and specific to people in the induction and maintenance phase. The committee was disappointed that the company did not provide these scenarios. It was also aware that considerably lower utility values for active ulcerative colitis were used in NICE's technology appraisal guidance on tofacitinib and ustekinumab. In the absence of additional scenarios, the committee concluded that the ERG's approach was reasonable, but recognised that the quality of life of people with active ulcerative colitis in the analysis was uncertain.\n\n## Comparator treatment sequences used in the NHS vary\n\nThe ERG noted that the company's model included relevant comparators and some treatment sequences used in NHS clinical practice. However, it also noted that the company could have explored additional treatment sequences. The clinical experts explained that in clinical practice if people with the disease have a loss of response and have produced antibodies on 1\xa0TNF‑alpha inhibitor, they would often be offered another TNF‑alpha inhibitor. Therefore, a treatment sequence of infliximab followed by another TNF‑alpha inhibitor (for example, adalimumab) and other combinations of anti-TNFs should be considered. The clinical experts said that the company's modelled treatment sequences did not fully reflect clinical practice, and some were less plausible (for example, using tofacitinib after vedolizumab). The committee was aware that ulcerative colitis is a heterogeneous disease and treatment choices are influenced by many factors. It was pleased that the company attempted to model treatment sequences and recognised that, because of the large number of possible treatment sequences, it was not practical to model them all. The committee noted that the company's choice of treatment sequences had a minimal effect on cost-effectiveness results. It concluded that a range of treatment sequences for moderately to severely active ulcerative colitis are plausible, and the company's modelled treatment sequences do not fully reflect clinical practice.\n\n## The cost of dose escalation for comparators should only be included if the clinical benefit is also included\n\nIn its model, the company used dose escalation for some comparators but not filgotinib. It clarified that dose escalation for filgotinib is not appropriate because there are only 2\xa0approved doses, 200\xa0mg and 100\xa0mg, and filgotinib 100\xa0mg is only approved for ulcerative colitis with moderate to severe renal impairment. The company explained that the dose of comparators is commonly escalated in NHS clinical practice, if allowed by the marketing authorisation. The ERG explained that the proportion of people who have dose escalation and the time to escalation is not certain. It noted that the company's approach was inconsistent because it applied additional costs for escalated doses, but not the additional clinical benefits associated with dose escalation. This favoured filgotinib. Therefore, the ERG considered that it was not appropriate to include the cost of dose escalation in its base case. The clinical experts explained that dose escalation is common to try to achieve remission or regain partially lost response. The committee recalled that it was not appropriate to include dose escalation for filgotinib and that it was not used in clinical trials of comparator treatments. The committee considered the ERG's approach more appropriate for decision making. It considered that, if the cost of dose escalation is included, its clinical benefit should also be included.\n\n## The ERG's approach of a consistent probability and quality of life impact of chronic pouchitis is appropriate\n\nThe company estimated the rates of long-term complications after surgery from Ferrante et al. (2012), in line with the approach in NICE's technology appraisal guidance on tofacitinib. Ferrante et al. reported that 46% of people developed at least 1\xa0episode of acute pouchitis and 19% developed chronic pouchitis. The company used the 46% figure to calculate the 10‑weekly constant probability of developing post-surgery complications for the 'post-surgery complications' health state, and assigned a lower utility score for the remainder of their lifetime in its model. The ERG explained that most people do not develop chronic pouchitis, and that acute pouchitis can be treated. Therefore, the ERG considered that 46% was not a correct estimate of the probability of developing chronic complications. Instead it used the value of 19%, which was consistent with the impact on quality of life applied in the model. The committee concluded that the ERG's approach of using the probability of chronic pouchitis was more appropriate for decision making.\n\n# Cost-effectiveness estimates\n\n## The most likely cost-effectiveness estimates are lower than those normally considered an acceptable use of NHS resources\n\nCost effectiveness was assessed by calculating net health benefit, because there were multiple comparators for each subgroup. The incremental net health benefit of filgotinib was compared with each comparator at a threshold of £20,000 and £30,000 per quality-adjusted life year (QALY) gained for each subgroup. The company's and ERG's base case results included the confidential commercial discounts, which means they cannot be reported here. However, the committee recalled that there were several uncertainties in the company's approach, specifically:\n\nno evidence was presented for efficacy estimates for filgotinib at third-line for the biologic-experienced subgroup (see section\xa03.4)\n\nthe results of the maintenance phase NMAs (see section\xa03.9)\n\nequal loss of response for the 'remission' and 'response without remission' health states (see section\xa03.12)\n\nuncertainty in quality-of-life estimates (see section\xa03.14)\n\nthe comparator treatment sequences did not fully reflect clinical practice (see section\xa03.15)\n\nthe application of dose escalation (see section\xa03.16).The committee noted that most of the uncertainties had minimal effect on cost-effectiveness results. It considered the biologic-naive and biologic-experienced subgroups separately. It concluded that, taking into account the uncertainty, the cost-effectiveness estimates for filgotinib compared with other treatments for moderately to severely active ulcerative colitis were below what NICE normally considers an acceptable use of NHS resources.\n\n# Innovation\n\n## The benefits of filgotinib are adequately captured in the cost-effectiveness analysis\n\nThe company considered filgotinib to be innovative because it is a second-generation JAK inhibitor that is a preferential and reversible inhibitor of JAK1. It explained that targeted inhibition of JAK1 could reduce inflammatory cytokine signalling in ulcerative colitis. Filgotinib is administered orally so there will be no additional costs associated with its use. The clinical experts noted that other treatments with similar class and efficacy are available. The committee acknowledged the benefits offered by filgotinib and that people value an oral treatment, but it noted that it had not been presented with evidence of any additional benefits that were not captured in the QALY measurements. The committee concluded that the benefits of filgotinib were adequately captured in the model.\n\n# Equalities consideration\n\n## There are no equalities issues relevant to the recommendations\n\nThe patient experts explained that for certain faith groups the impact of active disease and the effects of surgery may interfere with religious practices and cause distress. The committee did not consider this an equality issue that could be resolved by this appraisal. No other equality or social value judgement issues were identified."}	https://www.nice.org.uk/guidance/ta792	Evidence-based recommendations on filgotinib (Jyseleca) for moderately to severely active ulcerative colitis in adults when conventional or biological treatment cannot be tolerated, or the disease has responded inadequately or lost response to treatment.
e9738108b6ba2b4a3f965fd707527c87beada9fd	nice	Synthetic cartilage implant insertion for first metatarsophalangeal joint osteoarthritis (hallux rigidus)	Synthetic cartilage implant insertion for first metatarsophalangeal joint osteoarthritis (hallux rigidus) Evidence-based recommendations on synthetic cartilage implant insertion for first metatarsophalangeal joint osteoarthritis (hallux rigidus). This involves replacing damaged cartilage with an artificial (synthetic) implant. # Recommendations For people with advanced disease for whom arthrodesis is indicated, evidence on the safety of synthetic cartilage implant insertion for first metatarsophalangeal joint osteoarthritis (hallux rigidus) shows no major safety concerns in the short term. But evidence on efficacy is limited in quantity and quality. Therefore, for these people, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. For all other people with hallux rigidus, evidence on the safety of synthetic cartilage implant insertion for hallux rigidus shows no major safety concerns in the short term. But evidence on efficacy is inadequate in quantity and quality. Therefore, for these people, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. Clinicians wanting to do synthetic cartilage implant insertion for hallux rigidus for people with advanced disease for whom arthrodesis is otherwise indicated should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Make sure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Enter details about all people having synthetic cartilage implant insertion for first metatarsophalangeal joint osteoarthritis (hallux rigidus) onto the British Orthopaedic Foot & Ankle Society (BOFAS) Registry and review local clinical outcomes. Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every person having this procedure. Regularly review data on outcomes and safety for this procedure. Further research should include suitably powered randomised controlled trials. These should report details of patient selection, including stage of osteoarthritis, and patient-reported outcomes such as pain, mobility and quality of life, and long-term outcomes related to the implant.# The condition, current treatments and procedure # The condition Osteoarthritis is a common condition in which the surface of the joint becomes worn, and the adjacent bone thickens and forms osteophytes. It can affect the first metatarsophalangeal joint at the base of the big toe, which may become painful and stiff (hallux rigidus). # Current treatments Conservative treatments include exercise, physiotherapy, orthotics, analgesics, non-steroidal anti-inflammatory tablets and cream, and corticosteroid injections into the joint. Surgery may be needed if severe osteoarthritis of the first metatarsophalangeal joint does not respond to conservative treatments. If an osteophyte on the surface of the joint is the only problem, it can be trimmed (cheilectomy). The main surgical options for treating the whole joint are fusion (arthrodesis), osteotomy or joint replacement. Rarely, excision arthroplasty is offered. # The procedure Synthetic cartilage implant insertion for hallux rigidus is usually done under general or regional anaesthesia. A moulded cylindrical implant made of polyvinyl alcohol (a soft plastic-like substance) and saline is used with specifically designed single-use instruments. A small incision is made over the top of the big toe joint and a drill is used to remove enough bone to make an appropriately sized hole for the implant. The implant is placed into the hole in the bone and left slightly raised, providing a smooth and slippery surface in the area of the cartilage defect. Once the implant is in place, the incision is closed with sutures. Weight bearing can typically resume immediately after the procedure. The aim is to reduce pain and improve the toe's range of motion.	{'Recommendations': "For people with advanced disease for whom arthrodesis is indicated, evidence on the safety of synthetic cartilage implant insertion for first metatarsophalangeal joint osteoarthritis (hallux rigidus) shows no major safety concerns in the short term. But evidence on efficacy is limited in quantity and quality. Therefore, for these people, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nFor all other people with hallux rigidus, evidence on the safety of synthetic cartilage implant insertion for hallux rigidus shows no major safety concerns in the short term. But evidence on efficacy is inadequate in quantity and quality. Therefore, for these people, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nClinicians wanting to do synthetic cartilage implant insertion for hallux rigidus for people with advanced disease for whom arthrodesis is otherwise indicated should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nMake sure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nEnter details about all people having synthetic cartilage implant insertion for first metatarsophalangeal joint osteoarthritis (hallux rigidus) onto the British Orthopaedic Foot & Ankle Society (BOFAS) Registry and review local clinical outcomes.\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every person having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nFurther research should include suitably powered randomised controlled trials. These should report details of patient selection, including stage of osteoarthritis, and patient-reported outcomes such as pain, mobility and quality of life, and long-term outcomes related to the implant.", 'The condition, current treatments and procedure': "# The condition\n\nOsteoarthritis is a common condition in which the surface of the joint becomes worn, and the adjacent bone thickens and forms osteophytes. It can affect the first metatarsophalangeal joint at the base of the big toe, which may become painful and stiff (hallux rigidus).\n\n# Current treatments\n\nConservative treatments include exercise, physiotherapy, orthotics, analgesics, non-steroidal anti-inflammatory tablets and cream, and corticosteroid injections into the joint. Surgery may be needed if severe osteoarthritis of the first metatarsophalangeal joint does not respond to conservative treatments. If an osteophyte on the surface of the joint is the only problem, it can be trimmed (cheilectomy). The main surgical options for treating the whole joint are fusion (arthrodesis), osteotomy or joint replacement. Rarely, excision arthroplasty is offered.\n\n# The procedure\n\nSynthetic cartilage implant insertion for hallux rigidus is usually done under general or regional anaesthesia. A moulded cylindrical implant made of polyvinyl alcohol (a soft plastic-like substance) and saline is used with specifically designed single-use instruments. A small incision is made over the top of the big toe joint and a drill is used to remove enough bone to make an appropriately sized hole for the implant. The implant is placed into the hole in the bone and left slightly raised, providing a smooth and slippery surface in the area of the cartilage defect. Once the implant is in place, the incision is closed with sutures. Weight bearing can typically resume immediately after the procedure. The aim is to reduce pain and improve the toe's range of motion."}	https://www.nice.org.uk/guidance/ipg727	Evidence-based recommendations on synthetic cartilage implant insertion for first metatarsophalangeal joint osteoarthritis (hallux rigidus). This involves replacing damaged cartilage with an artificial (synthetic) implant.
51e6137c9f9b5d17359d3b7fdaf9e6fbad99580b	nice	Social work with adults experiencing complex needs	Social work with adults experiencing complex needs This guideline covers the planning, delivery and review of social work interventions for adults who have complex needs. It promotes ways for social work professionals, other care staff and people with complex needs to work together to make decisions about care and support. # Context 'Adults with complex needs' is not a defined clinical group but encompasses any adult needing a high level of support with many aspects of their daily life who relies on a range of health and social care services. These needs for support may result from illness, disability, broader life circumstances or any combination of these. Complex needs may be present from birth or may develop over the course of a person's life and may fluctuate. The nature of these needs, and the way society is organised to respond to them, means adults with complex needs often face multiple challenges to living as they would wish and accessing support when it is needed. They are consequently vulnerable to preventable secondary conditions and premature mortality. Social workers are one of the main professional groups who support adults with complex needs. They do this in a range of settings, on a long- or short-term basis. Their responsibilities include facilitating the local authority's duty to conduct needs assessments under the Care Act 2014. They also work with individuals and families to address identified needs, effect change and organise support. Social workers can help people with practical, social and interpersonal difficulties, and promote human rights and wellbeing. There are about 100,000 social workers registered in England in 2021, according to the Social work in England: emerging themes report by Social Work England. Most commonly they are employed in local authority social care settings, but also in health and voluntary sector services. As well as providing care directly, social workers have a key role in organising support from the wider social care sector and other agencies. They work in a challenging context. The King's Fund Social care 360 report in 2021 describes a rising demand for social care, but a reduction in how many people are receiving care, and that social care funding levels have only just returned to 2010 to 2011 levels, after a decade of lower real-terms investment. The Care Quality Commission State of Care report for 2019/20 reports that the quality of social care received by most people was good overall. However, it noted regional variation in access to and quality of care, the need for better integration and joined-up care between services, and that the COVID-19 pandemic is 'having a disproportionate effect on some groups of people, and is shining a light on existing inequality in the health and social care system'. In this context, it is vital that the organisation and delivery of social work is informed by the best available evidence about effective ways of working. The Chief Social Worker for Adults' annual report: 2018 to 2019 acknowledges evidence gaps for social work, setting as priorities knowing what works and developing a better evidence base for social work practice. This guideline was commissioned by the Department of Health and Social Care to meet this need and develop evidence-based recommendations for social work for adults with complex needs. The guideline was developed by a guideline committee following a detailed review of the evidence. It covers assessment and care management or support which is delivered by or led by social workers. It seeks to provide recommendations which are generalisable to the whole population of adults with complex needs. This guideline is for social workers, and organisations which employ social workers or commission social work services. It is also relevant for adults with complex needs and their involved family and informal carers, and for other professionals who work with social workers in supporting adults with complex needs. Adults with complex needs are defined as people aged 18 or over who need a high level of support with many aspects of their daily life, and relying on a range of health and social care services. This may be because of illness, disability, broader life circumstances or a combination of these. Complex needs may be present from birth or develop over the course of a person's life, and may fluctuate. Unless otherwise specified, when a recommendation refers to 'people' or 'the person', this is the adult with complex needs. This guideline does not replace statutory duties and good practice as set out in relevant legislation and guidance, including: Care Act 2014 and associated guidance Equality Act 2010 Mental Capacity Act 2005 Accessible Information Standard Human Rights Act 1998 Social Work England's professional standards. This guideline aims to complement legislation and guidance by providing evidence-based recommendations about how social work interventions including assessment, care management and support for adults with complex needs could be improved. Actions already required by law, or recommended in statutory guidance, are not replicated here unless there was evidence to suggest that these are not implemented consistently in practice, or there was a need to emphasise specific points relevant to social work interventions including assessment, care management and support for adults with complex needs. NICE guidelines cover health and care in England and therefore focus on English legislation. Other UK countries have to follow legislation from the Welsh Government, Scottish Government, and Northern Ireland Executive.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Principles of social work for adults with complex needs ## For social workers Treat people with respect and dignity, recognising and supporting their decisions and choices. In particular: show understanding of people's and their family's circumstances, and be non-judgemental respect the validity of the person's lived experience value their first-hand knowledge of their own needs to inform care planning use professional curiosity and professional judgement understand the power imbalance between the person and social workers. When first contacting someone, and throughout provision of support, the social worker should establish with the person or with their family, carers or people important to them whether there are any advocacy, sensory or communication needs or impairments, in line with recommendation 1.1.5 in the NICE guideline on people's experience in adult social care services (see also the NICE guideline on advocacy services for adults with health and social care needs). For any social work activity or process, the social worker should ensure that the person understands: the reasons for the activity or process (for example, an assessment, or care management and support) the aims of the activity or process, and how this relates to them the key processes that will be followed, ensuring the person knows these at the planning stage for the process or activity what will happen at each new stage in the process (for example, by giving the person information about any upcoming review meetings). Social workers should provide people with the support they need to be fully and actively involved in discussion and decision making, taking into account: whether the person has any familiarity or previous experience with statutory processes and support agencies whether the person might be reluctant to ask for help or raise issues because of personal, societal or other factors, such as stigma or mistrust of services the person's expectations and emotional state the person's wishes and needs for both family support, and for culturally specific support services. Social workers should ensure that they discuss and actively listen to the person's: history and life story family and community networks experience of disadvantage, discrimination or abuse wishes and aspirations past experiences of services. Social workers should discuss with the person how their experiences may impact on their care needs and preferences, and how any difficulties may be mitigated. In these discussions: avoid making assumptions about the individual's circumstances recognise that some people's prior positive or negative views and experiences of social work may impact on the relationship with the social worker and services. Social workers should explore with the person: their experiences of society and accessing services and the potential impact of intersectionality.Take these into account when planning care (for example, by liaising with appropriate support organisations). When planning support, social workers: must consider whether reasonable adjustments can be made to protect against, or help the person deal with, discrimination arising from a person's protected characteristics as defined by the Equality Act 2010, or from other life circumstances and experiences (see box 1) and record the rationale for the decision made. Protected characteristics of the Equality Act 2010 age disability gender reassignment marriage and civil partnership pregnancy and maternity race religion or belief sex sexual orientation. Life circumstances and experiences that could lead to discrimination or inequalities, including: modern slavery coercive control domestic abuse trafficking refugee status asylum seeking being a migrant being from a traveller community being a prisoner being an offender homelessness poor literacy learning difficulties learning disabilities cognitive impairment acquired brain injury autism communication impairment leaving care transitioning from children's to adults' care services sensory impairment substance misuse living in rural and isolated areas long-term conditions English not being a first language socio-economic status addictions. The social worker must inform the person, in accordance with the UK General Data Protection Regulation (GDPR) and the Data Protection Act 2018, about the extent and content of information sharing across agencies and within multidisciplinary teams, and their rights in relation to this. The social worker should be aware of NICE guidance about relevant conditions that could affect the person they work with and how they work with them. For example, the NICE guidelines on: autism spectrum disorder in adults challenging behaviour and learning disabilities cystic fibrosis depression in adults multiple sclerosis in adults psychosis and schizophrenia in adults. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on principles of social work for adults with complex needs (for social workers) . Full details of the evidence and the committee's discussion are in: evidence review A: needs assessment evidence review B: risk assessment evidence review C: supporting changing needs evidence review E: integrated working. Loading. Please wait. ## For organisations What is an 'organisation'? In the context of this guideline, organisations are bodies that employ social workers in a professional capacity. This can include local authority social care departments, health services, the criminal justice system, higher and further education and voluntary and community services. Organisations (see box 2) should consider making time allowances for social workers in caseloads so they can build relationships with people with complex needs. Recognise that building relationships may take longer with people who may have had negative experiences with services, or people concerned about stigma from being in contact with services. Organisations should provide continuous professional development for social workers that specifically covers equality and diversity, so they are competent and confident in: asking all people they support about their personal and social identity as well as circumstances or experiences that may lead to inequalities or discrimination (for example, related to characteristics listed in box 1) and understanding how their personal and social identity as well as circumstances or experiences may affect their lives, care needs and preferences. Organisations should provide continuous professional development to ensure that social workers have up-to-date relevant legal literacy and sufficient knowledge of, for example, the: Mental Capacity Act 2005 Mental Health Act 2007 Human Rights Act 1998 Equality Act 2010 Care Act 2014 Children Act 1989 relevant case law inherent jurisdiction of the High Court. Organisations, commissioners and social workers should: recognise that people with complex needs may experience the impact of intersectionality, resulting in increased inequalities in access to and outcomes of health and social care and take this into account when planning and delivering services so they are accessible and responsive to the whole range of people's needs (for example, if a person has multiple health and social care needs this could be addressed by multidisciplinary working between health and social care services – see the section on social workers and multidisciplinary teams: communication, support and collaboration). Organisations should develop a framework, in line with the Social Work England professional standards, to support social workers in contributing to an open and creative learning culture in which they can: discuss and share best practice to promote the rights, strength and wellbeing of people, families and communities reflect on their own practice and that of their colleagues share experiences and learn from each other about how to balance the rights of the individual with the risks to self and others. For other principles of improving people's experience in adult health and social care services, including the principles of care and communication, see the NICE guidelines on people's experience in adult social care services, patient experience in adult NHS services and service user experience in adult mental health. For guidance on how to make information accessible, see the NHS Accessible Information Standard. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on principles of social work for adults with complex needs (for organisations) . Full details of the evidence and the committee's discussion are in: evidence review B: risk assessment evidence review F: individual or family casework evidence review G: helping people connect with local communities. Loading. Please wait. # Assessment ## Needs assessment The social worker should give the person information about their upcoming needs assessment in a format that is in line with their needs and preferences, and is accessible to them. Ensure they have enough notice and time to review documents, and prepare for the assessment. In line with regulation 10 of the Care Act 2014, the social worker must inform carers of people with complex needs about their right to a carer's assessment (for more information, see the NICE guideline on supporting adult carers). The social worker should inform the person being assessed about where and how they can access information about their rights under relevant legislation, such as the Care Act 2014, the Human Rights Act 1998 or the Mental Capacity Act 2005 (for example, providing written or oral information or signposting to relevant online resources or agencies – see also the section on principles of social work for adults with complex needs for relevant links related to meeting communication needs). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment – needs assessment (providing information) . Full details of the evidence and the committee's discussion are in evidence review A: needs assessment. Loading. Please wait. The social worker should be aware that a needs assessment can be stressful for the person being assessed, and their families and carers. Ensure that assessment practices are designed to minimise stress whenever possible, including: using a flexible approach to tailor the assessment to the person's needs (for example, by amending the order of assessment questions) helping the person to understand assessment documentation when appropriate (for example, explaining complex concepts in a simple, clear way). Social workers should consider arranging a preparatory initial contact before the assessment itself if it will help the person with complex needs to participate fully in their assessment (in line with statutory guidance for a proportionate assessment in the Care Act 2014), taking into account: the urgency of the person's support need whether the person wants a preparatory initial contact, and if so whether they would prefer this as a home visit, virtual contact or a phone call whether the person would have substantial difficulty in being involved in the assessment and if so, whether an independent advocate should be provided for the assessment. The social worker should ask the person about their preferences for the practical arrangements of the assessment, such as: the time and place of the assessment remote or in-person assessment whether they would like a supported self-assessment whether they would like anyone to be present to support them, for example a family member, carer or an independent advocate. The social worker should take into account that when there is a concern about potential safeguarding issues, an in-person assessment is likely to be needed. If the person chooses supported self-assessment, the social worker should discuss the advantages and disadvantages of this option with them, taking into account the complexities of their needs. The social worker should offer people with complex needs individualised support to complete a self-assessment, such as: ensuring that they have complete information about what it involves, including the list of areas and questions which it covers involving advocacy services providing details of who to contact if they want to clarify or discuss any areas of the assessment giving reassurance that they can ask for an in-person assessment if their preference changes. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment – needs assessment (planning the assessment) . Full details of the evidence and the committee's discussion are in evidence review A: needs assessment. Loading. Please wait. The social workers must ensure that the information provided by supported self-assessment is an accurate reflection of the person's circumstances (in accordance with section 6.44 of the Care and support statutory guidance, 2021). This can be done by cross referencing it with information from other sources (this should typically include involved family and carers or the multidisciplinary team). The social worker must conduct the needs assessment for adults with complex needs in compliance with statutory guidance (see regulation 2(1) of the Care Act 2014), and taking account of the following: whether the person's needs arise from or are related to a physical or mental impairment or illness whether the person would have difficulties in achieving 2 or more of the 10 listed outcomes; see regulation 2(2) of the Care Act 2014 whether there is a significant impact on wellbeing whether there are any unmet needs that may relate to a condition or difficulty that may need input from other specialist services, for example from speech and language services or mental health services. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment – needs assessment (conducting the assessment) . Full details of the evidence and the committee's discussion are in evidence review A: needs assessment. Loading. Please wait. The social worker should give the person a draft copy of their assessment and reviews, and the opportunity to identify any inaccuracies, omissions or differences of perspective, before the assessment is finalised. The social worker should acknowledge and record in formal case notes and the care and support plan any differences of opinion about the needs assessment. The social worker should give people with complex needs, their families and carers and other people important to them information about the complaints procedure, including how to access it and how to lodge a complaint if they wish to about the process or the outcome of the assessment. If the person chooses a self-assessment, the organisation must provide them with relevant information that they hold about them and their carer's assessment if applicable, taking into account legal requirements related to consent (in line with sections 2 and 2 of the Care and Support Regulations 2014). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on needs assessment (recording and reviewing the assessment) . Full details of the evidence and the committee's discussion are in: evidence review A: needs assessment evidence review B: risk assessment. Loading. Please wait. ## Risk assessment Social workers should assess risks as part of a holistic process of assessing the person's strengths, needs and wishes. The social worker should discuss and record the person's views on involving family, carers, and other people important to them in the risk assessment in the formal case file. Let the person know that it has been recorded and share this information across relevant agencies and with other social workers when appropriate and necessary (in line with the UK GDPR and the Data Protection Act 2018). The social worker should consider conducting the risk assessment over several contacts, so that: there is an opportunity for rapport to develop between the social worker and person being assessed the person's perspective on risks, their strengths, needs and wishes, and their health, environment and support networks are understood. When planning a risk assessment, take into account the urgency of any situation that may need a risk assessment within a short timeframe (for example, in a single visit; see also the section on responding to an escalation of need, including urgent support). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk assessment (planning the risk assessment) . Full details of the evidence and the committee's discussion are in evidence review B: risk assessment. Loading. Please wait. The social worker should support the person to engage in advance care planning, including: planning to cover their wishes in the event of any future loss of capacity (see the section on advance care planning in the NICE guideline on decision making and mental capacity) developing a risk management plan. Where a social worker has reasonable cause to suspect a person has experienced, is experiencing or is at risk of abuse or neglect, they must follow local safeguarding policies. If a need for action is established, the social worker must follow statutory safeguarding processes as set out in regulation 42 of the Care Act 2014. For people with complex needs, social workers should tailor risk assessments to the person's strengths and needs and take into account beneficial and harmful outcomes, and their likelihood of occurring, including: risks to the person from their own behaviour (including accidents, self-neglect and suicide or self-harm) risks from others (including physical or sexual violence, psychological harm, neglect or exploitation) risks of harm to others risks of loss of independence or breakdown of caring arrangements. When assessing mental capacity, social workers must take account of section 1(4) of the Mental Capacity Act 2005, and not assume that the person lacks capacity because they have made a decision that the practitioner perceives as risky or unwise. See also the section on assessment of mental capacity in the NICE guideline on decision making and mental capacity, including recommendation 1.4.19 on the difficulty in assessing capacity in people with executive dysfunction. If a person lacks the mental capacity to make decisions related to risk, the social worker must seek and take into consideration their current wishes (and any relevant past wishes expressed at a time when they were believed to have capacity) about any decisions, in line with section 4(6) of the Mental Capacity Act 2005. For further details, see the NICE guideline on decision making and mental capacity. If a person makes a decision that is likely to put them at significant risk, the social worker should consider assessing their capacity to understand, retain and weigh up the relevant information about safety, taking into account: previous decisions and choices and the perspectives of involved family members, carers and multidisciplinary team members. Social workers should use plain language and terminology that is understandable and acceptable to the person. For example, talking about 'safety' or 'being careful', rather than 'risk' or 'self-neglect'. In discussions between the person and the social worker about risk, consider the use of a structured risk checklist. The risk assessment should: include discussion of what has caused previous problems and unplanned escalation of needs identify what interventions have worked previously to manage and reduce risks. When assessing risk, in accordance with Social Work England's professional standards, social workers should: think about how any assumptions or personal biases may have influenced their assessment (for example, assuming that frail people would not want to participate in physical activities) be reflective about their own values, and challenge the impact they have on their practice (for example, how they personally feel about tidiness when working with a person who is hoarding). Social workers should respect people's rights to make decisions that they (the social worker) perceive as risky or unwise when the person has capacity to do so. Do not use such decisions as a reason to refuse care. If a person with capacity declines an intervention aimed at reducing risk (see recommendation 1.2.22 for the types of risk that may need to be reduced), social workers should continue to work with them to find ways to minimise risks. If a person has been assessed as lacking capacity, then in accordance with the Mental Capacity Act 2005, social workers must: ascertain the person's best interests (using the best interests checklist in line with section 4 of the Mental Capacity Act 2005), including identifying whether there is a Lasting Power of Attorney or court-appointed deputy with appropriate decision-making powers to make best interests decisions ensure any restrictions or supervision in their care are proportionate to the risk of harm to the person take into account any less restrictive ways of meeting the person's needs and managing risks and use these where appropriate. Social workers should avoid over-reliance on risk prediction (such as 'high' or 'low' risk) during assessments and when recording risks, and instead specify strategies on how to respond to factors contributing to increased risk and reduce potential harms. When deciding whether to share information in circumstances where the person does not give consent, the social worker: must balance the rights of the person with complex needs under the Human Rights Act 1998, Article 8 (right to respect for private and family life) against the effect on children or individuals at risk if they do not share the information and should record all information-sharing decisions, and the reasons for those decisions, in line with the organisation's procedures and requirements. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk assessment (conducting the risk assessment) . Full details of the evidence and the committee's discussion are in: evidence review B: risk assessment evidence review C: supporting changing needs. Loading. Please wait. In complex risk management situations involving potential risks of serious harm, the social worker should initiate and participate in a case conference involving all relevant agencies to: share information (in line with the UK GDPR and the Data Protection Act 2018) and develop a coordinated risk management plan. The social worker should include the person (and the person's advocate, family and carers, if they wish them to be present) in case conferences for complex risk management situations involving potential risks of serious harm, unless doing so: would present a risk to (or cause an escalation of risk for) the person or would present a risk to any of the other parties involved (social workers, other care staff, or the person's advocate, family or carers). The social worker should ensure that relevant information on significant concerns about risks is shared and discussed with all necessary agencies (taking into account the legal requirements under the UK GDPR and the Data Protection Act 2018). The social worker should: give the person a draft copy of their risk assessment, and the opportunity to identify any inaccuracies, omissions or differences of perspectives, before the risk assessment is finalised acknowledge and record any differences of opinion about the assessment of risk in the risk assessment document and formal case notes. Social workers should review risk assessments: at least annually and if needed, in response to an identified change in the person's circumstances or change in risks. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk assessment (recording and reviewing the risk assessment) . Full details of the evidence and the committee's discussion are in: evidence review A: needs assessment evidence review B: risk assessment. Loading. Please wait. Organisations should: provide de-escalation training to staff to support their safety have systems for formally recording incidents of aggression, threats or abuse against staff. Organisations should support staff when they experience any safety-related incidents, for example by: debriefing them providing peer support providing counselling following serious incidents. Organisations should provide access to advice for social workers whenever they are working, including outside normal office hours, about immediate concerns related to the risk to the person with complex needs or others. Organisations should ensure the following are in place: training, including multi-agency training, to support staff in assessing risks thoroughly supervision structures to support staff and encourage reflective and inclusive practice (for example, a multidisciplinary team discussion about individual situations). Organisations should have a written strategy promoting a culture that supports staff in helping people with complex needs balance the benefits and harms relating to risk taking. This could include, for example, training and governance systems to support social workers with assessing complex and high-risk situations. For further principles of decision making in situations where people may lack capacity, see the NICE guideline on decision making and mental capacity. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk assessment (organisational support) . Full details of the evidence and the committee's discussion are in evidence review B: risk assessment. Loading. Please wait. # Individual or family casework Social workers should take account of the principles of social work for adults with complex needs when conducting individual or family casework. Social workers should help people with complex needs to identify personal goals and desired outcomes (for example, through task-focused approaches). Social workers must understand the options available through legal frameworks so they can effectively support the rights of the person and the rights (and limits of the rights) of family members, including in situations of conflict and challenge. For example: Care Act 2014's requirement for advocacy Mental Capacity Act 2005 requirements on deprivation of liberty safeguards and the Mental Capacity (Amendment) Act 2019 requirements on liberty protection safeguards Human Rights Act 1998 Safeguarding Vulnerable Groups Act 2006 Protection of Freedoms Act 2012. Organisations should consider training and support for social workers to promote the rights, strength and wellbeing of people and families (in line with Social Work England's professional standards) to gain specialised and advanced skills in family interventions (for example, behavioural family interventions, family group conferences and restorative approaches). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on individual or family casework . Full details of the evidence and the committee's discussion are in evidence review F: individual or family casework. Loading. Please wait. # Helping people to connect with local communities and reduce isolation To help people with complex needs develop social connections, social workers should talk to them about their social networks, strengths (using strengths and asset-based approaches), and preferences for activities and social contact. Social workers should help people to access a range of groups, social activities and social networks to meet their needs and preferences, looking across the community in addition to what is provided by health and social care services. This could be done by: identifying local community groups and networks, and resources (for example, social clubs, community gardens, faith and cultural groups, user-led social groups) finding out about these resources and whether they may meet the person's needs and preferences helping the person make contact with these groups and activities (for example, by arranging IT and digital training, using familiar and accessible places). Social workers should think creatively about the types of community resources and networks that they can put in place or support people to develop (for example, by active involvement in commissioning discussions and flexible use of personal budgets, including direct payments). The social worker should check with the person whether any new community connection is meaningful, beneficial to wellbeing and enjoyable, and if not support the person to find a more suitable alternative. Organisations and social workers should keep up to date with information on currently available community assets, and pass this information on to adults with complex needs and their families. For example by: creating lists of resources and updating them regularly allocating workers to identify resources liaising with community groups commissioning voluntary organisations to keep up-to-date resource lists. Organisations should make information available about their services, and other community resources to people with complex needs (for example, disabled people's user-led organisations and other community groups). This information should cover: catchment area, and people's right to access services outside of their catchment area eligibility criteria referral processes. For information on community engagement approaches that seek to improve health and wellbeing and reduce health inequalities, see the NICE guideline on community engagement: improving health and wellbeing and reducing health inequalities. For information aimed at engaging people over 65 years in activities to improve mental wellbeing, see the NICE guideline on mental wellbeing in over 65s: occupational therapy and physical activity interventions. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on helping people to connect with local communities and reduce isolation . Full details of the evidence and the committee's discussion are in: evidence review F: individual or family casework evidence review G: helping people connect with local communities. Loading. Please wait. # Supporting people to plan for the future, including considering changing needs, wishes and capabilities The social worker should provide information to support the health and wellbeing of carers in their caring role, and on how the carer can help support the person with complex needs. See also the recommendations on providing information and support to carers in the NICE guideline on supporting adult carers. Social workers should ensure that care planning meetings take place in the person's preferred location whenever possible and practical. Social workers should implement a rights-based approach to case management and care planning. This should reflect the following principles: promoting people's dignity and wellbeing respecting people's right to self-determination promoting and supporting participation taking a holistic approach focusing on people's strengths and not solely on their needs. Social workers should, when appropriate and wanted, include input from key support networks in the person's care plan. This should: be in collaboration with the person, and with their consent include paid and unpaid support networks (for example, family, carers and other people important to them). Social workers should respond to the person and their changing circumstances by: developing a plan that is flexible and responsive reviewing and revising the care plan in response to fluctuating, evolving or rapid changes developing and identifying options according to the person's needs, wishes and preferences (for example, by helping people connect with local communities as described in the section on helping people to connect with local communities and reduce isolation) ensuring consistency of care by integrating working across the range of health and social care services involved (see the section on the social worker's role in multidisciplinary teams). Social workers should ensure that, at time of writing or review, care plans: take account of the person's wishes and preferences state how the person's eligible and non-eligible needs would be best met identify how arrangements have been or will be made to meet eligible needs record any eligible needs which are unlikely to be met or only partially met, the reasons they cannot be met or only partially met and any potential actions that would allow them to be met in future. The social worker should ensure that the person has their work contact details so they can get in touch if their needs or circumstances change. Document this information in the person's care plan. The social worker should plan the review date of the care plan with the person (a review should happen at least once a year), or conduct an unplanned review as soon as possible if, for example: the person's needs escalate or reduce, and circumstances change (for example, after transfer from hospital) the person, or their carer, a family member, advocate or another person important to them requests it. Each social worker must (in line with Social Work England's professional standards): use supervision and feedback to critically reflect on their own practice, including how research and evidence has informed practice keep their practice up to date, and record how research, theories and frameworks inform practice and professional judgement contribute to an open, creative, learning culture in the workplace to discuss, reflect on and share best practice. Where possible, organisations should provide people who receive social work support with a named social worker. Organisations should provide social workers with regular practice-based supervision and support, ensuring organisational resources are sufficient to allow: continuity of named social workers or a clear handover if the social worker has to change adequate time to monitor and review cases responsiveness to unexpected change the ability to be flexible, when appropriate, to the needs of the person. To support people to plan for the future when they transition between services, settings or between levels of care, see the following NICE guidelines: transition between inpatient hospital settings and community or care home settings for adults with social care needs (in particular, section 1.5 on discharge planning) transition between inpatient mental health settings and community or care home settings (in particular, section 1.5 on discharge planning) transition from children's to adults' services for young people using health or social care services (in particular, section 1.2 on transition planning) intermediate care including reablement (in particular, section 1.7 on transition from intermediate care). To support people growing older with learning disabilities to plan for the future, see recommendations 1.4.5 to 1.4.7 in the NICE guideline on care and support for people growing older with learning disabilities. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting people to plan for the future including considering changing needs, wishes and capabilities . Full details of the evidence and the committee's discussion are in evidence review C: supporting changing needs evidence review F: individual or family casework. Loading. Please wait. # Responding to an escalation of need, including urgent support When responding to an unplanned escalation of need, social workers should take into account the person's wishes, preferences, social circumstances and cultural background (for example, if someone expresses a strong desire to stay at home, even if necessary care may more easily be provided in a residential or inpatient setting). In the event of an unplanned escalation of need, social workers (with consent from the person) should: assess the escalated need jointly with colleagues who have the most knowledge about the person's care, wherever practical (for example, requesting a community Care and Treatment Review or a case conference) consult on the response to the escalated need with: -ther involved practitioners and community organisations relevant family and social networks. When an unplanned escalation of need occurs, social workers must: explore the least restrictive alternatives to address the need (in accordance with section 1(6) of the Mental Capacity Act 2005) seek provision of interventions that will have the least detrimental impact on the person's rights and living situation. Social workers should establish whether a person with complex needs has any advance statement of their wishes or crisis planning, and must take these into account when planning care during a crisis. Document in the person's records how this has informed decision making and review the plan after an escalation of need. When responding to an escalation of need, as well as considering an advance statement if available, the social worker should take into account and document: the person's wishes and preferences the views of others (for example, family, carers, and other people important to them) concerned for the person's welfare. Organisations should ensure that social workers have access to prompt support and opportunities to be debriefed during and after their work with someone experiencing a crisis. This should include the opportunity for social workers to reflect on practice and the potential risk to themselves and the person. Local authorities should have arrangements in place to provide services that: are available 24 hours, so decisions on applications for detention under the Mental Health Act (in line with section 14.35 of the Mental Health Act 1983: Code of Practice) can be made at any time can respond promptly to a person's escalating need communicate any out-of-hours responses to escalating need quickly and clearly to daytime services. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on responding to an escalation of need, including urgent support . Full details of the evidence and the committee's discussion are in evidence review D: support during an escalation of need. Loading. Please wait. # Social workers and multidisciplinary teams: communication, support and collaboration Organisations should ensure that multidisciplinary teams develop a shared statement of values, core purposes and activities, and have clear objectives and aims to jointly work towards. Organisations should consider the routine sharing of information (in line with the UK GDPR and the Data Protection Act 2018), and of professional expertise and perspectives, within the multidisciplinary team (for example, with joint working, forums or team meetings, themed discussions, or by championing a particular multidisciplinary approach). Organisations should ensure there is clear communication within the multidisciplinary team by: holding multidisciplinary team meetings, including case discussions having mutual access to diaries when possible providing virtual means to stay in touch even when team members are working from different locations making use of informal opportunities to communicate (for example, staff networking events). Organisations and commissioners should provide interdisciplinary training to promote shared understanding of each role in the team, and the legal frameworks within which they work, as well as an understanding of the range of lived experiences of people with complex needs. This should: be provided across health and social care including other relevant settings as needed be co-produced with people with lived experience be ongoing be followed up with clear plans for implementing any best practice and lessons learnt from the training sessions. Organisations should support social workers in defining their role within multidisciplinary teams by: providing professional social work supervision, in particular when the team manager is not a social worker providing opportunities for peer supervision making joint training available that provides clarity about the role of the social worker within a multidisciplinary team providing bespoke, continuing professional development for social workers recognising and addressing differences in organisational culture between professionals involved in the team. To improve the efficiency of referral within multidisciplinary teams, health and social care organisations should simplify referral processes and referral pathways, for example by having clear and simple eligibility criteria. Organisations should think about co-location to support more efficient responses and opportunities for discussion within multidisciplinary teams where feasible. Organisations should develop shared formal agreements (including budgets and information sharing) early in the process of establishing integrated working to underpin accountability and decision making. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on social workers and multidisciplinary teams: communication, support and collaboration . Full details of the evidence and the committee's discussion are in evidence review E: integrated working. Loading. Please wait. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster. ## Debriefing Debriefing after a distressing or safety-related incident involves the social worker having an opportunity to speak to a manager or senior colleague as soon as possible after the incident. This can be used, for example, to acknowledge the difficult situation and look into any support the social worker needs, including psychological support or counselling. This could start a reflective process to identify any lessons or ways to improve practice in future. ## Intersectionality The term describes the interconnected nature of social categorisations such as age, disability, gender reassignment, pregnancy and maternity, race, religion or belief, sex and sexual orientation and other characteristics or experiences listed in box 1, regarded as creating overlapping and interdependent systems of discrimination or disadvantage. ## Professional curiosity Professional curiosity is to explore and understand what is happening with an individual or family; enquiring deeper and using skilled, proactive questioning and investigation. It is about comparing what the person is saying with what is observed and any other available information, questioning any incongruity, rather than making assumptions or taking things at face value, to provide appropriate and tailored support. ## Rights-based approach A rights-based approach ensures that both the standards and the principles of human rights are integrated into policy making, as well as the day-to-day running of organisations and social work practice. ## Strength and asset-based approaches Strengths and asset-based approaches in social care focus on what individuals and communities have, and how they can work together, rather than on what individuals or communities cannot do or do not have. The terms 'strengths' and 'assets' are often used interchangeably to apply to either individuals or communities. Personal strengths and assets can include relationships, experience, skills and aspirations. Community strengths and assets can include knowledge, people, spaces, networks and services. ## Task-focused approach This approach seeks actionable solutions to specific problems. It usually involves 4 steps: defining a target area to work on together agreeing specific goals and actions for both the social worker and the person they are supporting to help achieve these goals discussion and support about progress with, and impact of, agreed actions reviewing and deciding whether a further process of task-centred goal setting is needed or the process has been successfully completed. Task-focused work is typically relatively brief but can be applied flexibly across a range of social work contexts as stand-alone support or within a broader package of care. ## Wellbeing In the context of the guideline, wellbeing is defined in accordance to regulation 1(2) of Care Act 2014, which states: 'Wellbeing', in relation to an individual, means that individual's wellbeing so far as relating to any of the following: personal dignity (including treatment of the individual with respect) physical and mental health and emotional wellbeing protection from abuse and neglect control by the individual over day-to-day life (including over care and support, or support, provided to the individual and the way in which it is provided) participation in work, education, training or recreation social and economic wellbeing domestic, family and personal relationships suitability of living accommodation the individual's contribution to society.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Needs assessment From the perspective of everyone involved, what is the acceptability of strengths and rights-based approaches to social work assessment and what are the barriers and facilitators to delivering these? For a short explanation of why the committee made this recommendation for research, see the rationale section on needs assessment . Full details of the evidence and the committee's discussion are in evidence review A: needs assessment. Loading. Please wait. ## Risk assessment From the perspective of everyone involved, what works well and could be improved about the use of tools and checklists to support social work risk assessment for people with complex needs? For a short explanation of why the committee made this recommendation for research, see the rationale section on risk assessment . Full details of the evidence and the committee's discussion are in evidence review B: risk assessment. Loading. Please wait. ## Supporting people to plan for the future What is the effectiveness and cost-effectiveness of early, preventative support for people with complex needs? For a short explanation of why the committee made this recommendation for research, see the rationale section on supporting people to plan for the future . Full details of the evidence and the committee's discussion are in evidence review C: supporting changing needs. Loading. Please wait. ## Responding to an escalation of need What is the effectiveness and acceptability of social work interventions to support people with complex needs during an escalation of need? For a short explanation of why the committee made this recommendation for research, see the rationale section on responding to an escalation of need . Full details of the evidence and the committee's discussion are in evidence review D: support during an escalation of need. Loading. Please wait. ## Helping people to connect with local communities and reduce isolation What social and community support approaches are effective in promoting social inclusion of people with complex needs? For a short explanation of why the committee made this recommendation for research, see the rationale section on helping people connect with local communities and reduce isolation . Full details of the evidence and the committee's discussion are in evidence review G: helping people connect with local communities. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice or services. # Principles of social work for adults with complex needs ## For social workers Recommendations 1.1.1 to 1.1.10 The committee looked at a range of evidence to inform the recommendations, which are intended to underpin all social work with adults with complex needs. They also took the Human Rights Act 1998, the Equality Act 2010, the Care Act 2014 and the UK General Data Protection Regulation (GDPR) and the Data Protection Act 2018 into account to address potential inequalities and data protection issues (for example, in access to services or in the services that people with complex needs receive). They also drew on the professional standards from Social Work England, the Professional Capabilities Framework from the British Association for Social Workers (BASW) and the Code of Ethics from BASW. The committee discussed qualitative evidence related to supporting people to plan for the future that highlighted some of the barriers that could influence people's access to and participation with services (for example, poverty, which is associated with inadequate housing and limited access to support). Such barriers could, in turn, result in people who use services feeling shame about their health conditions or living circumstances. This could further isolate them and make it more challenging for providers to support them. The committee therefore made a recommendation to emphasise that social workers need to treat people with respect and dignity to prevent barriers developing, and to understand and take into account the different circumstances of people with complex needs and any of their past experiences of services. This is also in line with the Human Rights Act 1998 and the Equality Act 2010. There was some qualitative evidence related to approaches to needs assessments that showed people were not always aware of what to expect from an assessment, and that language could be a barrier to communicating with social workers during the assessment. The committee agreed that meeting these needs are important principles that would apply to all aspects of social work, so they decided to broaden the recommendation beyond just the assessment process. They recommended that the social worker find out whether an advocate is needed to support the person and help with communication, information and understanding the legal framework. The committee discussed that some people (for example, people with learning disabilities) may also have particular sensory needs or impairments (for example noise level or brightness of light) and therefore added that this should also be taken into account. Based on the same evidence, the committee also emphasised the importance of ensuring that all the person's communication needs and preferences are addressed, to help them to actively participate in discussions. They noted that this was already covered in the section on overarching principles in the NICE guideline on people's experience in adult social care services so they included a cross reference to this. There was also some qualitative evidence showing that people did not always understand the purpose of the needs assessment and what it would entail. The committee used this evidence to recommend that sufficient information is provided for all activities and processes so that the person can understand what is going to happen and why. This will mean they can make informed choices and actively participate in the assessment. The committee discussed the support that people may need to be actively involved in social work processes: qualitative evidence showed that cultural differences created challenges for practitioners qualitative evidence showed that not having family support can be detrimental to the person's wellbeing quantitative evidence showed that differences in perspective because of culture lead to care needs not being raised or recognised by social workers in the committee's own experience, people's life experiences, expectations and emotional state can have an impact on their care experiences, and consequently lead to inequalities and poorer outcomes. The committee made recommendations to address these problems. They also highlighted the positive impact of family support (if needed and wanted) which can help the person to be actively involved. The committee drew on both quantitative and qualitative evidence from the review of individual and family casework. They discussed the qualitative evidence that suggested people's cultural experiences and perspectives can differ from those of the practitioner, and that this may result in the practitioner making assumptions. Based on experience and expertise, the committee emphasised that the starting point would be relationship building to identify a person's characteristics that might predispose them to inequality in healthcare provision, by actively listening to the person. They highlighted that forming trusting relationships is the cornerstone of social work and that looking at all aspects of the person's life would ensure that the social work approach has the person with complex needs at its centre, and that any reasonable adjustments are being made in relation to those needs. They discussed that a record of reasonable adjustment decisions should be made to ensure that this was given due consideration. The committee noted that there was only a small amount of evidence, but acknowledged that this was a key area of social work that could lead to inequalities in access to care and care provision, if not addressed. In the absence of evidence for other experiences and circumstances that may lead to inequalities and discrimination, which may be multiple (see the definition of intersectionality), the committee applied the evidence about the challenges of cultural differences and assumption as well as their knowledge from the Equality Act to cover the protected characteristics as well as other life circumstances and experiences (see box 1). The committee noted that a lot of qualitative evidence on the social worker's role in multidisciplinary teams referred to information sharing as a potential facilitator to integrated working, as it provides continuity (and conversely, acts as a barrier if not present). They discussed, based on their experience, that information gets shared more about people with complex needs and between more agencies. There were concerns about the extent of information sharing, however. In the committee's experience, people with complex needs value continuity and consistency and generally think that it is a positive idea to share information, but they want to be informed when and what information is shared and with whom (whenever this is possible and appropriate, in line with UK GDPR and the Data Protection Act 2018). The committee decided that this is a principle that should not be restricted to multidisciplinary team working but applies to all social work practice. The committee agreed that people need to be reassured that there are legal limits on information sharing and that their data is protected, but also that sharing where possible would mean that they would not have to repeatedly tell their life stories. The committee discussed that there are a wide range of conditions, impairments or fluctuating health conditions that lead to complex needs. They discussed that the guideline should be viewed in the context of such needs and that social workers when meeting a person with a particular condition should be aware of the relevant condition-specific guidance associated with this. The committee decided to give some examples of the range of conditions that may be applicable. The committee noted that most of these recommendations would standardise practice, as they are actions that are mandated by legislation (particularly the Equality Act 2010, the Care Act 2014), and supported by Social Work England's professional standards or BASW's Professional Capabilities Framework. This is particularly in relation to information sharing, and active listening and relationship building. Return to recommendations ## For organisations Recommendations 1.1.11 to 1.1.16 The committee looked at a range of evidence to inform the recommendations, which are intended to underpin all social work with adults with complex needs. They also took into account the Human Rights Act 1998, the Equality Act 2010 (for example, to address inequalities in access to services or in the services that people with complex needs receive), the Care Act 2014, the UK GDPR and the Data Protection Act 2018 and the professional standards from Social Work England. The committee used qualitative evidence from the reviews on individual and family casework, and helping people to connect with local communities and reduce isolation. This showed that the social work approach that people received was not sufficiently long or in-depth enough to address their complex needs. Based on this evidence, the committee recommended organisations provide sufficient time to social workers to build relationships in order to reduce inequalities. The committee discussed that people's life experiences may have an impact on their care experiences, and consequently lead to inequalities in access to care and care provision and poorer outcomes. They recommended organisations support and train social workers to discuss people's personal and social identities, and life experiences. This is in line with professional standard 1.6 from Social Work England that outlines the role of the social worker to promote social justice, helping to confront and resolve issues of equality and inclusion. This would enable social workers to feel confident that they are providing an environment where people feel that they are free of discrimination, and emotional or physical harm, and feel safe in discussing the complex needs that they have. The committee highlighted that this would also improve wellbeing of people, but they discussed that the term wellbeing is sometimes interpreted only in physical health terms. They therefore decided to adopt the definition of wellbeing provided within regulation 1(2) of Care Act 2014. There was qualitative evidence that social workers value support, supervision and training. The committee discussed that being up to date with relevant legal frameworks was particularly important to their work. They recommended that organisations should support this with continuous professional development so that social workers continue to develop legal knowledge and therefore act in accordance to the law when carrying out their duties. Qualitative evidence showed that people felt existing services and interventions did not sufficiently address all their needs. This was also consistent with the committee's experience of current practice, and they emphasised that planning of services (commissioning and configuring) should take this into account to address potential inequalities in access to care and care provision. The committee discussed evidence related to responding to an escalation of need, and concluded as a general principle that organisations should ensure social workers be given appropriate training and support during and after response to an escalation of need. However, the committee also agreed this would benefit all areas of their work, so expanded the recommendation to be one for development of an overall framework for an open learning culture. The committee discussed that this was in line with Social Work England's professional standards which also emphasise that families and communities should be taken into consideration. This will support social workers in learning from each other, and make them better able to appraise situations generally, but also specifically assess appropriate levels of risks that can be taken. The committee noted that most of these recommendations would standardise practice. The recommendation that organisations should consider making time allowances to build relationships may lead to longer contact times than currently, but this would be balanced against better, individualised services and this was supported by the economic analysis. The recommendation on continuous professional development would address a current variation in practice in getting access and time for such training opportunities. Return to recommendations # Assessment – needs assessment ## Providing information Recommendations 1.2.1 to 1.2.3 As there was no quantitative evidence on the effectiveness of different approaches to social work needs assessments, the committee used the qualitative evidence supported by their own knowledge and experience to make recommendations. They also took into account the legal framework underpinning social work assessments (particularly the Care Act 2014) and standards of practice (according to Social Work England's professional standards or BASW's Professional Capabilities Framework). There was some evidence showing that people did not always understand the purpose of the needs assessment and what it would involve, so the committee recommended giving people accessible information on why it is needed, the objectives, and how it will be done so that they have time to prepare. This also included raising awareness with carers about their right to have a carer's assessment in line with regulation 10 of the Care Act 2014. They also discussed that better understanding and knowledge (including of statutory rights) about social work assessments, both in terms of what is involved and the likely outcome, would reduce anxiety and stress for the person with complex needs. They noted that the social work can play an important part in addressing this by signposting to relevant resources. Most of the recommendations will standardise rather than change practice, as they are actions that are mandated by the Care Act (such as giving sufficient information). Return to recommendations ## Planning the assessment Recommendations 1.2.4 to 1.2.9 As there was no quantitative evidence on the effectiveness of different approaches to social work needs assessments, the committee used the qualitative evidence supported by their own knowledge and experience to make recommendations. They also took into account the legal framework underpinning social work assessments (particularly the Care Act 2014) and standards of practice (according to Social Work England's professional standards or BASW's Professional Capabilities Framework). Based on their experience, the committee emphasised that social workers should conduct assessments in a way that would minimise stress for the person noting that this would lead to better relationships and engagement and would therefore impact positively on outcomes. The committee discussed the review findings which suggested people were not always able to express their preferences during assessment. Based on this the committee recommended that there could, in some circumstances, be a preparatory initial contact before the assessment as a way of overcoming these issues. The committee agreed that this can be particularly important if the person may have difficulties being actively involved in the assessment. To address such difficulties, support may be needed from an independent advocate in the assessment. A preparatory meeting could provide the opportunity to assess whether there are any adjustments that can be made or family members who can get involved and could help and support the person with complex needs throughout the process. However, regardless of whether a preparatory meeting is held or not, the committee highlighted that the practical arrangements for the assessments always need to be established before the assessment takes place. They discussed the benefits and challenges of remote (for example virtual) compared to in-person assessments. While there are some advantages of remote assessment (such as when an urgent assessment is needed) there are also disadvantages (such as not being able to get cues from the person's environment). While they could not categorically recommend 1 over the other, they highlighted that in cases of potential safeguarding concerns an in-person assessment would most likely be needed because missing any needs in these circumstances could have serious consequences. The committee discussed qualitative evidence of possible challenges with self-assessment; for example, participants in a study reported that the self-assessment format was not always adequate or appropriate for people with multiple needs. Based on this, the committee emphasised that discussions should take place with the person about the advantages and disadvantages of this option so that they can make an informed choice, and that the person should be reassured that they will be supported and can change their mind and have an in-person assessment instead. Most of the recommendations will standardise rather than change practice, as they are actions that are mandated by legislation such as the Care Act or based on Social Work England's professional standards or BASW's Professional Capabilities Framework. The recommendation for a preparatory initial contact is a change to current practice since this is not uniformly done across the country. This may lead to an increase in the number of contacts, which may cause a potential resource impact and increase demands on social worker time. However, the committee noted that a preparatory visit is an option rather than a mandatory requirement and could be a virtual contact or a phone call. The additional resources needed to have some such preparatory visits may be offset by improved outcomes from the person-centred approach, potentially improving quality of life and preventing expensive interventions later on, such as hospitalisation. Also, as it is only an option that services could use rather than something that should be implemented for everyone, the impact may be limited. Return to recommendations ## Conducting the assessment Recommendations 1.2.10 and 1.2.11 The committee used the Care and support statutory guidance and regulation 2(1) of the Care Act 2014 to make these recommendations. The committee noted that if self-assessment is chosen, the Care Act 2014 requires social workers to check that the information that is provided in the assessment is accurate, so they emphasised this in a recommendation. This could be achieved by gathering information from multidisciplinary team members or family and carers, where appropriate. Based on the committee's experience and expertise of the statutory guidance in relation to needs assessment, they discussed the content of the assessment and the related eligibility criteria. They agreed that it is important to highlight the questions that the social worker should take into account when deciding on the level of support that is needed in compliance with statutory guidance (eligibility outcomes of regulation 2(2) of the Care Act 2014). The committee discussed that some of the person's needs may be outside of the expertise of the social worker, for example communication or mental health needs, and it is important that specialist input is sought to address these needs. Most of the recommendations will standardise rather than change practice, as they are actions that are mandated by either the Care and Support Statutory Guidance or the Care Act. Return to recommendations ## Recording and reviewing the assessment Recommendations 1.2.12 to 1.2.15 As there was no quantitative evidence on the effectiveness of different approaches to social work needs assessments, the committee used the qualitative evidence supported by their own knowledge and experience to make recommendations. They also took into account the legal framework underpinning social work assessments (particularly the Care Act 2014) and standards of practice (according to Social Work England's professional standards or BASW's Professional Capabilities Framework). Evidence showed that people were not always given the opportunity to review their assessment details, so the committee made a recommendation to ensure that people have the opportunity to check the draft documents are accurate. The evidence also suggested that needs can be interpreted differently by the person with complex needs and the social worker, which can lead to misunderstandings about the support that is expected. The committee acknowledged that differences of opinion could arise between a range of individuals, such as professionals and family members or others involved. They therefore recommended that a record of such differences should be kept in case any future issues arise. The committee noted that this could lead to tensions between the person with complex needs and the social worker, and could sometimes lead to complaints being made. They therefore emphasised that not only is good record keeping important when differences arise, but also that people should be given information about the complaints procedure, so they know what to do if they feel the correct processes have not been followed or they disagree with the outcome of the assessment. In the context of self-assessment, the committee noted, based on their knowledge of legislation, that organisations have an obligation to provide the person who self-assesses with relevant information that they hold to help them in the process. The committee agreed that this was not always known by social workers and made a recommendation that this must be done to comply with legislation. There is a lack of quantitative evidence addressing approaches to needs assessment and their potential impact on wellbeing. Because of this, the committee prioritised this topic for a research recommendation on needs assessment. Most of the recommendations will standardise rather than change practice, as they are actions that are either mandated by the Care Act (such as giving sufficient information and support, or issues related to self-assessment) or extrapolated from it (such as preferences when arranging the assessment). The recommendation for a preparatory initial contact is a change to current practice, since this is not uniformly done across the country. This may lead to an increase in the number of contacts, with a potential resource impact and increasing demands on social worker time. However, the committee noted that it would not be routinely done and could be a virtual contact or a phone call. This may be offset by improved outcomes from the person-centred approach, potentially improving quality of life and preventing expensive interventions later on, such as hospitalisation. Also, as it is only an option that services could use rather than something that should be implemented for everyone, the impact may be limited. Return to recommendations # Assessment – risk assessment ## Planning the risk assessment Recommendations 1.2.16 to 1.2.19 The committee acknowledged the limitations of the evidence, including the lack of quantitative evidence on this topic, and the limitations of the included qualitative evidence (in relation to both the low number of studies and low quality of findings). They agreed to use the qualitative evidence, supported by their own experience, when making the recommendations. They also took into account relevant legislation, including the Mental Capacity Act 2005 and the Mental Health Act 2007 as well as the Human Rights Act 1998 and the UK GDPR and the Data Protection Act 2018. The committee were also aware that decisions around risk can be influenced by culture, personal beliefs, and coping strategies. They therefore also took into consideration the Equality Act 2010. The evidence highlighted that when people with complex needs, and their families and other people important to them were actively involved in the risk assessment process, it facilitated discussions with social workers around risks and helped them make decisions about care and support needs. The committee agreed that this was an essential component of social work and consistent with the legal framework. The committee agreed that for people with complex needs, and their families and other people important to them to be actively involved the process, it needs to be relevant to the person and therefore holistic, looking at the person's abilities and needs and taking their preferences into account. The committee noted that the evidence suggested that people found it useful when family members supported them. However, they cautioned against being prescriptive about this because not every person would want their families involved in the process. Therefore, the committee recommended that social workers discuss the person's views and preferences and that these be recorded and shared (in line with the UK GDPR and the Data Protection Act 2018) so that families are not inadvertently included in discussions if this would go against the wishes of the person with complex needs. The committee discussed the evidence relating to contextual risk assessment that showed that people found the risk assessment approach worked better when their individual circumstances were fully understood. The recommendations emphasise the need for social workers to develop a rapport with, and engage with, the person at risk. When possible and practical, the committee recommended that ideally this should be done over several contacts so that the person's circumstances and environment is fully understood. While the committee wanted to emphasise the need to build relationships and understand the person's circumstances and environment, they also acknowledged that in some situations when a person is at urgent risk, immediate action needs to be taken which may not allow time for several contacts. The recommendations reinforce current legislation and usual practice. While conducting risk assessments over several contacts (which could be a virtual contact or a phone call) is not consistently done across the country, and would add time to the assessment, this would improve outcomes through a better understanding of the person's situation and environment. However, rather than this being implemented for everyone the committee thought that this could be one of the considerations around the assessment and would therefore not significantly change practice. Return to recommendations ## Conducting the risk assessment Recommendations 1.2.20 to 1.2.34 The committee acknowledged the limitations of the evidence, including the lack of quantitative evidence on this topic, and the limitations of the included qualitative evidence (in relation to both the small number of studies and low quality of findings). They agreed to use the qualitative evidence, supported by their own experience, when making the recommendations. They also took into account relevant legislation, including the Mental Capacity Act 2005 and the Mental Health Act 2007 as well as the Human Rights Act 1998. The committee were also aware that decisions around risk can be influenced by culture, personal beliefs, and coping strategies. They therefore also took into consideration the Equality Act 2010. The committee noted the evidence related to assessing risk when a person lacks capacity, and so highlighted that risk assessments would also involve planning for the future so that the person's wishes are known in advance and a plan is in place to manage risk. They agreed that this would lead to better outcomes, since any risky situation can be managed in line with the person's preferences even if they later lack capacity to make decisions. The committee discussed that safeguarding issues can be noticed in the risk assessment process and that it is therefore a legal duty in line with the Care Act 2014 that the social worker adheres to local policies to keep the person safe. There was a lack of evidence about what works well and what could be improved in relation to the content of risk assessments, but despite this the committee agreed that it was important to provide guidance about what should be taken into account when conducting a risk assessment. They also discussed a guide about risk assessments from the Social Care Institute of Excellence and took this into account. In line with this, the committee recommended that to be effective the social worker should individualise the risk assessment and consider not only harmful outcomes but also where there are low risks and potential for good outcomes (for example, if the risks of harm from others and harm to others is low, it could mean that there is a good support network that the social worker could get involved to help with other potential risks that are high). The committee agreed to highlight categories of risks that would affect the person's safety and the safety of other people, as well as risks to their independence and the independence of others who may depend on them so that plans can be made to minimise them. The committee discussed their concerns that any risky decisions could lead the social worker to conclude that the person lacks capacity, and they therefore highlighted the legislation of the Mental Capacity Act 2005 which states that assessments of mental capacity should not be based on such assumptions. They discussed that such decisions can be challenging with some cognitive impairments, such as executive dysfunction, and therefore highlighted this in a cross reference to recommendation 1.4.19 of the NICE guideline on decision making and mental capacity. The committee were aware that people who lack capacity to make decisions related to risk were particularly vulnerable, and that therefore the legislation in section 4(6) of the Mental Capacity Act 2005 needs to be followed so that their current wishes can be established if possible. Even though an assumption should not be made that someone is lacking capacity, the committee did not want to leave someone vulnerable to risk if they do lack capacity, so they recommended that a person who makes a decision that would put themselves at significant risk should be considered for an assessment of capacity. Getting the views of people close to the person and members of the multidisciplinary team may be helpful to determine whether an assessment may be necessary. This is to ensure their safety, and potentially the safety of their family members or carers. The committee noted the qualitative evidence showing that people agreed that risk assessments work better when discussions take into account the words a person uses to describe risk and their understanding of risk. There was some evidence that checklists can help with this, but the committee was cautious to recommend these as a routine form of assessment as there are only a small number of validated checklists available, and so they would not address the range or complexities of risks for people with complex needs. They were also concerned that this could also be seen by the person as a tick box exercise, and so recommended that checklists be used as a starting point for a wider discussion including previous causes of an escalation of needs and what worked well before to minimise risk. Because of uncertainties with the evidence on the use of checklists and it being restricted to people with complex mental health needs, the committee also made a research recommendation on risk assessment. When reviewing evidence indicating that risk assessments worked better if social workers fully understand the person's perspectives of risk (when they have capacity to do so), the committee noted that this was consistent with their own experience. They therefore wanted to ensure that this was taken into account when assessing risk, but also that this should not stop social workers from providing necessary support if needed. The committee noted that this was in line with Social Work England's professional standards which advise social workers not to prejudge the person's state and also reflect on their own interpretations (which can be based on their own values), so as to avoid their own feelings around risk influencing their assessment. The committee discussed evidence highlighting that a risk assessment works well for people who have capacity when it balances a person's risk with their autonomy, and other evidence that showed understanding the person's perception of risk facilitates the process. They therefore highlighted that people can make their own decisions about risks or decline interventions (for example, keeping many personal belongings if they are hoarding items even if it makes it difficult to move around their home). However, such choices should not be a reason to stop working with them or providing care even if the social worker perceives these decisions to be risky or unwise. There was evidence related to detention under the Mental Capacity Act for people assessed as lacking capacity, and the committee used the principles of the Mental Capacity Act to highlight that the circumstances where potential risks for people who lack capacity could occur need to be carefully considered, including ascertaining the person's best interests, so that any restrictions made are proportionate and justified. There was evidence highlighting that it is difficult to define the seriousness of risk, which was consistent with the committee's experience that risk would vary from person to person. The committee discussed that in the absence of such definitions, risk assessments can potentially place too much emphasis on the use of generic risk categories such as 'high' and 'low' risk – these do not distinguish the severity of potential harms from their likelihood, and do not take into account the different circumstances and choices of the person at risk. Based on these discussions, the committee made recommendations which emphasised that when recording risks social workers need to assess the severity and likelihood of identified potential harms to inform a risk management plan. This should weigh potential harms against potential benefits of risk taking, and a person's needs and wishes. The committee acknowledged that the person at risk may not always give consent for their information to be shared. The committee identified the Human Rights Act 1998 underpins such decisions, and this was stated in the recommendations. The recommendations reinforce current legislation and usual practice. For advance decision making, while this is not a mandatory part of risk assessment it is commonly done, so the recommendation is likely to lead to standardised practice. Return to recommendations ## Recording and reviewing the risk assessment Recommendations 1.2.35 to 1.2.39 The committee acknowledged the limitations of the evidence, including the lack of quantitative evidence on this topic, and the limitations of the included qualitative evidence (in relation to both the limited number of studies and low quality of findings). They agreed to use the qualitative evidence, supported by their own experience, when making the recommendations. They also took into account legislation, under the UK GDPR and the Data Protection Act 2018. Based on their experience, the committee were keen to emphasise the need to balance any competing demands and perspectives of different organisations, and for different practitioners to be able to exercise their professional judgement. To achieve this, they recommended that, in complex situations involving potential risks of serious harm (for example these could be situations where there are many different opinions in the multidisciplinary team, potentially different complex harms or where 1 action to avoid 1 risk might bring about a further risk), social workers coordinate a case conference. Usually this would include the person and their family or carers but the committee decided that there are situations where a case conference could be a cause of distress for the person or may put a family member at risk. They therefore made a recommendation to highlight both that the person's and their family's involvement is important as well as situations when this may not be advisable. Also based on their experience, the committee discussed that, when there are significant concerns about risks, information ought to be shared between agencies to ensure the safety of the person with complex needs. However, they emphasised that this can only be done within the constraints of the legal framework within the UK GDPR and the Data Protection Act 2018. Evidence showed that people were not always given the opportunity to review their risk assessment, so the committee made a recommendation to ensure that people have the opportunity to check the draft documents are accurate. The evidence also suggested that disagreements could arise across different organisations and among different practitioners because of the varying ways in which risk is conceptualised and decisions on managing risk are made. The committee also noted that differences of opinion could arise among professionals, the person with complex needs, family members or others involved. They therefore recommended that a record of such differences should be kept in case any future issues arise from disagreements. The committee also noted that risk assessments need to be relevant, up to date and responsive to change and therefore, based on their experience, recommended that they are reviewed at least annually, or when circumstances change and a new review is needed. The recommendations reinforce current legislation and usual practice. Return to recommendations ## Organisational support Recommendations 1.2.40 to 1.2.45 The committee acknowledged the limitations of the evidence, including the lack of quantitative evidence on this topic, and the limitations of the included qualitative evidence (in relation to both the limited number of studies and low quality of findings). They agreed to use the qualitative evidence, supported by their own experience, when making the recommendations. The evidence showed that social workers valued support, particularly when they have experienced abuse, and ongoing training (including legal literacy). Based on the evidence and potential for high-risk situations, advice for social workers should be available whenever they are working, including outside normal office hours. The evidence showed that positive organisational cultures give social workers confidence in making risk assessments, and the committee drew on this to recommend a written strategy for training and support. The recommendations reinforce current legislation and usual practice. The availability of training on risk assessment for social workers varies, so there may be a resource impact where it is currently not available. However, this would lead to better outcomes by improving the knowledge and awareness of processes and approaches to assess risks. Having out-of-hours access to advice in relation to risk for social workers who do not work during office hours is common practice (such as using an on-call system), so should not be an additional resource impact in most cases. Return to recommendations # Individual or family casework Recommendations 1.3.1 to 1.3.4 ## Why the committee made the recommendations The committee drew on both quantitative and qualitative evidence to make recommendations. The committee discussed the quantitative evidence, which showed mixed results for social work approaches to individual and family casework. They discussed the evidence that showed that a stepped care intervention had an important benefit in terms of morbidity outcomes. This intervention had a number of components including guided self-help and problem solving. The qualitative evidence suggested that social work approaches, in particular goal setting, helped people to identify their priorities and think about ways to achieve these goals. Based on experience, the committee discussed the benefits of such approaches – in particular, those with components that seek solutions to defined areas and working to agreed goals to solve problems. They decided that they could not recommend the specific stepped care approach described in the study, as it was done in a different health and social care setting (Belgium and the Netherlands) and had many components that would make it difficult to implement. However, they noted that some of the components would fall into the category of task-focused approaches which are already used by social workers in the UK. Although the evidence showed benefit for a specific group, the committee agreed that the importance of identifying goals and outcomes (as is done in task-focused approaches) could be extrapolated to the wider population of adults with complex needs and recommended that people should be supported in this process. The committee highlighted legal frameworks that were in place to support the rights of the person as well as the rights of the family. They agreed that by doing this, social workers would better understand that their role is not necessarily to resolve conflict, but to uphold the rights of the person being supported. The committee looked at evidence around the challenges of involving family members in social work approaches to casework, and potential conflicts which may exist between family members and how safeguarding concerns may arise in some situations. They discussed the difficulties, as highlighted in the evidence, of ensuring family members participate and engage in interventions. However, they noted that there was little quantitative evidence on the effectiveness of any particular family intervention that had been carried out specifically by social workers to address these challenges. The committee was aware that there is a benefit from family interventions (for example, improving communication between family members), but that the evidence originates from other disciplines (for example, research in clinical psychology) and it is therefore unclear what the role of these interventions is in social work. However, to promote the rights and wellbeing of people and families (in line with Social Work England's professional standards) they felt such interventions could be considered with sufficient training, because the benefits of positive family relations and the social support that this could provide to the person with complex needs could lead to positive outcomes. ## How the recommendations might affect practice The recommendations aim to standardise practice rather than change it. Return to recommendations # Helping people to connect with local communities and reduce isolation Recommendations 1.4.1 to 1.4.7 ## Why the committee made the recommendations The committee discussed the quantitative evidence, which showed benefits for some outcomes but no differences for other outcomes. However, because of methodological biases, as well as uncertainty around the magnitude of the findings, the committee were less confident in relying completely on the quantitative evidence to support recommendations. There were some themes of the qualitative evidence that supplemented or provided an explanation for the lack of clear results in the quantitative evidence. This combination of quantitative outcomes and qualitative themes suggested that the relative lack of improvement in the quantitative outcomes could be explained by the qualitative evidence that social workers place importance on taking an individualised approach to achieve positive outcomes. The committee agreed that this was a reflection of their experience of practice and was therefore important to take into account. The committee made a recommendation based on the quantitative evidence that showed social work approaches to social inclusion had an important benefit over usual practice that mainly focused on the person's existing networks, as there was an improvement in perceived social support. The qualitative findings also highlighted the importance of thinking about the different levels of support a person may need. Based on the combination of the quantitative and qualitative evidence and drawing on their experience, the committee were confident to make a recommendation for the social worker to use a strengths-based, person-centred approach to help the person to develop connections with their local communities. The committee emphasised that approaches that do not solely focus on the person's needs would improve their confidence and contribute to their overall wellbeing by helping them to take steps to reduce isolation. The committee also made a recommendation for social workers to support access to a range of activities in the community. A number of qualitative themes supported this recommendation, including the benefits of taking an individualised approach to social inclusion activities (as people's preferences and needs will vary greatly). The findings also highlighted that participants felt community-based groups and resources could be more beneficial in matching people's needs than those provided by health and care services. The committee discussed the qualitative evidence around practitioners' views of social work approaches to social inclusion, which highlighted that the range of available groups and resources for people were not always adequate. As reducing isolation is beneficial to the person, the committee recommended social workers use creative approaches to see whether new resources could be developed. This also include the flexible use of personal budgets to support an activity. Support should also be given at an organisational level to help social workers find activities and groups that might match a person's interests. This relies on information being up to date, so the committee gave some examples of how this could be achieved. The committee discussed evidence that highlighted that it was important to take into account that the level of support needed varied depending on peoples' needs. They agreed that the support of the social worker should not end once a person has made contact with a group, but that this should be followed up with the person after they have joined a group to ensure that they benefitted from it. Based on experience, the committee agreed that it was important for organisations to provide information that is up to date about available community resources, as this would minimise barriers to accessing services (such as frustrations around contact details no longer being active, or activities no longer being available). The committee discussed the evidence around the barriers to connecting with communities or groups, that showed that an NHS trust's catchment area could be a barrier to this because it is assumed by practitioners and the person that people do not have the right to access groups that are outside the catchment area. The committee recognised that it was not within the scope of the guideline to make a recommendation about local authority catchment areas, but agreed to recommend that people are informed about their rights to receive services outside of their catchment areas to help address this. Based on their experience and knowledge, they expanded on this to alleviate other barriers to access, such as eligibility criteria and referral processes. Even though there was both quantitative and qualitative evidence to draw on, the committee felt that further evidence to clarify the best approach that social workers could take to help people connect with their local community is needed and so made a research recommendation on social and community support approaches to address this. ## How the recommendations might affect practice There is variation in practice in how much time is spent by social workers helping people connect to local communities. The recommendations will increase the time social workers spend researching, supporting and helping people to make connections in their communities. However, this potential change in practice could lead to improved outcomes by reducing the detrimental effects that loneliness can have on the person's health and wellbeing. Return to recommendations # Supporting people to plan for the future, including considering changing needs, wishes and capabilities Recommendations 1.5.1 to 1.5.13 ## Why the committee made the recommendations The committee discussed both quantitative and qualitative evidence. The quantitative evidence was of limited value because of the quality of the studies and applicability, as most of the included studies were not conducted in the UK so the care provision and legislation were different. They therefore focused on the qualitative evidence as it was of better quality, with themes that the committee agreed were more generalisable to the wider population (with more UK evidence and a wider range of complex needs included). The evidence suggested that when people have information and support in advance and understand the care planning process, this helps them to participate in planning for the future with their social worker. The committee highlighted the key role social workers play in communicating relevant information to people with complex needs, as well as to their support network, in a timely manner throughout the whole process. The committee emphasised that this would also include information and support for carers, which would have a positive impact on their own wellbeing as well as that of the person that they are providing care for. There was evidence that highlighted that the environment and service location can be an important facilitator to help the person feel safe and relaxed, and there was also benefit in having a location that provides easy access to case management services (this included visits to the person's home). The committee drew on this to recommend that care planning take place in the person's preferred location whenever possible. There was some limited evidence about the importance of building relationships and trust. This was consistent with the committee's experience that good relationships that include meaningful conversations to engage individuals are an important aspect of case management and care planning. Drawing on their own expertise, the committee recommended a rights-based approach to case management and care planning, focusing on the individual's rights according to the principles of the Human Rights Act 1998. This would improve people's outcomes by promoting their dignity and wellbeing, building on their strengths and supporting both their participation in the community and engagement with services. The committee discussed the qualitative evidence that highlighted the importance of existing relationships between adults with complex needs and their family members and carers, and also the wider community. Promoting such relationships may enhance the support networks available to adults with complex needs, which may in turn help minimise the potential for isolation. They discussed the importance of both paid and unpaid support networks (for example, family and personal assistants), and agreed that their input should be reflected in the care plan where appropriate. Based on evidence that highlighted that a barrier to successful planning for the future was not recognising quickly enough when needs change, the committee highlighted the benefits of a flexible and responsive approach. This should include regular reviews so that plans can be adjusted to ensure the person's safety and wellbeing. Based on the evidence about the challenges of planning and addressing all the person's needs, and supported by their own knowledge and experience, the committee were aware that social workers may not always be able to address the whole range of identified, eligible needs successfully at the point when the care plan is written or reviewed. It was acknowledged that in accordance with section 18 of the Care Act 2014, a local authority, having determined that a need is eligible, has a legal duty to meet this need. (See also section 10.10 of the Care and support statutory guidance, which describes what is meant by 'meeting a need'.) The committee decided that when writing or reviewing the care plan, social workers should note when a need has not yet been met, or is only partially met, to make it explicit that the need has to be addressed to meet the local authority's legal obligation. It was noted that the social worker and the person may have different views about the extent to which an eligible need has been sufficiently met, but it was decided that this could be captured in the care plan or at review. Exploring this when writing or reviewing the care plan would help identify reasons why some needs have not been sufficiently met, and indicate what might be needed to achieve this in future. In relation to this, the committee cited section 13.13 of the Care and support statutory guidance which describes the routes to reviewing care and support plans. While, based on their experience, a review should be planned with the person and take place at least once a year, the statutory guidance highlights that there can be situations where an unplanned review is necessary (for example, if needs change or if it is requested by the person or other people important to them). The committee discussed findings around working arrangements which identified certain conditions that enabled social workers to fulfil their roles more successfully, including autonomy, training, support and supervision. However, the evidence suggested that most social workers reported a lack of support from managers from their own organisations. The committee were keen to emphasise the importance of supporting social workers in their role so that in turn, adults with complex needs would be effectively supported. This was reflected in the committee's recommendation that organisations provide social workers with regular, practice-based supervision and support so they can be responsive to people's complex and fluctuating needs, and keep their knowledge and practice up to date. The committee discussed the evidence showing that continuity was valued in care planning, particularly because people with complex needs felt frustrated about having to tell their stories repeatedly. The committee noted that this was consistent with their experience that offering people access to a named social worker would benefit them in terms of providing such continuity of care, which would in turn enhance their health and wellbeing (where there are changes in social workers, continuity could be maintained by having clear handover processes in place). The committee made a research recommendation on supporting people to plan for the future to inform future guidelines that would address the gap in the effectiveness evidence relating to the evaluation of specific models of social work case management. ## How the recommendations might affect practice The recommendations will mainly standardise practice. There is some variation nationally in provision of a 'named' social worker so increased provision may have some resource impact, but this is already common practice for many services so this may be limited. Return to recommendations # Responding to an escalation of need, including urgent support Recommendations 1.6.1 to 1.6.7 ## Why the committee made the recommendations While some quantitative evidence was available, the committee decided not to make use of it when making recommendations, as only 1 small observational study with methodological limitations (such as lack of comparison group) was identified and the population was restricted to the specific needs of people with mental health conditions. Therefore, it was difficult to generalise to the wider population of people with complex needs. The committee drew on the more substantial qualitative evidence (from 8 studies) and supplemented this with their experience and knowledge to make advice applicable to the wider population of adults with complex needs. The committee used their expertise and knowledge of BASW's Professional Capabilities Framework – which sets out the ethical principles and critical reflection practices that a social worker must apply to guide their decision making – to recommend social workers consider a person's wishes, preferences, social circumstances and cultural background when planning during an escalation of need. This would help ensure that any decisions that are made are not based on the social worker's assumptions. The committee discussed the evidence that suggested practitioners who used the wider support network of friends and family to help with decision making during a Mental Health Act assessment facilitated the social worker's response to an escalation of needs. Based on this evidence and their experience, and statutory requirements, they decided to generalise this to the whole population for all situations of unplanned escalation of needs. They agreed that gathering information about the situation not only from the person's family and social networks, but also relevant practitioners would create a clearer picture of the situation (and any previous, similar situations) and would therefore likely lead to better solutions. The committee noted that usually this information could be gathered by phone or using virtual meetings (for example, virtual case conferences or Care and Treatment Reviews). The evidence that showed there was a lack of time and resources for social workers to look at alternative options to detention under the Mental Health Act in response to an escalation of need. However, in accordance with the Mental Capacity Act 2005 other less restrictive options need to be considered which can take time. They discussed that social workers in such circumstances can feel under pressure and may make rushed decisions. They drew on 1 of the principles of the Mental Capacity Act that highlights that whenever possible, options must be explored that are less restrictive of the person's rights and freedom of action. To ensure that this principle is upheld and to ensure that people with complex needs can maintain their independence and autonomy as much as possible in the event of an unplanned escalation of need, the committee made a recommendation to reinforce this legislative requirement. The committee used their knowledge, supported by legislation, to make recommendations on the use of a person's advance statements during decision making to ensure a personalised approach to care is taken. The committee noted that an advance statement could be any statement of a person's wishes and preferences which is not to be confused with a formal written document like an advanced directive related to medical treatment decisions. An advance statement should lead to better outcomes and satisfaction with services, as a person's wishes and preferences may have been informed by what has worked previously. However, the committee noted that individualised approaches are always needed, even if no advance statement has been made, to provide support in accordance with the person's wishes and preferences. The committee discussed the review finding that showed there was dissatisfaction that out-of-hours services were not always available. The committee were aware of legislation that supports 24-hour services and made a recommendation in favour of them so that prompt support can be provided in situations of an unplanned escalation of need in the context of Mental Health Act assessments in accordance with legislation (section 14.35 of the Mental Health Act Code of Practice). They noted that availability of services out of hours may prevent some hospital admissions or presentations to accident and emergency departments. They noted that, in their experience, use of out-of-hours services was not always well communicated with daytime services, so recommended that timely and clear communication take place between services to enable better continuity of support. To address the identified evidence being restricted to a narrow population, the committee made a research recommendation on responding to an escalation of need. ## How the recommendations might affect practice Most of the recommendations aim to standardise current practice and are supported by legislation. The recommendation for a joint assessment in some crisis situations would not have a significant resource impact or cause a change of practice, because this would usually be done by phone or virtually. The current availability of out-of-hours services is varied in the context of Mental Health Act assessments, but according to legislation (section 14.35 of the Mental Health Act Code of Practice) decisions on applications for the detention under the Mental Health Act should be covered over 24 hours so services should have such arrangement in place already. Return to recommendations # Social workers and multidisciplinary teams: communication, support and collaboration Recommendations 1.7.1 to 1.7.8 ## Why the committee made the recommendations The committee agreed that the features of the integrated services covered in the quantitative evidence were not directly applicable to the whole population of people with complex needs. They also noted other limitations in the evidence, such as concerns about the way the studies were conducted and had mixed or contradictory findings, with uncertainties about the size of effects that decreased the confidence in this evidence. Therefore, the committee made recommendations using the qualitative evidence together with their experience and expertise and legislation (the UK GDPR and the Data Protection Act 2018) as well as drawing on BASW's Professional Capabilities Framework and BASW's Charter for integrated working. They agreed that the qualitative evidence highlighted specific aspects that were key to successful integrated working. There was evidence indicating that having shared visions and aims helped to promote integrated working, because it led to an increased understanding between organisations and disciplines. The committee discussed the importance of this to help everyone in the team understand the context in which they work, even if they come from different disciplines. Having a clear strategy should improve team working because overall purposes and objectives can be defined, and everyone knows the part they play. Most of the available evidence related to organisational matters that can help or hinder multidisciplinary team working, rather than focusing on actions taken by individual social workers. This was consistent with the committee's experience of team members' willingness to work together, that they felt could be better supported by the organisations members work for. Supporting information sharing (in line with the UK GDPR and the Data Protection Act 2018) and providing opportunities for clear communication should lead to better teamwork, because members would understand each other's expertise and roles and have opportunities to share knowledge and learn from each other. It would also help team members define what role they can play in providing support to the person with complex needs. The committee also decided that information sharing relies on clear communication within the multidisciplinary team and suggested some measures to increase efficiency. The committee agreed that joint training opportunities would enable the sharing of skills and knowledge between professionals and help them understand each other's roles and responsibilities across different health and social care roles (as well as other relevant settings, for example voluntary sector organisations). This would enable team members to direct the person with complex needs to the practitioner who can provide the most relevant support. Based on the committee's experience, it was noted that training would need to include the views and perspectives of people with lived experience to give team members greater confidence in understanding the role that each of them can play in providing individualised care (as outlined in BASW's Professional Capabilities Framework). This would address addressing people's needs more effectively and in turn lead to improved outcomes. The committee agreed training should not only be about the theory, but also contain practical information with examples of best practice or lessons that have been learnt. This would mean training can be followed up and implemented to improve team working and to benefit people with lived experience (for example, using case studies that show how the principles of best practice of multidisciplinary team working could be applied). There was evidence on barriers to integrated working related to a lack of clarity of roles within integrated teams. Using the evidence on facilitators of integrated working, and drawing on BASW's Charter for integrated working, the committee made recommendations to support social workers in retaining their professional identity when working in an integrated team. This can lead to better outcomes, as the person with complex needs knows what to expect and from which person, so that they are aware which needs can be specifically addressed by a social worker. There was evidence that bureaucracy was often viewed as a barrier to effective integrated working within multidisciplinary teams, negatively impacting efficiency of referral within the team and causing delays. Simplifying referral processes and pathways (for example, with clear eligibility criteria) was seen as a solution for this and would likely improve outcomes by improving the speed and accuracy (in terms of going to the person most able to help) of referral. The committee discussed the evidence related to potential benefits of co-location which was assessed as high-quality thematic evidence and was also supported by the mixed method analysis of qualitative and quantitative evidence. They acknowledged that this could have a positive impact on services but would not always be feasible, practical and could be costly (particularly if it involves new premises), and therefore cannot be routinely implemented. However, the committee recommended that organisations should think about whether this could be a beneficial and achievable option for their particular service (for example, having a social work team in a hospital co-located with healthcare staff may improve joined-up services and could have practical benefits). The committee discussed evidence suggesting shared formal agreements help integrated working. This was in line with their experience, so they recommended such agreements should be used to support integrated teams, particularly in terms of shared decision making and accountability. The committee agreed this should also cover budgets, as the evidence showed that a lack of access to pooled budgets could create barriers to integrated working. ## How the recommendations might affect practice The recommendations largely reinforce current regulation and usual practice. There may be some short-term costs if office accommodation needs to be reconfigured to allow for co-location, although there should be no difference in costs once this has been achieved and potential cost savings through working efficiencies and economies of scale. If physical co-location is not feasible, measures to allow virtual co-location (such as diary sharing and virtual meetings) should involve negligible costs, if any, while allowing potential savings from more efficient and integrated working. Return to recommendations	{'Context': "'Adults with complex needs' is not a defined clinical group but encompasses any adult needing a high level of support with many aspects of their daily life who relies on a range of health and social care services. These needs for support may result from illness, disability, broader life circumstances or any combination of these. Complex needs may be present from birth or may develop over the course of a person's life and may fluctuate. The nature of these needs, and the way society is organised to respond to them, means adults with complex needs often face multiple challenges to living as they would wish and accessing support when it is needed. They are consequently vulnerable to preventable secondary conditions and premature mortality.\n\nSocial workers are one of the main professional groups who support adults with complex needs. They do this in a range of settings, on a long- or short-term basis. Their responsibilities include facilitating the local authority's duty to conduct needs assessments under the Care Act 2014. They also work with individuals and families to address identified needs, effect change and organise support. Social workers can help people with practical, social and interpersonal difficulties, and promote human rights and wellbeing.\n\nThere are about 100,000\xa0social workers registered in England in 2021, according to the Social work in England: emerging themes report by Social Work England. Most commonly they are employed in local authority social care settings, but also in health and voluntary sector services. As well as providing care directly, social workers have a key role in organising support from the wider social care sector and other agencies. They work in a challenging context. The King's Fund Social care 360 report in 2021 describes a rising demand for social care, but a reduction in how many people are receiving care, and that social care funding levels have only just returned to 2010\xa0to\xa02011 levels, after a decade of lower real-terms investment. The Care Quality Commission State of Care report for 2019/20 reports that the quality of social care received by most people was good overall. However, it noted regional variation in access to and quality of care, the need for better integration and joined-up care between services, and that the COVID-19 pandemic is 'having a disproportionate effect on some groups of people, and is shining a light on existing inequality in the health and social care system'.\n\nIn this context, it is vital that the organisation and delivery of social work is informed by the best available evidence about effective ways of working. The Chief Social Worker for Adults' annual report: 2018 to 2019 acknowledges evidence gaps for social work, setting as priorities knowing what works and developing a better evidence base for social work practice.\n\nThis guideline was commissioned by the Department of Health and Social Care to meet this need and develop evidence-based recommendations for social work for adults with complex needs. The guideline was developed by a guideline committee following a detailed review of the evidence. It covers assessment and care management or support which is delivered by or led by social workers. It seeks to provide recommendations which are generalisable to the whole population of adults with complex needs. This guideline is for social workers, and organisations which employ social workers or commission social work services. It is also relevant for adults with complex needs and their involved family and informal carers, and for other professionals who work with social workers in supporting adults with complex needs.\n\nAdults with complex needs are defined as people aged\xa018 or over who need a high level of support with many aspects of their daily life, and relying on a range of health and social care services. This may be because of illness, disability, broader life circumstances or a combination of these. Complex needs may be present from birth or develop over the course of a person's life, and may fluctuate. Unless otherwise specified, when a recommendation refers to 'people' or 'the person', this is the adult with complex needs.\n\nThis guideline does not replace statutory duties and good practice as set out in relevant legislation and guidance, including:\n\nCare Act 2014 and associated guidance\n\nEquality Act 2010\n\nMental Capacity Act 2005\n\nAccessible Information Standard\n\nHuman Rights Act 1998\n\nSocial Work England's professional standards.\n\nThis guideline aims to complement legislation and guidance by providing evidence-based recommendations about how social work interventions including assessment, care management and support for adults with complex needs could be improved. Actions already required by law, or recommended in statutory guidance, are not replicated here unless there was evidence to suggest that these are not implemented consistently in practice, or there was a need to emphasise specific points relevant to social work interventions including assessment, care management and support for adults with complex needs. NICE guidelines cover health and care in England and therefore focus on English legislation. Other UK countries have to follow legislation from the Welsh Government, Scottish Government, and Northern Ireland Executive.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Principles of social work for adults with complex needs\n\n## For social workers\n\nTreat people with respect and dignity, recognising and supporting their decisions and choices. In particular:\n\nshow understanding of people's and their family's circumstances, and be non-judgemental\n\nrespect the validity of the person's lived experience\n\nvalue their first-hand knowledge of their own needs to inform care planning\n\nuse professional curiosity and professional judgement\n\nunderstand the power imbalance between the person and social workers.\n\nWhen first contacting someone, and throughout provision of support, the social worker should establish with the person or with their family, carers or people important to them whether there are any advocacy, sensory or communication needs or impairments, in line with recommendation 1.1.5 in the NICE guideline on people's experience in adult social care services (see also the NICE guideline on advocacy services for adults with health and social care needs).\n\nFor any social work activity or process, the social worker should ensure that the person understands:\n\nthe reasons for the activity or process (for example, an assessment, or care management and support)\n\nthe aims of the activity or process, and how this relates to them\n\nthe key processes that will be followed, ensuring the person knows these at the planning stage for the process or activity\n\nwhat will happen at each new stage in the process (for example, by giving the person information about any upcoming review meetings).\n\nSocial workers should provide people with the support they need to be fully and actively involved in discussion and decision making, taking into account:\n\nwhether the person has any familiarity or previous experience with statutory processes and support agencies\n\nwhether the person might be reluctant to ask for help or raise issues because of personal, societal or other factors, such as stigma or mistrust of services\n\nthe person's expectations and emotional state\n\nthe person's wishes and needs for both family support, and for culturally specific support services.\n\nSocial workers should ensure that they discuss and actively listen to the person's:\n\nhistory and life story\n\nfamily and community networks\n\nexperience of disadvantage, discrimination or abuse\n\nwishes and aspirations\n\npast experiences of services.\n\nSocial workers should discuss with the person how their experiences may impact on their care needs and preferences, and how any difficulties may be mitigated. In these discussions:\n\navoid making assumptions about the individual's circumstances\n\nrecognise that some people's prior positive or negative views and experiences of social work may impact on the relationship with the social worker and services.\n\nSocial workers should explore with the person:\n\ntheir experiences of society and accessing services and\n\nthe potential impact of intersectionality.Take these into account when planning care (for example, by liaising with appropriate support organisations).\n\nWhen planning support, social workers:\n\nmust consider whether reasonable adjustments can be made to protect against, or help the person deal with, discrimination arising from a person's protected characteristics as defined by the Equality Act 2010, or from other life circumstances and experiences (see box\xa01) and\n\nrecord the rationale for the decision made.\n\nProtected characteristics of the Equality Act 2010\n\nage\n\ndisability\n\ngender reassignment\n\nmarriage and civil partnership\n\npregnancy and maternity\n\nrace\n\nreligion or belief\n\nsex\n\nsexual orientation.\n\nLife circumstances and experiences that could lead to discrimination or inequalities, including:\n\nmodern slavery\n\ncoercive control\n\ndomestic abuse\n\ntrafficking\n\nrefugee status\n\nasylum seeking\n\nbeing a migrant\n\nbeing from a traveller community\n\nbeing a prisoner\n\nbeing an offender\n\nhomelessness\n\npoor literacy\n\nlearning difficulties\n\nlearning disabilities\n\ncognitive impairment\n\nacquired brain injury\n\nautism\n\ncommunication impairment\n\nleaving care\n\ntransitioning from children's to adults' care services\n\nsensory impairment\n\nsubstance misuse\n\nliving in rural and isolated areas\n\nlong-term conditions\n\nEnglish not being a first language\n\nsocio-economic status\n\naddictions.\n\nThe social worker must inform the person, in accordance with the UK General Data Protection Regulation (GDPR) and the Data Protection Act 2018, about the extent and content of information sharing across agencies and within multidisciplinary teams, and their rights in relation to this.\n\nThe social worker should be aware of NICE guidance about relevant conditions that could affect the person they work with and how they work with them. For example, the NICE guidelines on:\n\nautism spectrum disorder in adults\n\nchallenging behaviour and learning disabilities\n\ncystic fibrosis\n\ndepression in adults\n\nmultiple sclerosis in adults\n\npsychosis and schizophrenia in adults.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on principles of social work for adults with complex needs (for social workers)\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: needs assessment\n\nevidence review\xa0B: risk assessment\n\nevidence review\xa0C: supporting changing needs\n\nevidence review\xa0E: integrated working.\n\nLoading. Please wait.\n\n## For organisations\n\nWhat is an 'organisation'?\n\nIn the context of this guideline, organisations are bodies that employ social workers in a professional capacity. This can include local authority social care departments, health services, the criminal justice system, higher and further education and voluntary and community services.\n\nOrganisations (see box\xa02) should consider making time allowances for social workers in caseloads so they can build relationships with people with complex needs. Recognise that building relationships may take longer with people who may have had negative experiences with services, or people concerned about stigma from being in contact with services.\n\nOrganisations should provide continuous professional development for social workers that specifically covers equality and diversity, so they are competent and confident in:\n\nasking all people they support about their personal and social identity as well as circumstances or experiences that may lead to inequalities or discrimination (for example, related to characteristics listed in box\xa01) and\n\nunderstanding how their personal and social identity as well as circumstances or experiences may affect their lives, care needs and preferences.\n\nOrganisations should provide continuous professional development to ensure that social workers have up-to-date relevant legal literacy and sufficient knowledge of, for example, the:\n\nMental Capacity Act 2005\n\nMental Health Act 2007\n\nHuman Rights Act 1998\n\nEquality Act 2010\n\nCare Act 2014\n\nChildren Act 1989\n\nrelevant case law\n\ninherent jurisdiction of the High Court.\n\nOrganisations, commissioners and social workers should:\n\nrecognise that people with complex needs may experience the impact of intersectionality, resulting in increased inequalities in access to and outcomes of health and social care and\n\ntake this into account when planning and delivering services so they are accessible and responsive to the whole range of people's needs (for example, if a person has multiple health and social care needs this could be addressed by multidisciplinary working between health and social care services – see the section on social workers and multidisciplinary teams: communication, support and collaboration).\n\nOrganisations should develop a framework, in line with the Social Work England professional standards, to support social workers in contributing to an open and creative learning culture in which they can:\n\ndiscuss and share best practice to promote the rights, strength and wellbeing of people, families and communities\n\nreflect on their own practice and that of their colleagues\n\nshare experiences and learn from each other about how to balance the rights of the individual with the risks to self and others.\n\nFor other principles of improving people's experience in adult health and social care services, including the principles of care and communication, see the NICE guidelines on people's experience in adult social care services, patient experience in adult NHS services and service user experience in adult mental health. For guidance on how to make information accessible, see the NHS Accessible Information Standard.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on principles of social work for adults with complex needs (for organisations)\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0B: risk assessment\n\nevidence review\xa0F: individual or family casework\n\nevidence review\xa0G: helping people connect with local communities.\n\nLoading. Please wait.\n\n# Assessment\n\n## Needs assessment\n\nThe social worker should give the person information about their upcoming needs assessment in a format that is in line with their needs and preferences, and is accessible to them. Ensure they have enough notice and time to review documents, and prepare for the assessment.\n\nIn line with regulation 10 of the Care Act 2014, the social worker must inform carers of people with complex needs about their right to a carer's assessment (for more information, see the NICE guideline on supporting adult carers).\n\nThe social worker should inform the person being assessed about where and how they can access information about their rights under relevant legislation, such as the Care Act 2014, the Human Rights Act 1998 or the Mental Capacity Act 2005 (for example, providing written or oral information or signposting to relevant online resources or agencies – see also the section on principles of social work for adults with complex needs for relevant links related to meeting communication needs).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment – needs assessment (providing information)\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: needs assessment.\n\nLoading. Please wait.\n\nThe social worker should be aware that a needs assessment can be stressful for the person being assessed, and their families and carers. Ensure that assessment practices are designed to minimise stress whenever possible, including:\n\nusing a flexible approach to tailor the assessment to the person's needs (for example, by amending the order of assessment questions)\n\nhelping the person to understand assessment documentation when appropriate (for example, explaining complex concepts in a simple, clear way).\n\nSocial workers should consider arranging a preparatory initial contact before the assessment itself if it will help the person with complex needs to participate fully in their assessment (in line with statutory guidance for a proportionate assessment in the Care Act 2014), taking into account:\n\nthe urgency of the person's support need\n\nwhether the person wants a preparatory initial contact, and if so whether they would prefer this as a home visit, virtual contact or a phone call\n\nwhether the person would have substantial difficulty in being involved in the assessment and if so, whether an independent advocate should be provided for the assessment.\n\nThe social worker should ask the person about their preferences for the practical arrangements of the assessment, such as:\n\nthe time and place of the assessment\n\nremote or in-person assessment\n\nwhether they would like a supported self-assessment\n\nwhether they would like anyone to be present to support them, for example a family member, carer or an independent advocate.\n\nThe social worker should take into account that when there is a concern about potential safeguarding issues, an in-person assessment is likely to be needed.\n\nIf the person chooses supported self-assessment, the social worker should discuss the advantages and disadvantages of this option with them, taking into account the complexities of their needs.\n\nThe social worker should offer people with complex needs individualised support to complete a self-assessment, such as:\n\nensuring that they have complete information about what it involves, including the list of areas and questions which it covers\n\ninvolving advocacy services\n\nproviding details of who to contact if they want to clarify or discuss any areas of the assessment\n\ngiving reassurance that they can ask for an in-person assessment if their preference changes.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment – needs assessment (planning the assessment)\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: needs assessment.\n\nLoading. Please wait.\n\nThe social workers must ensure that the information provided by supported self-assessment is an accurate reflection of the person's circumstances (in accordance with section 6.44 of the Care and support statutory guidance, 2021). This can be done by cross referencing it with information from other sources (this should typically include involved family and carers or the multidisciplinary team).\n\nThe social worker must conduct the needs assessment for adults with complex needs in compliance with statutory guidance (see regulation 2(1) of the Care Act 2014), and taking account of the following:\n\nwhether the person's needs arise from or are related to a physical or mental impairment or illness\n\nwhether the person would have difficulties in achieving 2 or more of the 10\xa0listed outcomes; see regulation 2(2) of the Care Act 2014\n\nwhether there is a significant impact on wellbeing\n\nwhether there are any unmet needs that may relate to a condition or difficulty that may need input from other specialist services, for example from speech and language services or mental health services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment – needs assessment (conducting the assessment)\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: needs assessment.\n\nLoading. Please wait.\n\nThe social worker should give the person a draft copy of their assessment and reviews, and the opportunity to identify any inaccuracies, omissions or differences of perspective, before the assessment is finalised.\n\nThe social worker should acknowledge and record in formal case notes and the care and support plan any differences of opinion about the needs assessment.\n\nThe social worker should give people with complex needs, their families and carers and other people important to them information about the complaints procedure, including how to access it and how to lodge a complaint if they wish to about the process or the outcome of the assessment.\n\nIf the person chooses a self-assessment, the organisation must provide them with relevant information that they hold about them and their carer's assessment if applicable, taking into account legal requirements related to consent (in line with sections 2 and 2 of the Care and Support [Assessment] Regulations 2014).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on needs assessment (recording and reviewing the assessment)\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: needs assessment\n\nevidence review\xa0B: risk assessment.\n\nLoading. Please wait.\n\n## Risk assessment\n\nSocial workers should assess risks as part of a holistic process of assessing the person's strengths, needs and wishes.\n\nThe social worker should discuss and record the person's views on involving family, carers, and other people important to them in the risk assessment in the formal case file. Let the person know that it has been recorded and share this information across relevant agencies and with other social workers when appropriate and necessary (in line with the UK GDPR and the Data Protection Act 2018).\n\nThe social worker should consider conducting the risk assessment over several contacts, so that:\n\nthere is an opportunity for rapport to develop between the social worker and person being assessed\n\nthe person's perspective on risks, their strengths, needs and wishes, and their health, environment and support networks are understood.\n\nWhen planning a risk assessment, take into account the urgency of any situation that may need a risk assessment within a short timeframe (for example, in a single visit; see also the section on responding to an escalation of need, including urgent support).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk assessment (planning the risk assessment)\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: risk assessment.\n\nLoading. Please wait.\n\nThe social worker should support the person to engage in advance care planning, including:\n\nplanning to cover their wishes in the event of any future loss of capacity (see the section on advance care planning in the NICE guideline on decision making and mental capacity)\n\ndeveloping a risk management plan.\n\nWhere a social worker has reasonable cause to suspect a person has experienced, is experiencing or is at risk of abuse or neglect, they must follow local safeguarding policies. If a need for action is established, the social worker must follow statutory safeguarding processes as set out in regulation 42 of the Care Act 2014.\n\nFor people with complex needs, social workers should tailor risk assessments to the person's strengths and needs and take into account beneficial and harmful outcomes, and their likelihood of occurring, including:\n\nrisks to the person from their own behaviour (including accidents, self-neglect and suicide or self-harm)\n\nrisks from others (including physical or sexual violence, psychological harm, neglect or exploitation)\n\nrisks of harm to others\n\nrisks of loss of independence or breakdown of caring arrangements.\n\nWhen assessing mental capacity, social workers must take account of section 1(4) of the Mental Capacity Act 2005, and not assume that the person lacks capacity because they have made a decision that the practitioner perceives as risky or unwise. See also the section on assessment of mental capacity in the NICE guideline on decision making and mental capacity, including recommendation 1.4.19 on the difficulty in assessing capacity in people with executive dysfunction.\n\nIf a person lacks the mental capacity to make decisions related to risk, the social worker must seek and take into consideration their current wishes (and any relevant past wishes expressed at a time when they were believed to have capacity) about any decisions, in line with section 4(6) of the Mental Capacity Act 2005. For further details, see the NICE guideline on decision making and mental capacity.\n\nIf a person makes a decision that is likely to put them at significant risk, the social worker should consider assessing their capacity to understand, retain and weigh up the relevant information about safety, taking into account:\n\nprevious decisions and choices and\n\nthe perspectives of involved family members, carers and multidisciplinary team members.\n\nSocial workers should use plain language and terminology that is understandable and acceptable to the person. For example, talking about 'safety' or 'being careful', rather than 'risk' or 'self-neglect'.\n\nIn discussions between the person and the social worker about risk, consider the use of a structured risk checklist.\n\nThe risk assessment should:\n\ninclude discussion of what has caused previous problems and unplanned escalation of needs\n\nidentify what interventions have worked previously to manage and reduce risks.\n\nWhen assessing risk, in accordance with Social Work England's professional standards, social workers should:\n\nthink about how any assumptions or personal biases may have influenced their assessment (for example, assuming that frail people would not want to participate in physical activities)\n\nbe reflective about their own values, and challenge the impact they have on their practice (for example, how they personally feel about tidiness when working with a person who is hoarding).\n\nSocial workers should respect people's rights to make decisions that they (the social worker) perceive as risky or unwise when the person has capacity to do so. Do not use such decisions as a reason to refuse care.\n\nIf a person with capacity declines an intervention aimed at reducing risk (see recommendation 1.2.22 for the types of risk that may need to be reduced), social workers should continue to work with them to find ways to minimise risks.\n\nIf a person has been assessed as lacking capacity, then in accordance with the Mental Capacity Act 2005, social workers must:\n\nascertain the person's best interests (using the best interests checklist in line with section 4 of the Mental Capacity Act 2005), including identifying whether there is a Lasting Power of Attorney or court-appointed deputy with appropriate decision-making powers to make best interests decisions\n\nensure any restrictions or supervision in their care are proportionate to the risk of harm to the person\n\ntake into account any less restrictive ways of meeting the person's needs and managing risks and use these where appropriate.\n\nSocial workers should avoid over-reliance on risk prediction (such as 'high' or 'low' risk) during assessments and when recording risks, and instead specify strategies on how to respond to factors contributing to increased risk and reduce potential harms.\n\nWhen deciding whether to share information in circumstances where the person does not give consent, the social worker:\n\nmust balance the rights of the person with complex needs under the Human Rights Act 1998, Article 8 (right to respect for private and family life) against the effect on children or individuals at risk if they do not share the information and\n\nshould record all information-sharing decisions, and the reasons for those decisions, in line with the organisation's procedures and requirements.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk assessment (conducting the risk assessment)\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0B: risk assessment\n\nevidence review\xa0C: supporting changing needs.\n\nLoading. Please wait.\n\nIn complex risk management situations involving potential risks of serious harm, the social worker should initiate and participate in a case conference involving all relevant agencies to:\n\nshare information (in line with the UK GDPR and the Data Protection Act 2018) and\n\ndevelop a coordinated risk management plan.\n\nThe social worker should include the person (and the person's advocate, family and carers, if they wish them to be present) in case conferences for complex risk management situations involving potential risks of serious harm, unless doing so:\n\nwould present a risk to (or cause an escalation of risk for) the person or\n\nwould present a risk to any of the other parties involved (social workers, other care staff, or the person's advocate, family or carers).\n\nThe social worker should ensure that relevant information on significant concerns about risks is shared and discussed with all necessary agencies (taking into account the legal requirements under the UK GDPR and the Data Protection Act 2018).\n\nThe social worker should:\n\ngive the person a draft copy of their risk assessment, and the opportunity to identify any inaccuracies, omissions or differences of perspectives, before the risk assessment is finalised\n\nacknowledge and record any differences of opinion about the assessment of risk in the risk assessment document and formal case notes.\n\nSocial workers should review risk assessments:\n\nat least annually and\n\nif needed, in response to an identified change in the person's circumstances or change in risks.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk assessment (recording and reviewing the risk assessment)\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: needs assessment\n\nevidence review\xa0B: risk assessment.\n\nLoading. Please wait.\n\nOrganisations should:\n\nprovide de-escalation training to staff to support their safety\n\nhave systems for formally recording incidents of aggression, threats or abuse against staff.\n\nOrganisations should support staff when they experience any safety-related incidents, for example by:\n\ndebriefing them\n\nproviding peer support\n\nproviding counselling following serious incidents.\n\nOrganisations should provide access to advice for social workers whenever they are working, including outside normal office hours, about immediate concerns related to the risk to the person with complex needs or others.\n\nOrganisations should ensure the following are in place:\n\ntraining, including multi-agency training, to support staff in assessing risks thoroughly\n\nsupervision structures to support staff and encourage reflective and inclusive practice (for example, a multidisciplinary team discussion about individual situations).\n\nOrganisations should have a written strategy promoting a culture that supports staff in helping people with complex needs balance the benefits and harms relating to risk taking. This could include, for example, training and governance systems to support social workers with assessing complex and high-risk situations.\n\nFor further principles of decision making in situations where people may lack capacity, see the NICE guideline on decision making and mental capacity.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk assessment (organisational support)\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: risk assessment.\n\nLoading. Please wait.\n\n# Individual or family casework\n\nSocial workers should take account of the principles of social work for adults with complex needs when conducting individual or family casework.\n\nSocial workers should help people with complex needs to identify personal goals and desired outcomes (for example, through task-focused approaches).\n\nSocial workers must understand the options available through legal frameworks so they can effectively support the rights of the person and the rights (and limits of the rights) of family members, including in situations of conflict and challenge. For example:\n\nCare Act 2014's requirement for advocacy\n\nMental Capacity Act 2005 requirements on deprivation of liberty safeguards and the Mental Capacity (Amendment) Act 2019 requirements on liberty protection safeguards\n\nHuman Rights Act 1998\n\nSafeguarding Vulnerable Groups Act 2006\n\nProtection of Freedoms Act 2012.\n\nOrganisations should consider training and support for social workers to promote the rights, strength and wellbeing of people and families (in line with Social Work England's professional standards) to gain specialised and advanced skills in family interventions (for example, behavioural family interventions, family group conferences and restorative approaches).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on individual or family casework\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: individual or family casework.\n\nLoading. Please wait.\n\n# Helping people to connect with local communities and reduce isolation\n\nTo help people with complex needs develop social connections, social workers should talk to them about their social networks, strengths (using strengths and asset-based approaches), and preferences for activities and social contact.\n\nSocial workers should help people to access a range of groups, social activities and social networks to meet their needs and preferences, looking across the community in addition to what is provided by health and social care services. This could be done by:\n\nidentifying local community groups and networks, and resources (for example, social clubs, community gardens, faith and cultural groups, user-led social groups)\n\nfinding out about these resources and whether they may meet the person's needs and preferences\n\nhelping the person make contact with these groups and activities (for example, by arranging IT and digital training, using familiar and accessible places).\n\nSocial workers should think creatively about the types of community resources and networks that they can put in place or support people to develop (for example, by active involvement in commissioning discussions and flexible use of personal budgets, including direct payments).\n\nThe social worker should check with the person whether any new community connection is meaningful, beneficial to wellbeing and enjoyable, and if not support the person to find a more suitable alternative.\n\nOrganisations and social workers should keep up to date with information on currently available community assets, and pass this information on to adults with complex needs and their families. For example by:\n\ncreating lists of resources and updating them regularly\n\nallocating workers to identify resources\n\nliaising with community groups\n\ncommissioning voluntary organisations to keep up-to-date resource lists.\n\nOrganisations should make information available about their services, and other community resources to people with complex needs (for example, disabled people's user-led organisations and other community groups). This information should cover:\n\ncatchment area, and people's right to access services outside of their catchment area\n\neligibility criteria\n\nreferral processes.\n\nFor information on community engagement approaches that seek to improve health and wellbeing and reduce health inequalities, see the NICE guideline on community engagement: improving health and wellbeing and reducing health inequalities. For information aimed at engaging people over 65\xa0years in activities to improve mental wellbeing, see the NICE guideline on mental wellbeing in over\xa065s: occupational therapy and physical activity interventions.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on helping people to connect with local communities and reduce isolation\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0F: individual or family casework\n\nevidence review\xa0G: helping people connect with local communities.\n\nLoading. Please wait.\n\n# Supporting people to plan for the future, including considering changing needs, wishes and capabilities\n\nThe social worker should provide information to support the health and wellbeing of carers in their caring role, and on how the carer can help support the person with complex needs. See also the recommendations on providing information and support to carers in the NICE guideline on supporting adult carers.\n\nSocial workers should ensure that care planning meetings take place in the person's preferred location whenever possible and practical.\n\nSocial workers should implement a rights-based approach to case management and care planning. This should reflect the following principles:\n\npromoting people's dignity and wellbeing\n\nrespecting people's right to self-determination\n\npromoting and supporting participation\n\ntaking a holistic approach\n\nfocusing on people's strengths and not solely on their needs.\n\nSocial workers should, when appropriate and wanted, include input from key support networks in the person's care plan. This should:\n\nbe in collaboration with the person, and with their consent\n\ninclude paid and unpaid support networks (for example, family, carers and other people important to them).\n\nSocial workers should respond to the person and their changing circumstances by:\n\ndeveloping a plan that is flexible and responsive\n\nreviewing and revising the care plan in response to fluctuating, evolving or rapid changes\n\ndeveloping and identifying options according to the person's needs, wishes and preferences (for example, by helping people connect with local communities as described in the section on helping people to connect with local communities and reduce isolation)\n\nensuring consistency of care by integrating working across the range of health and social care services involved (see the section on the social worker's role in multidisciplinary teams).\n\nSocial workers should ensure that, at time of writing or review, care plans:\n\ntake account of the person's wishes and preferences\n\nstate how the person's eligible and non-eligible needs would be best met\n\nidentify how arrangements have been or will be made to meet eligible needs\n\nrecord any eligible needs which are unlikely to be met or only partially met, the reasons they cannot be met or only partially met and any potential actions that would allow them to be met in future.\n\nThe social worker should ensure that the person has their work contact details so they can get in touch if their needs or circumstances change. Document this information in the person's care plan.\n\nThe social worker should plan the review date of the care plan with the person (a review should happen at least once a year), or conduct an unplanned review as soon as possible if, for example:\n\nthe person's needs escalate or reduce, and circumstances change (for example, after transfer from hospital)\n\nthe person, or their carer, a family member, advocate or another person important to them requests it.\n\nEach social worker must (in line with Social Work England's professional standards):\n\nuse supervision and feedback to critically reflect on their own practice, including how research and evidence has informed practice\n\nkeep their practice up to date, and record how research, theories and frameworks inform practice and professional judgement\n\ncontribute to an open, creative, learning culture in the workplace to discuss, reflect on and share best practice.\n\nWhere possible, organisations should provide people who receive social work support with a named social worker.\n\nOrganisations should provide social workers with regular practice-based supervision and support, ensuring organisational resources are sufficient to allow:\n\ncontinuity of named social workers or a clear handover if the social worker has to change\n\nadequate time to monitor and review cases\n\nresponsiveness to unexpected change\n\nthe ability to be flexible, when appropriate, to the needs of the person.\n\nTo support people to plan for the future when they transition between services, settings or between levels of care, see the following NICE guidelines:\n\ntransition between inpatient hospital settings and community or care home settings for adults with social care needs (in particular, section\xa01.5 on discharge planning)\n\ntransition between inpatient mental health settings and community or care home settings (in particular, section\xa01.5 on discharge planning)\n\ntransition from children's to adults' services for young people using health or social care services (in particular, section\xa01.2 on transition planning)\n\nintermediate care including reablement (in particular, section\xa01.7 on transition from intermediate care).\n\nTo support people growing older with learning disabilities to plan for the future, see recommendations 1.4.5 to 1.4.7 in the NICE guideline on care and support for people growing older with learning disabilities.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting people to plan for the future including considering changing needs, wishes and capabilities\xa0.\n\nFull details of the evidence and the committee's discussion are in\n\nevidence review\xa0C: supporting changing needs\n\nevidence review\xa0F: individual or family casework.\n\nLoading. Please wait.\n\n# Responding to an escalation of need, including urgent support\n\nWhen responding to an unplanned escalation of need, social workers should take into account the person's wishes, preferences, social circumstances and cultural background (for example, if someone expresses a strong desire to stay at home, even if necessary care may more easily be provided in a residential or inpatient setting).\n\nIn the event of an unplanned escalation of need, social workers (with consent from the person) should:\n\nassess the escalated need jointly with colleagues who have the most knowledge about the person's care, wherever practical (for example, requesting a community Care and Treatment Review or a case conference)\n\nconsult on the response to the escalated need with:\n\n\n\nother involved practitioners and community organisations\n\nrelevant family and social networks.\n\n\n\nWhen an unplanned escalation of need occurs, social workers must:\n\nexplore the least restrictive alternatives to address the need (in accordance with section 1(6) of the Mental Capacity Act 2005)\n\nseek provision of interventions that will have the least detrimental impact on the person's rights and living situation.\n\nSocial workers should establish whether a person with complex needs has any advance statement of their wishes or crisis planning, and must take these into account when planning care during a crisis. Document in the person's records how this has informed decision making and review the plan after an escalation of need.\n\nWhen responding to an escalation of need, as well as considering an advance statement if available, the social worker should take into account and document:\n\nthe person's wishes and preferences\n\nthe views of others (for example, family, carers, and other people important to them) concerned for the person's welfare.\n\nOrganisations should ensure that social workers have access to prompt support and opportunities to be debriefed during and after their work with someone experiencing a crisis. This should include the opportunity for social workers to reflect on practice and the potential risk to themselves and the person.\n\nLocal authorities should have arrangements in place to provide services that:\n\nare available 24 hours, so decisions on applications for detention under the Mental Health Act (in line with section 14.35 of the Mental Health Act 1983: Code of Practice) can be made at any time\n\ncan respond promptly to a person's escalating need\n\ncommunicate any out-of-hours responses to escalating need quickly and clearly to daytime services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on responding to an escalation of need, including urgent support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: support during an escalation of need.\n\nLoading. Please wait.\n\n# Social workers and multidisciplinary teams: communication, support and collaboration\n\nOrganisations should ensure that multidisciplinary teams develop a shared statement of values, core purposes and activities, and have clear objectives and aims to jointly work towards.\n\nOrganisations should consider the routine sharing of information (in line with the UK GDPR and the Data Protection Act 2018), and of professional expertise and perspectives, within the multidisciplinary team (for example, with joint working, forums or team meetings, themed discussions, or by championing a particular multidisciplinary approach).\n\nOrganisations should ensure there is clear communication within the multidisciplinary team by:\n\nholding multidisciplinary team meetings, including case discussions\n\nhaving mutual access to diaries when possible\n\nproviding virtual means to stay in touch even when team members are working from different locations\n\nmaking use of informal opportunities to communicate (for example, staff networking events).\n\nOrganisations and commissioners should provide interdisciplinary training to promote shared understanding of each role in the team, and the legal frameworks within which they work, as well as an understanding of the range of lived experiences of people with complex needs. This should:\n\nbe provided across health and social care including other relevant settings as needed\n\nbe co-produced with people with lived experience\n\nbe ongoing\n\nbe followed up with clear plans for implementing any best practice and lessons learnt from the training sessions.\n\nOrganisations should support social workers in defining their role within multidisciplinary teams by:\n\nproviding professional social work supervision, in particular when the team manager is not a social worker\n\nproviding opportunities for peer supervision\n\nmaking joint training available that provides clarity about the role of the social worker within a multidisciplinary team\n\nproviding bespoke, continuing professional development for social workers\n\nrecognising and addressing differences in organisational culture between professionals involved in the team.\n\nTo improve the efficiency of referral within multidisciplinary teams, health and social care organisations should simplify referral processes and referral pathways, for example by having clear and simple eligibility criteria.\n\nOrganisations should think about co-location to support more efficient responses and opportunities for discussion within multidisciplinary teams where feasible.\n\nOrganisations should develop shared formal agreements (including budgets and information sharing) early in the process of establishing integrated working to underpin accountability and decision making.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on social workers and multidisciplinary teams: communication, support and collaboration\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: integrated working.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Debriefing\n\nDebriefing after a distressing or safety-related incident involves the social worker having an opportunity to speak to a manager or senior colleague as soon as possible after the incident. This can be used, for example, to acknowledge the difficult situation and look into any support the social worker needs, including psychological support or counselling. This could start a reflective process to identify any lessons or ways to improve practice in future.\n\n## Intersectionality\n\nThe term describes the interconnected nature of social categorisations such as age, disability, gender reassignment, pregnancy and maternity, race, religion or belief, sex and sexual orientation and other characteristics or experiences listed in box\xa01, regarded as creating overlapping and interdependent systems of discrimination or disadvantage.\n\n## Professional curiosity\n\nProfessional curiosity is to explore and understand what is happening with an individual or family; enquiring deeper and using skilled, proactive questioning and investigation. It is about comparing what the person is saying with what is observed and any other available information, questioning any incongruity, rather than making assumptions or taking things at face value, to provide appropriate and tailored support.\n\n## Rights-based approach\n\nA rights-based approach ensures that both the standards and the principles of human rights are integrated into policy making, as well as the day-to-day running of organisations and social work practice.\n\n## Strength and asset-based approaches\n\nStrengths and asset-based approaches in social care focus on what individuals and communities have, and how they can work together, rather than on what individuals or communities cannot do or do not have. The terms 'strengths' and 'assets' are often used interchangeably to apply to either individuals or communities. Personal strengths and assets can include relationships, experience, skills and aspirations. Community strengths and assets can include knowledge, people, spaces, networks and services.\n\n## Task-focused approach\n\nThis approach seeks actionable solutions to specific problems. It usually involves 4 steps:\n\ndefining a target area to work on together\n\nagreeing specific goals and actions for both the social worker and the person they are supporting to help achieve these goals\n\ndiscussion and support about progress with, and impact of, agreed actions\n\nreviewing and deciding whether a further process of task-centred goal setting is needed or the process has been successfully completed.\n\nTask-focused work is typically relatively brief but can be applied flexibly across a range of social work contexts as stand-alone support or within a broader package of care.\n\n## Wellbeing\n\nIn the context of the guideline, wellbeing is defined in accordance to regulation 1(2) of Care Act 2014, which states:\n\n'Wellbeing', in relation to an individual, means that individual's wellbeing so far as relating to any of the following:\n\npersonal dignity (including treatment of the individual with respect)\n\nphysical and mental health and emotional wellbeing\n\nprotection from abuse and neglect\n\ncontrol by the individual over day-to-day life (including over care and support, or support, provided to the individual and the way in which it is provided)\n\nparticipation in work, education, training or recreation\n\nsocial and economic wellbeing\n\ndomestic, family and personal relationships\n\nsuitability of living accommodation\n\nthe individual's contribution to society.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Needs assessment\n\nFrom the perspective of everyone involved, what is the acceptability of strengths and rights-based approaches to social work assessment and what are the barriers and facilitators to delivering these?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on needs assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: needs assessment.\n\nLoading. Please wait.\n\n## Risk assessment\n\nFrom the perspective of everyone involved, what works well and could be improved about the use of tools and checklists to support social work risk assessment for people with complex needs?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on risk assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: risk assessment.\n\nLoading. Please wait.\n\n## Supporting people to plan for the future\n\nWhat is the effectiveness and cost-effectiveness of early, preventative support for people with complex needs?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on supporting people to plan for the future\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: supporting changing needs.\n\nLoading. Please wait.\n\n## Responding to an escalation of need\n\nWhat is the effectiveness and acceptability of social work interventions to support people with complex needs during an escalation of need?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on responding to an escalation of need\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: support during an escalation of need.\n\nLoading. Please wait.\n\n## Helping people to connect with local communities and reduce isolation\n\nWhat social and community support approaches are effective in promoting social inclusion of people with complex needs?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on helping people connect with local communities and reduce isolation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: helping people connect with local communities.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice or services.\n\n# Principles of social work for adults with complex needs\n\n## For social workers\n\nRecommendations 1.1.1 to 1.1.10\n\nThe committee looked at a range of evidence to inform the recommendations, which are intended to underpin all social work with adults with complex needs. They also took the Human Rights Act 1998, the Equality Act 2010, the Care Act 2014 and the UK General Data Protection Regulation (GDPR) and the Data Protection Act 2018 into account to address potential inequalities and data protection issues (for example, in access to services or in the services that people with complex needs receive). They also drew on the professional standards from Social Work England, the Professional Capabilities Framework from the British Association for Social Workers (BASW) and the Code of Ethics from BASW.\n\nThe committee discussed qualitative evidence related to supporting people to plan for the future that highlighted some of the barriers that could influence people's access to and participation with services (for example, poverty, which is associated with inadequate housing and limited access to support). Such barriers could, in turn, result in people who use services feeling shame about their health conditions or living circumstances. This could further isolate them and make it more challenging for providers to support them. The committee therefore made a recommendation to emphasise that social workers need to treat people with respect and dignity to prevent barriers developing, and to understand and take into account the different circumstances of people with complex needs and any of their past experiences of services. This is also in line with the Human Rights Act 1998 and the Equality Act 2010.\n\nThere was some qualitative evidence related to approaches to needs assessments that showed people were not always aware of what to expect from an assessment, and that language could be a barrier to communicating with social workers during the assessment. The committee agreed that meeting these needs are important principles that would apply to all aspects of social work, so they decided to broaden the recommendation beyond just the assessment process. They recommended that the social worker find out whether an advocate is needed to support the person and help with communication, information and understanding the legal framework. The committee discussed that some people (for example, people with learning disabilities) may also have particular sensory needs or impairments (for example noise level or brightness of light) and therefore added that this should also be taken into account. Based on the same evidence, the committee also emphasised the importance of ensuring that all the person's communication needs and preferences are addressed, to help them to actively participate in discussions. They noted that this was already covered in the section on overarching principles in the NICE guideline on people's experience in adult social care services so they included a cross reference to this.\n\nThere was also some qualitative evidence showing that people did not always understand the purpose of the needs assessment and what it would entail. The committee used this evidence to recommend that sufficient information is provided for all activities and processes so that the person can understand what is going to happen and why. This will mean they can make informed choices and actively participate in the assessment.\n\nThe committee discussed the support that people may need to be actively involved in social work processes:\n\nqualitative evidence showed that cultural differences created challenges for practitioners\n\nqualitative evidence showed that not having family support can be detrimental to the person's wellbeing\n\nquantitative evidence showed that differences in perspective because of culture lead to care needs not being raised or recognised by social workers\n\nin the committee's own experience, people's life experiences, expectations and emotional state can have an impact on their care experiences, and consequently lead to inequalities and poorer outcomes.\n\nThe committee made recommendations to address these problems. They also highlighted the positive impact of family support (if needed and wanted) which can help the person to be actively involved.\n\nThe committee drew on both quantitative and qualitative evidence from the review of individual and family casework. They discussed the qualitative evidence that suggested people's cultural experiences and perspectives can differ from those of the practitioner, and that this may result in the practitioner making assumptions. Based on experience and expertise, the committee emphasised that the starting point would be relationship building to identify a person's characteristics that might predispose them to inequality in healthcare provision, by actively listening to the person. They highlighted that forming trusting relationships is the cornerstone of social work and that looking at all aspects of the person's life would ensure that the social work approach has the person with complex needs at its centre, and that any reasonable adjustments are being made in relation to those needs. They discussed that a record of reasonable adjustment decisions should be made to ensure that this was given due consideration. The committee noted that there was only a small amount of evidence, but acknowledged that this was a key area of social work that could lead to inequalities in access to care and care provision, if not addressed. In the absence of evidence for other experiences and circumstances that may lead to inequalities and discrimination, which may be multiple (see the definition of intersectionality), the committee applied the evidence about the challenges of cultural differences and assumption as well as their knowledge from the Equality Act to cover the protected characteristics as well as other life circumstances and experiences (see box\xa01).\n\nThe committee noted that a lot of qualitative evidence on the social worker's role in multidisciplinary teams referred to information sharing as a potential facilitator to integrated working, as it provides continuity (and conversely, acts as a barrier if not present). They discussed, based on their experience, that information gets shared more about people with complex needs and between more agencies. There were concerns about the extent of information sharing, however. In the committee's experience, people with complex needs value continuity and consistency and generally think that it is a positive idea to share information, but they want to be informed when and what information is shared and with whom (whenever this is possible and appropriate, in line with UK GDPR and the Data Protection Act 2018). The committee decided that this is a principle that should not be restricted to multidisciplinary team working but applies to all social work practice. The committee agreed that people need to be reassured that there are legal limits on information sharing and that their data is protected, but also that sharing where possible would mean that they would not have to repeatedly tell their life stories.\n\nThe committee discussed that there are a wide range of conditions, impairments or fluctuating health conditions that lead to complex needs. They discussed that the guideline should be viewed in the context of such needs and that social workers when meeting a person with a particular condition should be aware of the relevant condition-specific guidance associated with this. The committee decided to give some examples of the range of conditions that may be applicable.\n\nThe committee noted that most of these recommendations would standardise practice, as they are actions that are mandated by legislation (particularly the Equality Act 2010, the Care Act 2014), and supported by Social Work England's professional standards or BASW's Professional Capabilities Framework. This is particularly in relation to information sharing, and active listening and relationship building.\n\nReturn to recommendations\n\n## For organisations\n\nRecommendations 1.1.11 to 1.1.16\n\nThe committee looked at a range of evidence to inform the recommendations, which are intended to underpin all social work with adults with complex needs. They also took into account the Human Rights Act 1998, the Equality Act 2010 (for example, to address inequalities in access to services or in the services that people with complex needs receive), the Care Act 2014, the UK GDPR and the Data Protection Act 2018 and the professional standards from Social Work England.\n\nThe committee used qualitative evidence from the reviews on individual and family casework, and helping people to connect with local communities and reduce isolation. This showed that the social work approach that people received was not sufficiently long or in-depth enough to address their complex needs. Based on this evidence, the committee recommended organisations provide sufficient time to social workers to build relationships in order to reduce inequalities.\n\nThe committee discussed that people's life experiences may have an impact on their care experiences, and consequently lead to inequalities in access to care and care provision and poorer outcomes. They recommended organisations support and train social workers to discuss people's personal and social identities, and life experiences. This is in line with professional standard 1.6 from Social Work England that outlines the role of the social worker to promote social justice, helping to confront and resolve issues of equality and inclusion. This would enable social workers to feel confident that they are providing an environment where people feel that they are free of discrimination, and emotional or physical harm, and feel safe in discussing the complex needs that they have. The committee highlighted that this would also improve wellbeing of people, but they discussed that the term wellbeing is sometimes interpreted only in physical health terms. They therefore decided to adopt the definition of wellbeing provided within regulation 1(2) of Care Act 2014.\n\nThere was qualitative evidence that social workers value support, supervision and training. The committee discussed that being up to date with relevant legal frameworks was particularly important to their work. They recommended that organisations should support this with continuous professional development so that social workers continue to develop legal knowledge and therefore act in accordance to the law when carrying out their duties.\n\nQualitative evidence showed that people felt existing services and interventions did not sufficiently address all their needs. This was also consistent with the committee's experience of current practice, and they emphasised that planning of services (commissioning and configuring) should take this into account to address potential inequalities in access to care and care provision.\n\nThe committee discussed evidence related to responding to an escalation of need, and concluded as a general principle that organisations should ensure social workers be given appropriate training and support during and after response to an escalation of need. However, the committee also agreed this would benefit all areas of their work, so expanded the recommendation to be one for development of an overall framework for an open learning culture. The committee discussed that this was in line with Social Work England's professional standards which also emphasise that families and communities should be taken into consideration. This will support social workers in learning from each other, and make them better able to appraise situations generally, but also specifically assess appropriate levels of risks that can be taken.\n\nThe committee noted that most of these recommendations would standardise practice. The recommendation that organisations should consider making time allowances to build relationships may lead to longer contact times than currently, but this would be balanced against better, individualised services and this was supported by the economic analysis. The recommendation on continuous professional development would address a current variation in practice in getting access and time for such training opportunities.\n\nReturn to recommendations\n\n# Assessment – needs assessment\n\n## Providing information\n\nRecommendations 1.2.1 to 1.2.3\n\nAs there was no quantitative evidence on the effectiveness of different approaches to social work needs assessments, the committee used the qualitative evidence supported by their own knowledge and experience to make recommendations. They also took into account the legal framework underpinning social work assessments (particularly the Care Act 2014) and standards of practice (according to Social Work England's professional standards or BASW's Professional Capabilities Framework).\n\nThere was some evidence showing that people did not always understand the purpose of the needs assessment and what it would involve, so the committee recommended giving people accessible information on why it is needed, the objectives, and how it will be done so that they have time to prepare. This also included raising awareness with carers about their right to have a carer's assessment in line with regulation 10 of the Care Act 2014.\n\nThey also discussed that better understanding and knowledge (including of statutory rights) about social work assessments, both in terms of what is involved and the likely outcome, would reduce anxiety and stress for the person with complex needs. They noted that the social work can play an important part in addressing this by signposting to relevant resources.\n\nMost of the recommendations will standardise rather than change practice, as they are actions that are mandated by the Care Act (such as giving sufficient information).\n\nReturn to recommendations\n\n## Planning the assessment\n\nRecommendations 1.2.4 to 1.2.9\n\nAs there was no quantitative evidence on the effectiveness of different approaches to social work needs assessments, the committee used the qualitative evidence supported by their own knowledge and experience to make recommendations. They also took into account the legal framework underpinning social work assessments (particularly the Care Act 2014) and standards of practice (according to Social Work England's professional standards or BASW's Professional Capabilities Framework).\n\nBased on their experience, the committee emphasised that social workers should conduct assessments in a way that would minimise stress for the person noting that this would lead to better relationships and engagement and would therefore impact positively on outcomes.\n\nThe committee discussed the review findings which suggested people were not always able to express their preferences during assessment. Based on this the committee recommended that there could, in some circumstances, be a preparatory initial contact before the assessment as a way of overcoming these issues. The committee agreed that this can be particularly important if the person may have difficulties being actively involved in the assessment. To address such difficulties, support may be needed from an independent advocate in the assessment. A preparatory meeting could provide the opportunity to assess whether there are any adjustments that can be made or family members who can get involved and could help and support the person with complex needs throughout the process. However, regardless of whether a preparatory meeting is held or not, the committee highlighted that the practical arrangements for the assessments always need to be established before the assessment takes place. They discussed the benefits and challenges of remote (for example virtual) compared to in-person assessments. While there are some advantages of remote assessment (such as when an urgent assessment is needed) there are also disadvantages (such as not being able to get cues from the person's environment). While they could not categorically recommend 1 over the other, they highlighted that in cases of potential safeguarding concerns an in-person assessment would most likely be needed because missing any needs in these circumstances could have serious consequences.\n\nThe committee discussed qualitative evidence of possible challenges with self-assessment; for example, participants in a study reported that the self-assessment format was not always adequate or appropriate for people with multiple needs. Based on this, the committee emphasised that discussions should take place with the person about the advantages and disadvantages of this option so that they can make an informed choice, and that the person should be reassured that they will be supported and can change their mind and have an in-person assessment instead.\n\nMost of the recommendations will standardise rather than change practice, as they are actions that are mandated by legislation such as the Care Act or based on Social Work England's professional standards or BASW's Professional Capabilities Framework. The recommendation for a preparatory initial contact is a change to current practice since this is not uniformly done across the country. This may lead to an increase in the number of contacts, which may cause a potential resource impact and increase demands on social worker time. However, the committee noted that a preparatory visit is an option rather than a mandatory requirement and could be a virtual contact or a phone call. The additional resources needed to have some such preparatory visits may be offset by improved outcomes from the person-centred approach, potentially improving quality of life and preventing expensive interventions later on, such as hospitalisation. Also, as it is only an option that services could use rather than something that should be implemented for everyone, the impact may be limited.\n\nReturn to recommendations\n\n## Conducting the assessment\n\nRecommendations 1.2.10 and 1.2.11\n\nThe committee used the Care and support statutory guidance and regulation 2(1) of the Care Act 2014 to make these recommendations.\n\nThe committee noted that if self-assessment is chosen, the Care Act 2014 requires social workers to check that the information that is provided in the assessment is accurate, so they emphasised this in a recommendation. This could be achieved by gathering information from multidisciplinary team members or family and carers, where appropriate.\n\nBased on the committee's experience and expertise of the statutory guidance in relation to needs assessment, they discussed the content of the assessment and the related eligibility criteria. They agreed that it is important to highlight the questions that the social worker should take into account when deciding on the level of support that is needed in compliance with statutory guidance (eligibility outcomes of regulation 2(2) of the Care Act 2014). The committee discussed that some of the person's needs may be outside of the expertise of the social worker, for example communication or mental health needs, and it is important that specialist input is sought to address these needs.\n\nMost of the recommendations will standardise rather than change practice, as they are actions that are mandated by either the Care and Support Statutory Guidance or the Care Act.\n\nReturn to recommendations\n\n## Recording and reviewing the assessment\n\nRecommendations 1.2.12 to 1.2.15\n\nAs there was no quantitative evidence on the effectiveness of different approaches to social work needs assessments, the committee used the qualitative evidence supported by their own knowledge and experience to make recommendations. They also took into account the legal framework underpinning social work assessments (particularly the Care Act 2014) and standards of practice (according to Social Work England's professional standards or BASW's Professional Capabilities Framework).\n\nEvidence showed that people were not always given the opportunity to review their assessment details, so the committee made a recommendation to ensure that people have the opportunity to check the draft documents are accurate.\n\nThe evidence also suggested that needs can be interpreted differently by the person with complex needs and the social worker, which can lead to misunderstandings about the support that is expected. The committee acknowledged that differences of opinion could arise between a range of individuals, such as professionals and family members or others involved. They therefore recommended that a record of such differences should be kept in case any future issues arise. The committee noted that this could lead to tensions between the person with complex needs and the social worker, and could sometimes lead to complaints being made. They therefore emphasised that not only is good record keeping important when differences arise, but also that people should be given information about the complaints procedure, so they know what to do if they feel the correct processes have not been followed or they disagree with the outcome of the assessment.\n\nIn the context of self-assessment, the committee noted, based on their knowledge of legislation, that organisations have an obligation to provide the person who self-assesses with relevant information that they hold to help them in the process. The committee agreed that this was not always known by social workers and made a recommendation that this must be done to comply with legislation.\n\nThere is a lack of quantitative evidence addressing approaches to needs assessment and their potential impact on wellbeing. Because of this, the committee prioritised this topic for a research recommendation on needs assessment.\n\nMost of the recommendations will standardise rather than change practice, as they are actions that are either mandated by the Care Act (such as giving sufficient information and support, or issues related to self-assessment) or extrapolated from it (such as preferences when arranging the assessment). The recommendation for a preparatory initial contact is a change to current practice, since this is not uniformly done across the country. This may lead to an increase in the number of contacts, with a potential resource impact and increasing demands on social worker time. However, the committee noted that it would not be routinely done and could be a virtual contact or a phone call. This may be offset by improved outcomes from the person-centred approach, potentially improving quality of life and preventing expensive interventions later on, such as hospitalisation. Also, as it is only an option that services could use rather than something that should be implemented for everyone, the impact may be limited.\n\nReturn to recommendations\n\n# Assessment – risk assessment\n\n## Planning the risk assessment\n\nRecommendations 1.2.16 to 1.2.19\n\nThe committee acknowledged the limitations of the evidence, including the lack of quantitative evidence on this topic, and the limitations of the included qualitative evidence (in relation to both the low number of studies and low quality of findings). They agreed to use the qualitative evidence, supported by their own experience, when making the recommendations. They also took into account relevant legislation, including the Mental Capacity Act 2005 and the Mental Health Act 2007 as well as the Human Rights Act 1998 and the UK GDPR and the Data Protection Act 2018. The committee were also aware that decisions around risk can be influenced by culture, personal beliefs, and coping strategies. They therefore also took into consideration the Equality Act 2010.\n\nThe evidence highlighted that when people with complex needs, and their families and other people important to them were actively involved in the risk assessment process, it facilitated discussions with social workers around risks and helped them make decisions about care and support needs. The committee agreed that this was an essential component of social work and consistent with the legal framework. The committee agreed that for people with complex needs, and their families and other people important to them to be actively involved the process, it needs to be relevant to the person and therefore holistic, looking at the person's abilities and needs and taking their preferences into account.\n\nThe committee noted that the evidence suggested that people found it useful when family members supported them. However, they cautioned against being prescriptive about this because not every person would want their families involved in the process. Therefore, the committee recommended that social workers discuss the person's views and preferences and that these be recorded and shared (in line with the UK GDPR and the Data Protection Act 2018) so that families are not inadvertently included in discussions if this would go against the wishes of the person with complex needs.\n\nThe committee discussed the evidence relating to contextual risk assessment that showed that people found the risk assessment approach worked better when their individual circumstances were fully understood. The recommendations emphasise the need for social workers to develop a rapport with, and engage with, the person at risk. When possible and practical, the committee recommended that ideally this should be done over several contacts so that the person's circumstances and environment is fully understood. While the committee wanted to emphasise the need to build relationships and understand the person's circumstances and environment, they also acknowledged that in some situations when a person is at urgent risk, immediate action needs to be taken which may not allow time for several contacts.\n\nThe recommendations reinforce current legislation and usual practice. While conducting risk assessments over several contacts (which could be a virtual contact or a phone call) is not consistently done across the country, and would add time to the assessment, this would improve outcomes through a better understanding of the person's situation and environment. However, rather than this being implemented for everyone the committee thought that this could be one of the considerations around the assessment and would therefore not significantly change practice.\n\nReturn to recommendations\n\n## Conducting the risk assessment\n\nRecommendations 1.2.20 to 1.2.34\n\nThe committee acknowledged the limitations of the evidence, including the lack of quantitative evidence on this topic, and the limitations of the included qualitative evidence (in relation to both the small number of studies and low quality of findings). They agreed to use the qualitative evidence, supported by their own experience, when making the recommendations. They also took into account relevant legislation, including the Mental Capacity Act 2005 and the Mental Health Act 2007 as well as the Human Rights Act 1998. The committee were also aware that decisions around risk can be influenced by culture, personal beliefs, and coping strategies. They therefore also took into consideration the Equality Act 2010.\n\nThe committee noted the evidence related to assessing risk when a person lacks capacity, and so highlighted that risk assessments would also involve planning for the future so that the person's wishes are known in advance and a plan is in place to manage risk. They agreed that this would lead to better outcomes, since any risky situation can be managed in line with the person's preferences even if they later lack capacity to make decisions.\n\nThe committee discussed that safeguarding issues can be noticed in the risk assessment process and that it is therefore a legal duty in line with the Care Act 2014 that the social worker adheres to local policies to keep the person safe.\n\nThere was a lack of evidence about what works well and what could be improved in relation to the content of risk assessments, but despite this the committee agreed that it was important to provide guidance about what should be taken into account when conducting a risk assessment. They also discussed a guide about risk assessments from the Social Care Institute of Excellence and took this into account. In line with this, the committee recommended that to be effective the social worker should individualise the risk assessment and consider not only harmful outcomes but also where there are low risks and potential for good outcomes (for example, if the risks of harm from others and harm to others is low, it could mean that there is a good support network that the social worker could get involved to help with other potential risks that are high). The committee agreed to highlight categories of risks that would affect the person's safety and the safety of other people, as well as risks to their independence and the independence of others who may depend on them so that plans can be made to minimise them.\n\nThe committee discussed their concerns that any risky decisions could lead the social worker to conclude that the person lacks capacity, and they therefore highlighted the legislation of the Mental Capacity Act 2005 which states that assessments of mental capacity should not be based on such assumptions. They discussed that such decisions can be challenging with some cognitive impairments, such as executive dysfunction, and therefore highlighted this in a cross reference to recommendation 1.4.19 of the NICE guideline on decision making and mental capacity.\n\nThe committee were aware that people who lack capacity to make decisions related to risk were particularly vulnerable, and that therefore the legislation in section 4(6) of the Mental Capacity Act 2005 needs to be followed so that their current wishes can be established if possible. Even though an assumption should not be made that someone is lacking capacity, the committee did not want to leave someone vulnerable to risk if they do lack capacity, so they recommended that a person who makes a decision that would put themselves at significant risk should be considered for an assessment of capacity. Getting the views of people close to the person and members of the multidisciplinary team may be helpful to determine whether an assessment may be necessary. This is to ensure their safety, and potentially the safety of their family members or carers.\n\nThe committee noted the qualitative evidence showing that people agreed that risk assessments work better when discussions take into account the words a person uses to describe risk and their understanding of risk. There was some evidence that checklists can help with this, but the committee was cautious to recommend these as a routine form of assessment as there are only a small number of validated checklists available, and so they would not address the range or complexities of risks for people with complex needs. They were also concerned that this could also be seen by the person as a tick box exercise, and so recommended that checklists be used as a starting point for a wider discussion including previous causes of an escalation of needs and what worked well before to minimise risk. Because of uncertainties with the evidence on the use of checklists and it being restricted to people with complex mental health needs, the committee also made a research recommendation on risk assessment.\n\nWhen reviewing evidence indicating that risk assessments worked better if social workers fully understand the person's perspectives of risk (when they have capacity to do so), the committee noted that this was consistent with their own experience. They therefore wanted to ensure that this was taken into account when assessing risk, but also that this should not stop social workers from providing necessary support if needed. The committee noted that this was in line with Social Work England's professional standards which advise social workers not to prejudge the person's state and also reflect on their own interpretations (which can be based on their own values), so as to avoid their own feelings around risk influencing their assessment.\n\nThe committee discussed evidence highlighting that a risk assessment works well for people who have capacity when it balances a person's risk with their autonomy, and other evidence that showed understanding the person's perception of risk facilitates the process. They therefore highlighted that people can make their own decisions about risks or decline interventions (for example, keeping many personal belongings if they are hoarding items even if it makes it difficult to move around their home). However, such choices should not be a reason to stop working with them or providing care even if the social worker perceives these decisions to be risky or unwise.\n\nThere was evidence related to detention under the Mental Capacity Act for people assessed as lacking capacity, and the committee used the principles of the Mental Capacity Act to highlight that the circumstances where potential risks for people who lack capacity could occur need to be carefully considered, including ascertaining the person's best interests, so that any restrictions made are proportionate and justified.\n\nThere was evidence highlighting that it is difficult to define the seriousness of risk, which was consistent with the committee's experience that risk would vary from person to person. The committee discussed that in the absence of such definitions, risk assessments can potentially place too much emphasis on the use of generic risk categories such as 'high' and 'low' risk – these do not distinguish the severity of potential harms from their likelihood, and do not take into account the different circumstances and choices of the person at risk. Based on these discussions, the committee made recommendations which emphasised that when recording risks social workers need to assess the severity and likelihood of identified potential harms to inform a risk management plan. This should weigh potential harms against potential benefits of risk taking, and a person's needs and wishes.\n\nThe committee acknowledged that the person at risk may not always give consent for their information to be shared. The committee identified the Human Rights Act 1998 underpins such decisions, and this was stated in the recommendations.\n\nThe recommendations reinforce current legislation and usual practice. For advance decision making, while this is not a mandatory part of risk assessment it is commonly done, so the recommendation is likely to lead to standardised practice.\n\nReturn to recommendations\n\n## Recording and reviewing the risk assessment\n\nRecommendations 1.2.35 to 1.2.39\n\nThe committee acknowledged the limitations of the evidence, including the lack of quantitative evidence on this topic, and the limitations of the included qualitative evidence (in relation to both the limited number of studies and low quality of findings). They agreed to use the qualitative evidence, supported by their own experience, when making the recommendations. They also took into account legislation, under the UK GDPR and the Data Protection Act 2018.\n\nBased on their experience, the committee were keen to emphasise the need to balance any competing demands and perspectives of different organisations, and for different practitioners to be able to exercise their professional judgement. To achieve this, they recommended that, in complex situations involving potential risks of serious harm (for example these could be situations where there are many different opinions in the multidisciplinary team, potentially different complex harms or where 1\xa0action to avoid 1\xa0risk might bring about a further risk), social workers coordinate a case conference. Usually this would include the person and their family or carers but the committee decided that there are situations where a case conference could be a cause of distress for the person or may put a family member at risk. They therefore made a recommendation to highlight both that the person's and their family's involvement is important as well as situations when this may not be advisable.\n\nAlso based on their experience, the committee discussed that, when there are significant concerns about risks, information ought to be shared between agencies to ensure the safety of the person with complex needs. However, they emphasised that this can only be done within the constraints of the legal framework within the UK GDPR and the Data Protection Act 2018.\n\nEvidence showed that people were not always given the opportunity to review their risk assessment, so the committee made a recommendation to ensure that people have the opportunity to check the draft documents are accurate.\n\nThe evidence also suggested that disagreements could arise across different organisations and among different practitioners because of the varying ways in which risk is conceptualised and decisions on managing risk are made. The committee also noted that differences of opinion could arise among professionals, the person with complex needs, family members or others involved. They therefore recommended that a record of such differences should be kept in case any future issues arise from disagreements.\n\nThe committee also noted that risk assessments need to be relevant, up to date and responsive to change and therefore, based on their experience, recommended that they are reviewed at least annually, or when circumstances change and a new review is needed.\n\nThe recommendations reinforce current legislation and usual practice.\n\nReturn to recommendations\n\n## Organisational support\n\nRecommendations 1.2.40 to 1.2.45\n\nThe committee acknowledged the limitations of the evidence, including the lack of quantitative evidence on this topic, and the limitations of the included qualitative evidence (in relation to both the limited number of studies and low quality of findings). They agreed to use the qualitative evidence, supported by their own experience, when making the recommendations.\n\nThe evidence showed that social workers valued support, particularly when they have experienced abuse, and ongoing training (including legal literacy). Based on the evidence and potential for high-risk situations, advice for social workers should be available whenever they are working, including outside normal office hours. The evidence showed that positive organisational cultures give social workers confidence in making risk assessments, and the committee drew on this to recommend a written strategy for training and support.\n\nThe recommendations reinforce current legislation and usual practice. The availability of training on risk assessment for social workers varies, so there may be a resource impact where it is currently not available. However, this would lead to better outcomes by improving the knowledge and awareness of processes and approaches to assess risks. Having out-of-hours access to advice in relation to risk for social workers who do not work during office hours is common practice (such as using an on-call system), so should not be an additional resource impact in most cases.\n\nReturn to recommendations\n\n# Individual or family casework\n\nRecommendations 1.3.1 to 1.3.4\n\n## Why the committee made the recommendations\n\nThe committee drew on both quantitative and qualitative evidence to make recommendations.\n\nThe committee discussed the quantitative evidence, which showed mixed results for social work approaches to individual and family casework. They discussed the evidence that showed that a stepped care intervention had an important benefit in terms of morbidity outcomes. This intervention had a number of components including guided self-help and problem solving. The qualitative evidence suggested that social work approaches, in particular goal setting, helped people to identify their priorities and think about ways to achieve these goals. Based on experience, the committee discussed the benefits of such approaches – in particular, those with components that seek solutions to defined areas and working to agreed goals to solve problems. They decided that they could not recommend the specific stepped care approach described in the study, as it was done in a different health and social care setting (Belgium and the Netherlands) and had many components that would make it difficult to implement. However, they noted that some of the components would fall into the category of task-focused approaches which are already used by social workers in the UK. Although the evidence showed benefit for a specific group, the committee agreed that the importance of identifying goals and outcomes (as is done in task-focused approaches) could be extrapolated to the wider population of adults with complex needs and recommended that people should be supported in this process.\n\nThe committee highlighted legal frameworks that were in place to support the rights of the person as well as the rights of the family. They agreed that by doing this, social workers would better understand that their role is not necessarily to resolve conflict, but to uphold the rights of the person being supported.\n\nThe committee looked at evidence around the challenges of involving family members in social work approaches to casework, and potential conflicts which may exist between family members and how safeguarding concerns may arise in some situations. They discussed the difficulties, as highlighted in the evidence, of ensuring family members participate and engage in interventions. However, they noted that there was little quantitative evidence on the effectiveness of any particular family intervention that had been carried out specifically by social workers to address these challenges. The committee was aware that there is a benefit from family interventions (for example, improving communication between family members), but that the evidence originates from other disciplines (for example, research in clinical psychology) and it is therefore unclear what the role of these interventions is in social work. However, to promote the rights and wellbeing of people and families (in line with Social Work England's professional standards) they felt such interventions could be considered with sufficient training, because the benefits of positive family relations and the social support that this could provide to the person with complex needs could lead to positive outcomes.\n\n## How the recommendations might affect practice\n\nThe recommendations aim to standardise practice rather than change it.\n\nReturn to recommendations\n\n# Helping people to connect with local communities and reduce isolation\n\nRecommendations 1.4.1 to 1.4.7\n\n## Why the committee made the recommendations\n\nThe committee discussed the quantitative evidence, which showed benefits for some outcomes but no differences for other outcomes. However, because of methodological biases, as well as uncertainty around the magnitude of the findings, the committee were less confident in relying completely on the quantitative evidence to support recommendations. There were some themes of the qualitative evidence that supplemented or provided an explanation for the lack of clear results in the quantitative evidence. This combination of quantitative outcomes and qualitative themes suggested that the relative lack of improvement in the quantitative outcomes could be explained by the qualitative evidence that social workers place importance on taking an individualised approach to achieve positive outcomes. The committee agreed that this was a reflection of their experience of practice and was therefore important to take into account.\n\nThe committee made a recommendation based on the quantitative evidence that showed social work approaches to social inclusion had an important benefit over usual practice that mainly focused on the person's existing networks, as there was an improvement in perceived social support. The qualitative findings also highlighted the importance of thinking about the different levels of support a person may need. Based on the combination of the quantitative and qualitative evidence and drawing on their experience, the committee were confident to make a recommendation for the social worker to use a strengths-based, person-centred approach to help the person to develop connections with their local communities. The committee emphasised that approaches that do not solely focus on the person's needs would improve their confidence and contribute to their overall wellbeing by helping them to take steps to reduce isolation.\n\nThe committee also made a recommendation for social workers to support access to a range of activities in the community. A number of qualitative themes supported this recommendation, including the benefits of taking an individualised approach to social inclusion activities (as people's preferences and needs will vary greatly). The findings also highlighted that participants felt community-based groups and resources could be more beneficial in matching people's needs than those provided by health and care services.\n\nThe committee discussed the qualitative evidence around practitioners' views of social work approaches to social inclusion, which highlighted that the range of available groups and resources for people were not always adequate. As reducing isolation is beneficial to the person, the committee recommended social workers use creative approaches to see whether new resources could be developed. This also include the flexible use of personal budgets to support an activity. Support should also be given at an organisational level to help social workers find activities and groups that might match a person's interests. This relies on information being up to date, so the committee gave some examples of how this could be achieved.\n\nThe committee discussed evidence that highlighted that it was important to take into account that the level of support needed varied depending on peoples' needs. They agreed that the support of the social worker should not end once a person has made contact with a group, but that this should be followed up with the person after they have joined a group to ensure that they benefitted from it.\n\nBased on experience, the committee agreed that it was important for organisations to provide information that is up to date about available community resources, as this would minimise barriers to accessing services (such as frustrations around contact details no longer being active, or activities no longer being available).\n\nThe committee discussed the evidence around the barriers to connecting with communities or groups, that showed that an NHS trust's catchment area could be a barrier to this because it is assumed by practitioners and the person that people do not have the right to access groups that are outside the catchment area. The committee recognised that it was not within the scope of the guideline to make a recommendation about local authority catchment areas, but agreed to recommend that people are informed about their rights to receive services outside of their catchment areas to help address this. Based on their experience and knowledge, they expanded on this to alleviate other barriers to access, such as eligibility criteria and referral processes.\n\nEven though there was both quantitative and qualitative evidence to draw on, the committee felt that further evidence to clarify the best approach that social workers could take to help people connect with their local community is needed and so made a research recommendation on social and community support approaches to address this.\n\n## How the recommendations might affect practice\n\nThere is variation in practice in how much time is spent by social workers helping people connect to local communities. The recommendations will increase the time social workers spend researching, supporting and helping people to make connections in their communities. However, this potential change in practice could lead to improved outcomes by reducing the detrimental effects that loneliness can have on the person's health and wellbeing.\n\nReturn to recommendations\n\n# Supporting people to plan for the future, including considering changing needs, wishes and capabilities\n\nRecommendations 1.5.1 to 1.5.13\n\n## Why the committee made the recommendations\n\nThe committee discussed both quantitative and qualitative evidence. The quantitative evidence was of limited value because of the quality of the studies and applicability, as most of the included studies were not conducted in the UK so the care provision and legislation were different. They therefore focused on the qualitative evidence as it was of better quality, with themes that the committee agreed were more generalisable to the wider population (with more UK evidence and a wider range of complex needs included).\n\nThe evidence suggested that when people have information and support in advance and understand the care planning process, this helps them to participate in planning for the future with their social worker. The committee highlighted the key role social workers play in communicating relevant information to people with complex needs, as well as to their support network, in a timely manner throughout the whole process. The committee emphasised that this would also include information and support for carers, which would have a positive impact on their own wellbeing as well as that of the person that they are providing care for.\n\nThere was evidence that highlighted that the environment and service location can be an important facilitator to help the person feel safe and relaxed, and there was also benefit in having a location that provides easy access to case management services (this included visits to the person's home). The committee drew on this to recommend that care planning take place in the person's preferred location whenever possible.\n\nThere was some limited evidence about the importance of building relationships and trust. This was consistent with the committee's experience that good relationships that include meaningful conversations to engage individuals are an important aspect of case management and care planning. Drawing on their own expertise, the committee recommended a rights-based approach to case management and care planning, focusing on the individual's rights according to the principles of the Human Rights Act 1998. This would improve people's outcomes by promoting their dignity and wellbeing, building on their strengths and supporting both their participation in the community and engagement with services.\n\nThe committee discussed the qualitative evidence that highlighted the importance of existing relationships between adults with complex needs and their family members and carers, and also the wider community. Promoting such relationships may enhance the support networks available to adults with complex needs, which may in turn help minimise the potential for isolation. They discussed the importance of both paid and unpaid support networks (for example, family and personal assistants), and agreed that their input should be reflected in the care plan where appropriate.\n\nBased on evidence that highlighted that a barrier to successful planning for the future was not recognising quickly enough when needs change, the committee highlighted the benefits of a flexible and responsive approach. This should include regular reviews so that plans can be adjusted to ensure the person's safety and wellbeing.\n\nBased on the evidence about the challenges of planning and addressing all the person's needs, and supported by their own knowledge and experience, the committee were aware that social workers may not always be able to address the whole range of identified, eligible needs successfully at the point when the care plan is written or reviewed. It was acknowledged that in accordance with section 18 of the Care Act 2014, a local authority, having determined that a need is eligible, has a legal duty to meet this need. (See also section 10.10 of the Care and support statutory guidance, which describes what is meant by 'meeting a need'.) The committee decided that when writing or reviewing the care plan, social workers should note when a need has not yet been met, or is only partially met, to make it explicit that the need has to be addressed to meet the local authority's legal obligation. It was noted that the social worker and the person may have different views about the extent to which an eligible need has been sufficiently met, but it was decided that this could be captured in the care plan or at review. Exploring this when writing or reviewing the care plan would help identify reasons why some needs have not been sufficiently met, and indicate what might be needed to achieve this in future.\n\nIn relation to this, the committee cited section 13.13 of the Care and support statutory guidance which describes the routes to reviewing care and support plans. While, based on their experience, a review should be planned with the person and take place at least once a year, the statutory guidance highlights that there can be situations where an unplanned review is necessary (for example, if needs change or if it is requested by the person or other people important to them).\n\nThe committee discussed findings around working arrangements which identified certain conditions that enabled social workers to fulfil their roles more successfully, including autonomy, training, support and supervision. However, the evidence suggested that most social workers reported a lack of support from managers from their own organisations. The committee were keen to emphasise the importance of supporting social workers in their role so that in turn, adults with complex needs would be effectively supported. This was reflected in the committee's recommendation that organisations provide social workers with regular, practice-based supervision and support so they can be responsive to people's complex and fluctuating needs, and keep their knowledge and practice up to date.\n\nThe committee discussed the evidence showing that continuity was valued in care planning, particularly because people with complex needs felt frustrated about having to tell their stories repeatedly. The committee noted that this was consistent with their experience that offering people access to a named social worker would benefit them in terms of providing such continuity of care, which would in turn enhance their health and wellbeing (where there are changes in social workers, continuity could be maintained by having clear handover processes in place).\n\nThe committee made a research recommendation on supporting people to plan for the future to inform future guidelines that would address the gap in the effectiveness evidence relating to the evaluation of specific models of social work case management.\n\n## How the recommendations might affect practice\n\nThe recommendations will mainly standardise practice. There is some variation nationally in provision of a 'named' social worker so increased provision may have some resource impact, but this is already common practice for many services so this may be limited.\n\nReturn to recommendations\n\n# Responding to an escalation of need, including urgent support\n\nRecommendations 1.6.1 to 1.6.7\n\n## Why the committee made the recommendations\n\nWhile some quantitative evidence was available, the committee decided not to make use of it when making recommendations, as only 1 small observational study with methodological limitations (such as lack of comparison group) was identified and the population was restricted to the specific needs of people with mental health conditions. Therefore, it was difficult to generalise to the wider population of people with complex needs. The committee drew on the more substantial qualitative evidence (from 8 studies) and supplemented this with their experience and knowledge to make advice applicable to the wider population of adults with complex needs.\n\nThe committee used their expertise and knowledge of BASW's Professional Capabilities Framework – which sets out the ethical principles and critical reflection practices that a social worker must apply to guide their decision making – to recommend social workers consider a person's wishes, preferences, social circumstances and cultural background when planning during an escalation of need. This would help ensure that any decisions that are made are not based on the social worker's assumptions.\n\nThe committee discussed the evidence that suggested practitioners who used the wider support network of friends and family to help with decision making during a Mental Health Act assessment facilitated the social worker's response to an escalation of needs. Based on this evidence and their experience, and statutory requirements, they decided to generalise this to the whole population for all situations of unplanned escalation of needs. They agreed that gathering information about the situation not only from the person's family and social networks, but also relevant practitioners would create a clearer picture of the situation (and any previous, similar situations) and would therefore likely lead to better solutions. The committee noted that usually this information could be gathered by phone or using virtual meetings (for example, virtual case conferences or Care and Treatment Reviews).\n\nThe evidence that showed there was a lack of time and resources for social workers to look at alternative options to detention under the Mental Health Act in response to an escalation of need. However, in accordance with the Mental Capacity Act 2005 other less restrictive options need to be considered which can take time. They discussed that social workers in such circumstances can feel under pressure and may make rushed decisions. They drew on 1\xa0of the principles of the Mental Capacity Act that highlights that whenever possible, options must be explored that are less restrictive of the person's rights and freedom of action. To ensure that this principle is upheld and to ensure that people with complex needs can maintain their independence and autonomy as much as possible in the event of an unplanned escalation of need, the committee made a recommendation to reinforce this legislative requirement.\n\nThe committee used their knowledge, supported by legislation, to make recommendations on the use of a person's advance statements during decision making to ensure a personalised approach to care is taken. The committee noted that an advance statement could be any statement of a person's wishes and preferences which is not to be confused with a formal written document like an advanced directive related to medical treatment decisions. An advance statement should lead to better outcomes and satisfaction with services, as a person's wishes and preferences may have been informed by what has worked previously. However, the committee noted that individualised approaches are always needed, even if no advance statement has been made, to provide support in accordance with the person's wishes and preferences.\n\nThe committee discussed the review finding that showed there was dissatisfaction that out-of-hours services were not always available. The committee were aware of legislation that supports 24-hour services and made a recommendation in favour of them so that prompt support can be provided in situations of an unplanned escalation of need in the context of Mental Health Act assessments in accordance with legislation (section 14.35 of the Mental Health Act Code of Practice). They noted that availability of services out of hours may prevent some hospital admissions or presentations to accident and emergency departments. They noted that, in their experience, use of out-of-hours services was not always well communicated with daytime services, so recommended that timely and clear communication take place between services to enable better continuity of support.\n\nTo address the identified evidence being restricted to a narrow population, the committee made a research recommendation on responding to an escalation of need.\n\n## How the recommendations might affect practice\n\nMost of the recommendations aim to standardise current practice and are supported by legislation. The recommendation for a joint assessment in some crisis situations would not have a significant resource impact or cause a change of practice, because this would usually be done by phone or virtually. The current availability of out-of-hours services is varied in the context of Mental Health Act assessments, but according to legislation (section 14.35 of the Mental Health Act Code of Practice) decisions on applications for the detention under the Mental Health Act should be covered over 24 hours so services should have such arrangement in place already.\n\nReturn to recommendations\n\n# Social workers and multidisciplinary teams: communication, support and collaboration\n\nRecommendations 1.7.1 to 1.7.8\n\n## Why the committee made the recommendations\n\nThe committee agreed that the features of the integrated services covered in the quantitative evidence were not directly applicable to the whole population of people with complex needs. They also noted other limitations in the evidence, such as concerns about the way the studies were conducted and had mixed or contradictory findings, with uncertainties about the size of effects that decreased the confidence in this evidence. Therefore, the committee made recommendations using the qualitative evidence together with their experience and expertise and legislation (the UK GDPR and the Data Protection Act 2018) as well as drawing on BASW's Professional Capabilities Framework and BASW's Charter for integrated working. They agreed that the qualitative evidence highlighted specific aspects that were key to successful integrated working.\n\nThere was evidence indicating that having shared visions and aims helped to promote integrated working, because it led to an increased understanding between organisations and disciplines. The committee discussed the importance of this to help everyone in the team understand the context in which they work, even if they come from different disciplines. Having a clear strategy should improve team working because overall purposes and objectives can be defined, and everyone knows the part they play.\n\nMost of the available evidence related to organisational matters that can help or hinder multidisciplinary team working, rather than focusing on actions taken by individual social workers. This was consistent with the committee's experience of team members' willingness to work together, that they felt could be better supported by the organisations members work for. Supporting information sharing (in line with the UK GDPR and the Data Protection Act 2018) and providing opportunities for clear communication should lead to better teamwork, because members would understand each other's expertise and roles and have opportunities to share knowledge and learn from each other. It would also help team members define what role they can play in providing support to the person with complex needs. The committee also decided that information sharing relies on clear communication within the multidisciplinary team and suggested some measures to increase efficiency.\n\nThe committee agreed that joint training opportunities would enable the sharing of skills and knowledge between professionals and help them understand each other's roles and responsibilities across different health and social care roles (as well as other relevant settings, for example voluntary sector organisations). This would enable team members to direct the person with complex needs to the practitioner who can provide the most relevant support. Based on the committee's experience, it was noted that training would need to include the views and perspectives of people with lived experience to give team members greater confidence in understanding the role that each of them can play in providing individualised care (as outlined in BASW's Professional Capabilities Framework). This would address addressing people's needs more effectively and in turn lead to improved outcomes. The committee agreed training should not only be about the theory, but also contain practical information with examples of best practice or lessons that have been learnt. This would mean training can be followed up and implemented to improve team working and to benefit people with lived experience (for example, using case studies that show how the principles of best practice of multidisciplinary team working could be applied).\n\nThere was evidence on barriers to integrated working related to a lack of clarity of roles within integrated teams. Using the evidence on facilitators of integrated working, and drawing on BASW's Charter for integrated working, the committee made recommendations to support social workers in retaining their professional identity when working in an integrated team. This can lead to better outcomes, as the person with complex needs knows what to expect and from which person, so that they are aware which needs can be specifically addressed by a social worker.\n\nThere was evidence that bureaucracy was often viewed as a barrier to effective integrated working within multidisciplinary teams, negatively impacting efficiency of referral within the team and causing delays. Simplifying referral processes and pathways (for example, with clear eligibility criteria) was seen as a solution for this and would likely improve outcomes by improving the speed and accuracy (in terms of going to the person most able to help) of referral.\n\nThe committee discussed the evidence related to potential benefits of co-location which was assessed as high-quality thematic evidence and was also supported by the mixed method analysis of qualitative and quantitative evidence. They acknowledged that this could have a positive impact on services but would not always be feasible, practical and could be costly (particularly if it involves new premises), and therefore cannot be routinely implemented. However, the committee recommended that organisations should think about whether this could be a beneficial and achievable option for their particular service (for example, having a social work team in a hospital co-located with healthcare staff may improve joined-up services and could have practical benefits).\n\nThe committee discussed evidence suggesting shared formal agreements help integrated working. This was in line with their experience, so they recommended such agreements should be used to support integrated teams, particularly in terms of shared decision making and accountability. The committee agreed this should also cover budgets, as the evidence showed that a lack of access to pooled budgets could create barriers to integrated working.\n\n## How the recommendations might affect practice\n\nThe recommendations largely reinforce current regulation and usual practice. There may be some short-term costs if office accommodation needs to be reconfigured to allow for co-location, although there should be no difference in costs once this has been achieved and potential cost savings through working efficiencies and economies of scale. If physical co-location is not feasible, measures to allow virtual co-location (such as diary sharing and virtual meetings) should involve negligible costs, if any, while allowing potential savings from more efficient and integrated working.\n\nReturn to recommendations"}	https://www.nice.org.uk/guidance/ng216	This guideline covers the planning, delivery and review of social work interventions for adults who have complex needs. It promotes ways for social work professionals, other care staff and people with complex needs to work together to make decisions about care and support.
e1dfde5730b33dc1e9766706c6f1e0477031f44e	nice	Romosozumab for treating severe osteoporosis	Romosozumab for treating severe osteoporosis Evidence-based recommendations on romosozumab (EVENITY) for severe osteoporosis in people after menopause who are at high risk of fracture. # Recommendations Romosozumab is recommended as an option for treating severe osteoporosis in people after menopause who are at high risk of fracture, only if: they have had a major osteoporotic fracture (spine, hip, forearm or humerus fracture) within 24 months (so are at imminent risk of another fracture) and the company provides romosozumab according to the commercial arrangement. This recommendation is not intended to affect treatment with romosozumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Current treatments for people with severe osteoporosis after menopause include bisphosphonates, such as alendronic acid, and other types of medicines, such as denosumab or teriparatide. The company proposes that romosozumab would only be used when there is an imminent fracture risk. It defines this as when a person has severe osteoporosis and has had a major osteoporotic fracture within 24 months. This is narrower than the marketing authorisation. Clinical trial evidence suggests that romosozumab followed by alendronic acid is more effective at reducing the risk of fractures than alendronic acid alone. Comparing romosozumab indirectly with other bisphosphonates and other medicines for this condition suggests that romosozumab is likely to be at least as effective at reducing the risk of fractures in people with osteoporosis after menopause. But the extent of the benefit is uncertain because of differences between the trial populations in the indirect comparisons. The most likely cost-effectiveness estimates for romosozumab followed by alendronic acid, compared with alendronic acid alone, are within what NICE normally considers an acceptable use of NHS resources. So, romosozumab is recommended.# Information about romosozumab # Marketing authorisation indication Romosozumab (EVENITY, UCB) is indicated for 'the treatment of severe osteoporosis in postmenopausal women at high risk of fracture'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for romosozumab. # Price The price for romosozumab is £427.75 for 2 pre-filled pens administered subcutaneously as a single monthly dose (BNF online, accessed October 2021). The company has a commercial arrangement. This makes romosozumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by UCB, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Severe osteoporosis can have a substantial effect on quality of life Osteoporosis is a progressive skeletal disorder. It is characterised by low bone mass and deterioration of the structure of bone tissue leading to an increase in bone fragility and risk of fracture. The patient experts explained that osteoporosis affects all aspects of daily life, including walking, eating and breathing. People with the disease often have difficulty doing day-to-day tasks. Fractures can be painful and have a substantial effect on a person's independence and are also associated with increased mortality. Because of this, people with osteoporosis live in fear of having another fracture. The patient experts explained how the physical changes from osteoporosis, such as loss of height or a stooped posture, can cause feelings of shame. The clinical experts explained that it is important to build bone strength and prevent fragility fractures, particularly in people at the highest risk of fracture. The committee concluded that severe osteoporosis can have a substantial effect on quality of life, and that this would be improved by preventing fragility fractures. # Treatment pathway and comparators ## People with severe osteoporosis would welcome a new treatment option The clinical experts explained that several treatment options are available for severe osteoporosis. These are chosen depending on fracture risk, the presence of previous fractures, and response to or tolerance of other treatments. These treatments can be broadly divided into 2 classes: anabolic (bone-forming) agents and anti-resorptive agents. For people at high risk of fracture, first-line treatment is usually oral bisphosphonates such as alendronic acid or risedronate sodium. However, oral bisphosphonates are either not tolerated or contraindicated in many people with osteoporosis, or the disease does not respond well to them. In this situation, another anti-resorptive treatment can be offered. This includes intravenous bisphosphonates, or a non-bisphosphonate such as denosumab or raloxifene. An anabolic non-bisphosphonate, teriparatide, is another option for people with a higher fracture risk. However, non-bisphosphonates can be difficult to administer and not everyone can have them. The clinical experts noted that evidence suggests that giving teriparatide as the first treatment before oral bisphosphonates may be more effective at reducing fracture risk, but NICE's technology appraisal guidance on raloxifene and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women only recommends teriparatide for the secondary prevention of osteoporotic fractures. Also, people can only have teriparatide once during their lifetime. There is an unmet need for people with very high fracture risk for whom current drugs are not suitable, or for those at particularly high risk of vertebral or hip fractures. Romosozumab has both anabolic and anti-resorptive properties, and is the first new treatment option for osteoporosis in several years. The patient experts agreed that romosozumab offered hope as an additional treatment option. The committee concluded that both patients and clinicians would welcome a new treatment option for severe osteoporosis. ## The population in which the company positioned romosozumab is narrower than the NICE scope and ARCH trial population The population in the NICE scope and the marketing authorisation was people after menopause who have severe osteoporosis and are at high risk of fracture (high risk of fracture was not further defined). The committee noted that the population in the company's main clinical trial (ARCH) was women with severe osteoporosis after menopause who are at high risk of fracture (high risk of fracture was defined as having had a major osteoporotic fracture ). The company's decision problem population was women with severe osteoporosis after menopause who were at high risk of fracture, where high risk of fracture was defined as having had a major osteoporotic fracture within 24 months. A major osteoporotic fracture was defined as a clinical spine, hip, forearm or humerus fracture. The company's decision problem population will be referred to as imminent fracture risk. The committee was aware that defining fracture risk can be complex and there are different ways and different factors that contribute to the definition of high risk. The committee concluded that for this evaluation it would use the ARCH trial definition of high risk (see section 3.6). It also concluded that the company's imminent fracture risk population was narrower than the NICE scope, the marketing authorisation and the ARCH trial. ## Romosozumab would be used in people at imminent fracture risk, regardless of previous treatment The company explained that it had positioned romosozumab in the imminent fracture risk population because these people are at much higher risk of another fracture compared with those who had had a fracture less recently. The company also clarified that the population in its submission was regardless of previous treatment. The clinical experts agreed that the risk of fracture is highest soon after a fracture. But they noted that duration of increased fracture risk can vary based on factors such as age and previous fracture location. The clinical experts also explained that the date of the previous fracture may not always be known, particularly for vertebral fractures. So, the company's decision problem population may be difficult to implement in clinical practice. Both clinical and patient experts agreed that romosozumab should be positioned regardless of previous treatment, but that ideally it should be available as a first-line treatment. The committee acknowledged that the company's imminent fracture risk population represents people with a high risk of fracture. However, it noted that most people in ARCH had not previously had treatment for osteoporosis (see section 3.6), so there was uncertainty around the efficacy of romosozumab in later lines of therapy. A response to consultation highlighted that in the STRUCTURE trial, romosozumab had a greater effect on bone mineral density (BMD) than teriparatide in people who had previously had bisphosphonates. STRUCTURE was a randomised, double-blind study in women after menopause with osteoporosis, providing data on romosozumab (n=218) compared with teriparatide (n=218). This gave some reassurance as to the efficacy of romosozumab regardless of previous treatment. The committee concluded that it would appraise romosozumab according to the company's proposed population. That is, people with severe osteoporosis after menopause who are at imminent fracture risk, regardless of previous treatment. ## Bisphosphonates and non-bisphosphonates are relevant comparators for romosozumab The committee recalled that it would appraise romosozumab regardless of previous treatment (see section 3.4). All of the comparators in the NICE scope are used for treating severe osteoporosis, with non-bisphosphonates largely offered after bisphosphonates (see section 3.2). As such, the committee concluded that both bisphosphonates and non-bisphosphonates are relevant comparators for romosozumab. # Clinical evidence ## ARCH is broadly generalisable to UK clinical practice The main source of clinical-effectiveness evidence for romosozumab was the ARCH trial. ARCH was a randomised, double-blind, multicentre trial comparing romosozumab followed by oral alendronic acid (n=2,046) with oral alendronic acid alone (n=2,047). People were randomised to have either romosozumab or alendronic acid for 12 months, followed by open-label oral alendronic acid for at least another 12 months in both arms. ARCH included ambulatory women after menopause aged 55 to 90 if they met at least 1 of the following criteria: A T‑score of ‑2.5 or less at the total hip or femoral neck and either 1 or more moderate or severe vertebral fractures, or 2 or more mild vertebral fractures A T‑score of ‑2.0 or less at the total hip or femoral neck and either 2 or more moderate or severe vertebral fractures, or a fracture of the proximal femur 3 to 24 months before randomisation.A T‑score relates to the measurement of BMD using central dual-energy X‑ray (DXA) scanning and is expressed as the number of standard deviations below peak BMD. ARCH was an event-driven trial. The primary analysis was done after all people had completed their month 24 visit and at least 330 people had a confirmed clinical fracture (median follow up was 33 months). The clinical experts explained that the baseline characteristics from ARCH suggested that the results would be generalisable to NHS clinical practice. The committee noted that only around 10% of people having romosozumab in ARCH had previously had treatment, so there was uncertainty around the effectiveness of romosozumab given after previous osteoporosis therapies. The committee concluded that ARCH was broadly generalisable to people who had not previously had treatment who had a high fracture risk and would have romosozumab in the NHS. ## Romosozumab followed by alendronic acid is more effective than alendronic acid alone In ARCH, the primary outcomes were the cumulative incidence of new vertebral fracture at month 24, and the cumulative incidence of clinical fracture at the time of primary analysis. Key secondary outcomes included the incidence of the following fracture types: non-vertebral, all fractures, new or worsening vertebral, major non-vertebral, hip, and major osteoporotic. Percentage change in BMD at the lumbar spine, total hip and femoral neck were other secondary outcomes. In the ARCH intention-to-treat (ITT) population, people randomised to the romosozumab arm had a 50% lower relative risk of vertebral fractures over 24 months than people having alendronic acid alone (relative risk 0.50, 95% confidence interval 0.38 to 0.66). A lower proportion of people having romosozumab (9.7%) had a clinical fracture compared with people having alendronic acid alone (13%), and this difference was statistically significant (hazard ratio 0.73, 95% CI 0.61 to 0.88). At the primary analysis there were also fewer people having romosozumab who had non-vertebral fractures (HR 0.81, 95% CI 0.66 to 0.99) or hip fractures (HR 0.62, 95% CI 0.42 to 0.92) compared with those having alendronic acid alone. People having romosozumab had a greater increase in BMD from baseline compared with people having alendronic acid alone, and this difference was statistically significant (adjusted p<0.001). The committee recalled that the company's decision problem population was narrower than ARCH (see section 3.3). The company stated that a post-hoc analysis of ARCH showed that the imminent fracture risk population had similar outcomes to the ITT population, but had not presented this evidence in its submission. At the first meeting, the committee concluded that romosozumab followed by alendronic acid is more effective than alendronic acid alone in the ARCH ITT population, but that the company had not provided evidence in the imminent fracture risk population. In response to consultation, the company presented a post-hoc analysis of ARCH comparing the results for people whose last major osteoporotic fracture was recent (less than 24 months) or not recent (more than 24 months). The recent fracture group corresponded to the company's imminent fracture risk population. The results showed that there were no statistically significant differences between the 2 groups for any of the primary or key secondary end points in ARCH. The company therefore considered that it was appropriate to generalise the results from the ARCH ITT population to the imminent fracture risk population. The ERG noted that there were considerable differences in the effectiveness results between the recent and not recent groups from ARCH for some end points, even though the results were not statistically significant. The clinical experts stated that the post-hoc analysis raised questions about the company's imminent fracture risk population. This was because people in ARCH whose last fracture was not recent had similar outcomes to people whose last fracture was recent. They considered that the ARCH ITT population may better represent the population that romosozumab should be used in. The committee noted that the post-hoc analysis should be interpreted with caution. However, it concluded that the results provided reassurance that romosozumab was similarly effective in the imminent fracture risk population as in the ARCH ITT population. ## Despite uncertainty, the indirect comparisons with other comparators are suitable for decision making There is no head-to-head evidence comparing romosozumab followed by alendronic acid with the other comparators in the NICE scope: risedronate sodium, ibandronic acid, zoledronic acid, denosumab, raloxifene and teriparatide. Therefore, the company did network meta-analyses (NMAs) to allow for indirect treatment comparisons with these comparators. The company could not include ibandronic acid in the NMAs because there were no trials at the licensed dose reporting fracture outcomes. The results of the company's NMAs showed that romosozumab followed by alendronic acid is significantly better than, or at least as good as, most comparators for most fracture outcomes at various time points. The ERG explained that these results were uncertain because of the differences between the study populations in the NMAs. Most studies included had differences in mean age, ethnicity, or the rate of prevalent vertebral fractures. The ERG noted that the company's NMAs were based on the ARCH ITT population rather than the imminent fracture risk population (see section 3.3). The ERG also noted that there was little direct evidence with which to assess inconsistency in the networks, and that the studies in the NMAs did not provide data consistently across timepoints. The ERG therefore considered only the comparisons between romosozumab, alendronic acid and placebo to have a low risk of bias, while all other comparisons had a high risk of bias. The committee agreed that the NMAs may be biased. At its first meeting, the committee considered that it would like to see NMAs adjusted for baseline risk, and treatment effect estimates centred around the imminent fracture risk population. In response to consultation, the company updated its NMAs to include the results from the post-hoc analysis for the recent fracture group (see section 3.7) as a scenario analysis. The results were consistent with the company's original NMAs using the ARCH ITT population. The company noted that this scenario analysis was likely to be more uncertain because it could not adjust the comparator trials to the imminent fracture risk population. The company also did meta-regressions to explore if baseline risk or any other covariates impacted the estimated treatment effects in the NMAs. The company used 2 approaches: adjusting for the rate of people with a history of vertebral fracture at baseline, and reducing the network to include trials with a placebo comparator and adjusting for the fracture rates in the placebo arm.With the exception of new vertebral fractures at 12 months, the results of the company's meta-regressions showed that neither vertebral fractures at baseline nor baseline risk significantly affected the treatment effects in the NMAs. So, the company considered that its original NMAs remained the most appropriate for decision making. The committee noted that the results of the baseline risk meta-regression had wide credible intervals, indicating a high level of uncertainty. The committee considered that both the company's original and updated NMAs had considerable uncertainty. Despite this, the updated NMAs provided reassurance that the relative efficacy of romosozumab compared with current standard care was likely to be similar in the imminent fracture risk and ARCH ITT populations. The committee therefore concluded that the results of the original NMAs using the full ARCH ITT population data were appropriate for decision making. ## More people having romosozumab had serious cardiovascular events in ARCH, but no imbalance was seen in another larger romosozumab study An imbalance in adjudicated serious cardiovascular events between treatment arms was seen in ARCH. In the romosozumab arm of ARCH, 16 people (0.8%) reported cardiac ischaemic events compared with 6 people (0.3%) in the alendronic acid arm in ARCH (odds ratio 2.65; 95% CI 1.03 to 6.77) after 12 months. Cerebrovascular events were reported by 16 people (0.8%) in the romosozumab arm and 7 people (0.3%) in the alendronic acid arm (OR 2.27; 95% CI 0.93 to 5.22). However, there was no difference in adjudicated serious cardiovascular events in the FRAME trial for people having romosozumab compared with placebo at 12 months. FRAME was a randomised, double-blind study in women after menopause with osteoporosis, providing data on romosozumab followed by denosumab (n=3,589) compared with placebo followed by denosumab (n=3,591). The committee noted that FRAME had a larger population than ARCH. In response to consultation, the company also noted that no imbalance in cardiovascular events had been seen in STRUCTURE (compared with teriparatide) and in a phase 2 trial compared with placebo. The committee was aware that romosozumab is contraindicated for people with previous myocardial infarction or stroke. The committee understood that there may be multiple reasons why ARCH showed an increased risk of cardiovascular events for people having romosozumab. These included romosozumab increasing the risk of cardiovascular events, or alendronic acid reducing the risk of cardiovascular events, or that this was a chance finding. The committee also understood that romosozumab should only be prescribed if the clinician and the person at high risk of fracture agreed that the benefit outweighed these risks. The committee concluded that there was a concern that people having romosozumab were more likely to experience cardiovascular events than those having alendronic acid alone, and that balancing the benefits and risks before starting romosozumab was essential. # Economic model ## The company's economic model is suitable for decision making The company used a Markov microsimulation model to estimate the cost effectiveness of romosozumab compared with alendronic acid, risedronate sodium, zoledronic acid, denosumab, raloxifene and teriparatide. The model included 5 health states: at risk, hip fracture, vertebral fracture, other fracture (non-hip, non-vertebral) and death. In the company's model, the risk of having a fracture was based on a combination of 4 components: the general population risk of fracture, the increased fracture risk associated with osteoporosis relative to the general population, the increased fracture risk because of having a recent fracture (the imminent fracture risk), and the reduction in risk from osteoporosis treatment. The treatment effect of romosozumab compared with alendronic acid on fracture risk was calculated by fitting parametric distributions to the Kaplan–Meier curves from ARCH to calculate time-dependent hazard rates. The ERG agreed that the company's model structure was appropriate for osteoporosis. It noted that the company had not presented information on how the parametric distributions had been fitted to the data from ARCH. It could therefore not assess if the distributions had been properly fitted or explore the effect of using alternative distributions. In response to consultation, the company explained that parametric curves were fitted to the hip fracture and non-vertebral fracture data from ARCH. It used an exponential model for romosozumab followed by alendronic acid and a log-normal model for alendronic acid alone to model hip fractures. For non-vertebral fractures, the company used a log-normal model for both treatment arms. The ERG noted that the company had not provided graphs comparing different parameterisations to the observed data, or tables detailing statistical fit. The committee concluded that the company's model was suitable for decision making but there was still some uncertainty about how the parametric distributions had been fitted to the data from the ARCH. ## How long people continue to have romosozumab is uncertain The length of osteoporosis treatment in clinical practice, particularly for oral bisphosphonates, is often shorter than intended. This was reflected in the company's model using rates of persistence. In its original base case, because of a lack of real-world data on romosozumab persistence, the company assumed that 90% of people would complete the 12‑month treatment period based on the persistence rates seen in the clinical trials. The ERG noted that the company's approach was inconsistent and likely biased, because the company had used clinical trial data to model persistence for romosozumab but not the comparators. It considered that real-world persistence on romosozumab would likely be lower than in the clinical trials, so it preferred to use a value of 80% for its base case. This was based on an assumption in a Swedish cost-effectiveness analysis by Söreskog et al. (2021). In response to consultation, the company did a Delphi panel with 18 clinical experts in the UK. The Delphi panel explored persistence on different osteoporosis treatments, and persistence on alendronic acid specifically as a follow-on treatment. The experts' consensus was that a slightly lower proportion of people would complete the 12‑month romosozumab treatment period than in the persistence rates seen in ARCH. The outputs of the Delphi panel are academic in confidence and cannot be reported here. The company considered that the true persistence rate estimates on romosozumab would likely be slightly higher in UK clinical practice than the Delphi panel estimates. Therefore, it continued to assume a 90% persistence on romosozumab at 12 months for its revised base case. The ERG reiterated that it was inconsistent to use real-world evidence to model persistence for the comparators, and clinical trial data to model persistence for romosozumab. Therefore, the ERG preferred to use a lower estimate of persistence on romosozumab in line with the Delphi panel for its revised base case. The company noted that the ERG's position was also inconsistent, in that it used different types of data to model persistence on romosozumab and alendronic acid. The committee was aware that the choice of persistence rates for romosozumab had a major effect on the cost-effectiveness results. The committee concluded that persistence on romosozumab was highly uncertain, and that it would consider cost-effectiveness scenarios using both the company's and ERG's preferred assumptions. ## More people are likely to continue having alendronic acid after romosozumab than having alendronic acid alone In its original base case, the company assumed that persistence on alendronic acid after romosozumab would be 85% of that of denosumab, based on the Swedish Prescribed Drug Register. These persistence rates were higher than what the company assumed persistence would be for alendronic acid alone, which it took from a different source. The ERG preferred to use data from the same study to model persistence for alendronic acid after romosozumab and alendronic acid alone. It favoured a study by Morley et al. (2020), which used recent data from the UK Clinical Practice Research Datalink (CPRD). The clinical experts broadly agreed with the ERG's preference for using persistence rates from Morley et al. However, they explained that persistence on alendronic acid after romosozumab would likely be higher than on alendronic acid alone, and that the ERG's modelled persistence on alendronic acid alone was too low. People having romosozumab would likely have more severe osteoporosis than those in the CPRD dataset, and would be more motivated to continue with treatment. The committee noted that the choice of persistence rates for alendronic acid after romosozumab had a major effect on the cost-effectiveness results. This was because once alendronic acid treatment is stopped, its effect is assumed to decrease to zero over time. The committee understood that in the ERG's base case, people having alendronic acid after romosozumab had a lower persistence at 6 months than people having alendronic acid alone after 24 months. It considered that this lacked face validity. At its first meeting, the committee requested to see a scenario with the same persistence rates from Morley et al. applied for alendronic acid in both arms, adjusted according to the total length of time after starting treatment, including romosozumab. In response to consultation, the company argued that assuming equal persistence on alendronic acid after romosozumab and alendronic acid alone is extremely conservative. The Delphi panel concluded that persistence on alendronic acid after romosozumab would be higher than on alendronic acid alone. To reflect this and the feedback from the clinical experts at the first committee meeting, the company adjusted the persistence rates for alendronic acid after romosozumab to be higher than those for alendronic acid alone at the equivalent time points using the data from Morley et al. For persistence on alendronic acid alone, the company used the unadjusted data from Morley et al. The ERG accepted that persistence on alendronic acid would be higher after romosozumab and considered that the company's adjusted persistence rates from Morley et al. were plausible. However, it noted that at 24 months in ARCH the persistence in both arms was the same. The committee questioned the validity of only adjusting the persistence rates for alendronic acid after romosozumab and not adjusting those for alendronic acid alone. However, it understood that the adjustment to Morley et al. was to account for the increased persistence after romosozumab, rather than the higher risk population. The committee considered whether the Delphi panel consensus estimates were more plausible than those from Morley et al., because this approach would use the same source of data for both treatment arms. It noted that the Delphi panel consensus was that people having romosozumab after alendronic acid would have a constant persistence from 12 to 60 months, which it considered implausible. The committee also considered that physicians can tend to overestimate persistence, which made the Delphi panel uncertain. It concluded that more people are likely to continue having alendronic acid after romosozumab than having alendronic acid alone. Using persistence rates from either Morley et al. or the Delphi panel would each have flaws, but the committee concluded that it was appropriate to consider both during decision making. ## The company's approach to modelling the effect of fractures on quality of life is appropriate In ARCH, health-related quality of life was assessed at pre-determined time points. The company noted that ARCH did not provide robust utility values sensitive to the effect of fractures, so it considered it inappropriate to use the quality-of-life data from ARCH in its model. Instead, it used the utility multipliers for fractures from the International Costs and Utilities Related to Osteoporotic Fractures Study (ICUROS), combined with the UK general population values from Szende et al. (2014) in line with the approach in NICE's technology appraisal guidance on bisphosphonates for treating osteoporosis (TA464). The ERG agreed with the company's approach of using fracture utility multipliers from the ICUROS study. However, the ERG noted that the values differed from TA464, and that the approach for modelling the effect of multiple fractures was also different. At its first meeting, the committee concluded that it is uncertain if the company's approach to modelling the effect of fractures on quality of life was appropriate. In response to consultation, the company presented a scenario using the fracture utility multipliers from TA464. This significantly reduced the incremental cost-effectiveness ratio (ICER), because there was a larger utility loss associated with vertebral fractures when using the TA464 fracture utility multipliers. The committee concluded that the fracture utility multipliers from ICUROS were more appropriate than TA464 because they were newer and based on a larger sample size. ## Excess mortality should be modelled after hip and vertebral fractures The company modelled the mortality risk of fractures by applying an increased relative mortality risk to the general population all-cause mortality risk. It took the all-cause mortality risks from the UK life tables from 2012 to 2014. The company reduced the relative risk of mortality associated with fractures to 30% to account for the higher mortality risk associated with general frailty in the fractured population. This was in line with recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Osteoporosis Foundation (IOF). The company assumed that hip, vertebral and other (non-hip, non-vertebral) fractures have a mortality risk. The ERG preferred to use more recent values for all-cause mortality from the UK life tables from 2017 to 2019, and was unclear why the company used UK life tables from 2012 to 2014. The ERG explained that the ESCEO and the IOF did not recommend modelling excess mortality for 'other' fractures. Because of a lack of clinical consensus on including excess mortality after vertebral fractures, it preferred to include excess mortality after hip fractures only. The clinical experts noted that early mortality may be higher after hip fractures, but that overall long-term mortality is similar after both hip and vertebral fractures. At its first meeting, the committee concluded that excess mortality should be modelled after hip and vertebral fractures. In response to consultation, the company updated its base case to exclude mortality linked to non-hip, non-vertebral fractures and included excess mortality after hip and vertebral fractures only. The committee was aware that the company continued to use the 2012 to 2014 UK life tables for all-cause mortality, despite the ERG's preference for using the more recent mortality rates. # Costs in the economic model ## Uncertainties around fracture costs have a minor effect on the cost-effectiveness results The company estimated the costs of hip (£13,293), vertebral (£2,897) and other (£2,131) fractures during the first year based on a UK study by Gutiérrez et al. (2011, 2012; updated using the Consumer Price Index ). The company estimated the costs of fractures in subsequent years based on Davis et al. (2016; updated using the CPI), but only applied these costs to hip and vertebral fractures. These costs were £115 and £361 respectively. The ERG noted that the company had taken the total fracture costs from Gutiérrez et al. but these studies also provided the incremental costs of people with fractures relative to matched controls. The ERG considered that incremental costs would be more specific to the fracture than total costs. It preferred to use these incremental cost estimates for hip (£5,369), vertebral (£1,465) and other (£877) fractures for its base case. The ERG noted that a similar approach was used in TA464, but acknowledged that the incremental costs from Gutiérrez et al. did not include rehabilitation costs. The committee noted that using total or incremental costs had a relatively minor impact on the cost-effectiveness results. However, it noted that rehabilitation costs were likely to be large, and omitting them may be inappropriate. At its first meeting, the committee concluded that incremental fracture costs were more appropriate than total costs, but that they should also include rehabilitation costs. In response to consultation, the company updated its base case to use the fracture costs from TA464. The committee concluded that using different approaches to calculate fracture costs had a minor effect on the cost-effectiveness results. ## The ERG's average cost associated with long-term care is appropriate for decision making The company explained that hip fractures are associated with increased admission to long-term care facilities. To account for this, the company applied daily long-term costs based on ESCEO and IOF guidelines and in line with TA464. It applied a daily long-term nursing home care cost of £112 based on an EU study, updated using the CPI and calculated based on the probability of being discharged to institutional care. The ERG preferred to use a daily long-term care cost of £67 for its base case based on unit costs from the Personal Social Services Research Unit (PSSRU; 2020), derived using a similar approach to TA464. At its first meeting, the committee concluded the costs associated with long-term care were uncertain. In response to consultation, the company explained that the ERG's assumption that 36% of people moving into long-term care are self-funded and do not incur any costs contrasts with NICE guidance which recommends that only those moving to residential care are self-funded. It explained the proportion of people moving to nursing homes is likely to increase with age, while the proportion of people who are self-funded is likely to decrease. Therefore, the company retained its original base case assumption. Because of the uncertainty, the ERG preferred to use an average of its original estimate and that of the company for its revised base case (£90 per day). The committee concluded that the ERG's revised average long-term care costs were appropriate for decision making. ## Romosozumab administration costs should be limited to a single nurse visit The company applied no drug administration costs for romosozumab in its original model. The company explained that it plans to set up a patient support programme which will include a homecare service, an adherence support program and training on delivering injections. The company also did not apply any administration costs for alendronic acid since it is taken orally. The ERG preferred not to consider the proposed patient support programme in its base case, and therefore included the romosozumab administration costs. The committee understood from NICE that the proposed patient support programme could not be considered within the appraisal. It noted that the patient support programme had little impact on the cost-effectiveness results but concluded that it should not be considered, in line with the guidance from NICE. In response to consultation, the company explained that romosozumab will be self-administered like other biologics already used in the NHS. In rare circumstances, NHS resource may be used only to provide the first administration of romosozumab, in line with clinical practice in NHS Scotland. To reflect this, the company updated its base case with 1 nurse visit only and assumed that the 11 remaining doses will be self-administered. The committee agreed that the company's updated base case was appropriate. ## It is uncertain if the treatment effect of romosozumab wanes over time In its model, the company assumed that the duration of the treatment effect of romosozumab is maintained for 5 years. After this, a dynamic offset (linear waning) of the treatment effect is assumed for another 5 years. At year 11, the company assumed there would be no treatment effect. The ERG explained that the Kaplan–Meier curves for time to first clinical fracture and time to first non-vertebral fracture show that there is a visible separation for romosozumab followed by alendronic acid compared with alendronic acid alone. However, the ERG also noted that the curves seem to converge from month 42 to month 48, and so questioned if the treatment effect of romosozumab may wane over time. The committee noted that the curves by month 48 were based on very small numbers of people having treatment and considered that it would be difficult to make any firm conclusions about treatment waning. It concluded that because of the small numbers of people having treatment towards the end of the curves, it was uncertain if the treatment effect of romosozumab wanes over time. ## It is appropriate to consider cost-effectiveness results both with and without the inclusion of cardiovascular adverse events The company's original model only included gastrointestinal adverse events that are associated with oral bisphosphonates. It excluded all other adverse events because of a lack of evidence and in line with NICE's technology appraisal guidance on raloxifene for the primary prevention of osteoporotic fragility fractures in postmenopausal women and raloxifene and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. The ERG noted that more people having romosozumab had serious cardiovascular events in ARCH than those having alendronic acid alone (see section 3.9). Although romosozumab is contraindicated for people with previous myocardial infarction or stroke (see section 3.9), the ERG was unclear if all cardiovascular events in ARCH happened in people with a history of myocardial infarction or stroke. The ERG explained that excluding events which happened in people who would not be contraindicated was inappropriate. Therefore, the ERG considered it was appropriate to include the costs and quality-of-life effect of serious cardiovascular events in its base case. The committee questioned if ARCH showed whether people for whom romosozumab was contraindicated had cardiovascular events. But the company responded that cardiovascular risk factors had not been collected at baseline. The committee was aware that NICE's guideline on osteoarthritis: care and management considered cardiovascular adverse events associated with non-steroidal anti-inflammatory drugs. Therefore, it was appropriate to consider them within the model. In response to consultation, the company updated its base case model to include cardiovascular events based on the rates in ARCH. It explained that the other romosozumab studies (see section 3.9) did not show any imbalances in cardiovascular events. Therefore, the inclusion of cardiovascular events based only on ARCH represented a conservative approach. The ERG agreed, noting that the company could have pooled cardiovascular events across the romosozumab studies. The committee noted there was still uncertainty around the inclusion of cardiovascular events in the model. The committee concluded it would consider results both with and without cardiovascular events in its decision making. # Cost-effectiveness estimates ## Romosozumab is cost effective for treating severe osteoporosis after menopause in people at imminent fracture risk The committee focused on the pairwise ICERs for romosozumab followed by alendronic acid compared with alendronic acid alone. The company's and ERG's deterministic base cases included the confidential Commercial Medicines Unit price for alendronic acid, which means they cannot be reported here. The committee recalled that there were several uncertainties in the modelling, specifically: the efficacy of romosozumab in the imminent fracture risk population (see section 3.7) the results of the NMAs (see section 3.8) the persistence on romosozumab (see section 3.11) and alendronic acid after romosozumab (see section 3.12) the fracture utility multipliers (see section 3.13) the effect of cardiovascular adverse events (see section 3.19).It understood that the key difference between the company and ERG base cases was the romosozumab persistence assumption, although the ERG had also made several other changes that had a small effect on the cost-effectiveness results. Because of the uncertainty around the following assumptions, the committee considered both the company and ERG base cases: with and without cardiovascular events with persistence rates based on the Delphi panel with the fracture utility multipliers from TA464.The committee noted that although the ERG base case was above the range NICE normally considers an acceptable use of NHS resources (that is, £20,000 to £30,000 per quality-adjusted life year gained), if the Delphi panel persistence rates were applied then the ICER would fall within an acceptable range. It noted that excluding cardiovascular events from the model would further reduce the ICER. The committee therefore considered that the most plausible ICER for romosozumab followed by alendronic acid compared with alendronic acid alone was likely to be below £30,000 per QALY gained. It concluded that romosozumab followed by alendronic acid is a cost-effective use of NHS resources. # Innovation ## Romosozumab is an innovative treatment for severe osteoporosis, but all relevant benefits are reflected in the cost-effectiveness estimates The company considered romosozumab to be innovative because it is a unique osteoporosis therapy that stimulates bone formation and decreases bone resorption. The company explained it is the first anti-sclerostin antibody to be licensed for use in Europe and the USA. The patient experts highlighted that romosozumab is the first new treatment to be available in 10 years. Patient experts also highlighted that romosozumab will offer a step change for treating severe osteoporosis. The clinical experts explained the benefits of romosozumab's dual mode of action over the current treatments. The committee acknowledged the benefits offered by romosozumab. However, it concluded that it had not been presented with evidence of any additional benefits that were not captured in the QALY measurements. # Equalities consideration ## There are no equalities issues relevant to the recommendations The patient experts explained that although romosozumab has a marketing authorisation for women after menopause, this should not prevent using romosozumab for men, because the benefits of treatment are likely to be similar. The committee noted that there may be some people who have been through the menopause but do not identify as a woman. The committee concluded that romosozumab will be considered within its marketing authorisation but that the recommendation need not specify sex. The company noted that osteoporosis is more common in women than men, and people of low socioeconomic status have increased fracture risk, higher mortality after fracture, longer hospital stays and greater risk of re-admission. However, issues related to differences in prevalence or incidence of a disease cannot be addressed in a technology appraisal. In response to consultation, a consultee highlighted that rare types of osteoporosis had not been considered. However, the committee did not consider this an equality issue that could be resolved by this appraisal. The committee concluded that no other equality issues raised were relevant since romosozumab is recommended.	{'Recommendations': 'Romosozumab is recommended as an option for treating severe osteoporosis in people after menopause who are at high risk of fracture, only if:\n\nthey have had a major osteoporotic fracture (spine, hip, forearm or humerus fracture) within 24\xa0months (so are at imminent risk of another fracture) and\n\nthe company provides romosozumab according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with romosozumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatments for people with severe osteoporosis after menopause include bisphosphonates, such as alendronic acid, and other types of medicines, such as denosumab or teriparatide. The company proposes that romosozumab would only be used when there is an imminent fracture risk. It defines this as when a person has severe osteoporosis and has had a major osteoporotic fracture within 24\xa0months. This is narrower than the marketing authorisation.\n\nClinical trial evidence suggests that romosozumab followed by alendronic acid is more effective at reducing the risk of fractures than alendronic acid alone. Comparing romosozumab indirectly with other bisphosphonates and other medicines for this condition suggests that romosozumab is likely to be at least as effective at reducing the risk of fractures in people with osteoporosis after menopause. But the extent of the benefit is uncertain because of differences between the trial populations in the indirect comparisons.\n\nThe most likely cost-effectiveness estimates for romosozumab followed by alendronic acid, compared with alendronic acid alone, are within what NICE normally considers an acceptable use of NHS resources. So, romosozumab is recommended.', 'Information about romosozumab': "# Marketing authorisation indication\n\nRomosozumab (EVENITY, UCB) is indicated for 'the treatment of severe osteoporosis in postmenopausal women at high risk of fracture'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for romosozumab.\n\n# Price\n\nThe price for romosozumab is £427.75 for 2\xa0pre-filled pens administered subcutaneously as a single monthly dose (BNF online, accessed October\xa02021). The company has a commercial arrangement. This makes romosozumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by UCB, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Severe osteoporosis can have a substantial effect on quality of life\n\nOsteoporosis is a progressive skeletal disorder. It is characterised by low bone mass and deterioration of the structure of bone tissue leading to an increase in bone fragility and risk of fracture. The patient experts explained that osteoporosis affects all aspects of daily life, including walking, eating and breathing. People with the disease often have difficulty doing day-to-day tasks. Fractures can be painful and have a substantial effect on a person's independence and are also associated with increased mortality. Because of this, people with osteoporosis live in fear of having another fracture. The patient experts explained how the physical changes from osteoporosis, such as loss of height or a stooped posture, can cause feelings of shame. The clinical experts explained that it is important to build bone strength and prevent fragility fractures, particularly in people at the highest risk of fracture. The committee concluded that severe osteoporosis can have a substantial effect on quality of life, and that this would be improved by preventing fragility fractures.\n\n# Treatment pathway and comparators\n\n## People with severe osteoporosis would welcome a new treatment option\n\nThe clinical experts explained that several treatment options are available for severe osteoporosis. These are chosen depending on fracture risk, the presence of previous fractures, and response to or tolerance of other treatments. These treatments can be broadly divided into 2\xa0classes: anabolic (bone-forming) agents and anti-resorptive agents. For people at high risk of fracture, first-line treatment is usually oral bisphosphonates such as alendronic acid or risedronate sodium. However, oral bisphosphonates are either not tolerated or contraindicated in many people with osteoporosis, or the disease does not respond well to them. In this situation, another anti-resorptive treatment can be offered. This includes intravenous bisphosphonates, or a non-bisphosphonate such as denosumab or raloxifene. An anabolic non-bisphosphonate, teriparatide, is another option for people with a higher fracture risk. However, non-bisphosphonates can be difficult to administer and not everyone can have them. The clinical experts noted that evidence suggests that giving teriparatide as the first treatment before oral bisphosphonates may be more effective at reducing fracture risk, but NICE's technology appraisal guidance on raloxifene and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women only recommends teriparatide for the secondary prevention of osteoporotic fractures. Also, people can only have teriparatide once during their lifetime. There is an unmet need for people with very high fracture risk for whom current drugs are not suitable, or for those at particularly high risk of vertebral or hip fractures. Romosozumab has both anabolic and anti-resorptive properties, and is the first new treatment option for osteoporosis in several years. The patient experts agreed that romosozumab offered hope as an additional treatment option. The committee concluded that both patients and clinicians would welcome a new treatment option for severe osteoporosis.\n\n## The population in which the company positioned romosozumab is narrower than the NICE scope and ARCH trial population\n\nThe population in the NICE scope and the marketing authorisation was people after menopause who have severe osteoporosis and are at high risk of fracture (high risk of fracture was not further defined). The committee noted that the population in the company's main clinical trial (ARCH) was women with severe osteoporosis after menopause who are at high risk of fracture (high risk of fracture was defined as having had a major osteoporotic fracture [see section\xa03.6]). The company's decision problem population was women with severe osteoporosis after menopause who were at high risk of fracture, where high risk of fracture was defined as having had a major osteoporotic fracture within 24\xa0months. A major osteoporotic fracture was defined as a clinical spine, hip, forearm or humerus fracture. The company's decision problem population will be referred to as imminent fracture risk. The committee was aware that defining fracture risk can be complex and there are different ways and different factors that contribute to the definition of high risk. The committee concluded that for this evaluation it would use the ARCH trial definition of high risk (see section\xa03.6). It also concluded that the company's imminent fracture risk population was narrower than the NICE scope, the marketing authorisation and the ARCH trial.\n\n## Romosozumab would be used in people at imminent fracture risk, regardless of previous treatment\n\nThe company explained that it had positioned romosozumab in the imminent fracture risk population because these people are at much higher risk of another fracture compared with those who had had a fracture less recently. The company also clarified that the population in its submission was regardless of previous treatment. The clinical experts agreed that the risk of fracture is highest soon after a fracture. But they noted that duration of increased fracture risk can vary based on factors such as age and previous fracture location. The clinical experts also explained that the date of the previous fracture may not always be known, particularly for vertebral fractures. So, the company's decision problem population may be difficult to implement in clinical practice. Both clinical and patient experts agreed that romosozumab should be positioned regardless of previous treatment, but that ideally it should be available as a first-line treatment. The committee acknowledged that the company's imminent fracture risk population represents people with a high risk of fracture. However, it noted that most people in ARCH had not previously had treatment for osteoporosis (see section\xa03.6), so there was uncertainty around the efficacy of romosozumab in later lines of therapy. A response to consultation highlighted that in the STRUCTURE trial, romosozumab had a greater effect on bone mineral density (BMD) than teriparatide in people who had previously had bisphosphonates. STRUCTURE was a randomised, double-blind study in women after menopause with osteoporosis, providing data on romosozumab (n=218) compared with teriparatide (n=218). This gave some reassurance as to the efficacy of romosozumab regardless of previous treatment. The committee concluded that it would appraise romosozumab according to the company's proposed population. That is, people with severe osteoporosis after menopause who are at imminent fracture risk, regardless of previous treatment.\n\n## Bisphosphonates and non-bisphosphonates are relevant comparators for romosozumab\n\nThe committee recalled that it would appraise romosozumab regardless of previous treatment (see section\xa03.4). All of the comparators in the NICE scope are used for treating severe osteoporosis, with non-bisphosphonates largely offered after bisphosphonates (see section\xa03.2). As such, the committee concluded that both bisphosphonates and non-bisphosphonates are relevant comparators for romosozumab.\n\n# Clinical evidence\n\n## ARCH is broadly generalisable to UK clinical practice\n\nThe main source of clinical-effectiveness evidence for romosozumab was the ARCH trial. ARCH was a randomised, double-blind, multicentre trial comparing romosozumab followed by oral alendronic acid (n=2,046) with oral alendronic acid alone (n=2,047). People were randomised to have either romosozumab or alendronic acid for 12\xa0months, followed by open-label oral alendronic acid for at least another 12\xa0months in both arms. ARCH included ambulatory women after menopause aged 55\xa0to 90 if they met at least 1 of the following criteria:\n\nA T‑score of ‑2.5 or less at the total hip or femoral neck and either 1 or more moderate or severe vertebral fractures, or 2 or more mild vertebral fractures\n\nA T‑score of ‑2.0 or less at the total hip or femoral neck and either 2 or more moderate or severe vertebral fractures, or a fracture of the proximal femur 3\xa0to 24\xa0months before randomisation.A T‑score relates to the measurement of BMD using central dual-energy X‑ray (DXA) scanning and is expressed as the number of standard deviations below peak BMD. ARCH was an event-driven trial. The primary analysis was done after all people had completed their month\xa024 visit and at least 330\xa0people had a confirmed clinical fracture (median follow up was 33\xa0months). The clinical experts explained that the baseline characteristics from ARCH suggested that the results would be generalisable to NHS clinical practice. The committee noted that only around 10% of people having romosozumab in ARCH had previously had treatment, so there was uncertainty around the effectiveness of romosozumab given after previous osteoporosis therapies. The committee concluded that ARCH was broadly generalisable to people who had not previously had treatment who had a high fracture risk and would have romosozumab in the NHS.\n\n## Romosozumab followed by alendronic acid is more effective than alendronic acid alone\n\nIn ARCH, the primary outcomes were the cumulative incidence of new vertebral fracture at month\xa024, and the cumulative incidence of clinical fracture at the time of primary analysis. Key secondary outcomes included the incidence of the following fracture types: non-vertebral, all fractures, new or worsening vertebral, major non-vertebral, hip, and major osteoporotic. Percentage change in BMD at the lumbar spine, total hip and femoral neck were other secondary outcomes. In the ARCH intention-to-treat (ITT) population, people randomised to the romosozumab arm had a 50% lower relative risk of vertebral fractures over 24\xa0months than people having alendronic acid alone (relative risk 0.50, 95% confidence interval [CI] 0.38 to 0.66). A lower proportion of people having romosozumab (9.7%) had a clinical fracture compared with people having alendronic acid alone (13%), and this difference was statistically significant (hazard ratio [HR] 0.73, 95% CI 0.61 to 0.88). At the primary analysis there were also fewer people having romosozumab who had non-vertebral fractures (HR 0.81, 95% CI 0.66 to 0.99) or hip fractures (HR 0.62, 95% CI 0.42 to 0.92) compared with those having alendronic acid alone. People having romosozumab had a greater increase in BMD from baseline compared with people having alendronic acid alone, and this difference was statistically significant (adjusted p<0.001). The committee recalled that the company's decision problem population was narrower than ARCH (see section\xa03.3). The company stated that a post-hoc analysis of ARCH showed that the imminent fracture risk population had similar outcomes to the ITT population, but had not presented this evidence in its submission. At the first meeting, the committee concluded that romosozumab followed by alendronic acid is more effective than alendronic acid alone in the ARCH ITT population, but that the company had not provided evidence in the imminent fracture risk population. In response to consultation, the company presented a post-hoc analysis of ARCH comparing the results for people whose last major osteoporotic fracture was recent (less than 24\xa0months) or not recent (more than 24\xa0months). The recent fracture group corresponded to the company's imminent fracture risk population. The results showed that there were no statistically significant differences between the 2\xa0groups for any of the primary or key secondary end points in ARCH. The company therefore considered that it was appropriate to generalise the results from the ARCH ITT population to the imminent fracture risk population. The ERG noted that there were considerable differences in the effectiveness results between the recent and not recent groups from ARCH for some end points, even though the results were not statistically significant. The clinical experts stated that the post-hoc analysis raised questions about the company's imminent fracture risk population. This was because people in ARCH whose last fracture was not recent had similar outcomes to people whose last fracture was recent. They considered that the ARCH ITT population may better represent the population that romosozumab should be used in. The committee noted that the post-hoc analysis should be interpreted with caution. However, it concluded that the results provided reassurance that romosozumab was similarly effective in the imminent fracture risk population as in the ARCH ITT population.\n\n## Despite uncertainty, the indirect comparisons with other comparators are suitable for decision making\n\nThere is no head-to-head evidence comparing romosozumab followed by alendronic acid with the other comparators in the NICE scope: risedronate sodium, ibandronic acid, zoledronic acid, denosumab, raloxifene and teriparatide. Therefore, the company did network meta-analyses (NMAs) to allow for indirect treatment comparisons with these comparators. The company could not include ibandronic acid in the NMAs because there were no trials at the licensed dose reporting fracture outcomes. The results of the company's NMAs showed that romosozumab followed by alendronic acid is significantly better than, or at least as good as, most comparators for most fracture outcomes at various time points. The ERG explained that these results were uncertain because of the differences between the study populations in the NMAs. Most studies included had differences in mean age, ethnicity, or the rate of prevalent vertebral fractures. The ERG noted that the company's NMAs were based on the ARCH ITT population rather than the imminent fracture risk population (see section\xa03.3). The ERG also noted that there was little direct evidence with which to assess inconsistency in the networks, and that the studies in the NMAs did not provide data consistently across timepoints. The ERG therefore considered only the comparisons between romosozumab, alendronic acid and placebo to have a low risk of bias, while all other comparisons had a high risk of bias. The committee agreed that the NMAs may be biased. At its first meeting, the committee considered that it would like to see NMAs adjusted for baseline risk, and treatment effect estimates centred around the imminent fracture risk population. In response to consultation, the company updated its NMAs to include the results from the post-hoc analysis for the recent fracture group (see section\xa03.7) as a scenario analysis. The results were consistent with the company's original NMAs using the ARCH ITT population. The company noted that this scenario analysis was likely to be more uncertain because it could not adjust the comparator trials to the imminent fracture risk population. The company also did meta-regressions to explore if baseline risk or any other covariates impacted the estimated treatment effects in the NMAs. The company used 2\xa0approaches:\n\nadjusting for the rate of people with a history of vertebral fracture at baseline, and\n\nreducing the network to include trials with a placebo comparator and adjusting for the fracture rates in the placebo arm.With the exception of new vertebral fractures at 12\xa0months, the results of the company's meta-regressions showed that neither vertebral fractures at baseline nor baseline risk significantly affected the treatment effects in the NMAs. So, the company considered that its original NMAs remained the most appropriate for decision making. The committee noted that the results of the baseline risk meta-regression had wide credible intervals, indicating a high level of uncertainty. The committee considered that both the company's original and updated NMAs had considerable uncertainty. Despite this, the updated NMAs provided reassurance that the relative efficacy of romosozumab compared with current standard care was likely to be similar in the imminent fracture risk and ARCH ITT populations. The committee therefore concluded that the results of the original NMAs using the full ARCH ITT population data were appropriate for decision making.\n\n## More people having romosozumab had serious cardiovascular events in ARCH, but no imbalance was seen in another larger romosozumab study\n\nAn imbalance in adjudicated serious cardiovascular events between treatment arms was seen in ARCH. In the romosozumab arm of ARCH, 16\xa0people (0.8%) reported cardiac ischaemic events compared with 6\xa0people (0.3%) in the alendronic acid arm in ARCH (odds ratio [OR] 2.65; 95% CI 1.03 to 6.77) after 12\xa0months. Cerebrovascular events were reported by 16\xa0people (0.8%) in the romosozumab arm and 7\xa0people (0.3%) in the alendronic acid arm (OR 2.27; 95% CI 0.93 to 5.22). However, there was no difference in adjudicated serious cardiovascular events in the FRAME trial for people having romosozumab compared with placebo at 12\xa0months. FRAME was a randomised, double-blind study in women after menopause with osteoporosis, providing data on romosozumab followed by denosumab (n=3,589) compared with placebo followed by denosumab (n=3,591). The committee noted that FRAME had a larger population than ARCH. In response to consultation, the company also noted that no imbalance in cardiovascular events had been seen in STRUCTURE (compared with teriparatide) and in a phase\xa02 trial compared with placebo. The committee was aware that romosozumab is contraindicated for people with previous myocardial infarction or stroke. The committee understood that there may be multiple reasons why ARCH showed an increased risk of cardiovascular events for people having romosozumab. These included romosozumab increasing the risk of cardiovascular events, or alendronic acid reducing the risk of cardiovascular events, or that this was a chance finding. The committee also understood that romosozumab should only be prescribed if the clinician and the person at high risk of fracture agreed that the benefit outweighed these risks. The committee concluded that there was a concern that people having romosozumab were more likely to experience cardiovascular events than those having alendronic acid alone, and that balancing the benefits and risks before starting romosozumab was essential.\n\n# Economic model\n\n## The company's economic model is suitable for decision making\n\nThe company used a Markov microsimulation model to estimate the cost effectiveness of romosozumab compared with alendronic acid, risedronate sodium, zoledronic acid, denosumab, raloxifene and teriparatide. The model included 5\xa0health states: at risk, hip fracture, vertebral fracture, other fracture (non-hip, non-vertebral) and death. In the company's model, the risk of having a fracture was based on a combination of 4\xa0components: the general population risk of fracture, the increased fracture risk associated with osteoporosis relative to the general population, the increased fracture risk because of having a recent fracture (the imminent fracture risk), and the reduction in risk from osteoporosis treatment. The treatment effect of romosozumab compared with alendronic acid on fracture risk was calculated by fitting parametric distributions to the Kaplan–Meier curves from ARCH to calculate time-dependent hazard rates. The ERG agreed that the company's model structure was appropriate for osteoporosis. It noted that the company had not presented information on how the parametric distributions had been fitted to the data from ARCH. It could therefore not assess if the distributions had been properly fitted or explore the effect of using alternative distributions. In response to consultation, the company explained that parametric curves were fitted to the hip fracture and non-vertebral fracture data from ARCH. It used an exponential model for romosozumab followed by alendronic acid and a log-normal model for alendronic acid alone to model hip fractures. For non-vertebral fractures, the company used a log-normal model for both treatment arms. The ERG noted that the company had not provided graphs comparing different parameterisations to the observed data, or tables detailing statistical fit. The committee concluded that the company's model was suitable for decision making but there was still some uncertainty about how the parametric distributions had been fitted to the data from the ARCH.\n\n## How long people continue to have romosozumab is uncertain\n\nThe length of osteoporosis treatment in clinical practice, particularly for oral bisphosphonates, is often shorter than intended. This was reflected in the company's model using rates of persistence. In its original base case, because of a lack of real-world data on romosozumab persistence, the company assumed that 90% of people would complete the 12‑month treatment period based on the persistence rates seen in the clinical trials. The ERG noted that the company's approach was inconsistent and likely biased, because the company had used clinical trial data to model persistence for romosozumab but not the comparators. It considered that real-world persistence on romosozumab would likely be lower than in the clinical trials, so it preferred to use a value of 80% for its base case. This was based on an assumption in a Swedish cost-effectiveness analysis by Söreskog et al. (2021). In response to consultation, the company did a Delphi panel with 18\xa0clinical experts in the UK. The Delphi panel explored persistence on different osteoporosis treatments, and persistence on alendronic acid specifically as a follow-on treatment. The experts' consensus was that a slightly lower proportion of people would complete the 12‑month romosozumab treatment period than in the persistence rates seen in ARCH. The outputs of the Delphi panel are academic in confidence and cannot be reported here. The company considered that the true persistence rate estimates on romosozumab would likely be slightly higher in UK clinical practice than the Delphi panel estimates. Therefore, it continued to assume a 90% persistence on romosozumab at 12\xa0months for its revised base case. The ERG reiterated that it was inconsistent to use real-world evidence to model persistence for the comparators, and clinical trial data to model persistence for romosozumab. Therefore, the ERG preferred to use a lower estimate of persistence on romosozumab in line with the Delphi panel for its revised base case. The company noted that the ERG's position was also inconsistent, in that it used different types of data to model persistence on romosozumab and alendronic acid. The committee was aware that the choice of persistence rates for romosozumab had a major effect on the cost-effectiveness results. The committee concluded that persistence on romosozumab was highly uncertain, and that it would consider cost-effectiveness scenarios using both the company's and ERG's preferred assumptions.\n\n## More people are likely to continue having alendronic acid after romosozumab than having alendronic acid alone\n\nIn its original base case, the company assumed that persistence on alendronic acid after romosozumab would be 85% of that of denosumab, based on the Swedish Prescribed Drug Register. These persistence rates were higher than what the company assumed persistence would be for alendronic acid alone, which it took from a different source. The ERG preferred to use data from the same study to model persistence for alendronic acid after romosozumab and alendronic acid alone. It favoured a study by Morley et al. (2020), which used recent data from the UK Clinical Practice Research Datalink (CPRD). The clinical experts broadly agreed with the ERG's preference for using persistence rates from Morley et al. However, they explained that persistence on alendronic acid after romosozumab would likely be higher than on alendronic acid alone, and that the ERG's modelled persistence on alendronic acid alone was too low. People having romosozumab would likely have more severe osteoporosis than those in the CPRD dataset, and would be more motivated to continue with treatment. The committee noted that the choice of persistence rates for alendronic acid after romosozumab had a major effect on the cost-effectiveness results. This was because once alendronic acid treatment is stopped, its effect is assumed to decrease to zero over time. The committee understood that in the ERG's base case, people having alendronic acid after romosozumab had a lower persistence at 6\xa0months than people having alendronic acid alone after 24\xa0months. It considered that this lacked face validity. At its first meeting, the committee requested to see a scenario with the same persistence rates from Morley et al. applied for alendronic acid in both arms, adjusted according to the total length of time after starting treatment, including romosozumab. In response to consultation, the company argued that assuming equal persistence on alendronic acid after romosozumab and alendronic acid alone is extremely conservative. The Delphi panel concluded that persistence on alendronic acid after romosozumab would be higher than on alendronic acid alone. To reflect this and the feedback from the clinical experts at the first committee meeting, the company adjusted the persistence rates for alendronic acid after romosozumab to be higher than those for alendronic acid alone at the equivalent time points using the data from Morley et al. For persistence on alendronic acid alone, the company used the unadjusted data from Morley et al. The ERG accepted that persistence on alendronic acid would be higher after romosozumab and considered that the company's adjusted persistence rates from Morley et al. were plausible. However, it noted that at 24\xa0months in ARCH the persistence in both arms was the same. The committee questioned the validity of only adjusting the persistence rates for alendronic acid after romosozumab and not adjusting those for alendronic acid alone. However, it understood that the adjustment to Morley et al. was to account for the increased persistence after romosozumab, rather than the higher risk population. The committee considered whether the Delphi panel consensus estimates were more plausible than those from Morley et al., because this approach would use the same source of data for both treatment arms. It noted that the Delphi panel consensus was that people having romosozumab after alendronic acid would have a constant persistence from 12 to 60\xa0months, which it considered implausible. The committee also considered that physicians can tend to overestimate persistence, which made the Delphi panel uncertain. It concluded that more people are likely to continue having alendronic acid after romosozumab than having alendronic acid alone. Using persistence rates from either Morley et al. or the Delphi panel would each have flaws, but the committee concluded that it was appropriate to consider both during decision making.\n\n## The company's approach to modelling the effect of fractures on quality of life is appropriate\n\nIn ARCH, health-related quality of life was assessed at pre-determined time points. The company noted that ARCH did not provide robust utility values sensitive to the effect of fractures, so it considered it inappropriate to use the quality-of-life data from ARCH in its model. Instead, it used the utility multipliers for fractures from the International Costs and Utilities Related to Osteoporotic Fractures Study (ICUROS), combined with the UK general population values from Szende et al. (2014) in line with the approach in NICE's technology appraisal guidance on bisphosphonates for treating osteoporosis (TA464). The ERG agreed with the company's approach of using fracture utility multipliers from the ICUROS study. However, the ERG noted that the values differed from TA464, and that the approach for modelling the effect of multiple fractures was also different. At its first meeting, the committee concluded that it is uncertain if the company's approach to modelling the effect of fractures on quality of life was appropriate. In response to consultation, the company presented a scenario using the fracture utility multipliers from TA464. This significantly reduced the incremental cost-effectiveness ratio (ICER), because there was a larger utility loss associated with vertebral fractures when using the TA464 fracture utility multipliers. The committee concluded that the fracture utility multipliers from ICUROS were more appropriate than TA464 because they were newer and based on a larger sample size.\n\n## Excess mortality should be modelled after hip and vertebral fractures\n\nThe company modelled the mortality risk of fractures by applying an increased relative mortality risk to the general population all-cause mortality risk. It took the all-cause mortality risks from the UK life tables from 2012 to 2014. The company reduced the relative risk of mortality associated with fractures to 30% to account for the higher mortality risk associated with general frailty in the fractured population. This was in line with recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Osteoporosis Foundation (IOF). The company assumed that hip, vertebral and other (non-hip, non-vertebral) fractures have a mortality risk. The ERG preferred to use more recent values for all-cause mortality from the UK life tables from 2017 to 2019, and was unclear why the company used UK life tables from 2012 to 2014. The ERG explained that the ESCEO and the IOF did not recommend modelling excess mortality for 'other' fractures. Because of a lack of clinical consensus on including excess mortality after vertebral fractures, it preferred to include excess mortality after hip fractures only. The clinical experts noted that early mortality may be higher after hip fractures, but that overall long-term mortality is similar after both hip and vertebral fractures. At its first meeting, the committee concluded that excess mortality should be modelled after hip and vertebral fractures. In response to consultation, the company updated its base case to exclude mortality linked to non-hip, non-vertebral fractures and included excess mortality after hip and vertebral fractures only. The committee was aware that the company continued to use the 2012 to 2014 UK life tables for all-cause mortality, despite the ERG's preference for using the more recent mortality rates.\n\n# Costs in the economic model\n\n## Uncertainties around fracture costs have a minor effect on the cost-effectiveness results\n\nThe company estimated the costs of hip (£13,293), vertebral (£2,897) and other (£2,131) fractures during the first year based on a UK study by Gutiérrez et al. (2011, 2012; updated using the Consumer Price Index [CPI]). The company estimated the costs of fractures in subsequent years based on Davis et al. (2016; updated using the CPI), but only applied these costs to hip and vertebral fractures. These costs were £115 and £361 respectively. The ERG noted that the company had taken the total fracture costs from Gutiérrez et al. but these studies also provided the incremental costs of people with fractures relative to matched controls. The ERG considered that incremental costs would be more specific to the fracture than total costs. It preferred to use these incremental cost estimates for hip (£5,369), vertebral (£1,465) and other (£877) fractures for its base case. The ERG noted that a similar approach was used in TA464, but acknowledged that the incremental costs from Gutiérrez et al. did not include rehabilitation costs. The committee noted that using total or incremental costs had a relatively minor impact on the cost-effectiveness results. However, it noted that rehabilitation costs were likely to be large, and omitting them may be inappropriate. At its first meeting, the committee concluded that incremental fracture costs were more appropriate than total costs, but that they should also include rehabilitation costs. In response to consultation, the company updated its base case to use the fracture costs from TA464. The committee concluded that using different approaches to calculate fracture costs had a minor effect on the cost-effectiveness results.\n\n## The ERG's average cost associated with long-term care is appropriate for decision making\n\nThe company explained that hip fractures are associated with increased admission to long-term care facilities. To account for this, the company applied daily long-term costs based on ESCEO and IOF guidelines and in line with TA464. It applied a daily long-term nursing home care cost of £112 based on an EU study, updated using the CPI and calculated based on the probability of being discharged to institutional care. The ERG preferred to use a daily long-term care cost of £67 for its base case based on unit costs from the Personal Social Services Research Unit (PSSRU; 2020), derived using a similar approach to TA464. At its first meeting, the committee concluded the costs associated with long-term care were uncertain. In response to consultation, the company explained that the ERG's assumption that 36% of people moving into long-term care are self-funded and do not incur any costs contrasts with NICE guidance which recommends that only those moving to residential care are self-funded. It explained the proportion of people moving to nursing homes is likely to increase with age, while the proportion of people who are self-funded is likely to decrease. Therefore, the company retained its original base case assumption. Because of the uncertainty, the ERG preferred to use an average of its original estimate and that of the company for its revised base case (£90 per day). The committee concluded that the ERG's revised average long-term care costs were appropriate for decision making.\n\n## Romosozumab administration costs should be limited to a single nurse visit\n\nThe company applied no drug administration costs for romosozumab in its original model. The company explained that it plans to set up a patient support programme which will include a homecare service, an adherence support program and training on delivering injections. The company also did not apply any administration costs for alendronic acid since it is taken orally. The ERG preferred not to consider the proposed patient support programme in its base case, and therefore included the romosozumab administration costs. The committee understood from NICE that the proposed patient support programme could not be considered within the appraisal. It noted that the patient support programme had little impact on the cost-effectiveness results but concluded that it should not be considered, in line with the guidance from NICE. In response to consultation, the company explained that romosozumab will be self-administered like other biologics already used in the NHS. In rare circumstances, NHS resource may be used only to provide the first administration of romosozumab, in line with clinical practice in NHS Scotland. To reflect this, the company updated its base case with 1\xa0nurse visit only and assumed that the 11\xa0remaining doses will be self-administered. The committee agreed that the company's updated base case was appropriate.\n\n## It is uncertain if the treatment effect of romosozumab wanes over time\n\nIn its model, the company assumed that the duration of the treatment effect of romosozumab is maintained for 5\xa0years. After this, a dynamic offset (linear waning) of the treatment effect is assumed for another 5\xa0years. At year\xa011, the company assumed there would be no treatment effect. The ERG explained that the Kaplan–Meier curves for time to first clinical fracture and time to first non-vertebral fracture show that there is a visible separation for romosozumab followed by alendronic acid compared with alendronic acid alone. However, the ERG also noted that the curves seem to converge from month\xa042 to month\xa048, and so questioned if the treatment effect of romosozumab may wane over time. The committee noted that the curves by month\xa048 were based on very small numbers of people having treatment and considered that it would be difficult to make any firm conclusions about treatment waning. It concluded that because of the small numbers of people having treatment towards the end of the curves, it was uncertain if the treatment effect of romosozumab wanes over time.\n\n## It is appropriate to consider cost-effectiveness results both with and without the inclusion of cardiovascular adverse events\n\nThe company's original model only included gastrointestinal adverse events that are associated with oral bisphosphonates. It excluded all other adverse events because of a lack of evidence and in line with NICE's technology appraisal guidance on raloxifene for the primary prevention of osteoporotic fragility fractures in postmenopausal women and raloxifene and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. The ERG noted that more people having romosozumab had serious cardiovascular events in ARCH than those having alendronic acid alone (see section\xa03.9). Although romosozumab is contraindicated for people with previous myocardial infarction or stroke (see section\xa03.9), the ERG was unclear if all cardiovascular events in ARCH happened in people with a history of myocardial infarction or stroke. The ERG explained that excluding events which happened in people who would not be contraindicated was inappropriate. Therefore, the ERG considered it was appropriate to include the costs and quality-of-life effect of serious cardiovascular events in its base case. The committee questioned if ARCH showed whether people for whom romosozumab was contraindicated had cardiovascular events. But the company responded that cardiovascular risk factors had not been collected at baseline. The committee was aware that NICE's guideline on osteoarthritis: care and management considered cardiovascular adverse events associated with non-steroidal anti-inflammatory drugs. Therefore, it was appropriate to consider them within the model. In response to consultation, the company updated its base case model to include cardiovascular events based on the rates in ARCH. It explained that the other romosozumab studies (see section\xa03.9) did not show any imbalances in cardiovascular events. Therefore, the inclusion of cardiovascular events based only on ARCH represented a conservative approach. The ERG agreed, noting that the company could have pooled cardiovascular events across the romosozumab studies. The committee noted there was still uncertainty around the inclusion of cardiovascular events in the model. The committee concluded it would consider results both with and without cardiovascular events in its decision making.\n\n# Cost-effectiveness estimates\n\n## Romosozumab is cost effective for treating severe osteoporosis after menopause in people at imminent fracture risk\n\nThe committee focused on the pairwise ICERs for romosozumab followed by alendronic acid compared with alendronic acid alone. The company's and ERG's deterministic base cases included the confidential Commercial Medicines Unit price for alendronic acid, which means they cannot be reported here. The committee recalled that there were several uncertainties in the modelling, specifically:\n\nthe efficacy of romosozumab in the imminent fracture risk population (see section\xa03.7)\n\nthe results of the NMAs (see section\xa03.8)\n\nthe persistence on romosozumab (see section\xa03.11) and alendronic acid after romosozumab (see section\xa03.12)\n\nthe fracture utility multipliers (see section\xa03.13)\n\nthe effect of cardiovascular adverse events (see section\xa03.19).It understood that the key difference between the company and ERG base cases was the romosozumab persistence assumption, although the ERG had also made several other changes that had a small effect on the cost-effectiveness results. Because of the uncertainty around the following assumptions, the committee considered both the company and ERG base cases:\n\nwith and without cardiovascular events\n\nwith persistence rates based on the Delphi panel\n\nwith the fracture utility multipliers from TA464.The committee noted that although the ERG base case was above the range NICE normally considers an acceptable use of NHS resources (that is, £20,000 to £30,000 per quality-adjusted life year [QALY] gained), if the Delphi panel persistence rates were applied then the ICER would fall within an acceptable range. It noted that excluding cardiovascular events from the model would further reduce the ICER. The committee therefore considered that the most plausible ICER for romosozumab followed by alendronic acid compared with alendronic acid alone was likely to be below £30,000 per QALY gained. It concluded that romosozumab followed by alendronic acid is a cost-effective use of NHS resources.\n\n# Innovation\n\n## Romosozumab is an innovative treatment for severe osteoporosis, but all relevant benefits are reflected in the cost-effectiveness estimates\n\nThe company considered romosozumab to be innovative because it is a unique osteoporosis therapy that stimulates bone formation and decreases bone resorption. The company explained it is the first anti-sclerostin antibody to be licensed for use in Europe and the USA. The patient experts highlighted that romosozumab is the first new treatment to be available in 10\xa0years. Patient experts also highlighted that romosozumab will offer a step change for treating severe osteoporosis. The clinical experts explained the benefits of romosozumab's dual mode of action over the current treatments. The committee acknowledged the benefits offered by romosozumab. However, it concluded that it had not been presented with evidence of any additional benefits that were not captured in the QALY measurements.\n\n# Equalities consideration\n\n## There are no equalities issues relevant to the recommendations\n\nThe patient experts explained that although romosozumab has a marketing authorisation for women after menopause, this should not prevent using romosozumab for men, because the benefits of treatment are likely to be similar. The committee noted that there may be some people who have been through the menopause but do not identify as a woman. The committee concluded that romosozumab will be considered within its marketing authorisation but that the recommendation need not specify sex. The company noted that osteoporosis is more common in women than men, and people of low socioeconomic status have increased fracture risk, higher mortality after fracture, longer hospital stays and greater risk of re-admission. However, issues related to differences in prevalence or incidence of a disease cannot be addressed in a technology appraisal. In response to consultation, a consultee highlighted that rare types of osteoporosis had not been considered. However, the committee did not consider this an equality issue that could be resolved by this appraisal. The committee concluded that no other equality issues raised were relevant since romosozumab is recommended."}	https://www.nice.org.uk/guidance/ta791	Evidence-based recommendations on romosozumab (EVENITY) for severe osteoporosis in people after menopause who are at high risk of fracture.
11af5c9beb45154aa9550fb00f4a85cd34f364c0	nice	Endoanchoring systems in endovascular aortic aneurysm repair	Endoanchoring systems in endovascular aortic aneurysm repair Evidence-based recommendations on endoanchoring systems in endovascular aortic aneurysm repair. This involves using an anchoring device to hold a stent in place to prevent leaks in an aneurysm repair. # Recommendations For people with unfavourable aneurysm morphology needing an endovascular aortic aneurysm repair (EVAR) as a primary procedure, or for people with an existing EVAR who need a secondary procedure, evidence on the safety of using endoanchoring systems is adequate. Evidence on efficacy is limited in quantity and quality. Therefore, for these people, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. For people with favourable aneurysm morphology needing an EVAR as a primary procedure, evidence on the safety of using endoanchoring systems is adequate. However, evidence on efficacy is inadequate in quantity and quality. Therefore, for these people, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. Clinicians wanting to use endoanchoring systems for people with unfavourable aneurysm morphology needing an EVAR as a primary procedure, or for people with an existing EVAR who need a secondary procedure should: Inform the clinical governance leads in their healthcare organisation. Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Enter details about everyone having endoanchoring systems in endovascular aortic aneurysm repair into the National Vascular Registry and review local clinical outcomes. Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure. Regularly review data on outcomes and safety for this procedure. Patient selection should be done by a multidisciplinary team. Further research should report details of patient selection and include longer-term outcomes.# The condition, current treatments and procedure # The condition Aortic aneurysms develop when the wall of the aorta weakens, causing it to bulge and form a balloon-like expansion. They can happen in the chest (thoracic aortic aneurysms) or, more commonly, below the diaphragm (abdominal aortic aneurysms). # Current treatments The standard treatment for aortic aneurysm is either open surgical or endovascular repair. During open surgical repair the aneurysm is opened and a graft is sewn in above and below the weakened area to allow normal blood flow. Endovascular repair is a minimally invasive alternative to open repair. A graft is mounted on a stent, which is inserted into the aorta through catheters placed in the femoral arteries. The stent–graft is deployed under X-ray guidance and positioned across the aneurysm. In endovascular aortic aneurysm repair (EVAR) procedures, the stent–graft can sometimes leak (endoleak) or move out of place (migrate), or a person's anatomy can make its placement difficult. Type 1 endoleaks happen around the top or bottom of grafts and are often caused by an inadequate seal. # The procedure Endoanchoring systems aim to improve the fixation of the stent–graft used in EVAR. They may be used prophylactically or therapeutically at the same time as the primary procedure or during a later, secondary procedure to treat an endoleak or migration. Endoanchoring implants are inserted under general or local anaesthesia. The implants are deployed through an applier device consisting of a catheter and a control handle. The catheter is advanced until the distal end contacts the stent–graft and vessel wall. The number of implants needed depends on the type of stent–graft and the size of the native vessel. They are placed as evenly as possible around the circumference of the stent–graft. The catheter is then removed, the holes in the femoral arteries are sutured and the groin wounds are closed.	{'Recommendations': "For people with unfavourable aneurysm morphology needing an endovascular aortic aneurysm repair (EVAR) as a primary procedure, or for people with an existing EVAR who need a secondary procedure, evidence on the safety of using endoanchoring systems is adequate. Evidence on efficacy is limited in quantity and quality. Therefore, for these people, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nFor people with favourable aneurysm morphology needing an EVAR as a primary procedure, evidence on the safety of using endoanchoring systems is adequate. However, evidence on efficacy is inadequate in quantity and quality. Therefore, for these people, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nClinicians wanting to use endoanchoring systems for people with unfavourable aneurysm morphology needing an EVAR as a primary procedure, or for people with an existing EVAR who need a secondary procedure should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nEnter details about everyone having endoanchoring systems in endovascular aortic aneurysm repair into the National Vascular Registry and review local clinical outcomes.\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a multidisciplinary team.\n\nFurther research should report details of patient selection and include longer-term outcomes.", 'The condition, current treatments and procedure': "# The condition\n\nAortic aneurysms develop when the wall of the aorta weakens, causing it to bulge and form a balloon-like expansion. They can happen in the chest (thoracic aortic aneurysms) or, more commonly, below the diaphragm (abdominal aortic aneurysms).\n\n# Current treatments\n\nThe standard treatment for aortic aneurysm is either open surgical or endovascular repair. During open surgical repair the aneurysm is opened and a graft is sewn in above and below the weakened area to allow normal blood flow. Endovascular repair is a minimally invasive alternative to open repair. A graft is mounted on a stent, which is inserted into the aorta through catheters placed in the femoral arteries. The stent–graft is deployed under X-ray guidance and positioned across the aneurysm.\n\nIn endovascular aortic aneurysm repair (EVAR) procedures, the stent–graft can sometimes leak (endoleak) or move out of place (migrate), or a person's anatomy can make its placement difficult. Type\xa01 endoleaks happen around the top or bottom of grafts and are often caused by an inadequate seal.\n\n# The procedure\n\nEndoanchoring systems aim to improve the fixation of the stent–graft used in EVAR. They may be used prophylactically or therapeutically at the same time as the primary procedure or during a later, secondary procedure to treat an endoleak or migration.\n\nEndoanchoring implants are inserted under general or local anaesthesia. The implants are deployed through an applier device consisting of a catheter and a control handle. The catheter is advanced until the distal end contacts the stent–graft and vessel wall. The number of implants needed depends on the type of stent–graft and the size of the native vessel. They are placed as evenly as possible around the circumference of the stent–graft. The catheter is then removed, the holes in the femoral arteries are sutured and the groin wounds are closed."}	https://www.nice.org.uk/guidance/ipg725	Evidence-based recommendations on endoanchoring systems in endovascular aortic aneurysm repair. This involves using an anchoring device to hold a stent in place to prevent leaks in an aneurysm repair.
12766503fc48187f66a850357e43c2e81a459863	nice	Supercapsular percutaneously assisted total hip arthroplasty for osteoarthritis	Supercapsular percutaneously assisted total hip arthroplasty for osteoarthritis Evidence-based recommendations on supercapsular percutaneously assisted total hip arthroplasty for osteoarthritis in adults. This involves replacing a hip using smaller cuts than are used in standard surgery. # Recommendations Evidence on the safety and efficacy of supercapsular percutaneously assisted total hip arthroplasty for osteoarthritis is limited in quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do supercapsular percutaneously assisted total hip arthroplasty for osteoarthritis should: Inform the clinical governance leads in their healthcare organisation. Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Enter details about all patients having supercapsular percutaneously assisted total hip arthroplasty for osteoarthritis onto the National Joint Registry and review local clinical outcomes. Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure. Regularly review data on outcomes and safety for this procedure. Further research should include suitably powered randomised controlled trials comparing this procedure with standard approaches to total hip arthroplasty. It should report details of patient selection, short-term outcomes and long-term outcomes.# The condition, current treatments and procedure # The condition Osteoarthritis, also known as degenerative joint disease, is a disorder of synovial joints. It occurs when damage triggers repair processes leading to structural changes in a joint. There are 2 main types of osteoarthritis: primary (more generalised osteoarthritis with unknown aetiology) and secondary (osteoarthritis with a known cause, such as injury or inflammation in the joint). When it affects the hip, symptoms include joint stiffness, pain and reduced function, such as difficulty walking. # Current treatments Care and management of osteoarthritis is described in NICE's guideline on osteoarthritis. Current management of hip osteoarthritis includes lifestyle changes (such as weight loss), physical or occupational therapy, medications and surgery (such as hip resurfacing, total hip arthroplasty and osteotomy). # The procedure Supercapsular percutaneously assisted total hip arthroplasty is also described as the 'SuperPath' approach. It is a minimally invasive approach to total hip arthroplasty. The aim, as with standard posterior or direct lateral approaches, is to reconstruct the hip to reduce symptoms and improve hip function, but with smaller cuts. The procedure is done under general or regional anaesthesia. The patient is usually put in the standard lateral decubitus position, with the hip in 45 degrees of flexion and 10 to 15 degrees of internal rotation. A cut is made superior to the greater trochanter. The gluteal fascia is cut, the gluteus maximus muscle is split, the gluteus medius and minimus muscles are retracted anteriorly and the piriformis tendon is retracted posteriorly. Once the joint capsule is exposed, it is cut from the base of the greater trochanter to 1 cm proximal to the acetabular rim. The femoral canal is then reamed and broached without dislocation. The femoral neck is osteotomised and the femoral head removed. A trial cup is placed into the acetabulum attached to an external alignment jig. A second skin portal is made distally and posteriorly once the correct acetabular position is set. A cannula is inserted to protect the adjacent sciatic nerve when using the power reamer. Once reamed, the acetabular components are inserted and a trial reduction done. The definitive components are inserted if the reduction is deemed satisfactory. The hip joint capsule is closed with a suture. Then the gluteal fascia and skin are closed with sutures. This procedure uses a specific set of implants and specialised instruments. Postoperative rehabilitation is recommended for muscle strengthening and mobility.	{'Recommendations': "Evidence on the safety and efficacy of supercapsular percutaneously assisted total hip arthroplasty for osteoarthritis is limited in quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do supercapsular percutaneously assisted total hip arthroplasty for osteoarthritis should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nEnter details about all patients having supercapsular percutaneously assisted total hip arthroplasty for osteoarthritis onto the National Joint Registry and review local clinical outcomes.\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nFurther research should include suitably powered randomised controlled trials comparing this procedure with standard approaches to total hip arthroplasty. It should report details of patient selection, short-term outcomes and long-term outcomes.", 'The condition, current treatments and procedure': "# The condition\n\nOsteoarthritis, also known as degenerative joint disease, is a disorder of synovial joints. It occurs when damage triggers repair processes leading to structural changes in a joint. There are 2\xa0main types of osteoarthritis: primary (more generalised osteoarthritis with unknown aetiology) and secondary (osteoarthritis with a known cause, such as injury or inflammation in the joint). When it affects the hip, symptoms include joint stiffness, pain and reduced function, such as difficulty walking.\n\n# Current treatments\n\nCare and management of osteoarthritis is described in NICE's guideline on osteoarthritis. Current management of hip osteoarthritis includes lifestyle changes (such as weight loss), physical or occupational therapy, medications and surgery (such as hip resurfacing, total hip arthroplasty and osteotomy).\n\n# The procedure\n\nSupercapsular percutaneously assisted total hip arthroplasty is also described as the 'SuperPath' approach. It is a minimally invasive approach to total hip arthroplasty. The aim, as with standard posterior or direct lateral approaches, is to reconstruct the hip to reduce symptoms and improve hip function, but with smaller cuts.\n\nThe procedure is done under general or regional anaesthesia. The patient is usually put in the standard lateral decubitus position, with the hip in 45\xa0degrees of flexion and 10\xa0to 15\xa0degrees of internal rotation. A cut is made superior to the greater trochanter. The gluteal fascia is cut, the gluteus maximus muscle is split, the gluteus medius and minimus muscles are retracted anteriorly and the piriformis tendon is retracted posteriorly. Once the joint capsule is exposed, it is cut from the base of the greater trochanter to 1\xa0cm proximal to the acetabular rim.\n\nThe femoral canal is then reamed and broached without dislocation. The femoral neck is osteotomised and the femoral head removed. A trial cup is placed into the acetabulum attached to an external alignment jig. A second skin portal is made distally and posteriorly once the correct acetabular position is set. A cannula is inserted to protect the adjacent sciatic nerve when using the power reamer. Once reamed, the acetabular components are inserted and a trial reduction done. The definitive components are inserted if the reduction is deemed satisfactory. The hip joint capsule is closed with a suture. Then the gluteal fascia and skin are closed with sutures.\n\nThis procedure uses a specific set of implants and specialised instruments. Postoperative rehabilitation is recommended for muscle strengthening and mobility."}	https://www.nice.org.uk/guidance/ipg726	Evidence-based recommendations on supercapsular percutaneously assisted total hip arthroplasty for osteoarthritis in adults. This involves replacing a hip using smaller cuts than are used in standard surgery.
52ef7a55cba60e747ff561f17857729691c9fe84	nice	Sleepio to treat insomnia and insomnia symptoms	Sleepio to treat insomnia and insomnia symptoms Evidence-based recommendations on Sleepio to treat insomnia and insomnia symptoms. # Recommendations Sleepio is recommended as a cost saving option for treating insomnia and insomnia symptoms in primary care for people who would otherwise be offered sleep hygiene or sleeping pills. For people who may be at higher risk of other sleep disorder conditions, such as in pregnancy, or in people with comorbidities, a medical assessment should be done before referral to Sleepio. More research or data collection is recommended on Sleepio for people who are eligible for face-to-face cognitive behavioural therapy for insomnia (CBT‑I) in primary care. This is because there is limited clinical evidence to show how effective Sleepio is compared with face-to-face CBT‑I. Find out more in the further research section. Why the committee made these recommendations Usual treatment for people with sleep problems is advice about sleep hygiene. Sleeping pills may also be considered if insomnia symptoms are likely to resolve soon. If insomnia symptoms are not likely to resolve soon, best practice is to refer for face-to-face CBT‑I, although its availability in the UK is limited. This clinical pathway is outlined in the British Association for Psychopharmacology (BAP) consensus statement on insomnia. People who may be at higher risk of other sleep disorders including sleep apnoea should have a medical assessment before referral to Sleepio. Sleepio is a digital self-help programme that includes CBT‑I. It could therefore increase patients' access to CBT‑I. It also increases the options available to GPs treating insomnia. Clinical evidence shows that Sleepio reduces insomnia symptoms compared with sleep hygiene and sleeping pills. There is no direct evidence of its effectiveness compared with face-to-face CBT‑I, so further research is recommended in this context. At a price of £45 per person, Sleepio is cost saving compared with usual treatment in primary care. This is based on an analysis of primary care resource use data before and after Sleepio was introduced in 9 GP practices. Healthcare costs were lower at 1 year, mostly because of fewer GP appointments and sleeping pills prescribed.# The technology # Technology Sleepio (Big Health) is a self-help sleep improvement programme based on cognitive behavioural therapy for insomnia (CBT‑I). It is primarily accessed through a website. There is a Sleepio app for iOS mobile and Android devices. The iOS app can be linked to a compatible wearable fitness tracker to monitor sleep (currently Fitbit and any other device that uses Apple's HealthKit). The Android app can be linked to Fitbit. The programme is structured around a sleep test, weekly interactive CBT‑I sessions and regular sleep diary entries. The sessions focus on identifying thoughts, feelings and behaviours that contribute to the symptoms of insomnia. Cognitive interventions aim to improve the way a person thinks about sleep and the behavioural interventions aim to promote a healthy sleep routine. The programme is designed to be completed in 6 weeks, but people have full access to the programme for 12 months from registration, including redoing sessions. They can also access electronic library articles, online tools and the online Sleepio user community. A daily sleep diary helps users track their progress and the programme tailors advice to individuals. Users can fill in the diary manually or the data can be automatically uploaded from a compatible wearable tracking device. # Care pathway The British Association for Psychopharmacology (BAP) consensus statement on insomnia describes treatment options for adults with poor sleep, which depend on how long they have had insomnia symptoms. People are first offered advice about sleep hygiene. If this does not work and they are severely impaired during the day, and it is causing significant distress, a 3- to 7‑day course of a non-benzodiazepine hypnotic medication can be considered. Hypnotic medication should only be considered if symptoms are likely to resolve quickly (for example because of a short-term stressor). If symptoms are not likely to resolve soon, face‑to‑face or digital CBT‑I should be offered. Currently, face-to-face CBT‑I is not routinely available on the NHS for most people with insomnia. A short-term course of hypnotic medication can be offered in addition to CBT‑I but should not be offered routinely. People should be offered follow‑up consultations every 2 to 4 weeks to review their symptoms. NICE's clinical knowledge summary on insomnia summarises the latest evidence on managing insomnia in primary care, based on whether it is short term (less than 3 months) or long term (more than 3 months). For both, the advice is to consider referral to a sleep clinic or neurology if the person has symptoms of another sleep disorder, and to address whatever might be causing the insomnia. It also advises making sure comorbidities such as anxiety and depression are managed. It gives the same advice on sleep hygiene, hypnotic medication and CBT‑I as BAP. People with insomnia often also have a mental health problem. NICE's guideline on common mental health problems recommends assessing people using the improving access to psychological therapies (IAPT) screening tools and validated scales. Treatment depends on symptom severity and includes education, monitoring, CBT and medication. # Innovative aspects Sleepio uses an artificial intelligence (AI) algorithm to provide people with tailored digital CBT‑I. There is also support available from a Sleepio community, which includes clinical experts and other people with insomnia. # Intended use Sleepio is primarily intended as an alternative to usual treatment, which includes sleep hygiene education and hypnotic medication. People can get Sleepio through self-referral, or through primary care or IAPT services. People who have mental health conditions managed in routine care who are using Sleepio may benefit from having a healthcare professional involved. # Training The company offers primary care training on prescribing Sleepio, technical training and set up. # Costs The cost of Sleepio is £45 (excluding VAT) per person who starts session 1 of the Sleepio programme. This price was proposed at consultation and differs from the previous cost models proposed by the company, which depended on regional uptake of Sleepio. The 2 previous cost models, the population-based and the tiered licence-based cost model, are outlined below. The population-based cost model involved a cost per head per year depending on the size of the population within a region. This cost was independent of the number of people that used Sleepio. The larger the population, the lower the cost per head. Because a fixed price is paid by NHS organisations each year, increased uptake led to an increase in cost savings. The tiered licence-based cost model was based on the number of people who had treatment with Sleepio. This was a tiered pricing system, so the cost per patient reduced as uptake increased beyond the number of people specified within each of the fixed tiers. For more details of these prices, see the supporting documents for Sleepio on the NICE website.For more details about the technology, see the website for Sleepio.# Evidence NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website. # Clinical evidence ## The clinical evidence comprises 28 studies, 12 of which are randomised controlled trials The EAC assessed 25 full text publications, an unpublished study and 2 abstracts. Twelve of the studies were randomised controlled trials (including 6 secondary analyses of randomised controlled trials). Six were non-randomised studies and there was 1 abstract. Also, the company provided the EAC with 2 unpublished, real-world evidence studies. For full details of the clinical evidence, see section 3 of the assessment report. Find the assessment report in the supporting documents for Sleepio on the NICE website. ## The 12 randomised controlled trials are relevant to the decision problem and show that Sleepio reduces symptoms of insomnia There is good quality evidence that Sleepio improves sleep in people with self-reported insomnia symptoms (according to DSM-5 , SCI and ISI measures). The most robust evidence for Sleepio comprises 12 randomised controlled trials, 10 of which used intention-to-treat analyses to control for high drop-out rates. The studies are small relative to the potential reach of Sleepio but are adequately powered and well reported. ## The UK population is well represented in the evidence for Sleepio The UK population is well represented in the evidence base for Sleepio, which includes 7 UK studies and 4 multinational studies that included UK populations. Four of the studies done in the UK were randomised controlled trials (Espie et al. 2012, Freeman et al. 2017, Denis et al. 2020 , Kyle et al. 2020); all concluded that Sleepio was more effective in reducing insomnia symptoms than the comparator (standard care, waiting list, placebo or attention control). ## The evidence is heterogenous The studies included in the assessment varied in design, population, outcome measures and comparators. Study participants included people with difficulty sleeping with or without medical and mental health comorbidities, and different durations of insomnia. The comparator differed between studies and often the description of standard care lacked clarity. It was unclear whether standard care included aspects of cognitive behavioural therapy for insomnia (CBT‑I), the hypnotic medication prescription, or both, and there was little information about what was offered as sleep hygiene education. ## There is limited evidence comparing Sleepio with face-to-face CBT-I or other forms of digital CBT-I The company acknowledged that the lack of evidence comparing Sleepio with face-to-face CBT or digital CBT‑I was a limitation. It said that face‑to‑face CBT‑I for insomnia is not routinely available on the NHS and is not scalable to the UK NHS population. There is a meta-analysis (Soh et al. 2020) that indicated that digital CBT‑I is non-inferior to face‑to‑face CBT‑I. A network meta-analysis (Hasan et al. 2022) compared various forms of digital CBT‑I with face-to-face CBT‑I. The authors concluded that web-based CBT‑I with a virtual or real therapist offers better outcomes than other digital CBT‑I approaches (web-based CBT‑I without a therapist, telephone-based CBT‑I and mobile app-based CBT‑I). Sleepio includes a virtual therapist. The authors also reported that, although web-based CBT‑I with a therapist resulted in reduced insomnia symptoms when compared with educational therapy, face‑to‑face CBT‑I was superior to both these interventions. The authors said that the meta-analysis included relatively few studies that included face-to-face CBT‑I and that the follow-up effects of digital CBT‑I were unavailable. There are currently no studies that compare Sleepio with other digital CBT‑I technologies. # Cost evidence ## The company used a single cohort spreadsheet model to compare the cost of Sleepio with treatment as usual and face-to-face CBT-I The company submitted 12 economic studies relevant to the economic assessment. The EAC found 3 of them met the decision problem. The company's economic analysis modelled a population of adults with insomnia symptoms. The model compared Sleepio with 2 comparators: treatment as usual (which includes sleep hygiene and sleep medication) and face-to-face CBT‑I. The model assumes that treatment with Sleepio is clinically equivalent to both comparators and so includes only the resource impact and no clinical outcomes. The company's analysis in the initial submission is based on the population-based price (see section 2.10). The cost impact and proportion of patients using Sleepio are based on data from Sampson et al. (2021). The key costs were: Sleepio at £45 per adult who starts session 1 of the programme. This price was proposed at consultation. The supporting documents for this guidance describe the cost model results with the other prices mentioned in section 2. Sleep hygiene at £0. Face-to-face CBT-I at £492 (this was changed by the EAC to £542 to account for inflation) per adult. Primary care resource use per user in years 1, 2 and 3 at £49.52, £43.52 and £42.05 respectively.For full details of the cost evidence, see section 4 of the assessment report in the supporting documents. ## The EAC concluded that the statistical analysis in Sampson et al. (2021) is robust The committee asked the EAC to review the statistical analysis described in Sampson et al. (2021) and explore if it was possible to link the NHS data with the data from Sleepio to better understand the outcomes associated with its use. Patient-level data was made available to the EAC, who replicated the multilevel generalised linear model described in the paper. It was not possible to link the NHS data to the data available from Sleepio users about usage and weekly sleep score. The EAC also investigated adding an individual patient level to the generalised linear model, the impact of seasonal adjustment, and relevant comorbidities. It found that the resource use saving results from the statistical model did not change significantly from those reported in the study (£6.64 compared with £5.53 per patient per year in the EAC model). It concluded that the Sampson et al. (2021) results are robust enough for use in the economic modelling for Sleepio. ## The EAC's updates to the cost model make Sleepio cost saving compared with treatment as usual After consultation, the EAC ran the cost model with the new price proposed at consultation. The base case shows that after 1 year, compared with treatment as usual, Sleepio is cost saving by £4.52 per person. If the results of resource savings at 1 year are extrapolated to 3 years, the cost savings are £90.08 per person. The EAC noted that with this price, the results do not depend on the uptake of the technology.# Committee discussion # Treatment pathway ## Sleepio can be used to treat symptoms of insomnia after primary care referral The evaluation considered Sleepio as a treatment for the symptoms of insomnia. The proposed patient population included people with symptoms or a diagnosis of insomnia. The committee accepted that this broad population was relevant and understood people could be referred to this technology by their GP or social prescriber if they live in a region where Sleepio is available. The committee accepted that insomnia symptoms are a common problem and that Sleepio has the potential to benefit many people. ## The most relevant comparator is treatment as usual including sleep hygiene advice and short-term medication Sleepio provides a sleep improvement programme based on cognitive behavioural therapy for insomnia (CBT‑I) for people with clinically diagnosed insomnia or symptoms of insomnia. Clinical experts explained that the gold standard treatment for clinically diagnosed insomnia that is unlikely to resolve soon is face-to-face CBT‑I, but its availability is limited in the NHS. Instead, they agreed that the most relevant comparator to treat clinically diagnosed insomnia and insomnia symptoms that are likely to resolve soon is 'treatment as usual', which includes sleep hygiene education and hypnotic medication. Several other digital technologies provide CBT‑I or other support for people with clinically diagnosed insomnia and insomnia symptoms, but their uptake and use is limited. The committee concluded that the appropriate comparator for people with clinically diagnosed insomnia and insomnia symptoms that are likely to resolve soon is treatment as usual consisting of sleep hygiene advice and short-term medication. ## Sleepio has the potential to provide another CBT-I option Clinical experts explained that digital CBT‑I, such as Sleepio and other digital CBT‑I technologies, increases the options available to primary and secondary care practitioners when treating insomnia. They explained that the gold standard treatment for insomnia is face-to-face CBT-I, but its availability is very limited in the NHS. The committee considered that there is space in the care pathway for Sleepio. It concluded that Sleepio has the potential to provide another option for people who would benefit from access to CBT‑I. # Clinical-effectiveness overview ## Sleepio is effective at reducing insomnia symptoms compared with treatment as usual The committee noted the large evidence base for Sleepio, and that the 28 studies in the evidence base included a range of patients who had a diagnosis or symptoms of insomnia. The external assessment centre (EAC) explained that changes in lifestyle are expected as part of treatment as usual, but it is unclear whether there was any explicit control for these factors in the evidence. The committee concluded that the evidence shows that Sleepio is more effective than treatment as usual in reducing symptoms of insomnia in adults. ## The limited evidence comparing Sleepio with face-to-face CBT-I means it should not be prescribed to people who would be offered face-to-face CBT-I The EAC explained that it did not identify any studies that compared Sleepio with other methods of delivering CBT‑I directly (for example face‑to‑face or other digital methods) and had clinical outcomes. Clinical experts confirmed that other digital devices are available that also deliver digital CBT‑I. They considered that the clinical effectiveness of Sleepio is likely to be comparable to other digital devices delivering CBT‑I as well as face-to-face CBT‑I, but recognised that there are some advantages to the latter. The committee noted that, although the Sleepio programme includes a virtual therapist, a real therapist is not present during any of the sessions. The EAC also highlighted 2 network meta-analyses (Soh et al. 2020 and Hasan et al. 2022) that explored the effectiveness of various digital CBT‑I and face-to-face CBT‑I and broadly concluded that the clinical effectiveness of these treatments is likely to be similar. The committee noted some limitations with these meta-analyses, for example few of the included studies assessed face-to-face CBT‑I. It recognised that the lack of comparative clinical evidence between Sleepio and face‑to‑face CBT‑I was a limitation in the evidence. The committee concluded that people should not be referred for Sleepio if they are eligible for and have access to face-to-face CBT-I. # Drop-out rates ## There are high drop-out rates with Sleepio, but these are thought to be consistent with other forms of CBT-I The evidence shows a high drop-out rate for people using Sleepio, from 11.2% (Luik et al. 2017) up to 61.6% (Freeman et al. 2017). High drop-out rates were also observed from the rollout of Sleepio in Buckinghamshire. These occurred throughout the programme from session 1 to session 5. The EAC highlighted that the definition of a drop-out varied among these studies. The committee noted that the meta-analysis (Soh et al. 2020) that compared digital CBT‑I (including Sleepio) and face-to-face CBT‑I reported similar levels of engagement and completion in both arms. Clinical experts explained that in some cases people's insomnia symptoms can resolve after sleep hygiene advice or active CBT‑I treatment. The Sleepio programme includes sleep hygiene advice and active CBT‑I treatment, and it is possible some people's symptoms may resolve before completing all 6 sessions of the programme. However, the reason for participants dropping out was not recorded, so people may have left the programme because their symptoms did not improve. The committee concluded that the direction of bias as a result of high drop-out rates with Sleepio is unclear, but recognised that high drop-out rates are common with CBT‑I in general and not specific to Sleepio. # Other patient benefits or issues ## Sleepio may be another option for pregnant women, who currently have fewer options to treat insomnia The EAC identified 2 studies that assessed digital CBT‑I in pregnant women (Felder et al. 2020 and Kalmbach et al. 2020). The studies concluded that Sleepio is more effective than control in treating insomnia symptoms. The clinical experts highlighted how important it is to do a medical assessment in pregnant women before referral to CBT‑I, because insomnia can mimic other conditions like restless legs, or it could be a consequence of undiagnosed sleep apnoea. The clinical experts also explained that, although hypnotic medication is avoided in pregnant women, some drugs are given for short courses when symptoms are likely to resolve soon. The committee concluded that Sleepio may be an alternative option for insomnia symptoms in pregnant women who have had a medical assessment to rule out other conditions. ## Following the Sleepio programme can be challenging but the Sleepio community provides support The patient expert described the sleep restriction component and quarter‑hour rule as particularly challenging aspects of the Sleepio programme that were difficult to implement, especially in the beginning. These challenges were also reported by people who responded to the patient survey. The patient expert said the support from the Sleepio website community was particularly helpful during this time. The company said that the community is monitored by volunteers with experience of using Sleepio. It also said that Sleepio users can access a weekly question and answer session on the Sleepio forum, facilitated by a clinical psychologist who specialises in insomnia. The committee noted the importance of the Sleepio community and its role in supporting people using Sleepio. ## Sleepio may be difficult to use for some people Sleepio requires access to a computer and the internet, which some people do not have at home. The patient expert said that it was possible to use Sleepio by accessing the internet occasionally (for example, at a public library) and keeping a paper sleep diary, but that this was more difficult. Some users of Sleepio may find it difficult to use a computer, such as people with a visual or cognitive impairment, limited manual dexterity or hearing impairment. The patient expert said that using Sleepio was relatively straightforward and that people with minimal computer skills could use it. But they agreed that some skill in using a computer is needed. They added that the Sleepio community can help people who need it. Also, Sleepio may be difficult to use for people who have limited English language skills. The company noted that the programme is being restructured so it can be translated into other languages. The committee accepted that Sleepio would be harder to use for some people with access or language restrictions. # Training ## Patient selection and the implementation model used for introducing Sleepio might affect patient uptake The company said that during the roll out of Sleepio they noticed that the different levels of training it provided for referring services (such as GP practices) affected the uptake of Sleepio. It said that training and support varies depending on the implementation model used to introduce it. In the 9 GP practices in Buckinghamshire, which used a comprehensive implementation model, the estimated uptake was 0.94%. Regions that did not have this implementation model had an uptake of 0.54% to 0.55% (Sampson et al. 2021). Clinical experts said patient selection was important to improve the chances of people using Sleepio properly and benefiting from it. They also said it would be helpful to give feedback to referrers, such as GPs, about how many people register to use Sleepio and what impact it has on their insomnia symptoms. This would help to understand outcomes and inform referral and training. The committee agreed that the training and support for referrers has an important effect on patient uptake. # Side effects and adverse events ## Adverse events are rare in people using Sleepio The EAC explained that very few adverse events were reported in the literature, and no serious adverse events were related to using Sleepio. Sleepio has been available in some regions of the NHS since 2013 and unpublished real-world evidence reports that over 100,000 people have used Sleepio in the UK. For full information about adverse events in the studies, see section 6 of the EAC's assessment report in the supporting documents. ## Sleepio is unlikely to harm people who have other sleeping disorders Clinical experts said that some people who present with symptoms of insomnia might have underlying conditions causing their symptoms. They explained that using Sleepio in this population may delay them having more appropriate treatment but is unlikely to cause harm. The company said that it has procedures in place for managing risk and adverse events but that they are uncommon. The committee concluded that Sleepio is unlikely to harm people who have sleeping difficulties because of an underlying condition. # Cost modelling overview ## There are uncertainties in the cost modelling because of the limited data available The resource use captured in the Sampson et al. (2021) study was used to inform the cost modelling. The statistical analysis in this study assumed that all changes in resource use over the study duration were because of the introduction of Sleepio. The committee had concerns about whether the variables included in the generalised linear model adequately captured all the important parameters, such as seasonal affect and comorbidities. The EAC reviewed the statistical analysis described in the study and confirmed that it was appropriate, and that it gave similar results to its own preferred statistical model. Despite some reassurance on the statistical analysis, the committee understood it was only possible to adjust for known confounders, and the quasi-experimental nature of the study means some uncertainty remains. The EAC also reported that it was not possible to link individual patient data from Sleepio with NHS resource use data. So, from the NHS data it is unclear which patients used Sleepio, if their symptoms improved with use, and what the associated resource impact was. This meant it was not possible to include remission status in the cost modelling. The committee accepted that the data available was limited, particularly around linking user data to NHS system data, and understood that this resulted in uncertainties in the cost modelling. # Potential for cost savings ## At the initial proposed prices, the technology was unlikely to be cost saving compared with treatment as usual When the population-based price proposed in the company submission was used in the EAC base case, Sleepio was cost incurring compared with treatment as usual after 1 year and 3 years. The main driver of the results was the uptake rate of the technology across the population. The EAC reduced the uptake rate to 0.58% from the company's estimate of 1%, and this increased the cost of Sleepio from £90 to £155.17 per user. The committee agreed with the EAC estimates and noted that any cost savings depended on the uptake rate. The tiered licence-based cost model was proposed after the first committee discussion and the price per user was updated to £66.11. When this cost was applied in the EAC base case, Sleepio was cost incurring by £16.59 per user at the end of year 1 but cost saving by £68.97 per user at 3 years. The committee did not agree that there was enough evidence to extrapolate the data to 3 years and concluded that the cost savings were uncertain. ## At the new proposed price, Sleepio is cost saving at 1 year compared with treatment as usual At consultation, the company proposed a price of £45 per user. When the EAC applied this new cost in its base case, Sleepio was cost saving compared with treatment as usual after 1 year, and the cost savings increased if benefits were extrapolated beyond 1 year. The committee noted that there were limitations in the economic modelling because of its dependence on the Sampson et al. (2021) study and the lack of remission outcomes. However, the committee decided on balance that at this price the technology was likely to be at least cost neutral and very likely cost saving, and decided to recommend it as an option for people with insomnia and insomnia symptoms who would otherwise receive treatment as usual. Both the company's and the EAC's cost models assumed Sleepio was clinically equivalent to face-to-face CBT‑I. This assumption was based on indirect evidence from several different digital CBT‑I interventions. The committee noted that the resource use for these models was based on the Sampson et al. (2021) study, which includes a large population with different severities of insomnia. It noted that it was not possible to identify people who would have been eligible for CBT‑I according to the criteria in NICE's clinical knowledge summary on insomnia, to evaluate the clinical effectiveness of Sleepio in that group. Derose et al. (2021) reported reduced resource use for Sleepio users compared with people attending face-to-face CBT‑I group sessions in the US. The committee noted however that no clinical outcomes were reported, and it was not clear how generalisable this study is to the NHS in terms of the patient characteristics and type of face-to-face CBT‑I used. It concluded that a study on people eligible for CBT‑I that includes both resource use data and clinical outcomes is needed to evaluate the resource impact of making Sleepio available to this population. # Further research ## A real-world study is suggested to compare the effectiveness of Sleepio with face-to-face CBT-I The committee concluded that more research is needed on the effectiveness of Sleepio as an alternative to face-to-face CBT‑I. It noted that there are some studies comparing Sleepio with face-to-face CBT‑I, but the evidence is limited. The committee acknowledged the difficulties of carrying out comparative research, given the accessibility issues with face-to-face CBT‑I in the NHS. It understood that a study based on real‑world evidence that collects clinical and resource use data in a population eligible for face-to-face CBT‑I, may be appropriate. It also considered a link between any Sleepio user data and resource use would help address uncertainties in the economic modelling. The committee also agreed that high-quality, non-UK based direct evidence could be acceptable.	{'Recommendations': "Sleepio is recommended as a cost saving option for treating insomnia and insomnia symptoms in primary care for people who would otherwise be offered sleep hygiene or sleeping pills.\n\nFor people who may be at higher risk of other sleep disorder conditions, such as in pregnancy, or in people with comorbidities, a medical assessment should be done before referral to Sleepio.\n\nMore research or data collection is recommended on Sleepio for people who are eligible for face-to-face cognitive behavioural therapy for insomnia (CBT‑I) in primary care. This is because there is limited clinical evidence to show how effective Sleepio is compared with face-to-face CBT‑I. Find out more in the further research section.\n\nWhy the committee made these recommendations\n\nUsual treatment for people with sleep problems is advice about sleep hygiene. Sleeping pills may also be considered if insomnia symptoms are likely to resolve soon. If insomnia symptoms are not likely to resolve soon, best practice is to refer for face-to-face CBT‑I, although its availability in the UK is limited. This clinical pathway is outlined in the British Association for Psychopharmacology (BAP) consensus statement on insomnia. People who may be at higher risk of other sleep disorders including sleep apnoea should have a medical assessment before referral to Sleepio.\n\nSleepio is a digital self-help programme that includes CBT‑I. It could therefore increase patients' access to CBT‑I. It also increases the options available to GPs treating insomnia.\n\nClinical evidence shows that Sleepio reduces insomnia symptoms compared with sleep hygiene and sleeping pills. There is no direct evidence of its effectiveness compared with face-to-face CBT‑I, so further research is recommended in this context.\n\nAt a price of £45 per person, Sleepio is cost saving compared with usual treatment in primary care. This is based on an analysis of primary care resource use data before and after Sleepio was introduced in 9\xa0GP practices. Healthcare costs were lower at 1\xa0year, mostly because of fewer GP appointments and sleeping pills prescribed.", 'The technology': "# Technology\n\nSleepio (Big Health) is a self-help sleep improvement programme based on cognitive behavioural therapy for insomnia (CBT‑I). It is primarily accessed through a website. There is a Sleepio app for iOS mobile and Android devices. The iOS app can be linked to a compatible wearable fitness tracker to monitor sleep (currently Fitbit and any other device that uses Apple's HealthKit). The Android app can be linked to Fitbit.\n\nThe programme is structured around a sleep test, weekly interactive CBT‑I sessions and regular sleep diary entries. The sessions focus on identifying thoughts, feelings and behaviours that contribute to the symptoms of insomnia. Cognitive interventions aim to improve the way a person thinks about sleep and the behavioural interventions aim to promote a healthy sleep routine. The programme is designed to be completed in 6\xa0weeks, but people have full access to the programme for 12\xa0months from registration, including redoing sessions. They can also access electronic library articles, online tools and the online Sleepio user community. A daily sleep diary helps users track their progress and the programme tailors advice to individuals. Users can fill in the diary manually or the data can be automatically uploaded from a compatible wearable tracking device.\n\n# Care pathway\n\nThe British Association for Psychopharmacology (BAP) consensus statement on insomnia describes treatment options for adults with poor sleep, which depend on how long they have had insomnia symptoms. People are first offered advice about sleep hygiene. If this does not work and they are severely impaired during the day, and it is causing significant distress, a 3- to 7‑day course of a non-benzodiazepine hypnotic medication can be considered. Hypnotic medication should only be considered if symptoms are likely to resolve quickly (for example because of a short-term stressor). If symptoms are not likely to resolve soon, face‑to‑face or digital CBT‑I should be offered. Currently, face-to-face CBT‑I is not routinely available on the NHS for most people with insomnia. A short-term course of hypnotic medication can be offered in addition to CBT‑I but should not be offered routinely. People should be offered follow‑up consultations every 2\xa0to 4\xa0weeks to review their symptoms.\n\nNICE's clinical knowledge summary on insomnia summarises the latest evidence on managing insomnia in primary care, based on whether it is short term (less than 3\xa0months) or long term (more than 3\xa0months). For both, the advice is to consider referral to a sleep clinic or neurology if the person has symptoms of another sleep disorder, and to address whatever might be causing the insomnia. It also advises making sure comorbidities such as anxiety and depression are managed. It gives the same advice on sleep hygiene, hypnotic medication and CBT‑I as BAP.\n\nPeople with insomnia often also have a mental health problem. NICE's guideline on common mental health problems recommends assessing people using the improving access to psychological therapies (IAPT) screening tools and validated scales. Treatment depends on symptom severity and includes education, monitoring, CBT and medication.\n\n# Innovative aspects\n\nSleepio uses an artificial intelligence (AI) algorithm to provide people with tailored digital CBT‑I. There is also support available from a Sleepio community, which includes clinical experts and other people with insomnia.\n\n# Intended use\n\nSleepio is primarily intended as an alternative to usual treatment, which includes sleep hygiene education and hypnotic medication. People can get Sleepio through self-referral, or through primary care or IAPT services. People who have mental health conditions managed in routine care who are using Sleepio may benefit from having a healthcare professional involved.\n\n# Training\n\nThe company offers primary care training on prescribing Sleepio, technical training and set up.\n\n# Costs\n\nThe cost of Sleepio is £45 (excluding VAT) per person who starts session\xa01 of the Sleepio programme. This price was proposed at consultation and differs from the previous cost models proposed by the company, which depended on regional uptake of Sleepio. The 2 previous cost models, the population-based and the tiered licence-based cost model, are outlined below.\n\nThe population-based cost model involved a cost per head per year depending on the size of the population within a region. This cost was independent of the number of people that used Sleepio. The larger the population, the lower the cost per head. Because a fixed price is paid by NHS organisations each year, increased uptake led to an increase in cost savings.\n\nThe tiered licence-based cost model was based on the number of people who had treatment with Sleepio. This was a tiered pricing system, so the cost per patient reduced as uptake increased beyond the number of people specified within each of the fixed tiers. For more details of these prices, see the supporting documents for Sleepio on the NICE website.For more details about the technology, see the website for Sleepio.", 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review.\xa0Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## The clinical evidence comprises 28 studies, 12 of which are randomised controlled trials\n\nThe EAC assessed 25 full text publications, an unpublished study and 2\xa0abstracts. Twelve of the studies were randomised controlled trials (including 6\xa0secondary analyses of randomised controlled trials). Six were non-randomised studies and there was 1\xa0abstract. Also, the company provided the EAC with 2\xa0unpublished, real-world evidence studies. For full details of the clinical evidence, see section\xa03 of the assessment report. Find the assessment report in the supporting documents for Sleepio on the NICE website.\n\n## The 12 randomised controlled trials are relevant to the decision problem and show that Sleepio reduces symptoms of insomnia\n\nThere is good quality evidence that Sleepio improves sleep in people with self-reported insomnia symptoms (according to DSM-5 [Diagnostic and Statistical Manual of Disorders 5], SCI [Sleep Condition Indicator] and ISI [Insomnia Severity Index] measures). The most robust evidence for Sleepio comprises 12\xa0randomised controlled trials, 10 of which used intention-to-treat analyses to control for high drop-out rates. The studies are small relative to the potential reach of Sleepio but are adequately powered and well reported.\n\n## The UK population is well represented in the evidence for Sleepio\n\nThe UK population is well represented in the evidence base for Sleepio, which includes 7\xa0UK studies and 4\xa0multinational studies that included UK populations. Four of the studies done in the UK were randomised controlled trials (Espie et al. 2012, Freeman et al. 2017, Denis et al. 2020 [pilot study], Kyle et al. 2020); all concluded that Sleepio was more effective in reducing insomnia symptoms than the comparator (standard care, waiting list, placebo or attention control).\n\n## The evidence is heterogenous\n\nThe studies included in the assessment varied in design, population, outcome measures and comparators. Study participants included people with difficulty sleeping with or without medical and mental health comorbidities, and different durations of insomnia. The comparator differed between studies and often the description of standard care lacked clarity. It was unclear whether standard care included aspects of cognitive behavioural therapy for insomnia (CBT‑I), the hypnotic medication prescription, or both, and there was little information about what was offered as sleep hygiene education.\n\n## There is limited evidence comparing Sleepio with face-to-face CBT-I or other forms of digital CBT-I\n\nThe company acknowledged that the lack of evidence comparing Sleepio with face-to-face CBT or digital CBT‑I was a limitation. It said that face‑to‑face CBT‑I for insomnia is not routinely available on the NHS and is not scalable to the UK NHS population. There is a meta-analysis (Soh\xa0et al. 2020) that indicated that digital CBT‑I is non-inferior to face‑to‑face CBT‑I. A network meta-analysis (Hasan et al. 2022) compared various forms of digital CBT‑I with face-to-face CBT‑I. The authors concluded that web-based CBT‑I with a virtual or real therapist offers better outcomes than other digital CBT‑I approaches (web-based CBT‑I without a therapist, telephone-based CBT‑I and mobile app-based CBT‑I). Sleepio includes a virtual therapist. The authors also reported that, although web-based CBT‑I with a therapist resulted in reduced insomnia symptoms when compared with educational therapy, face‑to‑face CBT‑I was superior to both these interventions. The authors said that the meta-analysis included relatively few studies that included face-to-face CBT‑I and that the follow-up effects of digital CBT‑I were unavailable. There are currently no studies that compare Sleepio with other digital CBT‑I technologies.\n\n# Cost evidence\n\n## The company used a single cohort spreadsheet model to compare the cost of Sleepio with treatment as usual and face-to-face CBT-I\n\nThe company submitted 12\xa0economic studies relevant to the economic assessment. The EAC found 3 of them met the decision problem. The company's economic analysis modelled a population of adults with insomnia symptoms. The model compared Sleepio with 2\xa0comparators: treatment as usual (which includes sleep hygiene and sleep medication) and face-to-face CBT‑I. The model assumes that treatment with Sleepio is clinically equivalent to both comparators and so includes only the resource impact and no clinical outcomes. The company's analysis in the initial submission is based on the population-based price (see section\xa02.10).\n\nThe cost impact and proportion of patients using Sleepio are based on data from Sampson et al. (2021). The key costs were:\n\nSleepio at £45 per adult who starts session\xa01 of the programme. This price was proposed at consultation. The supporting documents for this guidance describe the cost model results with the other prices mentioned in section\xa02.\n\nSleep hygiene at £0.\n\nFace-to-face CBT-I at £492 (this was changed by the EAC to £542 to account for inflation) per adult.\n\nPrimary care resource use per user in years\xa01,\xa02 and\xa03 at £49.52, £43.52 and £42.05 respectively.For full details of the cost evidence, see section\xa04 of the assessment report in the supporting documents.\n\n## The EAC concluded that the statistical analysis in Sampson et al. (2021) is robust\n\nThe committee asked the EAC to review the statistical analysis described in Sampson et al. (2021) and explore if it was possible to link the NHS data with the data from Sleepio to better understand the outcomes associated with its use. Patient-level data was made available to the EAC, who replicated the multilevel generalised linear model described in the paper. It was not possible to link the NHS data to the data available from Sleepio users about usage and weekly sleep score. The EAC also investigated adding an individual patient level to the generalised linear model, the impact of seasonal adjustment, and relevant comorbidities. It found that the resource use saving results from the statistical model did not change significantly from those reported in the study (£6.64 compared with £5.53 per patient per year in the EAC model). It concluded that the Sampson et al. (2021) results are robust enough for use in the economic modelling for Sleepio.\n\n## The EAC's updates to the cost model make Sleepio cost saving compared with treatment as usual\n\nAfter consultation, the EAC ran the cost model with the new price proposed at consultation. The base case shows that after 1\xa0year, compared with treatment as usual, Sleepio is cost saving by £4.52 per person. If the results of resource savings at 1\xa0year are extrapolated to 3\xa0years, the cost savings are £90.08 per person. The EAC noted that with this price, the results do not depend on the uptake of the technology.", 'Committee discussion': "# Treatment pathway\n\n## Sleepio can be used to treat symptoms of insomnia after primary care referral\n\nThe evaluation considered Sleepio as a treatment for the symptoms of insomnia. The proposed patient population included people with symptoms or a diagnosis of insomnia. The committee accepted that this broad population was relevant and understood people could be referred to this technology by their GP or social prescriber if they live in a region where Sleepio is available. The committee accepted that insomnia symptoms are a common problem and that Sleepio has the potential to benefit many people.\n\n## The most relevant comparator is treatment as usual including sleep hygiene advice and short-term medication\n\nSleepio provides a sleep improvement programme based on cognitive behavioural therapy for insomnia (CBT‑I) for people with clinically diagnosed insomnia or symptoms of insomnia. Clinical experts explained that the gold standard treatment for clinically diagnosed insomnia that is unlikely to resolve soon is face-to-face CBT‑I, but its availability is limited in the NHS. Instead, they agreed that the most relevant comparator to treat clinically diagnosed insomnia and insomnia symptoms that are likely to resolve soon is 'treatment as usual', which includes sleep hygiene education and hypnotic medication. Several other digital technologies provide CBT‑I or other support for people with clinically diagnosed insomnia and insomnia symptoms, but their uptake and use is limited. The committee concluded that the appropriate comparator for people with clinically diagnosed insomnia and insomnia symptoms that are likely to resolve soon is treatment as usual consisting of sleep hygiene advice and short-term medication.\n\n## Sleepio has the potential to provide another CBT-I option\n\nClinical experts explained that digital CBT‑I, such as Sleepio and other digital CBT‑I technologies, increases the options available to primary and secondary care practitioners when treating insomnia. They explained that the gold standard treatment for insomnia is face-to-face CBT-I, but its availability is very limited in the NHS. The committee considered that there is space in the care pathway for Sleepio. It concluded that Sleepio has the potential to provide another option for people who would benefit from access to CBT‑I.\n\n# Clinical-effectiveness overview\n\n## Sleepio is effective at reducing insomnia symptoms compared with treatment as usual\n\nThe committee noted the large evidence base for Sleepio, and that the 28\xa0studies in the evidence base included a range of patients who had a diagnosis or symptoms of insomnia. The external assessment centre (EAC) explained that changes in lifestyle are expected as part of treatment as usual, but it is unclear whether there was any explicit control for these factors in the evidence. The committee concluded that the evidence shows that Sleepio is more effective than treatment as usual in reducing symptoms of insomnia in adults.\n\n## The limited evidence comparing Sleepio with face-to-face CBT-I means it should not be prescribed to people who would be offered face-to-face CBT-I\n\nThe EAC explained that it did not identify any studies that compared Sleepio with other methods of delivering CBT‑I directly (for example face‑to‑face or other digital methods) and had clinical outcomes. Clinical experts confirmed that other digital devices are available that also deliver digital CBT‑I. They considered that the clinical effectiveness of Sleepio is likely to be comparable to other digital devices delivering CBT‑I as well as face-to-face CBT‑I, but recognised that there are some advantages to the latter. The committee noted that, although the Sleepio programme includes a virtual therapist, a real therapist is not present during any of the sessions. The EAC also highlighted 2\xa0network meta-analyses (Soh et al. 2020 and Hasan et al. 2022) that explored the effectiveness of various digital CBT‑I and face-to-face CBT‑I and broadly concluded that the clinical effectiveness of these treatments is likely to be similar. The committee noted some limitations with these meta-analyses, for example few of the included studies assessed face-to-face CBT‑I. It recognised that the lack of comparative clinical evidence between Sleepio and face‑to‑face CBT‑I was a limitation in the evidence. The committee concluded that people should not be referred for Sleepio if they are eligible for and have access to face-to-face CBT-I.\n\n# Drop-out rates\n\n## There are high drop-out rates with Sleepio, but these are thought to be consistent with other forms of CBT-I\n\nThe evidence shows a high drop-out rate for people using Sleepio, from 11.2% (Luik et al. 2017) up to 61.6% (Freeman et al. 2017). High drop-out rates were also observed from the rollout of Sleepio in Buckinghamshire. These occurred throughout the programme from session\xa01 to session\xa05. The EAC highlighted that the definition of a drop-out varied among these studies. The committee noted that the meta-analysis (Soh et al. 2020) that compared digital CBT‑I (including Sleepio) and face-to-face CBT‑I reported similar levels of engagement and completion in both arms. Clinical experts explained that in some cases people's insomnia symptoms can resolve after sleep hygiene advice or active CBT‑I treatment. The Sleepio programme includes sleep hygiene advice and active CBT‑I treatment, and it is possible some people's symptoms may resolve before completing all 6\xa0sessions of the programme. However, the reason for participants dropping out was not recorded, so people may have left the programme because their symptoms did not improve. The committee concluded that the direction of bias as a result of high drop-out rates with Sleepio is unclear, but recognised that high drop-out rates are common with CBT‑I in general and not specific to Sleepio.\n\n# Other patient benefits or issues\n\n## Sleepio may be another option for pregnant women, who currently have fewer options to treat insomnia\n\nThe EAC identified 2\xa0studies that assessed digital CBT‑I in pregnant women (Felder et al. 2020 and Kalmbach et al. 2020). The studies concluded that Sleepio is more effective than control in treating insomnia symptoms. The clinical experts highlighted how important it is to do a medical assessment in pregnant women before referral to CBT‑I, because insomnia can mimic other conditions like restless legs, or it could be a consequence of undiagnosed sleep apnoea. The clinical experts also explained that, although hypnotic medication is avoided in pregnant women, some drugs are given for short courses when symptoms are likely to resolve soon. The committee concluded that Sleepio may be an alternative option for insomnia symptoms in pregnant women who have had a medical assessment to rule out other conditions.\n\n## Following the Sleepio programme can be challenging but the Sleepio community provides support\n\nThe patient expert described the sleep restriction component and quarter‑hour rule as particularly challenging aspects of the Sleepio programme that were difficult to implement, especially in the beginning. These challenges were also reported by people who responded to the patient survey. The patient expert said the support from the Sleepio website community was particularly helpful during this time. The company said that the community is monitored by volunteers with experience of using Sleepio. It also said that Sleepio users can access a weekly question and answer session on the Sleepio forum, facilitated by a clinical psychologist who specialises in insomnia. The committee noted the importance of the Sleepio community and its role in supporting people using Sleepio.\n\n## Sleepio may be difficult to use for some people\n\nSleepio requires access to a computer and the internet, which some people do not have at home. The patient expert said that it was possible to use Sleepio by accessing the internet occasionally (for example, at a public library) and keeping a paper sleep diary, but that this was more difficult. Some users of Sleepio may find it difficult to use a computer, such as people with a visual or cognitive impairment, limited manual dexterity or hearing impairment. The patient expert said that using Sleepio was relatively straightforward and that people with minimal computer skills could use it. But they agreed that some skill in using a computer is needed. They added that the Sleepio community can help people who need it. Also, Sleepio may be difficult to use for people who have limited English language skills. The company noted that the programme is being restructured so it can be translated into other languages. The committee accepted that Sleepio would be harder to use for some people with access or language restrictions.\n\n# Training\n\n## Patient selection and the implementation model used for introducing Sleepio might affect patient uptake\n\nThe company said that during the roll out of Sleepio they noticed that the different levels of training it provided for referring services (such as GP practices) affected the uptake of Sleepio. It said that training and support varies depending on the implementation model used to introduce it. In the 9\xa0GP practices in Buckinghamshire, which used a comprehensive implementation model, the estimated uptake was 0.94%. Regions that did not have this implementation model had an uptake of 0.54%\xa0to\xa00.55% (Sampson et al. 2021). Clinical experts said patient selection was important to improve the chances of people using Sleepio properly and benefiting from it. They also said it would be helpful to give feedback to referrers, such as GPs, about how many people register to use Sleepio and what impact it has on their insomnia symptoms. This would help to understand outcomes and inform referral and training. The committee agreed that the training and support for referrers has an important effect on patient uptake.\n\n# Side effects and adverse events\n\n## Adverse events are rare in people using Sleepio\n\nThe EAC explained that very few adverse events were reported in the literature, and no serious adverse events were related to using Sleepio. Sleepio has been available in some regions of the NHS since 2013 and unpublished real-world evidence reports that over 100,000\xa0people have used Sleepio in the UK. For full information about adverse events in the studies, see section\xa06 of the EAC's assessment report in the supporting documents.\n\n## Sleepio is unlikely to harm people who have other sleeping disorders\n\nClinical experts said that some people who present with symptoms of insomnia might have underlying conditions causing their symptoms. They explained that using Sleepio in this population may delay them having more appropriate treatment but is unlikely to cause harm. The company said that it has procedures in place for managing risk and adverse events but that they are uncommon. The committee concluded that Sleepio is unlikely to harm people who have sleeping difficulties because of an underlying condition.\n\n# Cost modelling overview\n\n## There are uncertainties in the cost modelling because of the limited data available\n\nThe resource use captured in the Sampson et al. (2021) study was used to inform the cost modelling. The statistical analysis in this study assumed that all changes in resource use over the study duration were because of the introduction of Sleepio. The committee had concerns about whether the variables included in the generalised linear model adequately captured all the important parameters, such as seasonal affect and comorbidities. The EAC reviewed the statistical analysis described in the study and confirmed that it was appropriate, and that it gave similar results to its own preferred statistical model. Despite some reassurance on the statistical analysis, the committee understood it was only possible to adjust for known confounders, and the quasi-experimental nature of the study means some uncertainty remains. The EAC also reported that it was not possible to link individual patient data from Sleepio with NHS resource use data. So, from the NHS data it is unclear which patients used Sleepio, if their symptoms improved with use, and what the associated resource impact was. This meant it was not possible to include remission status in the cost modelling. The committee accepted that the data available was limited, particularly around linking user data to NHS system data, and understood that this resulted in uncertainties in the cost modelling.\n\n# Potential for cost savings\n\n## At the initial proposed prices, the technology was unlikely to be cost saving compared with treatment as usual\n\nWhen the population-based price proposed in the company submission was used in the EAC base case, Sleepio was cost incurring compared with treatment as usual after 1\xa0year and 3\xa0years. The main driver of the results was the uptake rate of the technology across the population. The EAC reduced the uptake rate to 0.58% from the company's estimate of 1%, and this increased the cost of Sleepio from £90\xa0to\xa0£155.17 per user. The committee agreed with the EAC estimates and noted that any cost savings depended on the uptake rate. The tiered licence-based cost model was proposed after the first committee discussion and the price per user was updated to £66.11. When this cost was applied in the EAC base case, Sleepio was cost incurring by £16.59 per user at the end of year\xa01 but cost saving by £68.97 per user at 3\xa0years. The committee did not agree that there was enough evidence to extrapolate the data to 3\xa0years and concluded that the cost savings were uncertain.\n\n## At the new proposed price, Sleepio is cost saving at 1 year compared with treatment as usual\n\nAt consultation, the company proposed a price of £45 per user. When the EAC applied this new cost in its base case, Sleepio was cost saving compared with treatment as usual after 1\xa0year, and the cost savings increased if benefits were extrapolated beyond 1\xa0year. The committee noted that there were limitations in the economic modelling because of its dependence on the Sampson et al. (2021) study and the lack of remission outcomes. However, the committee decided on balance that at this price the technology was likely to be at least cost neutral and very likely cost saving, and decided to recommend it as an option for people with insomnia and insomnia symptoms who would otherwise receive treatment as usual.\n\nBoth the company's and the EAC's cost models assumed Sleepio was clinically equivalent to face-to-face CBT‑I. This assumption was based on indirect evidence from several different digital CBT‑I interventions. The committee noted that the resource use for these models was based on the Sampson et al. (2021) study, which includes a large population with different severities of insomnia. It noted that it was not possible to identify people who would have been eligible for CBT‑I according to the criteria in NICE's clinical knowledge summary on insomnia, to evaluate the clinical effectiveness of Sleepio in that group. Derose et al. (2021) reported reduced resource use for Sleepio users compared with people attending face-to-face CBT‑I group sessions in the US. The committee noted however that no clinical outcomes were reported, and it was not clear how generalisable this study is to the NHS in terms of the patient characteristics and type of face-to-face CBT‑I used. It concluded that a study on people eligible for CBT‑I that includes both resource use data and clinical outcomes is needed to evaluate the resource impact of making Sleepio available to this population.\n\n# Further research\n\n## A real-world study is suggested to compare the effectiveness of Sleepio with face-to-face CBT-I\n\nThe committee concluded that more research is needed on the effectiveness of Sleepio as an alternative to face-to-face CBT‑I. It noted that there are some studies comparing Sleepio with face-to-face CBT‑I, but the evidence is limited. The committee acknowledged the difficulties of carrying out comparative research, given the accessibility issues with face-to-face CBT‑I in the NHS. It understood that a study based on real‑world evidence that collects clinical and resource use data in a population eligible for face-to-face CBT‑I, may be appropriate. It also considered a link between any Sleepio user data and resource use would help address uncertainties in the economic modelling. The committee also agreed that high-quality, non-UK based direct evidence could be acceptable."}	https://www.nice.org.uk/guidance/mtg70	Evidence-based recommendations on Sleepio to treat insomnia and insomnia symptoms.
44f05e4b1760033a1e2e9c68f3ccf1dcff2f131e	nice	Tepotinib for treating advanced non-small-cell lung cancer with MET gene alterations	Tepotinib for treating advanced non-small-cell lung cancer with MET gene alterations Evidence-based recommendations on tepotinib (Tepmetko) for treating advanced non-small-cell lung cancer (NSCLC) with MET gene alterations in adults. # Recommendations Tepotinib is recommended, within its marketing authorisation, as an option for treating advanced non-small-cell lung cancer (NSCLC) with METex14 skipping alterations in adults, only if the company provides tepotinib according to the commercial arrangement. Why the committee made these recommendations Standard care for advanced METex14 skipping NSCLC is usually chemo-immunotherapy. People have different treatments depending on their PD‑L1 tumour proportion score and whether they have squamous or non-squamous NSCLC. Clinical trial evidence suggests a clinical benefit for tepotinib. It has been indirectly compared with other treatments in 2 ways, but the results of both are uncertain. Tepotinib meets NICE's criteria to be considered a life-extending drug at the end of life for people who have had previous treatment, but not for people who have not had previous treatment. For both groups, the cost-effectiveness estimates are within the range NICE normally considers an acceptable use of NHS resources. So, tepotinib is recommended.# Information about tepotinib # Marketing authorisation indication Tepotinib (Tepmetko, Merck) is indicated for 'the treatment of adult patients with advanced non-small-cell lung cancer (NSCLC) harbouring mesenchymal-epithelial transition factor gene (MET) exon 14 (METex14) skipping alterations'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for tepotinib. # Price The list price of tepotinib is £7,200 for 60×250‑mg tablets. The company has a commercial arrangement. This makes tepotinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Merck, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # A new targeted treatment ## People with METex14 skipping NSCLC would welcome a new oral treatment option that is well tolerated There is no defined treatment pathway specific to METex14 skipping non-small-cell lung cancer (NSCLC) because there are no targeted treatments available in the UK. People with METex14 skipping NSCLC are offered the same standard care as people with NSCLC without this specific oncogenic biomarker. These treatments include chemotherapy (such as platinum-doublet chemotherapy), immunotherapy (such as pembrolizumab) and combinations of chemotherapy and immunotherapy (chemo-immunotherapy). The clinical experts explained that people with METex14 skipping NSCLC have a poorer prognosis than people without this biomarker. They tend to be older than people with other oncogenic-driven NSCLC, and so treating this population can be challenging because of comorbidities and overall frailty. The clinical experts further explained that this population would benefit from the favourable side effect profile of tepotinib compared with chemotherapy and chemo-immunotherapy. In addition, these people would benefit from the reduced treatment administration burden offered by an oral therapy that does not need day-unit attendance, as is the case for chemotherapy and chemo-immunotherapy. The clinical experts stated that, if recommended across its marketing authorisation, tepotinib would likely be offered as a first-line treatment for people with METex14 skipping NSCLC confirmed by genomic testing. They clarified that testing for METex14 skipping mutations is variable across the UK. Because of this, clinicians would continue to use other first-line treatment options until the mutation is confirmed. Tepotinib may therefore be used at other points in the treatment pathway, in line with its marketing authorisation, but the number of people who have already had treatment is expected to reduce when genomic panel testing is nationally available. The committee agreed that there is a clear unmet need in this patient population. It concluded that people with METex14 skipping NSCLC would welcome a new oral treatment option that is well tolerated. # Population and subgroups ## Untreated and treated subgroups should be considered separately In its original evidence submission, the company base-case population comprised all people with METex14 skipping NSCLC regardless of whether or not they had already had treatment. The NICE scope stated that the population should be addressed according to specific subgroups, if possible. These subgroups were defined as previous treatment (treated or untreated), histology (squamous or non-squamous), and level of PD‑L1 expression. This was because the comparators differed according to these subgroups. The company explained that the base case in its original evidence submission did not consider subgroups by treatment line or histology because, given the small number of people with METex14 skipping NSCLC, using all patients across treatment lines allowed for a larger data set for the indirect comparisons. The company considered that anyone with this condition would be offered tepotinib regardless of PD‑L1 expression or histology. In addition, clinical experts consulted by the company considered that the clinical-effectiveness results for tepotinib in the overall population should be generalisable regardless of histology. The ERG agreed that the data limitations made it difficult to present results for true subgroups, such as histology and PD‑L1 status. But it stressed that by presenting results for the overall population, the company had grouped together people who would be eligible for different comparator treatments. The committee agreed that the treatments recommended by NICE for NSCLC differ based on treatment line (untreated or treated), histology (squamous or non-squamous), and PD‑L1 tumour proportion score (below 50%, or 50% and above). By grouping together people on the basis of having METex14 skipping NSCLC only, the company's base-case analysis potentially masked any variation in treatment effect and cost effectiveness between people who would have different comparator treatments. The committee acknowledged the practical difficulties faced by the company, but did not consider that the company's approach was appropriate. At the first meeting, the committee concluded that it would prefer to consider the cost-effectiveness results for previously treated and untreated disease separately. The company provided this analysis for the second committee meeting (see section 3.9 and section 3.13). ## The majority of the available evidence is for untreated non-squamous NSCLC with METex14 skipping alterations The clinical experts explained that most METex14 skipping NSCLC is of non-squamous histology. The committee noted that the evidence was primarily for that histology. It recalled that tepotinib, if recommended across its marketing authorisation, would mostly be offered to people with untreated METex14 skipping NSCLC (see section 3.1). At consultation, the company acknowledged that untreated non-squamous NSCLC with METex14 skipping alterations was the key treatment population for this appraisal. However, it highlighted that previously treated and squamous NSCLC with METex14 skipping alterations are also important, as outlined by clinical expert feedback in its evidence submission. The committee agreed that the previously treated and squamous groups should be considered fully, in line with the marketing authorisation. It understood that the evidence for these groups is limited, and that the majority of available evidence is for untreated non-squamous NSCLC with METex14 skipping alterations. # Comparators ## Chemo-immunotherapy is the most relevant comparator for untreated non-squamous NSCLC with METex14 skipping alterations In its original evidence submission, the company did not compare tepotinib with the specific comparators outlined in the NICE scope. Instead, it compared tepotinib with 2 grouped treatment classes: chemotherapy and immunotherapy. This was because of the limited data available to model specific comparator treatments (see section 3.7). The company did not include chemo-immunotherapy as a comparator in the overall population. The clinical experts explained that this did not reflect UK clinical practice, where chemo-immunotherapy is the most commonly used treatment. The Cancer Drugs Fund clinical lead agreed that people with untreated non-squamous METex14 skipping NSCLC would usually have either immunotherapy (pembrolizumab monotherapy) or chemo-immunotherapy (pembrolizumab with pemetrexed and platinum chemotherapy), depending on their PD‑L1 tumour proportion score. The company agreed and, for the second meeting, provided new analyses for the comparators relevant to UK clinical practice (see section 3.9), presented separately for the untreated and treated populations. This included a comparison with pembrolizumab plus pemetrexed and platinum as its new base case for the untreated group. Recalling its preference for analyses presented separately for untreated and treated populations (see section 3.2), the committee concluded that the company had made all efforts to provide the most relevant analyses for specific populations, including chemo-immunotherapy as the most relevant comparator for untreated non-squamous NSCLC with METex14 skipping alterations. # Clinical effectiveness ## The clinical evidence for tepotinib is uncertain because it is based on 1 single-arm study that may not be generalisable to NHS practice The evidence for tepotinib comes from the VISION clinical trial. This is an ongoing, single-arm, open-label, phase‑2 trial including people with advanced (locally advanced or metastatic) NSCLC with METex14 skipping alterations or MET amplification. The primary outcome of the trial is objective response rate. Secondary outcomes include duration of response, progression-free survival, overall survival and health-related quality of life. A total of 152 people with METex14 skipping alterations were enrolled into cohort A. Cohort C is a confirmatory cohort recruited at a later time point, enrolling 123 additional people with METex14 skipping alterations. Cohort B enrolled people with MET amplification, and so this cohort is not relevant to the appraisal. The trial recruited people from Asia (23%), North America (26%) and Europe (51%), but not from any UK centres. The clinical experts noted that the response rate in VISION was higher than would be expected with current standard treatments. From the February 2021 data cut-off, using cohort A, the objective response rate in the overall population was 46.7% (95% confidence interval 38.6 to 55.0), and was slightly higher in people having first-line treatment (50.7%) than in those having second-line treatment (43.4%). The median progression-free survival was 10.8 months (95% CI 8.3 to 12.4), and the median overall survival was 19.1 months (95% CI 15.2 to 22.1), with results being consistent across first- and second-line treatment. The committee noted that the median overall survival was higher in the previously treated group, which is counter to expectations. However, it agreed that VISION suggests that tepotinib is clinically effective. It also noted that the distribution of subsequent treatments in VISION meant that the results may not be generalisable to NHS clinical practice (see section 3.14). The committee felt that a randomised controlled trial should have been conducted or planned as a confirmatory study, as this would considerably reduce many sources of uncertainty. It did not agree with the company that this was impractical because of low numbers of patients with METex14 skipping NSCLC, because it has been done in other similar populations with comparable population sizes. The committee concluded that basing the evidence on 1 single-arm study meant that there was substantial uncertainty in the data for tepotinib. This was particularly because the survival data was immature, and the lack of comparative data made assessing comparative effectiveness challenging. ## Using the data from cohort A plus cohort C has little effect on the results, but is preferable In its original evidence submission, the company used the data from cohort A exclusively for its cost-effectiveness analysis. This was because the patient-level data from cohort C was only available shortly before the submission date. The committee noted that the Kaplan–Meier plots for progression-free survival and overall survival based on cohort A were almost identical to those based on cohort A plus cohort C. The company emphasised that the patient characteristics and outcomes were very similar for cohort A compared with cohort A plus cohort C. It did not expect that any minor differences, such as a small improvement in median overall survival and lower median time on treatment for cohort A plus cohort C compared with cohort A, would make much difference to the cost-effectiveness results. The company considered that any differences resulting from using cohort A plus cohort C would likely favour tepotinib. The ERG agreed that the differences were likely inconsequential. However, because overall survival was slightly better for cohort A plus cohort C than for cohort A alone, using this data could slightly increase the likelihood that tepotinib would be cost effective. At the first meeting, the committee agreed that using the data from cohort A was acceptable, and that using the data from cohort A plus cohort C would have little effect on the results. However, it concluded that if the data from cohort A plus cohort C could be used in the cost-effectiveness analysis, then this would be preferable. The company provided this new analysis during consultation, and the committee concluded that this approach was preferable. ## The company did indirect treatment comparisons to establish the relative efficacy of tepotinib Because VISION is a single-arm trial, indirect treatment comparisons were needed to establish the relative efficacy of tepotinib. There was no comparator clinical trial data in METex14 skipping NSCLC, so in its original evidence submission the company developed a real-world cohort from patient-level data specifically for NSCLC with this genetic biomarker. The company took this data from 3 non-interventional studies it had done: NIS‑0015, NIS‑0035 and COTA. Further data from people with METex14 skipping NSCLC was available from a study by Wong et al. (2021), which the company also used. NIS‑0015 comprised complete data on 39 people with MET mutations from a US electronic medical records database. NIS‑0035 comprised data on 86 people with MET mutations from electronic medical records from a variety of countries, but not from the UK. COTA comprised 202 complete patient records with at least 1 data point from a real-world database from the US and Canada. Wong et al. was a retrospective review of treatments and outcomes for 41 people with METex14 skipping mutations in Canada. Because patient numbers were too small to compare tepotinib with all the individual comparators in the NICE scope, the company did indirect treatment comparisons of tepotinib with 2 grouped treatment classes: chemotherapy and immunotherapy. Very few people had chemo-immunotherapy in the real-world cohort. So, the company estimated survival for people with untreated METex14 skipping NSCLC having chemo-immunotherapy by applying hazard ratios from KEYNOTE‑189 to the chemotherapy survival curves derived from its real-world cohort (see section 3.12). KEYNOTE‑189 was a trial of pembrolizumab plus chemotherapy compared with chemotherapy alone in people with advanced non-squamous NSCLC without epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations. The company noted that its approach of using grouped comparators had been used in previous submissions to NICE in NSCLC and other oncology indications. It applied the same inclusion and exclusion criteria as used in the VISION trial to the real-world patient data, to form a comparable dataset. The company used propensity scoring to achieve a balance of patient characteristics between tepotinib and the 2 grouped comparators, and to adjust for possible confounding. Data from 66 people who had chemotherapy and 51 people who had immunotherapy was available to conduct the indirect treatment comparisons. The ERG agreed that propensity scoring was the most appropriate method to adjust the indirect treatment comparisons. The committee noted that the company's real-world cohort did not include any people from the UK. The clinical experts explained that the treatments received, and subsequent treatments, did not match the treatments that are used in the UK. This was particularly the case for the low number of people having chemo-immunotherapy in the real-world cohort. ## The company's original indirect treatment comparison results are highly uncertain The results of the indirect treatment comparisons showed that tepotinib had a statistically significant progression-free survival benefit compared with both chemotherapy and immunotherapy. Tepotinib did not have a statistically significant overall survival benefit compared with either chemotherapy or immunotherapy. The clinical experts considered that the overall survival results from the indirect treatment comparisons did not reflect what would be expected in clinical practice, particularly for chemotherapy. The committee agreed that the results of the indirect treatment comparisons were inconsistent and counter to expectations, with chemotherapy sometimes appearing to be more effective than immunotherapy. This could be partially explained by a lack of generalisability to the UK population, because of the mix of comparator treatments and because people in VISION and from the matched comparator cohort were fitter than would be seen in UK clinical practice. The indirect treatment comparisons were also based on small sample sizes, and may not have been robust for other unknown methodological reasons. However, the committee considered that this cast doubt on the extent of improved overall survival compared with chemotherapy or immunotherapy. The clinical experts and Cancer Drugs Fund clinical lead suggested that the company could consider basing the indirect treatment comparisons on data from comparator trials in people without specific oncogenic biomarkers. This may be more robust because it would allow larger comparator patient numbers. At the first committee meeting, the committee agreed that these analyses may have value, but acknowledged that there would be uncertainty because the comparator trial populations would be different to that of tepotinib. The company reiterated its view that the original indirect treatment comparisons were in the correct METex14 skipping NSCLC population and should be considered. But it agreed to provide new indirect treatment analyses using data from comparator trials in people without specific oncogenic biomarkers for the second committee meeting (see section 3.9). The committee concluded that the results of the company's original indirect treatment comparisons were highly uncertain but should be taken into account in its decision making. ## The company did new indirect treatment comparisons using data from VISION and trials in wild-type NSCLC At consultation, the company updated its original indirect treatment comparison with an additional dataset. This did not substantially alter the results. The company also provided new indirect treatment comparisons. Instead of comparing VISION data with real-world cohorts of people with METex14 skipping NSCLC, the new comparisons were between VISION and data from trials in wild-type NSCLC, without any specific oncogenic biomarkers. The company selected the most relevant trial for each comparator treatment, in consultation with clinical experts. The committee agreed with the choice of trials but questioned the choice of the TAX320 study for docetaxel monotherapy (Fossella et al. 2003) because treatment of NSCLC has changed so much since this study was conducted. The company explained that it was selected because the other potential source of data for docetaxel was a trial that had a high proportion of treatment crossover with immunotherapy. This would therefore confound the results of any analyses. The TAX320 trial predates immunotherapy treatments for NSCLC, and so contained no such treatment crossover. The company used matching-adjusted indirect comparisons (MAICs) to compare VISION with the trials in wild-type NSCLC. Both the company and the ERG agreed that this approach has important limitations. The ERG explained that in a MAIC it is the intervention trial population that is matched to the comparator trial population, and that this introduces a risk of bias because the population being matched to is people with wild-type rather than METex14 NSCLC. Also, the matching process involved substantial reductions in the sample sizes of the VISION cohort. The ERG explained that the extent of the reductions suggested that substantial re‑weighting of individuals was needed to balance the 2 populations in terms of the prognostic criteria identified. The committee understood that this reduction in the VISION sample sizes suggests a lack of generalisability of the indirect comparison results to the population in the decision problem, which is METex14 skipping NSCLC. ## The company's new indirect treatment comparisons are also uncertain but are appropriate for decision making The committee recalled that the company's new approach to the indirect treatment comparisons did allow comparison with the specific treatments that are relevant to NHS clinical practice, depending on treatment line and histology, whereas the original company approach only allowed for comparison of tepotinib with grouped treatment classes, and excluded chemo-immunotherapy because of a lack of real-world data for this key comparison. The company reiterated its view that the real-world cohort comparisons should be considered because they are specific to METex14 skipping NSCLC. The ERG agreed with this, but stated that neither approach was clearly superior to the other and the choice was a trade-off between different types of uncertainty. Accepting the limitations of the MAIC approach, the company chose this new analysis for its base case. The committee agreed that the new MAICs were uncertain because of the risk of bias and reduced generalisability to the METex14 skipping NSCLC population caused by the re‑weighting of VISION to the comparator wild-type populations. It concluded that the new MAICs for each comparison had limitations but were appropriate for decision making. # The company's economic model ## The structure of the company's model is appropriate for decision making The company used a partitioned-survival economic model that included 3 health states: progression-free, progressed and death. The ERG agreed with the choice of model, but explained that a state-transition model may have offered benefits. The committee concluded that the model was generally appropriate and consistent with the models used in other appraisals for NSCLC. ## The company's original overall survival extrapolations for the comparators are implausible In its original evidence submission, the company produced Kaplan–Meier curves from the VISION trial data for tepotinib and from the real-world cohort data for the comparators. The company then fitted different parametric survival models, piecewise models and spline models to the individual patient data. It considered statistical fit, visual assessment, and expert opinion on the clinical plausibility of the long-term survival profile to select the most plausible extrapolations. The clinical experts consulted by the company considered that the best models according to statistical fit either under- or overestimated survival for the comparators. For this reason, the company's clinical experts selected alternative survival models. The ERG explained that the company's clinical expert elicitation was likely to have introduced some bias. It noted that the comparative efficacy of tepotinib was highly dependent on the choice of extrapolations, and that fitting them independently for each comparator added uncertainty. To explore the uncertainty, the ERG produced alternative (but not preferred) scenarios using extrapolations based only on statistical fit. The company did not consider any bias to have been introduced by seeking clinical expert opinion. It noted that such opinion was critical to establishing the clinical plausibility of the extrapolations. In response to technical engagement, the company referenced external sources to validate its choice of extrapolations, such as trials in wild-type NSCLC and published real-world studies in METex14 skipping NSCLC. The clinical experts at the committee meeting had concerns over the long-term overall survival estimates for the comparators. They agreed that they were higher than would be seen in NHS clinical practice, particularly for chemotherapy and chemo-immunotherapy. The committee concluded that the company's original overall survival extrapolations for the comparators were implausible. ## The company's new overall survival extrapolations for the comparators are also uncertain but are acceptable for decision making At consultation, the company provided new survival extrapolations based on its new MAICs comparing VISION to comparator data from trials in wild-type NSCLC (see section 3.9). Based on clinical expert opinion, fit of the curves and long-term plausibility, the company selected the log-logistic curve for overall survival and progression-free survival, for both the tepotinib and chemo-immunotherapy treatment arms for the untreated population. In the previously treated population comparison with docetaxel, the company selected the log-normal curve for overall survival and the log-logistic curve for progression-free survival in the comparator arm, and the exponential curve for overall survival and the log-normal curve for progression-free survival in the tepotinib arm. In the previously treated population comparison with docetaxel with or without nintedanib, the company selected the exponential curve for overall survival and the log-logistic curve for progression-free survival in the comparator arm, and the log-normal curve for overall survival and the log-normal curve for progression-free survival in the tepotinib arm. The ERG would have preferred survival to have been estimated jointly for tepotinib and the comparators using the pseudo-patient level data, but acknowledged that this would be approximated because the log-logistic curve was selected for both treatments in the base case. It further explained that the selection of curves largely depended on the views of the clinical experts, and that the choice was highly uncertain. Most of the alternative options were also clinically plausible because of the immaturity of the data, in particular for tepotinib, and because of the closeness of the curves. Despite the inherent uncertainty, the ERG suggested that the company had selected one of the curves that estimated the greatest overall survival for chemo-immunotherapy in its base case comparison with tepotinib. However, the committee noted that this was based on a hypothesis that tepotinib is superior to chemo-immunotherapy, and that the evidence to support this is not without uncertainty. Most alternative choices estimated a greater relative treatment effect for tepotinib. The ERG stated that it would not have selected alternative curves based on the information available. The committee concluded that, despite the inherent uncertainty in the survival extrapolation, the company's preferred survival extrapolations were acceptable for decision making. ## Subsequent treatment distributions based on prior treatment status in NHS practice are appropriate for decision making Subsequent treatment costs were applied in the company model as a one-off average cost per patient after disease progression. For its base case, the company used subsequent treatment distributions from VISION for tepotinib and from the real-world cohort for the comparators. This matched efficacy and costs in the model. The company also provided a scenario analysis for subsequent treatments using UK distributions based on clinical expert input. The clinical experts stated that the UK distributions estimated by the company better reflected NHS clinical practice than those based on VISION and the real-world cohort. This was because in the latter, some people had crizotinib as a subsequent treatment, which is not used in this population in the UK. However, the clinical experts noted that separate distributions were needed for people having chemo-immunotherapy and based on prior treatment status. The committee understood that the cost-effectiveness results were highly sensitive to the subsequent treatment assumptions. At the first meeting, the committee concluded that the subsequent treatment assumptions in the model were uncertain, and that they should reflect NHS clinical practice. At consultation, the company's new indirect treatment comparison (see section 3.9) allowed for analysis of tepotinib compared with specific comparators, in line with NICE guidance and NHS clinical practice. The company reiterated its opinion that the treatment distributions used in its original analysis were not too dissimilar to NHS clinical practice, with only a small minority of treatments used not available in the NHS, mainly crizotinib. For its new analysis, the company asked clinical experts about the subsequent treatments used in the NHS, by treatment line and histology. The company's new economic model assumed that 100% of people in the untreated population would have a subsequent treatment after tepotinib. Of these, in the base-case comparison with pembrolizumab plus pemetrexed and platinum, 90% were assumed to have nintedanib plus docetaxel, and 10% to have docetaxel monotherapy. In the previously treated subgroup, there were no subsequent treatments after either docetaxel monotherapy or docetaxel plus nintedanib. The committee recalled that nintedanib is recommended for NSCLC of adenocarcinoma histology only, and that 79% of METex14 skipping NSCLC is of adenocarcinoma histology. It also recalled that people with METex14 skipping NSCLC tend to be older, less fit, and have more comorbidities than the broader NSCLC population (see section 3.1). The Cancer Drugs Fund clinical lead suggested that these factors mean that people with this specific oncogenic driver are less likely to get docetaxel plus nintedanib than docetaxel monotherapy, because of the adverse events associated with nintedanib. For these reasons, fewer than 100% of people will have subsequent treatment, and the company's scenario analysis of 50% was likely to be closer to the true number seen in NHS clinical practice. The committee further agreed that of the 50% who do have subsequent treatment, less than 90% would receive docetaxel plus nintedanib. The committee considered that 50% receiving that combination and 50% receiving docetaxel monotherapy would likely better reflect clinical practice and that these proportions should be used in the company's base case. The committee concluded that these preferred assumptions for subsequent treatment distributions would be used in its decision making. ## There is uncertainty about the most appropriate time-on-treatment model for tepotinib, but the company's base case is likely appropriate The company followed a similar process for extrapolating time on treatment as it did for extrapolating survival (see section 3.12). The company chose the generalised gamma curve for tepotinib despite the exponential and log-logistic models having the best statistical fit. The company explained that this was because the extended tail in the Kaplan–Meier plot was an artefact of patient censoring, and that clinical expert opinion suggested that almost nobody would be having tepotinib after 5 years. The ERG explained that other models were tried at technical engagement, but none were better fitting than the parametric models originally explored by the company. It suggested that the generalised gamma curve chosen may be the most appropriate model, but that the choice was associated with considerable uncertainty. The committee concluded that the generalised gamma model was likely to be appropriate, but that this was uncertain. # End of life ## Life expectancy for people with METex14 skipping NSCLC is likely to be less than 2 years in the previously treated subgroup only The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. At the first committee meeting, the company suggested that life expectancy for people having chemotherapy in the overall population was less than 2 years, but not for people having immunotherapy. The company considered that life expectancy was also less than 2 years for people having either chemotherapy or immunotherapy in the previously treated subgroup. The committee recalled that neither the indirect treatment comparison results or overall survival extrapolations in the company's original evidence submission could be considered robust. But, it noted that they both likely overestimated overall survival for the comparators. The clinical experts stated that life expectancy for people with METex14 skipping NSCLC is likely to be less than 2 years, regardless of treatment. At the second meeting, the committee noted that the median life expectancies from the company's new indirect treatment comparisons and the mean life expectancies from the model were based on comparisons between tepotinib and wild-type NSCLC, and so could not be used to estimate life expectancy for the METex14 skipping NSCLC comparator populations. The company did not provide relevant end of life data for the untreated subgroup, because the company and ERG agreed that the end of life criteria would not be met in this subgroup. The committee concluded that the end of life criteria were not met for this group. It recalled that results from the company's real-world indirect treatment comparison suggested that life expectancy was less than 2 years in the previously treated setting, regardless of treatment. The committee further concluded that for people who have had treatment for METex14 skipping NSCLC, life expectancy is likely to be less than 2 years. ## Tepotinib extends life by more than 3 months in the previously treated subgroup, so it meets the end of life criteria The clinical experts felt that it was clinically plausible that tepotinib extends overall survival to some extent. However, the committee noted that the company's original indirect treatment comparisons did not show a statistically significant overall survival benefit for tepotinib in the overall population, and that the confidence intervals were wide. At the second meeting, the committee considered the company's new MAIC analyses and understood that these comparisons were with wild-type NSCLC. These were considered in addition to the company's original observational data from the METex14 skipping population. For the previously treated subgroup, tepotinib had a median overall survival benefit of substantially more than 3 months. The median overall survival benefit from the MAIC and the mean overall survival benefit from the model are academic in confidence and cannot be reported here. The committee concluded that tepotinib meets the end of life criteria in the previously treated subgroup. # Cost-effectiveness estimates ## Tepotinib is recommended for advanced METex14 skipping NSCLC At the first meeting, the committee agreed that there were problems with the company's original modelling approach in terms of the comparators used and modelling of comparator effectiveness. It noted the high level of uncertainty in the model, particularly around: the results of the indirect treatment comparisons (see sections 3.7 to 3.10) the comparator overall survival extrapolations (see section 3.12 and section 3.13) the subsequent treatment distributions (see section 3.14).Because of this, the committee did not consider the company's or the ERG's original base cases to be suitable for decision making. At the second committee meeting, the company presented new cost-effectiveness analyses using the MAIC comparisons between tepotinib and the specific comparators most commonly used in NHS clinical practice: pembrolizumab plus pemetrexed and platinum in the untreated subgroup (company base case), and docetaxel with or without nintedanib for the previously treated subgroup. The incremental cost-effectiveness ratios (ICERs) were calculated with confidential comparator patient access scheme discounts included, and so cannot be reported here. The ICERs were also calculated with the committee's preferred subsequent treatment assumptions incorporated (see section 3.14). The committee noted that the ICER for the untreated group was within the range that NICE considers to be a cost-effective use of NHS resources. In the previously treated subgroup, where the end of life criteria were met, the ICERs were within the range that could be considered a cost-effective use of NHS resources for a life-extending drug at the end of life. Tepotinib is therefore recommended for routine use for METex14 skipping NSCLC. # Other factors ## There are no relevant equality issues No relevant equalities issues were identified. ## The cost-effectiveness calculations capture tepotinib's benefits The committee noted that tepotinib is an oral drug, and it specifically targets METex14 skipping NSCLC. It understood from the clinical expert and patient expert feedback that tepotinib would be an improvement over the current treatments, and agreed that it would be beneficial. The committee considered that the model structure should have been able to capture the benefits and costs of tepotinib in terms of health-related quality of life and quality-adjusted life year (QALYs) gained. It had not been presented with evidence of any additional benefits that were not captured in the QALY calculations.	{'Recommendations': "Tepotinib is recommended, within its marketing authorisation, as an option for treating advanced non-small-cell lung cancer (NSCLC) with METex14 skipping alterations in adults, only if the company provides tepotinib according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nStandard care for advanced METex14 skipping NSCLC is usually chemo-immunotherapy. People have different treatments depending on their PD‑L1 tumour proportion score and whether they have squamous or non-squamous NSCLC.\n\nClinical trial evidence suggests a clinical benefit for tepotinib. It has been indirectly compared with other treatments in 2\xa0ways, but the results of both are uncertain.\n\nTepotinib meets NICE's criteria to be considered a life-extending drug at the end of life for people who have had previous treatment, but not for people who have not had previous treatment.\n\nFor both groups, the cost-effectiveness estimates are within the range NICE normally considers an acceptable use of NHS resources. So, tepotinib is recommended.", 'Information about tepotinib': "# Marketing authorisation indication\n\nTepotinib (Tepmetko, Merck) is indicated for 'the treatment of adult patients with advanced non-small-cell lung cancer (NSCLC) harbouring mesenchymal-epithelial transition factor gene (MET) exon 14 (METex14) skipping alterations'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for tepotinib.\n\n# Price\n\nThe list price of tepotinib is £7,200 for 60×250‑mg tablets. The company has a commercial arrangement. This makes tepotinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Merck, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# A new targeted treatment\n\n## People with METex14 skipping NSCLC would welcome a new oral treatment option that is well tolerated\n\nThere is no defined treatment pathway specific to METex14 skipping non-small-cell lung cancer (NSCLC) because there are no targeted treatments available in the UK. People with METex14 skipping NSCLC are offered the same standard care as people with NSCLC without this specific oncogenic biomarker. These treatments include chemotherapy (such as platinum-doublet chemotherapy), immunotherapy (such as pembrolizumab) and combinations of chemotherapy and immunotherapy (chemo-immunotherapy). The clinical experts explained that people with METex14 skipping NSCLC have a poorer prognosis than people without this biomarker. They tend to be older than people with other oncogenic-driven NSCLC, and so treating this population can be challenging because of comorbidities and overall frailty. The clinical experts further explained that this population would benefit from the favourable side effect profile of tepotinib compared with chemotherapy and chemo-immunotherapy. In addition, these people would benefit from the reduced treatment administration burden offered by an oral therapy that does not need day-unit attendance, as is the case for chemotherapy and chemo-immunotherapy. The clinical experts stated that, if recommended across its marketing authorisation, tepotinib would likely be offered as a first-line treatment for people with METex14 skipping NSCLC confirmed by genomic testing. They clarified that testing for METex14 skipping mutations is variable across the UK. Because of this, clinicians would continue to use other first-line treatment options until the mutation is confirmed. Tepotinib may therefore be used at other points in the treatment pathway, in line with its marketing authorisation, but the number of people who have already had treatment is expected to reduce when genomic panel testing is nationally available. The committee agreed that there is a clear unmet need in this patient population. It concluded that people with METex14 skipping NSCLC would welcome a new oral treatment option that is well tolerated.\n\n# Population and subgroups\n\n## Untreated and treated subgroups should be considered separately\n\nIn its original evidence submission, the company base-case population comprised all people with METex14 skipping NSCLC regardless of whether or not they had already had treatment. The NICE scope stated that the population should be addressed according to specific subgroups, if possible. These subgroups were defined as previous treatment (treated or untreated), histology (squamous or non-squamous), and level of PD‑L1 expression. This was because the comparators differed according to these subgroups. The company explained that the base case in its original evidence submission did not consider subgroups by treatment line or histology because, given the small number of people with METex14 skipping NSCLC, using all patients across treatment lines allowed for a larger data set for the indirect comparisons. The company considered that anyone with this condition would be offered tepotinib regardless of PD‑L1 expression or histology. In addition, clinical experts consulted by the company considered that the clinical-effectiveness results for tepotinib in the overall population should be generalisable regardless of histology. The ERG agreed that the data limitations made it difficult to present results for true subgroups, such as histology and PD‑L1 status. But it stressed that by presenting results for the overall population, the company had grouped together people who would be eligible for different comparator treatments. The committee agreed that the treatments recommended by NICE for NSCLC differ based on treatment line (untreated or treated), histology (squamous or non-squamous), and PD‑L1 tumour proportion score (below 50%, or 50% and above). By grouping together people on the basis of having METex14 skipping NSCLC only, the company's base-case analysis potentially masked any variation in treatment effect and cost effectiveness between people who would have different comparator treatments. The committee acknowledged the practical difficulties faced by the company, but did not consider that the company's approach was appropriate. At the first meeting, the committee concluded that it would prefer to consider the cost-effectiveness results for previously treated and untreated disease separately. The company provided this analysis for the second committee meeting (see section\xa03.9 and section\xa03.13).\n\n## The majority of the available evidence is for untreated non-squamous NSCLC with METex14 skipping alterations\n\nThe clinical experts explained that most METex14 skipping NSCLC is of non-squamous histology. The committee noted that the evidence was primarily for that histology. It recalled that tepotinib, if recommended across its marketing authorisation, would mostly be offered to people with untreated METex14 skipping NSCLC (see section\xa03.1). At consultation, the company acknowledged that untreated non-squamous NSCLC with METex14 skipping alterations was the key treatment population for this appraisal. However, it highlighted that previously treated and squamous NSCLC with METex14 skipping alterations are also important, as outlined by clinical expert feedback in its evidence submission. The committee agreed that the previously treated and squamous groups should be considered fully, in line with the marketing authorisation. It understood that the evidence for these groups is limited, and that the majority of available evidence is for untreated non-squamous NSCLC with METex14 skipping alterations.\n\n# Comparators\n\n## Chemo-immunotherapy is the most relevant comparator for untreated non-squamous NSCLC with METex14 skipping alterations\n\nIn its original evidence submission, the company did not compare tepotinib with the specific comparators outlined in the NICE scope. Instead, it compared tepotinib with 2\xa0grouped treatment classes: chemotherapy and immunotherapy. This was because of the limited data available to model specific comparator treatments (see section\xa03.7). The company did not include chemo-immunotherapy as a comparator in the overall population. The clinical experts explained that this did not reflect UK clinical practice, where chemo-immunotherapy is the most commonly used treatment. The Cancer Drugs Fund clinical lead agreed that people with untreated non-squamous METex14 skipping NSCLC would usually have either immunotherapy (pembrolizumab monotherapy) or chemo-immunotherapy (pembrolizumab with pemetrexed and platinum chemotherapy), depending on their PD‑L1 tumour proportion score. The company agreed and, for the second meeting, provided new analyses for the comparators relevant to UK clinical practice (see section\xa03.9), presented separately for the untreated and treated populations. This included a comparison with pembrolizumab plus pemetrexed and platinum as its new base case for the untreated group. Recalling its preference for analyses presented separately for untreated and treated populations (see section\xa03.2), the committee concluded that the company had made all efforts to provide the most relevant analyses for specific populations, including chemo-immunotherapy as the most relevant comparator for untreated non-squamous NSCLC with METex14 skipping alterations.\n\n# Clinical effectiveness\n\n## The clinical evidence for tepotinib is uncertain because it is based on 1\xa0single-arm study that may not be generalisable to NHS practice\n\nThe evidence for tepotinib comes from the VISION clinical trial. This is an ongoing, single-arm, open-label, phase‑2 trial including people with advanced (locally advanced or metastatic) NSCLC with METex14 skipping alterations or MET amplification. The primary outcome of the trial is objective response rate. Secondary outcomes include duration of response, progression-free survival, overall survival and health-related quality of life. A total of 152\xa0people with METex14 skipping alterations were enrolled into cohort\xa0A. Cohort\xa0C is a confirmatory cohort recruited at a later time point, enrolling 123\xa0additional people with METex14 skipping alterations. Cohort\xa0B enrolled people with MET amplification, and so this cohort is not relevant to the appraisal. The trial recruited people from Asia (23%), North America (26%) and Europe (51%), but not from any UK centres. The clinical experts noted that the response rate in VISION was higher than would be expected with current standard treatments. From the February 2021 data cut-off, using cohort\xa0A, the objective response rate in the overall population was 46.7% (95% confidence interval [CI] 38.6 to 55.0), and was slightly higher in people having first-line treatment (50.7%) than in those having second-line treatment (43.4%). The median progression-free survival was 10.8\xa0months (95% CI 8.3 to 12.4), and the median overall survival was 19.1\xa0months (95% CI 15.2 to 22.1), with results being consistent across first- and second-line treatment. The committee noted that the median overall survival was higher in the previously treated group, which is counter to expectations. However, it agreed that VISION suggests that tepotinib is clinically effective. It also noted that the distribution of subsequent treatments in VISION meant that the results may not be generalisable to NHS clinical practice (see section\xa03.14). The committee felt that a randomised controlled trial should have been conducted or planned as a confirmatory study, as this would considerably reduce many sources of uncertainty. It did not agree with the company that this was impractical because of low numbers of patients with METex14 skipping NSCLC, because it has been done in other similar populations with comparable population sizes. The committee concluded that basing the evidence on 1\xa0single-arm study meant that there was substantial uncertainty in the data for tepotinib. This was particularly because the survival data was immature, and the lack of comparative data made assessing comparative effectiveness challenging.\n\n## Using the data from cohort\xa0A plus cohort\xa0C has little effect on the results, but is preferable\n\nIn its original evidence submission, the company used the data from cohort\xa0A exclusively for its cost-effectiveness analysis. This was because the patient-level data from cohort\xa0C was only available shortly before the submission date. The committee noted that the Kaplan–Meier plots for progression-free survival and overall survival based on cohort\xa0A were almost identical to those based on cohort\xa0A plus cohort\xa0C. The company emphasised that the patient characteristics and outcomes were very similar for cohort\xa0A compared with cohort\xa0A plus cohort\xa0C. It did not expect that any minor differences, such as a small improvement in median overall survival and lower median time on treatment for cohort\xa0A plus cohort\xa0C compared with cohort\xa0A, would make much difference to the cost-effectiveness results. The company considered that any differences resulting from using cohort\xa0A plus cohort\xa0C would likely favour tepotinib. The ERG agreed that the differences were likely inconsequential. However, because overall survival was slightly better for cohort\xa0A plus cohort\xa0C than for cohort\xa0A alone, using this data could slightly increase the likelihood that tepotinib would be cost effective. At the first meeting, the committee agreed that using the data from cohort\xa0A was acceptable, and that using the data from cohort\xa0A plus cohort\xa0C would have little effect on the results. However, it concluded that if the data from cohort\xa0A plus cohort\xa0C could be used in the cost-effectiveness analysis, then this would be preferable. The company provided this new analysis during consultation, and the committee concluded that this approach was preferable.\n\n## The company did indirect treatment comparisons to establish the relative efficacy of tepotinib\n\nBecause VISION is a single-arm trial, indirect treatment comparisons were needed to establish the relative efficacy of tepotinib. There was no comparator clinical trial data in METex14 skipping NSCLC, so in its original evidence submission the company developed a real-world cohort from patient-level data specifically for NSCLC with this genetic biomarker. The company took this data from 3\xa0non-interventional studies it had done: NIS‑0015, NIS‑0035 and COTA. Further data from people with METex14 skipping NSCLC was available from a study by Wong et al. (2021), which the company also used. NIS‑0015 comprised complete data on 39\xa0people with MET mutations from a US electronic medical records database. NIS‑0035 comprised data on 86\xa0people with MET mutations from electronic medical records from a variety of countries, but not from the UK. COTA comprised 202\xa0complete patient records with at least 1\xa0data point from a real-world database from the US and Canada. Wong et al. was a retrospective review of treatments and outcomes for 41\xa0people with METex14 skipping mutations in Canada. Because patient numbers were too small to compare tepotinib with all the individual comparators in the NICE scope, the company did indirect treatment comparisons of tepotinib with 2\xa0grouped treatment classes: chemotherapy and immunotherapy. Very few people had chemo-immunotherapy in the real-world cohort. So, the company estimated survival for people with untreated METex14 skipping NSCLC having chemo-immunotherapy by applying hazard ratios from KEYNOTE‑189 to the chemotherapy survival curves derived from its real-world cohort (see section\xa03.12). KEYNOTE‑189 was a trial of pembrolizumab plus chemotherapy compared with chemotherapy alone in people with advanced non-squamous NSCLC without epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations. The company noted that its approach of using grouped comparators had been used in previous submissions to NICE in NSCLC and other oncology indications. It applied the same inclusion and exclusion criteria as used in the VISION trial to the real-world patient data, to form a comparable dataset. The company used propensity scoring to achieve a balance of patient characteristics between tepotinib and the 2\xa0grouped comparators, and to adjust for possible confounding. Data from 66\xa0people who had chemotherapy and 51\xa0people who had immunotherapy was available to conduct the indirect treatment comparisons. The ERG agreed that propensity scoring was the most appropriate method to adjust the indirect treatment comparisons. The committee noted that the company's real-world cohort did not include any people from the UK. The clinical experts explained that the treatments received, and subsequent treatments, did not match the treatments that are used in the UK. This was particularly the case for the low number of people having chemo-immunotherapy in the real-world cohort.\n\n## The company's original indirect treatment comparison results are highly uncertain\n\nThe results of the indirect treatment comparisons showed that tepotinib had a statistically significant progression-free survival benefit compared with both chemotherapy and immunotherapy. Tepotinib did not have a statistically significant overall survival benefit compared with either chemotherapy or immunotherapy. The clinical experts considered that the overall survival results from the indirect treatment comparisons did not reflect what would be expected in clinical practice, particularly for chemotherapy. The committee agreed that the results of the indirect treatment comparisons were inconsistent and counter to expectations, with chemotherapy sometimes appearing to be more effective than immunotherapy. This could be partially explained by a lack of generalisability to the UK population, because of the mix of comparator treatments and because people in VISION and from the matched comparator cohort were fitter than would be seen in UK clinical practice. The indirect treatment comparisons were also based on small sample sizes, and may not have been robust for other unknown methodological reasons. However, the committee considered that this cast doubt on the extent of improved overall survival compared with chemotherapy or immunotherapy. The clinical experts and Cancer Drugs Fund clinical lead suggested that the company could consider basing the indirect treatment comparisons on data from comparator trials in people without specific oncogenic biomarkers. This may be more robust because it would allow larger comparator patient numbers. At the first committee meeting, the committee agreed that these analyses may have value, but acknowledged that there would be uncertainty because the comparator trial populations would be different to that of tepotinib. The company reiterated its view that the original indirect treatment comparisons were in the correct METex14 skipping NSCLC population and should be considered. But it agreed to provide new indirect treatment analyses using data from comparator trials in people without specific oncogenic biomarkers for the second committee meeting (see section\xa03.9). The committee concluded that the results of the company's original indirect treatment comparisons were highly uncertain but should be taken into account in its decision making.\n\n## The company did new indirect treatment comparisons using data from VISION and trials in wild-type NSCLC\n\nAt consultation, the company updated its original indirect treatment comparison with an additional dataset. This did not substantially alter the results. The company also provided new indirect treatment comparisons. Instead of comparing VISION data with real-world cohorts of people with METex14 skipping NSCLC, the new comparisons were between VISION and data from trials in wild-type NSCLC, without any specific oncogenic biomarkers. The company selected the most relevant trial for each comparator treatment, in consultation with clinical experts. The committee agreed with the choice of trials but questioned the choice of the TAX320 study for docetaxel monotherapy (Fossella et al. 2003) because treatment of NSCLC has changed so much since this study was conducted. The company explained that it was selected because the other potential source of data for docetaxel was a trial that had a high proportion of treatment crossover with immunotherapy. This would therefore confound the results of any analyses. The TAX320 trial predates immunotherapy treatments for NSCLC, and so contained no such treatment crossover. The company used matching-adjusted indirect comparisons (MAICs) to compare VISION with the trials in wild-type NSCLC. Both the company and the ERG agreed that this approach has important limitations. The ERG explained that in a MAIC it is the intervention trial population that is matched to the comparator trial population, and that this introduces a risk of bias because the population being matched to is people with wild-type rather than METex14 NSCLC. Also, the matching process involved substantial reductions in the sample sizes of the VISION cohort. The ERG explained that the extent of the reductions suggested that substantial re‑weighting of individuals was needed to balance the 2\xa0populations in terms of the prognostic criteria identified. The committee understood that this reduction in the VISION sample sizes suggests a lack of generalisability of the indirect comparison results to the population in the decision problem, which is METex14 skipping NSCLC.\n\n## The company's new indirect treatment comparisons are also uncertain but are appropriate for decision making\n\nThe committee recalled that the company's new approach to the indirect treatment comparisons did allow comparison with the specific treatments that are relevant to NHS clinical practice, depending on treatment line and histology, whereas the original company approach only allowed for comparison of tepotinib with grouped treatment classes, and excluded chemo-immunotherapy because of a lack of real-world data for this key comparison. The company reiterated its view that the real-world cohort comparisons should be considered because they are specific to METex14 skipping NSCLC. The ERG agreed with this, but stated that neither approach was clearly superior to the other and the choice was a trade-off between different types of uncertainty. Accepting the limitations of the MAIC approach, the company chose this new analysis for its base case. The committee agreed that the new MAICs were uncertain because of the risk of bias and reduced generalisability to the METex14 skipping NSCLC population caused by the re‑weighting of VISION to the comparator wild-type populations. It concluded that the new MAICs for each comparison had limitations but were appropriate for decision making.\n\n# The company's economic model\n\n## The structure of the company's model is appropriate for decision making\n\nThe company used a partitioned-survival economic model that included 3\xa0health states: progression-free, progressed and death. The ERG agreed with the choice of model, but explained that a state-transition model may have offered benefits. The committee concluded that the model was generally appropriate and consistent with the models used in other appraisals for NSCLC.\n\n## The company's original overall survival extrapolations for the comparators are implausible\n\nIn its original evidence submission, the company produced Kaplan–Meier curves from the VISION trial data for tepotinib and from the real-world cohort data for the comparators. The company then fitted different parametric survival models, piecewise models and spline models to the individual patient data. It considered statistical fit, visual assessment, and expert opinion on the clinical plausibility of the long-term survival profile to select the most plausible extrapolations. The clinical experts consulted by the company considered that the best models according to statistical fit either under- or overestimated survival for the comparators. For this reason, the company's clinical experts selected alternative survival models. The ERG explained that the company's clinical expert elicitation was likely to have introduced some bias. It noted that the comparative efficacy of tepotinib was highly dependent on the choice of extrapolations, and that fitting them independently for each comparator added uncertainty. To explore the uncertainty, the ERG produced alternative (but not preferred) scenarios using extrapolations based only on statistical fit. The company did not consider any bias to have been introduced by seeking clinical expert opinion. It noted that such opinion was critical to establishing the clinical plausibility of the extrapolations. In response to technical engagement, the company referenced external sources to validate its choice of extrapolations, such as trials in wild-type NSCLC and published real-world studies in METex14 skipping NSCLC. The clinical experts at the committee meeting had concerns over the long-term overall survival estimates for the comparators. They agreed that they were higher than would be seen in NHS clinical practice, particularly for chemotherapy and chemo-immunotherapy. The committee concluded that the company's original overall survival extrapolations for the comparators were implausible.\n\n## The company's new overall survival extrapolations for the comparators are also uncertain but are acceptable for decision making\n\nAt consultation, the company provided new survival extrapolations based on its new MAICs comparing VISION to comparator data from trials in wild-type NSCLC (see section\xa03.9). Based on clinical expert opinion, fit of the curves and long-term plausibility, the company selected the log-logistic curve for overall survival and progression-free survival, for both the tepotinib and chemo-immunotherapy treatment arms for the untreated population. In the previously treated population comparison with docetaxel, the company selected the log-normal curve for overall survival and the log-logistic curve for progression-free survival in the comparator arm, and the exponential curve for overall survival and the log-normal curve for progression-free survival in the tepotinib arm. In the previously treated population comparison with docetaxel with or without nintedanib, the company selected the exponential curve for overall survival and the log-logistic curve for progression-free survival in the comparator arm, and the log-normal curve for overall survival and the log-normal curve for progression-free survival in the tepotinib arm. The ERG would have preferred survival to have been estimated jointly for tepotinib and the comparators using the pseudo-patient level data, but acknowledged that this would be approximated because the log-logistic curve was selected for both treatments in the base case. It further explained that the selection of curves largely depended on the views of the clinical experts, and that the choice was highly uncertain. Most of the alternative options were also clinically plausible because of the immaturity of the data, in particular for tepotinib, and because of the closeness of the curves. Despite the inherent uncertainty, the ERG suggested that the company had selected one of the curves that estimated the greatest overall survival for chemo-immunotherapy in its base case comparison with tepotinib. However, the committee noted that this was based on a hypothesis that tepotinib is superior to chemo-immunotherapy, and that the evidence to support this is not without uncertainty. Most alternative choices estimated a greater relative treatment effect for tepotinib. The ERG stated that it would not have selected alternative curves based on the information available. The committee concluded that, despite the inherent uncertainty in the survival extrapolation, the company's preferred survival extrapolations were acceptable for decision making.\n\n## Subsequent treatment distributions based on prior treatment status in NHS practice are appropriate for decision making\n\nSubsequent treatment costs were applied in the company model as a one-off average cost per patient after disease progression. For its base case, the company used subsequent treatment distributions from VISION for tepotinib and from the real-world cohort for the comparators. This matched efficacy and costs in the model. The company also provided a scenario analysis for subsequent treatments using UK distributions based on clinical expert input. The clinical experts stated that the UK distributions estimated by the company better reflected NHS clinical practice than those based on VISION and the real-world cohort. This was because in the latter, some people had crizotinib as a subsequent treatment, which is not used in this population in the UK. However, the clinical experts noted that separate distributions were needed for people having chemo-immunotherapy and based on prior treatment status. The committee understood that the cost-effectiveness results were highly sensitive to the subsequent treatment assumptions. At the first meeting, the committee concluded that the subsequent treatment assumptions in the model were uncertain, and that they should reflect NHS clinical practice. At consultation, the company's new indirect treatment comparison (see section\xa03.9) allowed for analysis of tepotinib compared with specific comparators, in line with NICE guidance and NHS clinical practice. The company reiterated its opinion that the treatment distributions used in its original analysis were not too dissimilar to NHS clinical practice, with only a small minority of treatments used not available in the NHS, mainly crizotinib. For its new analysis, the company asked clinical experts about the subsequent treatments used in the NHS, by treatment line and histology. The company's new economic model assumed that 100% of people in the untreated population would have a subsequent treatment after tepotinib. Of these, in the base-case comparison with pembrolizumab plus pemetrexed and platinum, 90% were assumed to have nintedanib plus docetaxel, and 10% to have docetaxel monotherapy. In the previously treated subgroup, there were no subsequent treatments after either docetaxel monotherapy or docetaxel plus nintedanib. The committee recalled that nintedanib is recommended for NSCLC of adenocarcinoma histology only, and that 79% of METex14 skipping NSCLC is of adenocarcinoma histology. It also recalled that people with METex14 skipping NSCLC tend to be older, less fit, and have more comorbidities than the broader NSCLC population (see section\xa03.1). The Cancer Drugs Fund clinical lead suggested that these factors mean that people with this specific oncogenic driver are less likely to get docetaxel plus nintedanib than docetaxel monotherapy, because of the adverse events associated with nintedanib. For these reasons, fewer than 100% of people will have subsequent treatment, and the company's scenario analysis of 50% was likely to be closer to the true number seen in NHS clinical practice. The committee further agreed that of the 50% who do have subsequent treatment, less than 90% would receive docetaxel plus nintedanib. The committee considered that 50% receiving that combination and 50% receiving docetaxel monotherapy would likely better reflect clinical practice and that these proportions should be used in the company's base case. The committee concluded that these preferred assumptions for subsequent treatment distributions would be used in its decision making.\n\n## There is uncertainty about the most appropriate time-on-treatment model for tepotinib, but the company's base case is likely appropriate\n\nThe company followed a similar process for extrapolating time on treatment as it did for extrapolating survival (see section\xa03.12). The company chose the generalised gamma curve for tepotinib despite the exponential and log-logistic models having the best statistical fit. The company explained that this was because the extended tail in the Kaplan–Meier plot was an artefact of patient censoring, and that clinical expert opinion suggested that almost nobody would be having tepotinib after 5\xa0years. The ERG explained that other models were tried at technical engagement, but none were better fitting than the parametric models originally explored by the company. It suggested that the generalised gamma curve chosen may be the most appropriate model, but that the choice was associated with considerable uncertainty. The committee concluded that the generalised gamma model was likely to be appropriate, but that this was uncertain.\n\n# End of life\n\n## Life expectancy for people with METex14 skipping NSCLC is likely to be less than 2\xa0years in the previously treated subgroup only\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. At the first committee meeting, the company suggested that life expectancy for people having chemotherapy in the overall population was less than 2\xa0years, but not for people having immunotherapy. The company considered that life expectancy was also less than 2\xa0years for people having either chemotherapy or immunotherapy in the previously treated subgroup. The committee recalled that neither the indirect treatment comparison results or overall survival extrapolations in the company's original evidence submission could be considered robust. But, it noted that they both likely overestimated overall survival for the comparators. The clinical experts stated that life expectancy for people with METex14 skipping NSCLC is likely to be less than 2\xa0years, regardless of treatment. At the second meeting, the committee noted that the median life expectancies from the company's new indirect treatment comparisons and the mean life expectancies from the model were based on comparisons between tepotinib and wild-type NSCLC, and so could not be used to estimate life expectancy for the METex14 skipping NSCLC comparator populations. The company did not provide relevant end of life data for the untreated subgroup, because the company and ERG agreed that the end of life criteria would not be met in this subgroup. The committee concluded that the end of life criteria were not met for this group. It recalled that results from the company's real-world indirect treatment comparison suggested that life expectancy was less than 2\xa0years in the previously treated setting, regardless of treatment. The committee further concluded that for people who have had treatment for METex14 skipping NSCLC, life expectancy is likely to be less than 2\xa0years.\n\n## Tepotinib extends life by more than 3\xa0months in the previously treated subgroup, so it meets the end of life criteria\n\nThe clinical experts felt that it was clinically plausible that tepotinib extends overall survival to some extent. However, the committee noted that the company's original indirect treatment comparisons did not show a statistically significant overall survival benefit for tepotinib in the overall population, and that the confidence intervals were wide. At the second meeting, the committee considered the company's new MAIC analyses and understood that these comparisons were with wild-type NSCLC. These were considered in addition to the company's original observational data from the METex14 skipping population. For the previously treated subgroup, tepotinib had a median overall survival benefit of substantially more than 3\xa0months. The median overall survival benefit from the MAIC and the mean overall survival benefit from the model are academic in confidence and cannot be reported here. The committee concluded that tepotinib meets the end of life criteria in the previously treated subgroup.\n\n# Cost-effectiveness estimates\n\n## Tepotinib is recommended for advanced METex14 skipping NSCLC\n\nAt the first meeting, the committee agreed that there were problems with the company's original modelling approach in terms of the comparators used and modelling of comparator effectiveness. It noted the high level of uncertainty in the model, particularly around:\n\nthe results of the indirect treatment comparisons (see sections\xa03.7 to 3.10)\n\nthe comparator overall survival extrapolations (see section\xa03.12 and section\xa03.13)\n\nthe subsequent treatment distributions (see section\xa03.14).Because of this, the committee did not consider the company's or the ERG's original base cases to be suitable for decision making. At the second committee meeting, the company presented new cost-effectiveness analyses using the MAIC comparisons between tepotinib and the specific comparators most commonly used in NHS clinical practice: pembrolizumab plus pemetrexed and platinum in the untreated subgroup (company base case), and docetaxel with or without nintedanib for the previously treated subgroup. The incremental cost-effectiveness ratios (ICERs) were calculated with confidential comparator patient access scheme discounts included, and so cannot be reported here. The ICERs were also calculated with the committee's preferred subsequent treatment assumptions incorporated (see section\xa03.14). The committee noted that the ICER for the untreated group was within the range that NICE considers to be a cost-effective use of NHS resources. In the previously treated subgroup, where the end of life criteria were met, the ICERs were within the range that could be considered a cost-effective use of NHS resources for a life-extending drug at the end of life. Tepotinib is therefore recommended for routine use for METex14 skipping NSCLC.\n\n# Other factors\n\n## There are no relevant equality issues\n\nNo relevant equalities issues were identified.\n\n## The cost-effectiveness calculations capture tepotinib's benefits\n\nThe committee noted that tepotinib is an oral drug, and it specifically targets METex14 skipping NSCLC. It understood from the clinical expert and patient expert feedback that tepotinib would be an improvement over the current treatments, and agreed that it would be beneficial. The committee considered that the model structure should have been able to capture the benefits and costs of tepotinib in terms of health-related quality of life and quality-adjusted life year (QALYs) gained. It had not been presented with evidence of any additional benefits that were not captured in the QALY calculations."}	https://www.nice.org.uk/guidance/ta789	Evidence-based recommendations on tepotinib (Tepmetko) for treating advanced non-small-cell lung cancer (NSCLC) with MET gene alterations in adults.
c7b3acc3e8052e66e97a1f7940505b9dc97e0741	nice	Personalised external aortic root support (PEARS) using mesh to prevent aortic root expansion and aortic dissection in people with Marfan syndrome	Personalised external aortic root support (PEARS) using mesh to prevent aortic root expansion and aortic dissection in people with Marfan syndrome Evidence-based recommendations on personalised external aortic root support (PEARS) using mesh to prevent aortic root expansion and aortic dissection in people with Marfan syndrome. This involves opening the chest through the breastbone and wrapping a mesh around the outside of the aorta at the part closest to the heart. # Recommendations Evidence is adequate on the short-term safety and efficacy of personalised external aortic root support (PEARS) using mesh to prevent aortic root expansion and aortic dissection in people with Marfan syndrome. Evidence on long-term outcomes is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do PEARS using mesh to prevent aortic root expansion and aortic dissection in people with Marfan syndrome should: Inform the clinical governance leads in their healthcare organisation. Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Patient selection should be done by a multidisciplinary team. The procedure should only be done in specialist centres with experience of managing this condition, by surgeons trained and experienced in aortic root surgery. Further research should report details of patient selection, including aortic diameter, and long-term outcomes, including evidence of disease progression, such as dilation and dissection of the aortic root.# The condition, current treatments and procedure # The condition Marfan syndrome is a genetic disorder of the connective tissues. One effect of it is that the wall of the aorta can weaken and progressively widen. The wall can tear (dissection) and possibly rupture, which is often fatal. The strongest predictors of dissection are the aortic root size and the rate of change in size over time. # Current treatments Conventional treatment involves pre-emptive surgery to replace the ascending aorta with an artificial fabric graft. Some clinicians recommend this when the aortic diameter is 45 mm or more. The aortic valve is also usually replaced but may be conserved. People can experience considerable anxiety waiting for their aorta to reach the size threshold recommended for surgery. If the person has a mechanical valve implanted, they need lifelong anticoagulation. If a bioprosthetic valve is used, it is likely to eventually fail, and the person will need another operation. Valve‑sparing root replacement surgery, in which the aorta is replaced with a tube graft and the native aortic valve is conserved, is also suitable for some people with normal valve function. This is technically more challenging, and people may need further surgery to replace the aortic valve at a later date. # The procedure The aim of personalised external aortic root support (PEARS) using mesh in people with Marfan syndrome is to reinforce the aortic root and ascending aorta to prevent enlargement and subsequent dissection or rupture. The native aortic valve is left intact so there is no need for lifelong anticoagulation after the procedure. This is a particular advantage for young women considering future conception. Cardiopulmonary bypass is usually not needed, and the operative time is shorter than for traditional aortic root replacement. The first step of the procedure is to do imaging studies of the ascending aorta and aortic root. Computer-aided design is used to create a 3‑dimensional model of the aorta, which is then used to make a bespoke external polymer mesh support. The mesh is soft, flexible and porous. Openings for the coronary arteries are fashioned into the mesh support. Under general anaesthesia, a median sternotomy is done, and the aorta is dissected away from adjacent structures and proximal to the coronary arteries. The mesh support is passed behind the aorta, sutured up the front and secured to the aortoventricular junction. It fully encircles the aortic root and extends from the region of the valve annulus to the origin of the brachiocephalic artery.	{'Recommendations': "Evidence is adequate on the short-term safety and efficacy of personalised external aortic root support (PEARS) using mesh to prevent aortic root expansion and aortic dissection in people with Marfan syndrome. Evidence on long-term outcomes is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do PEARS using mesh to prevent aortic root expansion and aortic dissection in people with Marfan syndrome should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a multidisciplinary team.\n\nThe procedure should only be done in specialist centres with experience of managing this condition, by surgeons trained and experienced in aortic root surgery.\n\nFurther research should report details of patient selection, including aortic diameter, and long-term outcomes, including evidence of disease progression, such as dilation and dissection of the aortic root.", 'The condition, current treatments and procedure': '# The condition\n\nMarfan syndrome is a genetic disorder of the connective tissues. One effect of it is that the wall of the aorta can weaken and progressively widen. The wall can tear (dissection) and possibly rupture, which is often fatal. The strongest predictors of dissection are the aortic root size and the rate of change in size over time.\n\n# Current treatments\n\nConventional treatment involves pre-emptive surgery to replace the ascending aorta with an artificial fabric graft. Some clinicians recommend this when the aortic diameter is 45\xa0mm or more. The aortic valve is also usually replaced but may be conserved. People can experience considerable anxiety waiting for their aorta to reach the size threshold recommended for surgery.\n\nIf the person has a mechanical valve implanted, they need lifelong anticoagulation. If a bioprosthetic valve is used, it is likely to eventually fail, and the person will need another operation. Valve‑sparing root replacement surgery, in which the aorta is replaced with a tube graft and the native aortic valve is conserved, is also suitable for some people with normal valve function. This is technically more challenging, and people may need further surgery to replace the aortic valve at a later date.\n\n# The procedure\n\nThe aim of personalised external aortic root support (PEARS) using mesh in people with Marfan syndrome is to reinforce the aortic root and ascending aorta to prevent enlargement and subsequent dissection or rupture. The native aortic valve is left intact so there is no need for lifelong anticoagulation after the procedure. This is a particular advantage for young women considering future conception. Cardiopulmonary bypass is usually not needed, and the operative time is shorter than for traditional aortic root replacement.\n\nThe first step of the procedure is to do imaging studies of the ascending aorta and aortic root. Computer-aided design is used to create a 3‑dimensional model of the aorta, which is then used to make a bespoke external polymer mesh support. The mesh is soft, flexible and porous. Openings for the coronary arteries are fashioned into the mesh support.\n\nUnder general anaesthesia, a median sternotomy is done, and the aorta is dissected away from adjacent structures and proximal to the coronary arteries. The mesh support is passed behind the aorta, sutured up the front and secured to the aortoventricular junction. It fully encircles the aortic root and extends from the region of the valve annulus to the origin of the brachiocephalic artery.'}	https://www.nice.org.uk/guidance/ipg724	Evidence-based recommendations on personalised external aortic root support (PEARS) using mesh to prevent aortic root expansion and aortic dissection in people with Marfan syndrome. This involves opening the chest through the breastbone and wrapping a mesh around the outside of the aorta at the part closest to the heart.
b8a6282e00764c9b881cdb512d92303341425557	nice	Vaccine uptake in the general population	Vaccine uptake in the general population This guideline aims to increase the uptake of all vaccines provided on the NHS routine UK immunisation schedule by everyone who is eligible. It supports the aims of the NHS Long Term Plan, which includes actions to improve immunisation coverage by GPs (including the changes to vaccinations and immunisations detailed in the 2021/2022 and 2022/23 GP contracts) and support a narrowing of health inequalities. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Service organisation These recommendations should be read together with the NICE guideline on flu vaccination: increasing uptake. ## Named vaccination leads Ensure that each organisation that commissions, provides or organises vaccination services has a named vaccination lead with responsibility (as relevant) for ensuring that: vaccination records are validated and updated people who are eligible for vaccination are identified invitations and reminders are sent to people eligible for vaccination vaccines are administered and recorded there is coordination between providers and other services involved in organising and reporting vaccinations. GP practices and child health information services (CHIS) understand each other's reporting systems and processes best practice is followed for ordering, storing, distributing and disposing of vaccines (see the Green book for more information). Commissioners and providers should ensure that the named vaccination leads have access to the relevant information and facilities they need to carry out their role. Nominate a named person in each primary care provider to be responsible for identifying people who are housebound and need vaccination. Social care providers and providers of other non-healthcare services (who are asked to identify people eligible for vaccination opportunistically ) should identify a named lead responsible for the organisation's approach to: identifying people who are eligible for vaccination and ensuring that it is clear where to signpost these people to get vaccinated or to obtain further information. In supported living settings and care homes, the named vaccination lead should also ensure that there is a policy in place covering what actions to take in response to vaccination invitation letters for residents. For secondary and tertiary care providers who do not provide vaccinations, ensure that there is a named vaccination lead who can identify people eligible for vaccination and signpost them to relevant services. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on named vaccination leads . Full details of the evidence and the committee's discussion are in: evidence review A: identification and recording of vaccination eligibility and status evidence review D: interventions to increase the uptake of routine vaccines by improving access. Loading. Please wait. ## Designing and raising awareness of payment schemes These recommendations are for regional and local commissioners of NHS vaccination services. Raise awareness among healthcare professionals and providers: about payments and funding streams to support the delivery of vaccination services, including those for populations with low vaccination rates that submission of information about vaccination uptake directly affects any linked organisational incentive payments. When designing incentive schemes for providers, take into account that using incentives to prioritise certain vaccinations could have unintended consequences on the uptake of other vaccinations. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on designing and raising awareness of payment schemes . Full details of the evidence and the committee's discussion are in evidence review G: interventions to increase the uptake of routine vaccines by improving infrastructure. Loading. Please wait. ## Making vaccination services accessible and tailoring to local needs NHS commissioners and NHS providers should ensure that they identify: local population needs barriers to vaccine uptake (see box 1) areas or populations with low vaccine uptake (see box 2). They should do this using data from the Joint Strategic Needs Assessment and other data sources. Box 1 Some key barriers to routine vaccine uptake Inflexible and inconvenient clinic times and locations Perceived lack of balanced information (including misinformation) Language and literacy problems Insufficient time in consultations to discuss concerns about vaccinations Lack of staff training in how to discuss vaccinations effectively Uncertainty about vaccine safety and effectiveness Uncertainty about whether vaccines are needed (including how severe the diseases are or how likely it is that someone will be exposed to the disease) Previous negative experiences of vaccination Lack of trust in the government, drug companies and the healthcare system Religious or cultural views that are against vaccination (this may relate to specific vaccinations, for example HPV ) Individual barriers such as needle phobia or sensory impairment. Box 2 Some population groups that are known to have low vaccine uptake or be at risk of low uptake People from some minority ethnic family backgrounds People from Gypsy, Roma and Traveller communities People with physical or learning disabilities People from some religious communities (for example, Orthodox Jewish) New migrants and asylum seekers Looked-after children and young people Children of young or lone parents Children from large families People who live in an area of high deprivation Babies or children who are hospitalised or have a chronic illness, and their siblings People not registered with a GP* People from non-English-speaking families* People who are homeless* Communities with low uptake other than those listed above may also be identified specifically in your local area. Sources: UK Health Security Agency (previously Public Health England) Health Equity Audit of the National Immunisation Programme, apart from those marked with an asterisk, which were raised by the committee. In areas with low vaccine uptake, commissioners and providers should consider introducing targeted interventions to: -vercome identified local barriers to vaccination (see box 1) address identified inequalities in vaccine uptake between different population groups (see box 2 and the UK Health Security Agency immunisation equalities strategy).If introducing these interventions, develop them as part of a system-wide approach. Commissioners and providers should ensure that they: Involve people in the local community when identifying barriers to vaccine uptake and when making decisions about accessibility of services (see the section on involving people in peer and lay roles to represent local needs and priorities in the NICE guideline on community engagement). Tailor service opening hours and locations for vaccinations to meet local needs. This should include providing multiple opportunities for people eligible for vaccination to have their vaccinations at a time and location convenient to them. Locations such as community pharmacies, clinics people attend regularly, and GP practices could be used. Provide a range of accessible options for booking appointments (such as telephone booking and online systems). Take into account that some people may need additional support to use these systems. Consider using sites outside healthcare settings as settings for vaccination clinics, such as mobile vaccination units, children and family centres, or community or faith centres that provide a more family friendly environment, if this would address specific local barriers to vaccine uptake. Consider providing vaccination services during extended hours and extended access appointments in evenings and weekends for people who may find it difficult to attend at other times. These services could be in primary care or community pharmacies, or be provided by a centralised service in each local area. If possible, provide these as part of existing out-of-hours services. Commissioners and providers should coordinate vaccination services between providers to minimise wastage where vaccine supply is limited. GP practices should ensure that contractual obligations and best practice on patient registration is followed (for example, not requiring immigration status or proof of address). For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on making vaccination services accessible and tailoring to local needs . Full details of the evidence and the committee's discussion are in evidence review D: interventions to increase the uptake of routine vaccines by improving access. Loading. Please wait. ## Audit and feedback NHS commissioners should ensure that there is a coordinated system in place for a quarterly cycle of feedback and audits of vaccine uptake data that can be compared against similar providers at a local and national level. Providers should use available data to review current and past activity to help with continuous improvement. To help increase vaccine uptake in the future, vaccine services should: evaluate initiatives for improving the uptake of routine or COVID‑19 vaccinations carried out during the SARS‑CoV‑2 pandemic, and identify initiatives that could be used to increase the uptake of routine vaccination programmes. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on audit and feedback . Full details of the evidence and the committee's discussion are in: evidence review G: interventions to increase the uptake of routine vaccines by improving infrastructure evidence review H: multicomponent interventions to increase uptake of routine vaccines evidence review K: COVID-19 call for evidence. Loading. Please wait. ## Training and education for health and social care practitioners Vaccination leads (see recommendation 1.1.4) should ensure that health and social care practitioners and other related staff who are in contact with people eligible for vaccination, but do not administer vaccines, have ongoing education about vaccination. These could include: Practitioners working in primary care settings, including GP practices, optometry, dental practices and community pharmacies. Secondary care practitioners, for example in clinics for children with chronic conditions, emergency departments or wards such as oncology, antenatal or neonatal. Social care practitioners who may have contact with carers and other eligible groups, such as people with learning disabilities. This may include contact during home visits, individual needs assessments and carers' assessments. Ensure that education for health and social care practitioners and other related staff who are in contact with people eligible for vaccination, but do not administer vaccines, includes: an understanding of who is eligible for vaccination on the NHS routine UK immunisation schedule awareness of barriers to vaccination (see box 1) benefits and risks of vaccination where to signpost people for further information and vaccination.Tailor the level and content of the information to the person's role. Healthcare practitioners who administer vaccines should be given the time, resources and support to: Undertake mandatory training before administering vaccines (UKHSA national minimum standards and core curriculum for immunisation training for registered healthcare practitioners). Include training on vaccination as part of their continuing professional development plan, including how to have effective and sensitive conversations about vaccination. Ask people for any questions and concerns they may have about vaccination and give them personalised responses (or signpost people to relevant sources). Provide tailored information on the risks and benefits of vaccination. Understand when a vaccine is contraindicated, for example for people with certain allergies or conditions, and when it can still be delivered, and be able to discuss this with the person concerned (see recommendation 1.2.18). Overcome particular individual barriers to vaccination such as those experienced by people who have a learning disability, needle phobia or sensory impairment. Offer and administer vaccines. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on training and education for health and social care practitioners . Full details of the evidence and the committee's discussion are in: evidence review E: education interventions to increase the uptake of routine vaccines evidence review H: multicomponent interventions to increase uptake of routine vaccines. Loading. Please wait. ## Appointments and consultations Providers should ensure that there is sufficient time in an appointment or consultation to: allow the healthcare professional and individual, family member or carer (as appropriate) to have a discussion where any concerns can be identified and addressed. This could include using written information or websites to help the discussion gain informed consent administer vaccines complete documentation.For information on how to support people to make informed decisions, see the NICE guideline on shared decision making. For a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on appointments and consultations . Full details of the evidence and the committee's discussion are in evidence review E: education interventions to increase the uptake of routine vaccines. Loading. Please wait. # Identifying eligibility, giving vaccinations and recording vaccination status These recommendations should be read together with the NICE guideline on flu vaccination: increasing uptake. NICE has produced a visual summary on identifying people eligible for vaccination and opportunistic vaccination. ## Using compatible systems and processes Ensure that compatible systems or processes are in place to enable vaccination records to be shared and transferred effectively and in a timely way between different parts of the healthcare system, including other vaccination providers such as community pharmacies. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on using compatible systems and processes . Full details of the evidence and the committee's discussion are in evidence review A: identification and recording of vaccination eligibility and status. Loading. Please wait. ## Keeping records up to date Child health information services (CHIS) should ensure that their vaccination records are updated within 5 days or within service specifications if they exist, whichever is shorter, in response to new information about a person's vaccination status. GP practices should ensure that their vaccination records are updated within 2 weeks (or as specified in the GP contract if shorter) in response to new information about a person's vaccination status. GP practices should use an up-to-date clinical system template that includes relevant SNOMED CT codes to record vaccinations. GP practices should validate their vaccination records at least monthly against data sources received. Check registered populations and vaccine eligibility and status, investigate any discrepancies and correct the record accordingly. CHIS should give GP practices a monthly update (or as specified in the CHIS contract if shorter) on children who are not up to date with their vaccinations. GP practices should inform CHIS if 3 invitations for vaccination are made but a child remains unvaccinated (see recommendation 1.3.16). GP practices should ensure that they have up-to-date medical records, phone numbers, email addresses and addresses for people who are eligible for vaccination, or their family members or carers (as appropriate). Include the person's preferred methods of contact (such as letters, texts, emails or phone calls) and whether there are additional literacy issues or language needs. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on keeping records up to date . Full details of the evidence and the committee's discussion are in evidence review A: identification and recording of vaccination eligibility and status. Loading. Please wait. ## Identifying people eligible for vaccination and opportunistic vaccination Use every opportunity to identify people eligible for vaccination. This could include: at registration in general practice during health and developmental reviews as part of the healthy child programme and health visitor and school nursing targeted contacts during the annual learning disability health check for people with learning disabilities when making contact with people in healthcare settings, community health clinics, sexual health services or drug and alcohol services (including hospitals, emergency departments, inpatient services, rehabilitation services and general practice) when making contact with women who are trying to conceive or have a newly confirmed pregnancy, and at antenatal and postnatal reviews -n admission to day care, nurseries, schools, special needs schools, pupil referral units, and further and higher education -n admission to care homes and supported living settings when people visit community pharmacies for health advice, a medication review or an NHS New Medicine Service, or to collect prescriptions during home visits for healthcare or social care any health service contact with people who are homeless when new migrants, including asylum seekers, arrive in the country within 7 days of arrival in prisons and young offender institutions, during any contact with healthcare services in these places, and when people leave as part of a looked-after child or young person's health plan, and during initial health assessments, and annual and statutory reviews (see also the NICE guideline on looked-after children and young people) any contact with home-educated children during occupational health checks for everyone who works in a clinical or social care setting, even if their role is not healthcare related. Offer people (or their family members or carers, as appropriate) access to online systems or apps to allow them to view and check their NHS vaccination records (or those of their child or the person they care for). Providers of online systems or apps should ensure that people automatically have access to their vaccination status as part of their electronic records as the default option. Use the NHS summary care record, or any other available vaccination records (including records held by the person), to opportunistically identify people who are eligible for vaccination. Unless a person has a documented (or reliable verbal) vaccine history, assume that they are not immunised, and plan a full course of immunisations (see the UKHSA guidance on vaccination of individuals with uncertain or incomplete immunisation status). GP practices should ensure that there is a mechanism in place to check the vaccination status of people registered as temporary residents and offer any vaccinations needed. Providers should routinely use prompts and reminders from electronic medical records to opportunistically identify people who are eligible and due or overdue for vaccination. Add prompts to the records of parents or carers (as appropriate) if children are overdue vaccinations. Midwives should offer vaccination to pregnant women during routine antenatal visits, as recommended by the Green book and the NHS routine UK immunisation schedule. If the midwife cannot administer the vaccine, they should signpost women to vaccination services, drop-in clinics or their GP practice. When uncertainties exist around contraindications and allergies, consult the Green book and seek expert help if needed. When people eligible for vaccination have been identified opportunistically: Healthcare professionals should: if possible, discuss any outstanding vaccinations with them (or their family members or carers, as appropriate) and offer vaccination immediately -therwise, encourage them to book an appointment to discuss the vaccinations or an appointment for vaccination think about referring a child's parents or carers to the health visitor or school nurse, as age appropriate. Non-healthcare practitioners should signpost them to vaccination services.See also recommendation 1.2.15. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on identifying people eligible for vaccination and opportunistic vaccination . Full details of the evidence and the committee's discussion are in: evidence review A: identification and recording of vaccination eligibility and status evidence review C: reminders interventions to increase the uptake of routine vaccines evidence review D: interventions to increase the uptake of routine vaccines by improving access evidence review E: education interventions to increase the uptake of routine vaccines evidence review H: multicomponent interventions to increase the uptake of routine vaccines. Loading. Please wait. ## Recording vaccination offers and administration When offering a vaccination, record in the GP record or other medical record whether it was accepted or declined or there was no response (see recommendation 1.3.20). The person administering the vaccine should ensure that information is recorded accurately and consistently, regardless of where the vaccine is administered, and includes: details of consent to the vaccination (including if someone else has consented on the person's behalf, and that person's relationship to them) the dose, batch number, expiry date, vaccine name and vaccine product name the date, route and site of administration any reported adverse reactions whether the vaccine was administered under Patient Specific Directions or Patient Group Directions. (See the NICE guideline on patient group directions.) Providers should ensure that clinical and patient-held records (including records held on behalf of children) are updated at the time of the vaccination. If the patient-held record is not available at the appointment, give the person a printed record of the vaccination and ensure that the patient-held record is updated at a subsequent healthcare appointment. Providers should use electronic health record templates with compulsory data fields to support accurate recording of vaccination offers and administration (see recommendations 1.2.15 and 1.2.16). Providers should ensure that vaccinations are reported promptly (within 5 working days, or in line with required standards if shorter) to GP practices and child health information services (CHIS) (if relevant). Where commissioned locally, CHIS should send details of vaccinations administered outside of the GP practice to GP practices within 2 weeks or as specified in the CHIS contract if shorter. Providers should ensure that the information they provide to GP practices and CHIS is clear and in a readily accessible format that minimises the need for manual re-entry of data. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on recording vaccination offers and administration . Full details of the evidence and the committee's discussion are in evidence review A: identification and recording of vaccination eligibility and status. Loading. Please wait. # Invitations, reminders and escalation of contact These recommendations should be read together with the NICE guideline on flu vaccination: increasing uptake. ## System organisation and accessibility issues NHS England public health commissioning teams and screening and immunisation teams should ensure that there is a coordinated system in place at the local level for providers to send out invitations and reminders. Consider sending invitations and reminders for different vaccinations together (for example, the pneumococcal vaccine with the flu vaccine). If possible, ensure that the information, invitation and any subsequent reminders are given in a format and language appropriate for the person and their family members or carers (as appropriate). Ensure that the information, invitation and any subsequent reminders meet the person's communication needs (see NHS England's Accessible Information Standard). For more guidance on giving people information and discussing their preferences, see the NICE guidelines on patient experience in adult NHS services and shared decision making. Give people who have come from outside the UK: details of the NHS vaccine schedule, how it is delivered, where and by whom if they: have started vaccinations before arrival and not completed them or are eligible for vaccination. help to access healthcare, if needed.Be aware that expectations of who delivers vaccine services may differ by cultural background. If people need to provide consent for vaccination but need additional support with decision-making (such as people with learning disabilities) or if they may lack mental capacity, follow the recommendations on supporting decision-making in the NICE guideline on decision-making and mental capacity. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on system organisation and accessibility issues . Full details of the evidence and the committee's discussion are in: evidence review C: reminders interventions to increase the uptake of routine vaccines evidence review E: education interventions to increase the uptake of routine vaccines evidence review I: interventions to increase vaccine uptake by targeting acceptability evidence review J: acceptability and effectiveness of interventions to increase routine vaccine uptake. Loading. Please wait. ## Vaccinations for babies, infants and preschool-aged children, and adults NICE has produced the following visual summaries: Vaccinations for young children and older people: invitations, reminders and escalation of contact Vaccinations for pregnant women: invitations, reminders and escalation of contact. Invite people who are eligible for vaccination or their family members or carers (as appropriate) to book an appointment or attend an open access clinic. Do this opportunistically during consultations if possible, or by letter, email, phone call or text. Use the person's preferred method of communication for invitations if possible. Practitioners working in maternity services and other healthcare practitioners who have contact with pregnant women should ensure that pregnant women are invited for vaccination or signposted to vaccination services or drop-in clinics. Ensure that the following people (or their family members or carers, as appropriate) know how to get home visits for vaccination if they cannot attend vaccination clinics or other settings where vaccinations are available: people who live in care homes or residential settings people who are housebound babies and children whose parents or carers are housebound.See also recommendation 1.3.6 and the NICE guideline on managing medicines in care homes. Consider sending the vaccination invitation and any subsequent reminders from a healthcare professional or service that is known to the person or their family members or carers, such as a school, GP practice, doctor, nurse, midwife or health visitor. Ensure that the vaccination invitation contains: The vaccines being offered (named in full) and the targeted diseases. A statement that the NHS and the relevant provider (with the type of provider specified) recommends the vaccination. Details on contacting a healthcare professional (for example, practice nurse, GP, school nurse or pharmacist) to discuss any concerns the person (or their family members or carers) might have (including about possible contraindications or allergies that could affect whether the person can have a vaccination). Instructions for how to book an appointment at a vaccination clinic, if relevant, or where and when drop-in clinics are held. If possible, include options for online booking. A reminder to bring any relevant patient-held records for updating. If space allows, include the following in the vaccination invitation or provide links: Information on the vaccines, including: the potential severity of the targeted diseases the risks and benefits of vaccination, including individual benefits (including to the baby for maternal pertussis vaccination) and population benefits (protecting other people in their community) if relevant, the importance of having all doses of a vaccination course if relevant, why some vaccines are given at specific ages (for example, the HPV vaccine). Instructions for accessing additional videos and information (including interactive information and decision tools) from trusted sources such as the Oxford University's Vaccine Knowledge Project, NHS England and the World Health Organization. Include hyperlinks or QR codes if possible. Information about what to expect at the appointment. Ensure that the parents or carers (as appropriate) of babies who are in neonatal care units when they are eligible for their vaccinations receive relevant information (see recommendations 1.3.11 and 1.3.12) and are made aware of when and how their baby's vaccinations will take place. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on initial invitations . Full details of the evidence and the committee's discussion are in: evidence review C: reminders interventions to increase the uptake of routine vaccines evidence review E: education interventions to increase the uptake of routine vaccines evidence review H: multicomponent interventions to increase the uptake of routine vaccines. Loading. Please wait. Providers (such as GP practices) should identify people who do not respond to invitations or attend clinics, vaccination appointments or other settings where vaccinations are available and send a reminder. (See also recommendation 1.3.10.) Confirm that the person has received the reminder. At a pregnant woman's first appointment after the 20‑week scan, antenatal care providers should check whether they have been offered and accepted vaccination against pertussis in this pregnancy. If not, ensure they receive offers of vaccination or reminders (as relevant) at subsequent antenatal appointments or during any contact with their GP, midwife, health visitor or any other healthcare provider. Talk to parents or carers (as appropriate) of children aged 5 or under who have not responded to a reminder if a vaccination delay is approaching: weeks, for immunisations for babies up to age 1 year months, for immunisations for children aged 1 year and over. Explore with them the reasons for their lack of response and try to address any issues they raise. For pregnant women and older people who do not respond to reminders, consider more direct contact such as a phone call. Explore with them the reasons for their lack of response and try to address any issues they raise. Consider a multidisciplinary approach to address any issues raised in recommendations 1.3.16 and 1.3.17, involving other relevant health and social care practitioners such as health visitors, social workers or key workers, while respecting the person's decision if they refuse vaccination. Consider home visits for people who have difficulty travelling to vaccination services. Discuss immunisation and offer them or their children (as relevant) vaccinations there and then (or arrange a convenient time in the future). If someone declines an offer of vaccination, record this with the reason why, if given, and make sure they know how to get a vaccination at a later date if they change their mind. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reminders and escalation of contact . Full details of the evidence and the committee's discussion are in: evidence review C: reminders interventions to increase the uptake of routine vaccines evidence review D: interventions to increase the uptake of routine vaccines by improving access evidence review H: multicomponent interventions to increase the uptake of routine vaccines. Loading. Please wait. Commissioners should consider involving local authorities, health visitors, or the community or voluntary sector to ensure that people who are not registered with a GP practice are identified and have opportunities to access relevant vaccinations. This could include homeless people and other transient populations. See also recommendation 1.2.9 on opportunistic identification, box 2 and the NICE guideline on integrated health and social care for people experiencing homelessness. Commissioners should ensure that people who are not registered with a GP practice are aware that they are eligible for NHS vaccinations, and where and how to access them. CHIS should identify children who are eligible for vaccination but are not registered with a GP practice. Where commissioned, they should send invitations to parents and carers or ensure this cohort is highlighted to the service commissioner. This might include children from Traveller, Gypsy and Roma communities, newly arrived immigrants or asylum seekers. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on people who are not registered with a GP practice . Full details of the evidence and the committee's discussion are in evidence review C: reminders interventions to increase the uptake of routine vaccines. Loading. Please wait. ## Vaccinations for school-aged children and young people When administering vaccinations to secondary school-aged children and young people, do this in schools if possible. NICE has produced a visual summary on vaccinations for school-aged children and young people: invitations, reminders and escalation of contact. School-aged immunisation providers and schools should work together to organise and carry out vaccinations for secondary school-aged children and young people. Ensure that schools are involved in sending invitations (including consent forms) for vaccinations on behalf of the providers to pupils who attend school. Make the format of the invitation accessible to parents and secondary school-aged children and young people. Ensure that the invitation, information and consent form are available in a digital format, with non-digital options available where needed. Providers should ensure that young people and their parents or carers (as appropriate) have reliable information about vaccines that covers risks and benefits to help them to make informed decisions. The information should include who can consent to vaccination (Gillick competence) as well as the information listed in recommendations 1.3.11 and 1.3.12 (as appropriate). See also the NICE guideline on babies, children and young people's experience of healthcare. Providers and schools should work together to ensure that school-based education about vaccines is available in an age-appropriate format to children and young people to increase their understanding about vaccinations. Providers should offer incentives, such as a ticket for a prize draw, that encourage the return of consent forms. If a completed consent form is not returned, send a reminder. Phone the child or young person's parents or carers (as appropriate) to ask for verbal consent if they have not responded by the time preparations are being made for vaccination day. If contact cannot be made, involve other health and social care providers who may be involved with the family to help gain consent. Be aware that young people under 16 can give their own consent to vaccination if they are assessed to be Gillick competent. Include an assessment for capacity to consent in the absence of parental consent or if there has been parental refusal, in line with guidance on consent in the Green book and from professional bodies such as the General Medical Council's advice on making decisions. School-aged immunisation services should ensure that they have a policy in place to support school-aged immunisation teams in assessing Gillick competence. Include guidance on what action to take when a young person's vaccination preference is different from that of their parents or carers. Commissioners should ensure that school-aged immunisation services offer catch-up vaccination sessions to children and young people who are not up to date with their school-aged vaccination schedule. If children and young people who are not up to date with their school-aged vaccinations miss the catch-up sessions, alternative provision should be made for them to be offered the vaccinations. Where children and young people are not up to date with any vaccinations that are not part of the school-aged programme, signpost parents and carers (as appropriate) to their GP to ensure that the children and young people can be offered these vaccinations. CHIS should provide information to school nursing teams to help them identify children and young people who are not up to date with their preschool vaccinations. Commissioners of vaccination services for school-aged children should ensure that children and young people who do not attend schools where vaccinations are provided are invited for vaccination at another setting. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on vaccinations for school-aged children and young people . Full details of the evidence and the committee's discussion are in: evidence review C: reminders interventions to increase the uptake of routine vaccines evidence review D: interventions to increase the uptake of routine vaccines by improving access evidence review J: acceptability and effectiveness of interventions to increase routine vaccine uptake. Loading. Please wait. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster. ## Family members or carers People with legal responsibility for decision-making for a person who is eligible for vaccination but cannot make this decision for themselves. These include parents of babies, children and young people and may also include other family members or guardians or carers if they have this responsibility (for example, if they hold a lasting power of attorney in health and welfare for another adult). See the Green book: chapter 2 on consent for more details. ## Housebound People who are unable to leave their home environment through physical or psychological illness. The decision about whether someone is classified as housebound should be made according to relevant local or national policies. This terminology is used to maintain consistency with NHS documents and websites. ## Low vaccine uptake An area or population in which uptake of a particular vaccine is lower than the national or regional average, as reported in the Public Health Outcomes Framework. This recommends a 95% vaccine coverage target for UK routine childhood vaccination programmes, with at least 90% coverage in each defined area. The performance indicators are set out in section 7A of the NHS public health functions agreement. See annex B of the NHS public health functions agreement 2019/2021. ## Older people Adults who are eligible for routine vaccination on the UK schedule, excluding pregnancy-related vaccinations. At the time of publication (May 2022), the UK schedule had routine vaccinations for adults who are aged 65 years and over, but this is expected to change in line with the reduction in age of eligibility for the shingles vaccination. Consult the Green book for information about current age limits and vaccinations for older people. ## Pregnant women Women who are pregnant as well as trans or non-binary people who are pregnant. This terminology is used to maintain consistency with NHS documents and websites.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Increasing vaccination uptake in populations with low uptake What are the most effective and acceptable interventions to increase uptake in populations or groups with low routine vaccine uptake in the UK? For a short explanation of why the committee made this recommendation for research, see the rationale section on initial invitations . Full details of the evidence and the committee's discussion are in evidence review B: barriers to, and facilitators for, vaccine uptake. Loading. Please wait. ## Incentives aimed at individuals, family members and carers What is the effectiveness and acceptability of incentives to increase uptake of routine vaccines in the UK? For a short explanation of why the committee made this recommendation for research, see the rationale section on vaccinations for school-aged children and young people . Full details of the evidence and the committee's discussion are in evidence review G: interventions to increase the uptake of routine vaccines by improving infrastructure. Loading. Please wait. ## Quasi-mandation of vaccinations What is the effectiveness and acceptability of quasi-mandation to increase vaccine uptake of routine vaccines? For a short explanation of why the committee made this recommendation for research, see the rationale section on vaccinations for school-aged children and young people . Full details of the evidence and the committee's discussion are in evidence review G: interventions to increase the uptake of routine vaccines by improving infrastructure. Loading. Please wait. ## Tailoring Immunisation Programmes Is the use of the World Health Organization 'Tailoring Immunisation Programmes' approach an effective way of designing interventions to increase vaccine uptake in a UK context? For a short explanation of why the committee made this recommendation for research, see the rationale section on vaccinations for school-aged children and young people . Full details of the evidence and the committee's discussion are in evidence review J: acceptability and effectiveness of interventions to increase routine vaccine uptake. Loading. Please wait. ## Framing content in vaccination invitations What is the relative effectiveness and acceptability of different styles of phrasing content in a vaccination invitation in the UK? For a short explanation of why the committee made this recommendation for research, see the rationale section on initial invitations . Full details of the evidence and the committee's discussion are in evidence review E: education interventions to increase the uptake of routine vaccines. Loading. Please wait. # Other recommendations for research ## Increasing vaccination uptake in older people What are the most effective and acceptable interventions to increase routine vaccine uptake in older people in the UK? For a short explanation of why the committee made this recommendation for research, see the rationale section on initial invitations . Full details of the evidence and the committee's discussion are in evidence review B: barriers to, and facilitators for, vaccine uptake. Loading. Please wait. ## HPV vaccination for boys What are the most effective and acceptable strategies to increase HPV (human papillomavirus) vaccine uptake in boys in the UK? For a short explanation of why the committee made this recommendation for research, see the rationale section on vaccinations for school-aged children and young people . Full details of the evidence and the committee's discussion are in evidence review B: barriers to, and facilitators for, vaccine uptake. Loading. Please wait. ## Increasing pertussis vaccination uptake by pregnant women What are the most effective and acceptable interventions to increase pertussis vaccine uptake in pregnant women in the UK? For a short explanation of why the committee made this recommendation for research, see the rationale section on initial invitations . Full details of the evidence and the committee's discussion are in evidence review F: interventions to increase the uptake of routine vaccines for pregnant women. Loading. Please wait. ## Provider incentives What is the effectiveness and acceptability of giving incentives to providers to increase immunisation rates in the UK? For a short explanation of why the committee made this recommendation for research, see the rationale section on designing and raising awareness of payment schemes . Full details of the evidence and the committee's discussion are in evidence review G: interventions to increase the uptake of routine vaccines by improving infrastructure. Loading. Please wait. ## School-based versus GP-based catch-up campaigns What is the effectiveness and acceptability of school-based catch-up vaccination sessions compared with GP-based catch-up campaigns in the UK? For a short explanation of why the committee made this recommendation for research, see the rationale section on vaccinations for school-aged children and young people . Full details of the evidence and the committee's discussion are in evidence review J: acceptability and effectiveness of interventions to increase routine vaccine uptake. Loading. Please wait. ## Incentives for school-aged vaccinations What levels and types of incentives are effective and acceptable for increasing vaccination uptake in a school-aged population in the UK? For a short explanation of why the committee made this recommendation for research, see the rationale section on vaccinations for school-aged children and young people . Full details of the evidence and the committee's discussion are in evidence review J: acceptability and effectiveness of interventions to increase routine vaccine uptake. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Named vaccination leads Recommendations 1.1.1 to 1.1.6 ## Why the committee made the recommendations The committee recognised several key stages in the vaccination process, such as identifying people eligible for vaccination. But based on their experience, they agreed that without a named vaccination lead, vaccine-related tasks for each organisation that provides or organises vaccinations may not be prioritised and completed, given the many other conflicting demands on people's time. Having a named lead would solve this issue. Named commissioner leads would be expected to liaise with the provider vaccination services to ensure that the vaccination process runs smoothly. They would not necessarily carry out the functions themselves but would be responsible for making sure they happened by involving other people with the required skill sets. People who are housebound are less likely to be vaccinated because they cannot attend appointments or vaccination clinics. Having a named person in each GP practice to identify these people will help to ensure that they are vaccinated. The committee were keen to promote opportunistic vaccinations as part of their overall strategy to increase uptake, and for this to take place in a range of settings (see recommendations in the section on identifying people eligible for vaccination and opportunistic vaccination). They recognised that it was not possible to vaccinate people in some non-healthcare settings, such as during home visits for social care. But these settings do provide opportunities to signpost people to vaccination services and having a named lead would help ensure that there is a strategy in place to do this. The committee were also aware that in some places, such as supported living settings and care homes, there is not always a clear procedure about what should happen if a vaccine invitation is received. This could result in the residents missing out on vaccinations. Having policies in place to ensure these invites are responded to would help avoid this, whether this is in their home or a clinical setting. Other healthcare settings where vaccines are not routinely administered, such as hospitals or other secondary or tertiary care providers, could also be used for opportunistic identification. In these settings, the named lead could be any suitably trained healthcare professional, such as a nurse, doctor or pharmacist. ## How the recommendations might affect practice These recommendations are not expected to need significant additional resources. It is likely that the named vaccination leads in healthcare settings would be existing members of staff. There are likely to be some small costs for the reallocation and reorganisation of tasks to the named lead in each scenario, but all of the activities should already be part of usual practice, and the benefits of having a named lead to ensure these tasks are carried out is expected to outweigh these costs. Although checking for eligibility for vaccination is not always usual practice in non-healthcare settings, it is unlikely to be a resource-intensive task. Many GP practices already have a register of people who are housebound that the nominated lead could use. In practices that do not have a register, the lead could identify them by reviewing people who decline vaccination because they cannot attend the surgery and coding them appropriately. This is not expected to have a significant resource impact. Return to recommendations # Designing and raising awareness of payment schemes Recommendations 1.1.7 to 1.1.8 ## Why the committee made the recommendations Although funding is already available for vaccination programmes, the committee agreed that in their experience, healthcare professionals and providers are not always aware of all the funding streams available to them, particularly if they change frequently or are only available for short periods of time. Therefore, it is important for commissioners to raise awareness of these funding options because access to more funding will help providers to develop their vaccination schemes, potentially increasing access to vaccinations. In addition, the committee wanted to raise awareness among healthcare providers about the need to submit data on vaccination uptake rates to enable them to take advantage of organisational incentives such as those provided by the Quality and Outcomes Framework for GPs. There was some evidence that provider incentives could increase the uptake of routine vaccinations. However, this evidence comprised a small number of non-UK-based studies. Although organisational incentives for vaccination are currently in use in the UK, they are subject to change, and it is unclear what types and levels of incentives are most effective in the UK. The committee therefore included a recommendation for research on provider incentives. The committee expressed concern that targets for some vaccinations may inadvertently result in those vaccinations being prioritised over other, non-targeted, vaccines. It is therefore important that commissioners consider the potential for unintended consequences when designing incentive schemes for providers. By highlighting these considerations, the committee thought that commissioners and providers should be able to develop ways to mitigate any reductions in the uptake of non-incentivised vaccinations that are detected using local uptake data. These could involve reminding professionals about the importance of other non-incentivised vaccinations. ## How the recommendations might affect services Raising awareness about funding streams and payments for providers is unlikely to need any additional resources because it could be done as part of existing communications between commissioners and providers. Because the funding streams already exist, no additional resources to provide funding would be needed. Making commissioners aware of potential unintended consequences of prioritising certain vaccinations when using incentives is unlikely to need additional resources. This could be communicated to commissioners during the process of designing incentive schemes. Return to recommendations # Making vaccination services accessible and tailoring to local needs Recommendations 1.1.9 to 1.1.15 ## Why the committee made the recommendations Based on their experience and the qualitative evidence, the committee agreed that it is important for commissioners and providers to identify the needs of their local communities because this will help them to tailor their vaccination services to address these needs. It will also allow them to identify areas of low uptake where targeted interventions may be needed, such as allowing extra time for healthcare professionals to identify and contact people eligible for vaccination. Using a Joint Strategic Needs Assessment will make sure that the local community is involved in determining local needs and priorities. The committee did not state a single threshold for identifying areas of low vaccine uptake because uptake can vary greatly between different vaccines, leading to the need for separate vaccine-specific thresholds. Also, there may be some areas that have high vaccine uptake overall but subpopulations with low uptake. However, they did include a definition of the term low vaccine uptake, which includes links to information about targets for specific vaccinations. Targeted interventions could also involve developing ways for people to access vaccinations more easily, although the specific interventions used will vary depending on the local area, the community and its culture. Developing these interventions using a system-wide approach to addressing uptake would make them as relevant to the local community as possible. This could include using services in the community, such as nurseries, schools and colleges, and involving community and faith leaders. By including people from different populations and organisations, it will be easier to develop effective interventions for particular groups with low vaccine uptake. The use of targeted interventions in areas of low uptake could potentially reduce some of the barriers to vaccination and increase vaccine uptake. This could also help to reduce inequalities between population groups and between areas of higher and lower vaccine uptake. Although the specific barriers to uptake will vary between population groups, the committee thought it was important to highlight some of the key barriers that were identified during guideline development (box 1). These barriers were chosen on the basis that they were raised frequently across the age groups covered by the guideline or highlighted by the committee during discussions. The list is not exhaustive (see evidence review B for more details and additional barriers) but is intended to raise awareness of some of the common issues that may prevent people from accessing or consenting to vaccinations. The committee also included a list of population groups that are known to have low levels of vaccine uptake (box 2). Although this list is not exhaustive, it should give providers an indication about which populations may need more consideration when developing vaccination programmes. The committee noted that although people from some minority ethnic family backgrounds, such as those in the Black Caribbean, Somali and Polish communities, often have lower vaccine uptake than White British communities, the communities with low vaccine uptake can vary by immunisation programme, as well as by area. Evidence showed that inconvenient times and locations for vaccinations were barriers to uptake, and that providing alternative locations improved uptake. The committee were also aware that difficulties with booking appointments can be a barrier to being vaccinated and that people have different needs when booking appointments. For example, some people may find online booking systems convenient and easy to use, whereas others may lack the equipment or skill to use them. Therefore, having a range of different booking options would make this process more accessible. The committee agreed that offering vaccinations outside normal hours and having a range of settings would increase the number of people who are able to attend and access the services. However, they recognised that the specific needs will vary between different populations and that services need to be tailored to meet these needs. So they decided against recommending specific ways to increase access because public health teams and providers would know best how to meet local needs and understand local barriers to access. However, as part of this process, care would need to be taken to ensure that expanding the range of settings did not increase wastage of vaccines associated with unused stocks or lead to shortages of vaccines in some settings due to under-ordering to avoid wastage. GP practices, for example, would need to be able to plan their orders based on the numbers of eligible people. The committee also highlighted the importance of involving the local community in making decisions over the accessibility of services because increased community engagement could help ensure that services meet local needs and make it easier for people to be vaccinated. The evidence identified a range of barriers to vaccine uptake for specific populations, such as immigrants and the Traveller, Roma and Gypsy communities. This included problems with registering with a GP practice, which makes it harder for people to be identified as eligible and invited for vaccination, or for them to book vaccination appointments. The committee were aware that some providers may ask for specific information, such as immigration status and proof or address, at registration. Therefore, they decided it was important to highlight that this type of information is not needed, and that primary care providers should ensure that their patient registration systems follow the standards of best practice. This will remove unnecessary barriers to accessing vaccination services. ## How the recommendations might affect services The ability to design services based on local needs will mean that providers can address any barriers to vaccination specific to their communities, thereby providing the opportunity to increase vaccine uptake and address inequalities in these areas. The impact on practice will therefore vary between areas. If the targeted interventions result in increased vaccine uptake, they are likely to also have time-saving and cost-saving benefits in the longer term, such as reducing the workload needed to identify, contact and vaccinate people who do not initially get vaccinated. Identifying local population needs and tailoring hours and locations of vaccination services to meet those needs is not expected to need significant additional resources. This is already expected in current practice, and these recommendations are aimed at making this identification and tailoring of services more consistent across the country. Providing multiple opportunities and locations for more convenient vaccination is likely to be associated with some additional resource use. However, some of the costs are likely to be offset by the significant savings and other benefits from avoiding disease outbreaks and their associated care costs, and saving practitioner time for chasing up people who have missed vaccination. However, some of the savings and other benefits may be from a different operational budget than the funding for these activities. Increasing the opportunities for vaccination may be particularly beneficial in some areas, such as rural areas, where there may be fewer GP practices and pharmacies and a greater distance to travel to access services. Although there may still be a cost associated with this recommendation, it is expected to be small and the benefits of providing more accessible vaccination locations are expected to outweigh the costs. Providing a range of accessible options for booking appointments is not expected to need additional resources, as most vaccine providers should already have accessible methods of contact. Having a range of booking options would be beneficial not only for vaccination but also for various healthcare needs. Therefore, any resource impact would be shared across these areas and have a broader benefit. Out-of-hours or weekend services for vaccination would be associated with a significant resource burden if provided on top of existing services solely for the purpose of delivering vaccinations. Combining them with existing out-of-hours provision will help to contain costs. Return to recommendations # Audit and feedback Recommendations 1.1.16 to 1.1.18 ## Why the committee made the recommendations The evidence from studies on the effects of audit and feedback was inconclusive and varied in quality due to limitations with the design of some studies. These studies frequently included additional interventions such as provider education or bonuses, which made the effects of audit and feedback harder to isolate. Some showed increased vaccine uptake whereas in others, the studies could not detect a difference in uptake between the interventions and control (usual care or another non-vaccine-related intervention). In particular, 1 study was identified that used a multicomponent provider intervention that included audits and feedback with provider reminders and education, and this showed greater vaccine uptake than usual care. This study provided support for the use of multiple interventions including audit and feedback to increase uptake. It also reflected the committee's experience of the benefits to providers and healthcare professionals of being aware of their current vaccination activity and how it compares with other similar providers. The committee recommended provider education and the use of alerts to facilitate opportunistic vaccination by providers (see the rationales for training and education for health and social care practitioners and identifying people eligible for vaccination and opportunistic vaccination). They also agreed that feedback needs to be available regularly to help providers keep track of their progress. In addition, if providers make use of this data, it can help to develop practices for continuous improvement as well as providing opportunities to share examples of good practice or effective interventions with similar providers. While the guideline was in development, many vaccination initiatives were introduced that aimed to increase the uptake of COVID-19 vaccines or ensure the continued and increased uptake of routine vaccinations during the pandemic. It was too soon for these initiatives to be evaluated as part of the current guideline development process because there is currently little evidence available relating to the effectiveness of these new initiatives. The committee agreed that it was important that these interventions (and others that may be introduced later in the pandemic) be formally evaluated in the future so that any effective interventions that are considered to be transferable, particularly those that raise vaccination rates in areas of low uptake, can be applied to routine vaccination programmes. ## How the recommendations might affect services These recommendations are not expected to need significant additional resources. Feedback and review are already current practice in some areas and the data on vaccine uptake is already reported. There may be an additional cost associated with compiling these feedback reports. But this is expected to be small, given that the task would probably be within the remit of an existing job role in most organisations. Evaluating initiatives used to increase vaccine uptake during the coronavirus pandemic is not expected to need significant additional resources. This is because the data on vaccine uptake will probably have already been collected, and any costs associated with compiling this evidence are likely to be small. There is likely to be an administrative cost associated with evaluating this evidence, but it is not expected to be significant, and this evaluation is likely to be a one-off activity. However, repeat evaluations may be needed to assess the longer-term impacts of these initiatives on COVID‑19 vaccination rates and on the rates of vaccine uptake in routine vaccination programmes if they are applied to them. This could have some additional cost implications in the future. Return to recommendations # Training and education for health and social care practitioners Recommendations 1.1.19 to 1.1.21 ## Why the committee made the recommendations There was very limited evidence for the effect of provider education or information alone on vaccine uptake. However, this intervention was a component of several multicomponent studies that showed increased vaccine uptake. In particular, 1 study of multicomponent provider interventions that included education for practitioners showed an increase in vaccine uptake compared with usual care. Qualitative evidence also highlighted how education can help healthcare practitioners feel confident when discussing vaccination with people, and that some practitioners need training in how to administer vaccines. The committee acknowledged that the UK Health Security Agency (UKHSA; previously Public Health England ) core curriculum for immunisation training for registered healthcare practitioners sets out content to be covered by practitioners who are administering vaccinations. However, they agreed that providers should be given the time to undertake this training and to revisit it as part of their continuing professional development because a lack of support and dedicated time could act as a barrier to completing it. Having effective conversations about vaccination can be particularly helpful when trying to address vaccine hesitancy. It might include, for example, adapting what content to discuss to help address people's questions and concerns, or how to deliver and discuss the content. It can also include discussing sensitive issues around stigma, such as those that may be associated with HIV. In addition, the committee were aware that people with some allergies or conditions may think that they are unable to have a vaccination because they think it is contraindicated. But this is often not the case. If healthcare practitioners understand when a vaccine is contraindicated, or are able to seek further information or advice to determine this, and discuss these concerns with the person, fewer people may be prevented from being vaccinated. The committee recognised that there is a broad range of access needs and agreed that having an awareness of how to make suitable adjustments to overcome some specific individual barriers to vaccination would help improve access to vaccination for a range of people. The committee also agreed that vaccine-related education is important for people, such as staff in GP practices and those who work in social care, who do not give vaccinations but are in contact with those eligible for it. Using their experience, the committee agreed that these people need a basic knowledge of immunisation practices and issues so that they can hold simple conversations about the benefits of vaccination and are able to signpost people to relevant sources of more detailed information. In comparison, healthcare staff who do not administer vaccines may need a greater understanding of these topics to enable them to hold useful conversations with people. Therefore, the content and depth of information provided to the people covered by this recommendation should vary depending on their specific role, and this should be considered when deciding what training to provide to different staff members. These recommendations are aimed at increasing staff confidence when discussing vaccinations, and at making every contact count to increase the opportunities for people to discuss and receive vaccinations. ## How the recommendations might affect services These recommendations are not expected to need significant additional resources. The lower intensity education for health and social care staff not directly involved in administering vaccines is likely to need some additional resources to compile the information. However, the content is generally freely available, and the costs associated with delivering it could be contained by providing materials (such as a booklet or accessible webpage) rather than delivering education in person. Delivering education materials in this way is not expected to have a significant resource impact, even in heterogeneous groups such as social care practitioners whose education packages may not necessarily include information on vaccination. Healthcare practitioners who administer vaccinations already have to complete mandatory training. Ensuring that there is time and resources for this training and for including training as part of continuing professional development is not expected to have a substantial impact because this is generally already current practice. Return to recommendations # Appointments and consultations Recommendation 1.1.22 ## Why the committee made the recommendation There are several stages in each vaccination appointment, including discussing any questions or concerns that a person has about vaccination, gaining consent, administering vaccines and completing the necessary documentation. Despite this, vaccination appointments can be relatively short. The evidence highlighted that a lack of time during consultations can lead to rushed or incomplete discussions about vaccinations and therefore be a barrier to uptake. So the committee decided that it was important to highlight each of the stages of a vaccination appointment and the need to allocate sufficient time for each one, although they were unable to say how long the appointment should be. Providing sufficient time for appointments may help to improve vaccination rates for people who have concerns by allowing them time to discuss safety and other issues with a trained healthcare provider. It also means that providers would have enough time to accurately record vaccinations. Having suitable literature available to support discussions will help people to make informed decisions. The choice of literature should be based on people's individual needs, such as whether it is needed in a different language or whether easy read materials are needed. ## How the recommendation might affect services This recommendation is not expected to have a substantial resource impact because although additional staff time can be costly, it is expected that only a relatively small proportion of people eligible for vaccination will need a longer appointment for the purposes of addressing specific concerns. Additionally, the activities that should be carried out during a vaccination appointment are already current practice, so it is not likely that the recommendations will result in longer appointments. Return to recommendation # Using compatible systems and processes Recommendation 1.2.1 ## Why the committee made the recommendation The committee were aware of issues about the compatibility of different systems used by different providers to record vaccination status. This can make it difficult to coordinate the updating of vaccination records between different systems. It can also be time-consuming if this cannot be done automatically. Improving the ability for data to be transferred between these systems would increase the accuracy and timeliness of vaccination record updates. Improved record sharing could also make it easier for healthcare professionals in a variety of settings to be able to opportunistically check the vaccination status of people who are consulting them for other reasons if the appropriate permissions are in place. The committee recognised that updating these systems to improve compatibility could be a big, time consuming and expensive task. They noted that compatible processes could be used instead to try to overcome some of the problems discussed above. For example, processes could be put in place to ensure that providers are recording vaccination data in a way that can be easily understood by other providers and used to accurately update their records. ## How the recommendation might affect practice Although updating systems used by different providers could be expensive and time consuming, it is not expected that these costs would fall on the individual trusts or providers, and costs could be contained by using compatible processes where possible. Return to recommendation # Keeping records up to date Recommendations 1.2.2 to 1.2.8 ## Why the committee made the recommendations Based on their expertise and experience, the committee agreed that it was important to ensure that records at GP practices and child health information services (CHIS) are accurate and up to date to help identify people eligible for vaccination. Vaccines administered by other providers need adding to GP records. The committee agreed that a 2‑week time limit was a realistic timeframe for this work given the competing demands for time in GP practices. If GP practices use the bulk transfers of information about children who are not up to date with their vaccinations provided by CHIS, this will help keep their records up to date. The GP practices can also use this information to facilitate their targeting of unvaccinated children for vaccination invitations and reminders. Informing CHIS if a child remains unvaccinated after 3 invitations means that they can provide additional follow-up. The committee noted that discrepancies can occur between GP records and other sources of information, such as records from CHIS, pharmacies that provide vaccinations for older people and providers in any other settings. These can result in people not being identified as eligible for vaccination or being wrongly identified as eligible when they have already been vaccinated or have moved out of the area. Investigating and resolving any such discrepancies regularly should improve the identification and recording of eligibility and status. Using up-to-date clinical system templates should also help with accurate record keeping. The incorrect or inconsistent use of clinical coding is another source of discrepancies in vaccination records. Therefore, relevant SNOMED CT codes should help to reduce inconsistencies. When a person has been identified as eligible for vaccination, it is important that their GP practice can contact them easily to invite them to be vaccinated. Some of the studies using invitations and reminders interventions reported issues with out-of-date contact details or use of unsuitable types of reminders, such as text messages for people who do not own a mobile phone. The qualitative evidence showed that an inability to speak English relatively fluently or understand the spoken or written language is a barrier to vaccine uptake for some people because it can make it harder to register at a GP practice and book appointments, and to ask for or understand information about vaccinations. In addition, low literacy levels can prevent people from accessing written information and may occur with or without the language barriers mentioned above. By making it clear whether a person has specific language or literacy requirements, it is more likely that any communications they receive will be in a language and format that they can understand. ## How the recommendations might affect practice The resource use associated with ensuring that patient contact details are up to date is likely to be variable. For most of the population, it will be straightforward and there will be no cost impact. But more intensive methods will be needed for some people, such as those who have frequent changes of address or those who have no fixed address. However, collecting contact information is necessary not only for vaccine reminders but also for various healthcare needs, so any resource impact would be shared across these areas and have a broader benefit. Regular validation of vaccination records against other sources by GP practices will lead to an increase in workload initially. However, once the current records have been checked, this workload would be expected to drop to a lower level because fewer discrepancies would be found. The other recommendations in this section are not expected to need significant additional resources. Some small administrative costs may be incurred from allocating time for these tasks, but the tasks themselves should already be being done so should not need additional resources. Return to recommendations # Identifying people eligible for vaccination and opportunistic vaccination Recommendations 1.2.9 to 1.2.19 ## Why the committee made the recommendations Based on their expertise and experience, the committee agreed that as well as inviting people for vaccination routinely (see the recommendations on invitations, reminders and escalation of contact), opportunistic identification and vaccination are important parts of an integrated strategy to increase vaccine uptake in the general population. This was supported by evidence showing that opportunistic vaccination in some settings increased vaccine uptake. In the absence of specific evidence about how and where to opportunistically identify people eligible for routine vaccinations, the committee based their recommendation on recommendation 1.3.1 in the NICE guideline on flu vaccination: increasing uptake. The committee added several settings, including those outside the healthcare system, and points of contact with the healthcare system where they agreed that people eligible for vaccination could be identified. They also included some specific groups that may need more specific approaches (such as people who misuse alcohol, are homeless, use drugs, are asylum seekers or are in prisons). Because these people may not be in routine contact with the healthcare system, special consideration is needed to assess their eligibility for vaccination. The committee also noted that looked-after children and young people and those who are educated at home or outside mainstream schooling are particularly at risk of missing vaccinations. The list is not intended to be exhaustive. The committee were aware of several barriers to opportunistic vaccination. For example, the lack of an integrated record-keeping system makes it hard for people eligible for vaccination to be identified. The committee agreed that if people can easily check their immunisation status, or that of their child or the person they care for using online systems such as digital apps, this would help them to stay up to date with their vaccinations. However, the committee were aware that routine vaccination records are not automatically available even when a person has signed up to the NHS app or has requested access to their GP records. People may need to contact their GP practice to activate access to the vaccination records section of their GP record, whereas ideally these would be available by default. The NHS app currently shows COVID‑19 vaccinations and this functionality could be expanded to include routine vaccination status. NHS summary care records could also be used to identify people eligible for vaccination. However, these records are not accessible to all healthcare professionals and cannot be checked by non-healthcare staff. In these cases, the committee agreed that any other available vaccination record, such as patient-held records, could be used for opportunistic identification. There are additional issues with identification if there are uncertainties about someone's eligibility for vaccination, such as when someone has potential contraindications or allergies. Using the Green book, seeking expert advice or consulting other additional information (such as the British HIV Association guidelines on the use of vaccines in HIV-positive adults 2015) will help ensure that people are not missing out on vaccinations unnecessarily. Further issues with identification may occur when people have uncertain vaccination histories. For example, this could be because they have come from outside the UK or they have moved around a lot within the UK. The committee were aware of the UKHSA (previously PHE) guidance on vaccinating people with uncertain or incomplete immunisation status. It states that, unless there is a documented or reliable verbal vaccine history, people should be assumed to be not immunised and a full course of immunisations planned. The committee agreed with this approach because duplicating vaccinations is generally not harmful but remaining unvaccinated could leave people open to infection. The committee also noted that, in their experience, it can be more difficult to ensure that people who are registered as temporary residents have their vaccination status checked. It is important that GP practices have a mechanism in place to identify these people and assess their eligibility for vaccination to ensure that they are not overlooked. The evidence showed that reminders to the provider in electronic medical records were effective at increasing vaccine uptake. The committee therefore wanted to highlight their use as prompts for opportunistic conversations about due and overdue vaccinations. The provider could then offer immediate vaccination if possible. Adding prompts to the records of parents or carers of children who are overdue vaccinations can help start discussions about vaccination for the children. There was no evidence on invitations or reminders specifically for pregnant women, but the committee were confident that the evidence of the effectiveness of reminders for the other age groups and life stages would also apply to this group (see the rationale section on initial invitations for more details). The Green book recommends pertussis vaccination for pregnant women between 16 and 32 weeks, so the committee decided that it would be appropriate for midwives to opportunistically offer and remind women of this vaccination during routine antenatal visits. The evidence showed that opportunistic vaccination increased uptake and was consistent with a making every contact count approach. Ideally, people eligible for vaccination would be able to discuss their outstanding vaccinations and be offered vaccination immediately. But the committee were aware that this may not be possible in all healthcare settings and would not be possible in non-healthcare settings, so alternative options are needed. Referring parents or carers to the health visitor or school nurse will not always be necessary, as the parent or carer may agree to vaccination or decide to book an appointment to discuss vaccinations. However, when referrals do take place, the services should be able to provide parents and carers with additional support and information about childhood vaccinations. ## How the recommendations might affect practice Using more opportunities to identify people eligible for vaccination may lead to an increase in the numbers of people who are vaccinated on the spot or signposted to vaccination services. Healthcare settings that are not normally involved in vaccination may start to identify people eligible for vaccination and administer vaccines. Vaccinations provided as part of the routine UK immunisation schedule have already been assessed to be cost effective, and therefore increasing the number of people vaccinated is also expected to be cost effective. Using existing records to facilitate opportunistic vaccination is not expected to need significant additional resources because the mechanisms for sharing and accessing these records are already in place. Opportunistic identification, offers and vaccinations are not expected to need significant additional resources. Existing records can be used to check eligibility for opportunistic vaccination, and mechanisms for sharing and accessing these records are already in place. Opportunistic vaccination is not likely to incur additional resources, because it would only be offered at venues where there is already vaccine storage available and where practitioners are qualified to give vaccinations. Where vaccinations cannot be given, practitioners would simply need to know what local services to signpost people to or where people should book appointments to discuss vaccination or be vaccinated. Ensuring automatic access to electronic records is not expected to need additional resources because the mechanisms for making these records available to patients through the NHS app are already in place, for example, COVID‑19 vaccination status. Return to recommendations # Recording vaccination offers and administration Recommendations 1.2.20 to 1.2.26 ## Why the committee made the recommendations The committee based these recommendations on information from the NHS England enhanced service specifications for GP contracts covering pneumococcal, pertussis and shingles vaccinations, and committee expertise. All of these specifications include a requirement to record vaccination offers, consent and details about the vaccine, including batch and site of administration, and adverse reactions. The committee included the dose of the vaccine, route and site of administration and details of consent on the basis of information for public health practitioners on immunisation in the Green book. Recording when vaccinations have been declined should ensure that people are not repeatedly offered unwanted vaccinations. Also recording the reason for the refusal could provide information for future discussions to try to address why the person declined vaccination and overcome any barriers. If this information is available at a population level, this could help public health teams locally or nationally when designing strategies to increase vaccine uptake by targeting key barriers for the general population or specific subgroups. Recording a lack of response will enable non-responders to be followed up. The committee also agreed that updating patient-held records with information about new vaccinations will ensure that people are aware of their vaccination status (or the status of the people they care for) and are able to request or chase up vaccinations if they wish to. Because some people may not have their vaccination record with them at the time of vaccination, the committee thought it was important for a printout to be provided as a temporary measure until the main record can be updated. However, they agreed it was best to update the records when the vaccinations are administered where possible because it could not be guaranteed that the record would be updated accurately later. The committee agreed that accurate and timely updating of clinical records after vaccination is essential. One method to ensure accuracy and consistency of patient records is the use of compulsory vaccination fields in electronic health records. Providers also need to promptly report vaccinations to primary care, if the vaccination is carried out elsewhere, and to child health information services (CHIS) (if relevant). Child health information services can play an additional role in helping ensure that GP-held vaccination records are up to date by regularly sending information about new vaccinations to GP practices, where this service is commissioned in the local area. The 2‑week time limit was based on committee consensus regarding a reasonable time period for this information to be relayed to the GP practice. However, the CHIS specification or local contracts may specify a different time period. The committee noted that in some cases, the data supplied by other providers and CHIS needs to be reformatted before it can be added to patient records. This can be time consuming, therefore ensuring that the information is supplied in a format that is clear and readily accessible will help the GP practice. ## How the recommendations might affect practice Recording offers and administration of vaccines is expected to be associated with some administrative costs to set up and record this information, but these costs are expected to be small. It should save staff time – and therefore future costs – when following up people and processing information. GP practices already update their records when vaccination notifications are reported from other providers, and having to do this within a certain timeframe is not expected to lead to additional work. Providers already report information on vaccinations to primary care and CHIS. If the information is reported in a clear and readily accessible format, this may save GP practices time in not having to chase up inaccessible or unclear reports. The recommendations on what to record when vaccinations are carried out broadly reflect current practice, and the additional detail about vaccination offers is not expected to take much additional time to record. Using compulsory data fields in electronic health record templates is not expected to need additional resources because this is already possible and is simple to implement with current systems. Return to recommendations # System organisation and accessibility issues Recommendations 1.3.1 to 1.3.6 ## Why the committee made the recommendations The committee agreed that several processes needed to be in place to ensure that invitations and reminders were effective. They agreed that encouraging cooperation between providers and the local healthcare system would avoid duplication of effort. For example, the child health information services department could be contracted at the local level to send out invitations for young children (primary and preschool) on behalf of GP practices. The evidence showed that bundling flu and pneumococcal vaccination invitations and reminders together was more cost effective than targeting pneumococcal vaccination separately. The committee agreed that sending invitations and reminders for different vaccinations together could be an effective way to increase vaccination uptake and reduce the number of reminders and vaccination appointments needed in some cases. However, they noted that this might not be clinically appropriate or effective for all combinations of vaccinations. The qualitative evidence highlighted that some people (including some immigrants and people from Traveller, Gypsy and Roma communities) experience language barriers, and some cannot read or write in their own language. This can prevent them from accessing information about vaccines and make it harder for them to navigate the UK healthcare system to obtain vaccinations. Providing invitations and reminders in a language and format that the person, their family member or carer (as appropriate) can understand should help to increase vaccine uptake. The qualitative evidence highlighted that some people from abroad had difficulties registering with GP practices to access NHS services. Differences in vaccination schedules between countries can also cause confusion. The committee therefore agreed that giving people information about the UK vaccination schedule could help them determine their eligibility for vaccination on the UK schedule. The committee also recognised that information alone might be insufficient and that some people might need help to understand the information and access healthcare. For example, for pregnant women and children under the age of 5 this could include involving health visitors. The committee were also aware that the people who administer vaccinations can vary between the UK and other countries, and this can make some people hesitant about vaccination. Giving people from other countries information about who administers vaccinations in the UK, and where this takes place, can reassure people about what is standard practice and potentially remove 1 of the barriers to vaccination. Some people may need additional support to access vaccinations. This could be provided by health visitors for pregnant women and children under 5. The committee discussed how consent can be a barrier to vaccination for some adults who need support with decision-making or who may lack the mental capacity to consent. Although there was no evidence for these populations, the committee thought it was important to promote equality by ensuring that all people are given the support necessary to make informed decisions on vaccination. They noted that the NICE guideline on decision-making and mental capacity provides healthcare professionals with guidance on what to consider when discussing consent for adult vaccinations. ## How the recommendations might affect practice These recommendations are not expected to need significant additional resources. They are either easily incorporated into current practice, are required by law, or are anticipated to have lower administration costs by combining services for multiple vaccinations. Return to recommendations # Initial invitations Recommendations 1.3.7 to 1.3.13 ## Why the committee made the recommendations The evidence showed that invitations or reminders were more effective than controls (mainly usual care, the format of which varied between different studies) at increasing vaccine uptake in all age groups (apart from pregnant women, see below) that have routine vaccinations. Reminders of different types were better than usual care at increasing vaccine uptake. However, in most cases the evidence did not show whether particular types of invitations or reminders were more effective than others. Evidence that did show a difference came from single trials with small numbers of participants. Therefore, the committee agreed that a variety of methods could be used to contact people eligible for vaccination, based on the evidence and the 2019 GP contract. The committee agreed that 1 of the recipients' preferred methods of contact should be used when sending out invitations and noted that invitations given face-to-face in other appointments (opportunistic invitations) were also likely to be effective. There was no evidence on whether invitations were effective in increasing vaccine uptake among pregnant women, but the committee agreed that the advice that applies to invitations for the general population should apply for pregnant women. Pregnant women have regular contact with their midwives, as well as other healthcare practitioners such as health visitors, general practice nurses and GPs. Therefore, they could receive in-person invitations, be signposted to vaccination services or offered vaccination during these appointments. The committee agreed that some people, such as people living in care homes or other residential settings and those who are housebound, may be unable to attend vaccination clinics or other settings where vaccinations are available and are therefore at risk of remaining unvaccinated. The committee agreed that it is important that these people or their family members or carers (as appropriate) can arrange home visits for vaccination. The qualitative evidence showed that healthcare providers who have built relationships with people (or their parents or carers) are likely to be trusted and able to positively influence the decision to vaccinate. However, not everyone has regular contact with a particular provider, and medical records that would be used to generate invitations may not show who a person has most contact with. The committee were also aware that in some areas, standardised invitations from a more centralised service are used, which may be difficult to personalise. Therefore, the committee agreed that using the name of a provider or service that is known to the person in the invitation and any subsequent reminders might be useful. There was some evidence that education or information slightly increased vaccine uptake compared with usual care or another control intervention when all the studies were analysed together. However, most of the individual studies did not show that these interventions were better. The qualitative evidence highlighted barriers to vaccination that could be addressed by providing information or education, but there was little detailed evidence to suggest how these barriers could be overcome successfully. Because of the limitations above and taking into account that educational interventions are more expensive and labour intensive than giving information, the committee recommended providing information instead. The committee agreed that it was helpful to provide this information with the invitations. The committee were aware that the invitations may differ in size depending on their format and they therefore came up with a list of points the invitation should contain to be useful. They also recommended a second list of items to include if space allowed. Although additional information would be too detailed for some types of invitations, such as text messages, it would be helpful to include this information in other types of invites if possible, such as those sent by post or email. For items that should be included: The qualitative evidence showed that people did not necessarily link vaccinations to the prevention of specific diseases. For example, people did not always connect HPV (human papillomavirus) vaccination to the prevention of cervical cancer. The qualitative evidence showed that many people trusted the NHS and that people were more likely to accept recommendations to be vaccinated from healthcare practitioners that they trusted. Some people may not attend vaccination appointments if they have not had their questions answered in advance. Providing contact details should make arranging this discussion easier. The committee agreed that letting people know about drop-in clinics can help those who find it difficult to get to appointments. They also discussed how giving people hyperlinks to book directly could make it easier to book appointments. A reminder to bring any patient-held records enables providers to keep vaccination records up to date and means that people are aware of their current vaccination status. For items that should be included if space allows: The qualitative evidence showed that some people underestimate the severity of certain diseases (for example, measles and shingles), and improved understanding of these issues may help increase the belief in the necessity of the vaccine and motivate people to be vaccinated. The committee agreed with the qualitative evidence that many people are worried about vaccine side effects and think they are being understated or hidden. Clearly explaining the benefits of vaccinations compared with the risk and severity of the of the illness in comparison with side effects could help encourage people to have vaccines. Explaining individual and population benefits may help persuade people in under-vaccinated areas understand the additional benefits of vaccination to their communities. Studies show that many people did not understand the need for maternal pertussis vaccination to protect the baby during pregnancy and were worried about adverse effects during the baby's development. Many people do not finish vaccination courses and do not understand why they should have boosters, so the committee agreed that an explanation of these issues is important to help people be properly protected. Studies showed that people did not necessarily understand why HPV vaccination was offered to young people before they were likely to be sexually active. Therefore, giving information about why a vaccination is given at a particular age may help to increase uptake. The qualitative evidence showed that people wanted information about vaccines from reliable sources but were unsure where to look. Providing links to trusted sites could help answer any outstanding questions about vaccines or the vaccination process, and interactive tools could help with the decision-making process. In addition, evidence from 1 quantitative study showed an increase in pertussis vaccine uptake in pregnant women using an interactive tool compared with non-specific advice about vaccinations in general. The committee agreed that a variety of options would be best because, in their experience, different people prefer different formats of information and not everyone has access to a smartphone to be able to use QR codes. The qualitative evidence showed that people found attending a vaccination appointment for the first time or during the COVID‑19 pandemic could be a stressful experience and that uncertainty about the process and safety was likely to be a barrier to attendance. Explaining the process and any COVID‑19-related safety measures could remove this barrier. It is also important that the parents or carers of babies in neonatal units are given this information. As some of these vaccinations may take place in the hospital, rather than with their GP, it is important that parents and carers are aware of how and when their baby's vaccinations will take place. The committee were interested in whether certain methods of framing information within invitations would be more effective at encouraging vaccine uptake than others (for example, gaining immunity to disease versus avoiding catching a disease). None of the identified studies looked at this directly and so the committee wrote a recommendation for research on framing content in vaccination invitations. The committee noted that there was a shortage of evidence for interventions to increase the uptake of routine vaccinations in pregnant women (pertussis vaccination) and older people (shingles and pneumococcal vaccinations), with this being particularly pronounced for the former group. The committee therefore made a recommendation for research to try to stimulate more research about effective interventions to increase pertussis vaccination uptake for pregnant women and another recommendation for research for older people. Finally, the committee agreed that it is especially important to try to increase routine vaccine uptake in groups, communities or populations with low uptake. They noted that there was limited evidence for groups of particular interest: Travellers, Gypsy and Roma; looked-after children and children not in mainstream education; migrants, asylum seekers and religious groups; and that the evidence was mainly qualitative in nature. Therefore, the committee included a recommendation for research to stimulate research on effective interventions to increase uptake in these and other groups of people with low routine vaccine uptake. ## How the recommendations might affect practice These recommendations are not expected to need significant additional resources. The format and content of invitations, and who these invitations are addressed from, are expected to be easily incorporated into the current approach to invitations. Ensuring that people (or their family members or carers) who live in care homes or residential settings, or who are housebound, are aware of how to access home visits for vaccination is unlikely to need substantial additional resources, because access to home visits is already in the GP contract and is common practice for people who are unable to attend clinics. Ensuring that parents or carers of babies who are in neonatal care units receive the relevant information about vaccinations, including when and how their baby's vaccinations will take place, is not expected to need additional resources, as this information is readily available and communication with those parents or carers should already be established. Return to recommendations # Reminders and escalation of contact Recommendations 1.3.14 to 1.3.20 ## Why the committee made the recommendations The committee agreed that it is important to identify people who do not respond to invitations or do not attend scheduled clinics or vaccination appointments, because these people may respond to a reminder. In addition, some people may not have up-to-date contact details, for example if they have moved house recently, so it is important to check that they have received the invitation and reminder. This may mean using another method of contact in some cases, such as a phone call or text message. For pregnant women, the Green book recommends vaccination between 16 and 32 weeks of pregnancy. Therefore, reminders can be provided at antenatal appointments after the 20‑week scan or when they have contact with a GP or other healthcare provider, such as health visitor. For babies and young children whose parents or carers (as appropriate) have not responded to the reminder, the committee agreed that the follow-up needs to occur rapidly and needs a conversation. Delays may cause some parents to think it was acceptable to defer vaccination. This could lead to them delaying subsequent vaccinations, which would expose the child to a higher risk of getting the diseases targeted by the vaccines. The time limits recommended were based on committee consensus aimed at preventing delays. The limits were shortest for babies because they have vaccinations due at 2, 3 and 4 months old and it is important that these are carried out in a timely manner as discussed above. Reminders for older people are less time sensitive because they can be vaccinated for shingles and pneumonia over a period of several years. The committee acknowledged that invitations and reminders (or call-recall) activity is limited for certain vaccinations in the GP contract. However, they agreed that it was important to highlight the approaches and processes that were most effective at increasing vaccine uptake to promote best practice, based on the evidence. They also noted that the GP contract does not prevent people going beyond these requirements, and groups who are not covered by call-recall can be identified opportunistically. There was qualitative evidence to show that if a person does not respond after being sent a reminder, an escalating system of contact can be effective in increasing uptake. The committee agreed that this approach matched their experience, and it was also supported by quantitative evidence from a study looking at an escalating reminders intervention that showed an increase in the number of people being vaccinated, with the intervention compared with usual care. The committee agreed that initial vaccine invitations and reminders should use methods – such as a text or email – that are not labour intensive or costly. For people who continue not to respond, escalating reminders may initially involve a phone call from a GP receptionist, then from the practice nurse and finally from the GP, until the person is vaccinated or declines vaccination. However, this approach could be resource intensive and the evidence did not show that using escalating reminders was more effective than other forms of reminders. Despite this, the committee agreed that these more intensive methods of contact represented an appropriate use of NHS resources because the group of people needing to be contacted in this manner is likely to be relatively small and to consist of people in groups or communities with lower vaccination rates. An economic analysis of the cost effectiveness of direct conversations with parents and carers of babies and toddlers who are behind on their vaccinations showed that the average cost per additional person vaccinated when using a direct contact intervention was estimated to be lower than the fee for the service that GPs receive for administering vaccines. On this basis, the committee agreed that the direct contact intervention would be a cost-effective use of resources. The committee also noted the very serious negative consequences of the diseases vaccinated against in babies and toddlers (and the high costs of treating those conditions) and were therefore confident that this would be an acceptable use of resources. The committee agreed that when contact is made with a person who has not responded to an invitation or reminder to be vaccinated, it is important to try to understand the reasons behind the lack of response or delay in vaccination because this could enable any barriers to vaccination to be addressed. For example, if the person is concerned about vaccine safety and side effects, a conversation about this at the time of contact or a consultation with a nurse or GP may be able to encourage them to be vaccinated. In other cases, if access is a barrier to vaccination, then telling the person about out-of-hours clinics and other settings for vaccination may enable them or their children to be vaccinated. The committee agreed that in some cases, a multidisciplinary approach could be helpful in overcoming barriers to vaccination. People such as social workers and health visitors may already be in direct contact with a person who has not responded to vaccination invitations and reminders and may therefore have more opportunities to discuss immunisation with them. Health visitors have multiple mandated contacts with the families of babies and young children under 2 years as part of the Healthy Child Programme (2021). They could use these as opportunities to discuss, educate, signpost and support families to access immunisations if they were made aware of unvaccinated children. This could also include implementing local interventions such as 'was not brought' protocols if there are frequent missed appointments and a lack of response to invitations. This information could be supplied by child health information services directly to the health visitors, but there might need to be a local agreement for health visitors to take on this work. Evidence showed that providing vaccinations at home increased uptake compared with usual care. However, the committee were aware that home visits would be costly so they should be reserved for people who are unable to travel to vaccination clinics, appointments or other settings where vaccinations are available. Using these restrictions should ensure that the proportion of the population who would need home visits would be small because they would be offered only when all other routes to vaccination have been exhausted. This recommendation should help ensure that people who are housebound, for example, are vaccinated, and also improve access for other underserved populations, thereby reducing inequalities. The committee agreed that it was important to record when people declined to be vaccinated so they were not offered vaccinations repeatedly, because this can be annoying and a waste of resources. However, they recognised that people can change their minds, so they wanted to make them aware that the offer of vaccination remains open if they wanted to take it up in the future. ## How the recommendations might affect practice Direct conversations with parents and carers of babies and toddlers who are behind with their vaccinations are likely to have additional costs for staff time. Identifying and providing additional reminders or offers of pertussis vaccination to pregnant women not already immunised is not expected to need additional resources, because these reminders can be given at existing antenatal appointments, and midwives already have a patient record in which vaccination status can be checked. Escalation of contact is likely to need additional resources because it is generally associated with more intensive tasks that need more staff time. Home vaccination visits would be associated with considerable additional resource use but the proportion of the population who would need them would be small because home visits would be offered only when all other routes to vaccination have been exhausted. Return to recommendations # People who are not registered with a GP practice Recommendations 1.3.21 to 1.3.23 ## Why the committee made the recommendations The committee were aware that some people such as some Travellers, Gypsy and Roma, homeless people, immigrants and asylum seekers are not registered with a GP practice and so will not receive vaccination invitations or reminders unless a different approach is taken to identify them. This is also reflected in the qualitative evidence, which showed that some Travellers, Gypsy and Roma and immigrants have difficulty registering with a GP practice and accessing healthcare from the NHS. The committee agreed that unless these people are made aware that they are eligible for NHS vaccinations and given help to access them, they are unlikely to be vaccinated. The committee agreed that local authorities, health visitors or community involvement could help to ensure that these people are not overlooked for vaccinations. Children who are not registered with a GP practice may still be known to child health information services (CHIS). In these cases, where they are commissioned to, CHIS can send invitations to parents or supply this information to the service commissioner directly. CHIS can also include a message to encourage the parent or carer (as appropriate) to register the child with a GP practice. However, it is likely that some children will not be registered with either service and will need to be identified using alternative approaches (see recommendation 1.3.21). ## How the recommendations might affect practice Involving local authorities, health visitors or the community or voluntary sector in identifying people not registered with a GP practice and ensuring they have opportunities to access vaccination may have an impact on resource use, but the committee considered this to be an appropriate use of NHS resources. Outbreaks of vaccine-preventable diseases are very costly and have significant health consequences for the population, so it is worth the additional effort of identifying and vaccinating people not registered with a GP practice. Identifying people not registered with a GP practice is not only necessary for vaccination but for various healthcare needs, so any resource impact would be shared across these areas and have a broader benefit. Raising awareness about eligibility and how to access vaccination for people not registered with a GP practice is not expected to need additional resources. It is current practice to provide leaflets to new migrants about what vaccines are on the UK immunisation schedule, and where and how to access these. This information already exists and would be simple to pass on to people not registered with a GP practice once they have been identified. Ensuring that invitations are sent to parents or carers of children not registered with a GP practice is not expected to need significant additional resources because CHIS already have a register of children, whether they are registered with a GP practice or not, and this information can be passed on to those sending out invitations for vaccination. Return to recommendations # Vaccinations for school-aged children and young people Recommendations 1.3.24 to 1.3.39 ## Why the committee made the recommendations The committee agreed, based on their experience, that vaccinating school-aged children and young people at school was the most efficient and convenient way to vaccinate this population. But they recognised that this may not be possible in all cases because not all school-aged children and young people attend school. The committee agreed, based on their experience, that although vaccination programmes for school-aged children and young people are unique enough to need a separate set of recommendations, the main steps of the process are the same as for the other age groups and life stages. They all involve an initial invitation for vaccination, a reminder and then an escalation of contact for people who do not respond. However, the invitations are sent by schools on behalf of the vaccination providers. The qualitative evidence highlighted logistical barriers that providers face with running vaccination sessions in schools and that these could be overcome with support from the schools involved. However, they noted that schools may not always prioritise vaccinations and that it is very important that providers have a good relationship with the school to facilitate sending invitations to eligible pupils and running the school-aged vaccination sessions. Invitations, information and consent forms are often provided in a digital format. Making non-digital options available will help parents, children and young people who are unable to access digital content to make informed decisions and will help reduce inequalities. The evidence for young people aged 11 to 18 years eligible for HPV vaccination consistently highlighted that young people want to be involved in discussions about vaccination. The committee therefore agreed that information provided about the vaccinations needs to be aimed at both the parents or carers (as appropriate) and the young people themselves. The general contents of the information would be the same as for vaccinations for young children and adults but tailored to the relevant vaccinations for this age group. Although not discussed in the evidence, the committee decided that it was important for the information to also cover Gillick competence so that both parents and young people are fully aware of all the options for vaccine consent. They also agreed that sending the invitation for vaccination to the young people and secondary school-aged children as well as to the parents or carers would help them be involved in the process. The committee agreed that school-based education is a key method of ensuring that children and young people understand the importance of vaccinations and can ask questions about their concerns. This was mentioned in the qualitative evidence as 1 of the acceptable methods of giving young people information about vaccinations and is already standard practice in some schools. They agreed that this education should be age appropriate and may involve school nurses, depending on commissioned service specifications. The committee agreed that 1 of the main barriers to school vaccinations is the low rate of return of consent forms. This means that school immunisation teams are unaware of whether parents or carers consent to their child being vaccinated and they have to spend time chasing up people who do not respond. One study indicated that a programme that incentivises the return of consent forms could increase the number of forms returned, and that most of these consent forms were about vaccination acceptance. The committee agreed that in their experience, for school-aged vaccinations, a positive consent form would lead to vaccination and therefore that this intervention was likely to increase the number of children and young people who are vaccinated. In addition, although some incentives, such as prize draws, will have an associated cost, this is expected to be offset by a reduction in the time and costs of nurses having to contact parents and carers of children and young people who have not returned their consent form. The committee discussed the acceptability of incentivising other parts of the vaccination process. However, they decided that incentivising consent form return rather than vaccination is likely to be more acceptable, because it is encouraging decision-making rather than the vaccination itself. There was some concern over the ethics and effectiveness of the financial incentive used in the study because in some communities, such as faith schools, a money-based incentive could be perceived as gambling and be inappropriate and ineffective. As a result, the committee did not specify the exact type of incentive in the recommendation so that local providers can make their own decisions on what is most appropriate for their local community. The committee agreed that a reminder should be sent out in cases where the consent form has not been returned. However, even with invitations and standard reminders, there will still be some young people who do not return a consent form and a more direct method of contact (a phone call) can be made before vaccination day or even on vaccination day if there is time. The committee discussed other ways to encourage families to return consent forms and thought that contact from other health and social care providers who already know the family, such as school nurses, could be helpful. In addition, the committee noted that catch-up sessions would ensure that children and young people who are not up to date with their vaccinations have other opportunities to be vaccinated. These sessions are currently limited to children and young people who have missed school-aged vaccinations, but they could be expanded to provide opportunities to catch up on earlier preschool vaccinations. Where children or young people are unable to attend the school-aged catch-up sessions, for example because of sickness, exclusion or extended leave, alternative provisions are necessary to ensure that they can be offered their overdue vaccinations. This could involve signposting to GPs or other places where the vaccinations are available. There was a shortage of evidence for catch-up campaigns, with only a single study identified that provided results in favour of school-based catch-up sessions over referring pupils to GP practices in the UK. The committee took this evidence into account and used their clinical experience of the importance of catch-up sessions to make a recommendation on this topic. However, they also included a recommendation for research on school-based versus GP-based catch-up campaigns to increase the evidence base and to examine the acceptability of catch-up sessions in these settings. To help with identifying these children and young people, child health information services can provide vaccination histories to providers. The committee agreed that it was important to highlight that young people under 16 may be able to consent to their own vaccinations if they are assessed to have the competence and understanding to appreciate what it involves. These young people are said to be Gillick competent. The assessment of Gillick competence, and when it was appropriate for young people to be assessed for competence and allowed to consent to vaccination for themselves, was a key discussion point. The committee decided that if the consent form had not been returned, and it was not possible to contact parents or carers, young people should be assessed for Gillick competence. They also agreed that young people whose parents or carers had refused consent should be given the opportunity to be assessed for competence. They thought that this should be done at the earliest opportunity, which could include on the day of the vaccination session if possible. However, they recognised that at times this assessment might be difficult to carry out on vaccination day itself because of the potentially large numbers of young people involved. In these situations, there may be more capacity to carry out these assessments before catch-up vaccination sessions. Committee discussions also highlighted the need for school immunisation teams to feel supported if they are assessing for Gillick competence; in particular when young peoples' wishes differ from that of their parents or carers. Therefore, they thought it important for providers to have policies to support local teams with these decisions. The committee made several recommendations for research that were linked to school-aged vaccinations or that came out of discussions relating to school-aged vaccinations. Although the committee made a recommendation for incentivising consent form return for school-aged vaccinations, this was based on evidence for a financial incentive for consent form return. It was unclear whether non-financial incentives would also be effective in this setting and what levels of financial or non-financial incentives would be effective. The committee wrote a recommendation for research on incentives for school-aged vaccinations. They were also interested in whether incentives would be effective and acceptable for other age groups or life stages and so they wrote a similar recommendation for research on incentives aimed at individuals, family members and carers. Another potential method of increasing vaccine uptake in school-aged children and young people and the wider populations is using mandates. The evidence looked at mandating vaccinations or education to allow access to schools in the US. However, very few studies were identified that looked at the effectiveness of mandation, and the qualitative evidence about acceptability was mixed. The committee therefore made a recommendation for research on quasi-mandation of vaccinations. There was limited quantitative and qualitative evidence for HPV vaccination in boys because routine HPV vaccination for boys has only recently been introduced in many countries, including the UK and US. The committee agreed that it is important to understand whether similar barriers and facilitators apply to HPV vaccination for boys as for girls and whether the same interventions are effective for them. They made a recommendation for research on HPV vaccination for boys to reflect this. Finally, the committee discussed whether using the World Health Organization 'Tailoring Immunisation Programmes' approach would be an effective way of designing interventions to increase vaccine uptake in a UK context. Some qualitative evidence was identified that used this approach, but it was unclear if it had been used to help design any of the interventions included in this guideline. The committee made a recommendation for research on Tailoring Immunisation Programmes. The committee were aware that not all children and young people attend schools where vaccinations are available. These include those who do not attend school at all, such as those who are home educated, chronically unwell, have local authority tutoring, and those in faith or independent schools that do not routinely hold vaccination sessions, or those in young offender institutions. These children and young people could be at risk of not being vaccinated but it was unclear to the committee how they could be identified effectively using the current system. They therefore agreed that it would be best for commissioners of the vaccination services for school-aged children to ensure that systems are put in place to identify and vaccinate these people. ## How the recommendations might affect practice These strategies are already current practice in most schools and are unlikely to have a resource impact. Offering one-off vaccination days to vaccinate children at school is likely to be less resource intensive than contacting and booking appointments for children individually in other settings. Invitations and reminders for routinely offered school-aged vaccination programmes are not expected to have a substantial resource impact because the recommended activities are current practice in most schools that provide mass vaccination days. Providing a specification for the approach to these reminders is unlikely to have resource implications. Ensuring that school-based vaccination education is accessible to children and young people is not expected to have a substantial resource impact, because this information is readily available and could simply be distributed to children and young people during school hours. If more providers offer an incentive for returning consent forms, this is likely to increase the number of forms returned, which may lead to an increase in vaccine uptake. Although some incentives, such as prize draws, will have an associated cost, this is expected to be offset by a reduction in the time and costs of nurses having to contact parents and carers of children and young people who have not returned their consent form. The NHS already uses incentives (such as prize draws) to obtain feedback for certain initiatives, so this is not a completely new approach. These incentives do not necessarily have to be expensive or complicated, and lower or zero cost incentives such as school-based perks (for example, being able to go to the front of the lunch queue) could be used instead to contain costs. Involving other health and social care providers that are in contact with the family to help gain consent where contact cannot be made through the school is not expected to need significant additional resources, because this is likely to be for a smaller group, and those people should already be in contact with the family. Putting policies in place for assessing Gillick competence may increase the vaccination team's confidence in performing the assessment, thereby increasing the number of young people who are assessed for competence and allowed to consent to their own vaccination. This will help to reduce 1 of the barriers to vaccination and potentially increase vaccine uptake in this group. Child health information services already hold vaccination records of children and young people, so identifying those who are not up to date with preschool vaccinations and informing the school nursing teams is not expected to need significant additional resources. This is not expected to need significant additional resources because local authorities already have a duty to know which children and young people do not attend schools where vaccinations are provided, and they have contact details for their parents or carers. Local authorities could therefore contact these people on behalf of vaccination providers to arrange vaccination in a suitable setting. Return to recommendations# Context Vaccinations provide personal and population-level protection against many diseases. High vaccine uptake rates create population-level protection, leading to herd immunity. This protects both immunised and non-immunised people. Examples of non-immunised people include those who are highly susceptible to disease such as newborn babies and older people, and people who cannot be vaccinated for medical reasons or for whom vaccines are contraindicated. By contrast, vaccines for some diseases such as shingles only protect those who receive them and provide minimal indirect protection to other people. The UK routine vaccination schedule covers key vaccinations for different stages in life including childhood, adolescence, pregnancy and old age (currently 65 years and older). Although vaccination coverage in general in the UK is relatively high, uptake varies between vaccines, areas and the age groups they are targeted at. For example, 5-in-1 coverage of children measured at 5 years was 95.2% in 2019/2020, whereas 83.9% of Year 9 girls completed the 2‑dose HPV (human papillomavirus) vaccination course in 2018/19. By contrast, from April 2018 to March 2019, shingles vaccine uptake for the 70‑year‑old routine cohort was only 31.9%, pneumococcal vaccine uptake for all people aged 65 and over was 69.2% and pertussis vaccine coverage in pregnant women was 68.8%. Vaccination coverage needs to be actively maintained, and ideally increased, in the face of increasing vaccine scepticism and misinformation. In addition, certain population groups (such as Travellers, Gypsy and Roma, refugees and asylum seekers) have lower levels of vaccination than the general public. Additional or different actions may be needed to increase their vaccination rates. Reasons for low uptake may include poor access to healthcare services; inaccurate claims about safety and effectiveness, which can lead to increased concerns and a reduction in the perceived need for vaccines; and insufficient capacity in the healthcare system to provide vaccinations. In addition, problems with the recording of vaccination status and poor identification of people who are eligible to be vaccinated may have contributed to low uptake.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Service organisation\n\nThese recommendations should be read together with the NICE guideline on flu vaccination: increasing uptake.\n\n## Named vaccination leads\n\nEnsure that each organisation that commissions, provides or organises vaccination services has a named vaccination lead with responsibility (as relevant) for ensuring that:\n\nvaccination records are validated and updated\n\npeople who are eligible for vaccination are identified\n\ninvitations and reminders are sent to people eligible for vaccination\n\nvaccines are administered and recorded\n\nthere is coordination between providers and other services involved in organising and reporting vaccinations.\n\nGP practices and child health information services (CHIS) understand each other's reporting systems and processes\n\nbest practice is followed for ordering, storing, distributing and disposing of vaccines (see the Green book for more information).\n\nCommissioners and providers should ensure that the named vaccination leads have access to the relevant information and facilities they need to carry out their role.\n\nNominate a named person in each primary care provider to be responsible for identifying people who are housebound and need vaccination.\n\nSocial care providers and providers of other non-healthcare services (who are asked to identify people eligible for vaccination opportunistically [see recommendation\xa01.2.9]) should identify a named lead responsible for the organisation's approach to:\n\nidentifying people who are eligible for vaccination and\n\nensuring that it is clear where to signpost these people to get vaccinated or to obtain further information.\n\nIn supported living settings and care homes, the named vaccination lead should also ensure that there is a policy in place covering what actions to take in response to vaccination invitation letters for residents.\n\nFor secondary and tertiary care providers who do not provide vaccinations, ensure that there is a named vaccination lead who can identify people eligible for vaccination and signpost them to relevant services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on named vaccination leads\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: identification and recording of vaccination eligibility and status\n\nevidence review\xa0D: interventions to increase the uptake of routine vaccines by improving access.\n\nLoading. Please wait.\n\n## Designing and raising awareness of payment schemes\n\nThese recommendations are for regional and local commissioners of NHS vaccination services.\n\nRaise awareness among healthcare professionals and providers:\n\nabout payments and funding streams to support the delivery of vaccination services, including those for populations with low vaccination rates\n\nthat submission of information about vaccination uptake directly affects any linked organisational incentive payments.\n\nWhen designing incentive schemes for providers, take into account that using incentives to prioritise certain vaccinations could have unintended consequences on the uptake of other vaccinations.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on designing and raising awareness of payment schemes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: interventions to increase the uptake of routine vaccines by improving infrastructure.\n\nLoading. Please wait.\n\n## Making vaccination services accessible and tailoring to local needs\n\nNHS commissioners and NHS providers should ensure that they identify:\n\nlocal population needs\n\nbarriers to vaccine uptake (see box 1)\n\nareas or populations with low vaccine uptake (see box 2). They should do this using data from the Joint Strategic Needs Assessment and other data sources.\n\nBox 1 Some key barriers to routine vaccine uptake\n\nInflexible and inconvenient clinic times and locations\n\nPerceived lack of balanced information (including misinformation)\n\nLanguage and literacy problems\n\nInsufficient time in consultations to discuss concerns about vaccinations\n\nLack of staff training in how to discuss vaccinations effectively\n\nUncertainty about vaccine safety and effectiveness\n\nUncertainty about whether vaccines are needed (including how severe the diseases are or how likely it is that someone will be exposed to the disease)\n\nPrevious negative experiences of vaccination\n\nLack of trust in the government, drug companies and the healthcare system\n\nReligious or cultural views that are against vaccination (this may relate to specific vaccinations, for example HPV [human papillomavirus])\n\nIndividual barriers such as needle phobia or sensory impairment.\n\nBox 2 Some population groups that are known to have low vaccine uptake or be at risk of low uptake\n\nPeople from some minority ethnic family backgrounds\n\nPeople from Gypsy, Roma and Traveller communities\n\nPeople with physical or learning disabilities\n\nPeople from some religious communities (for example, Orthodox Jewish)\n\nNew migrants and asylum seekers\n\nLooked-after children and young people\n\nChildren of young or lone parents\n\nChildren from large families\n\nPeople who live in an area of high deprivation\n\nBabies or children who are hospitalised or have a chronic illness, and their siblings\n\nPeople not registered with a GP\n\nPeople from non-English-speaking families\n\nPeople who are homeless*\n\nCommunities with low uptake other than those listed above may also be identified specifically in your local area.\n\nSources: UK Health Security Agency (previously Public Health England) Health Equity Audit of the National Immunisation Programme, apart from those marked with an asterisk, which were raised by the committee.\n\nIn areas with low vaccine uptake, commissioners and providers should consider introducing targeted interventions to:\n\novercome identified local barriers to vaccination (see box 1)\n\naddress identified inequalities in vaccine uptake between different population groups (see box 2 and the UK Health Security Agency [UKHSA, previously Public Health England; PHE] immunisation equalities strategy).If introducing these interventions, develop them as part of a system-wide approach.\n\nCommissioners and providers should ensure that they:\n\nInvolve people in the local community when identifying barriers to vaccine uptake and when making decisions about accessibility of services (see the section on involving people in peer and lay roles to represent local needs and priorities in the NICE guideline on community engagement).\n\nTailor service opening hours and locations for vaccinations to meet local needs. This should include providing multiple opportunities for people eligible for vaccination to have their vaccinations at a time and location convenient to them. Locations such as community pharmacies, clinics people attend regularly, and GP practices could be used.\n\nProvide a range of accessible options for booking appointments (such as telephone booking and online systems). Take into account that some people may need additional support to use these systems.\n\nConsider using sites outside healthcare settings as settings for vaccination clinics, such as mobile vaccination units, children and family centres, or community or faith centres that provide a more family friendly environment, if this would address specific local barriers to vaccine uptake.\n\nConsider providing vaccination services during extended hours and extended access appointments in evenings and weekends for people who may find it difficult to attend at other times. These services could be in primary care or community pharmacies, or be provided by a centralised service in each local area. If possible, provide these as part of existing out-of-hours services.\n\nCommissioners and providers should coordinate vaccination services between providers to minimise wastage where vaccine supply is limited.\n\nGP practices should ensure that contractual obligations and best practice on patient registration is followed (for example, not requiring immigration status or proof of address).\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on making vaccination services accessible and tailoring to local needs\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: interventions to increase the uptake of routine vaccines by improving access.\n\nLoading. Please wait.\n\n## Audit and feedback\n\nNHS commissioners should ensure that there is a coordinated system in place for a quarterly cycle of feedback and audits of vaccine uptake data that can be compared against similar providers at a local and national level.\n\nProviders should use available data to review current and past activity to help with continuous improvement.\n\nTo help increase vaccine uptake in the future, vaccine services should:\n\nevaluate initiatives for improving the uptake of routine or COVID‑19 vaccinations carried out during the SARS‑CoV‑2 pandemic, and\n\nidentify initiatives that could be used to increase the uptake of routine vaccination programmes.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on audit and feedback\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0G: interventions to increase the uptake of routine vaccines by improving infrastructure\n\nevidence review\xa0H: multicomponent interventions to increase uptake of routine vaccines\n\nevidence review\xa0K: COVID-19 call for evidence.\n\nLoading. Please wait.\n\n## Training and education for health and social care practitioners\n\nVaccination leads (see recommendation 1.1.4) should ensure that health and social care practitioners and other related staff who are in contact with people eligible for vaccination, but do not administer vaccines, have ongoing education about vaccination. These could include:\n\nPractitioners working in primary care settings, including GP practices, optometry, dental practices and community pharmacies.\n\nSecondary care practitioners, for example in clinics for children with chronic conditions, emergency departments or wards such as oncology, antenatal or neonatal.\n\nSocial care practitioners who may have contact with carers and other eligible groups, such as people with learning disabilities. This may include contact during home visits, individual needs assessments and carers' assessments.\n\nEnsure that education for health and social care practitioners and other related staff who are in contact with people eligible for vaccination, but do not administer vaccines, includes:\n\nan understanding of who is eligible for vaccination on the NHS routine UK immunisation schedule\n\nawareness of barriers to vaccination (see box 1)\n\nbenefits and risks of vaccination\n\nwhere to signpost people for further information and vaccination.Tailor the level and content of the information to the person's role.\n\nHealthcare practitioners who administer vaccines should be given the time, resources and support to:\n\nUndertake mandatory training before administering vaccines (UKHSA [previously PHE] national minimum standards and core curriculum for immunisation training for registered healthcare practitioners).\n\nInclude training on vaccination as part of their continuing professional development plan, including how to have effective and sensitive conversations about vaccination.\n\nAsk people for any questions and concerns they may have about vaccination and give them personalised responses (or signpost people to relevant sources).\n\nProvide tailored information on the risks and benefits of vaccination.\n\nUnderstand when a vaccine is contraindicated, for example for people with certain allergies or conditions, and when it can still be delivered, and be able to discuss this with the person concerned (see recommendation\xa01.2.18).\n\nOvercome particular individual barriers to vaccination such as those experienced by people who have a learning disability, needle phobia or sensory impairment.\n\nOffer and administer vaccines.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on training and education for health and social care practitioners\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0E: education interventions to increase the uptake of routine vaccines\n\nevidence review\xa0H: multicomponent interventions to increase uptake of routine vaccines.\n\nLoading. Please wait.\n\n## Appointments and consultations\n\nProviders should ensure that there is sufficient time in an appointment or consultation to:\n\nallow the healthcare professional and individual, family member or carer (as appropriate) to have a discussion where any concerns can be identified and addressed. This could include using written information or websites to help the discussion\n\ngain informed consent\n\nadminister vaccines\n\ncomplete documentation.For information on how to support people to make informed decisions, see the NICE guideline on shared decision making.\n\nFor a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on appointments and consultations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E:\xa0education interventions to increase the uptake of routine vaccines.\n\nLoading. Please wait.\n\n# Identifying eligibility, giving vaccinations and recording vaccination status\n\nThese recommendations should be read together with the NICE guideline on flu vaccination: increasing uptake.\n\nNICE has produced a visual summary on identifying people eligible for vaccination and opportunistic vaccination.\n\n## Using compatible systems and processes\n\nEnsure that compatible systems or processes are in place to enable vaccination records to be shared and transferred effectively and in a timely way between different parts of the healthcare system, including other vaccination providers such as community pharmacies.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on using compatible systems and processes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: identification and recording of vaccination eligibility and status.\n\nLoading. Please wait.\n\n## Keeping records up to date\n\nChild health information services (CHIS) should ensure that their vaccination records are updated within 5\xa0days or within service specifications if they exist, whichever is shorter, in response to new information about a person's vaccination status.\n\nGP practices should ensure that their vaccination records are updated within 2\xa0weeks (or as specified in the GP contract if shorter) in response to new information about a person's vaccination status.\n\nGP practices should use an up-to-date clinical system template that includes relevant SNOMED\xa0CT codes to record vaccinations.\n\nGP practices should validate their vaccination records at least monthly against data sources received. Check registered populations and vaccine eligibility and status, investigate any discrepancies and correct the record accordingly.\n\nCHIS should give GP practices a monthly update (or as specified in the CHIS contract if shorter) on children who are not up to date with their vaccinations.\n\nGP practices should inform CHIS if 3 invitations for vaccination are made but a child remains unvaccinated (see recommendation\xa01.3.16).\n\nGP practices should ensure that they have up-to-date medical records, phone numbers, email addresses and addresses for people who are eligible for vaccination, or their family members or carers (as appropriate). Include the person's preferred methods of contact (such as letters, texts, emails or phone calls) and whether there are additional literacy issues or language needs.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on keeping records up to date\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: identification and recording of vaccination eligibility and status.\n\nLoading. Please wait.\n\n## Identifying people eligible for vaccination and opportunistic vaccination\n\nUse every opportunity to identify people eligible for vaccination. This could include:\n\nat registration in general practice\n\nduring health and developmental reviews as part of the healthy child programme and health visitor and school nursing targeted contacts\n\nduring the annual learning disability health check for people with learning disabilities\n\nwhen making contact with people in healthcare settings, community health clinics, sexual health services or drug and alcohol services (including hospitals, emergency departments, inpatient services, rehabilitation services and general practice)\n\nwhen making contact with women who are trying to conceive or have a newly confirmed pregnancy, and at antenatal and postnatal reviews\n\non admission to day care, nurseries, schools, special needs schools, pupil referral units, and further and higher education\n\non admission to care homes and supported living settings\n\nwhen people visit community pharmacies for health advice, a medication review or an NHS New Medicine Service, or to collect prescriptions\n\nduring home visits for healthcare or social care\n\nany health service contact with people who are homeless\n\nwhen new migrants, including asylum seekers, arrive in the country\n\nwithin 7\xa0days of arrival in prisons and young offender institutions, during any contact with healthcare services in these places, and when people leave\n\nas part of a looked-after child or young person's health plan, and during initial health assessments, and annual and statutory reviews (see also the NICE guideline on looked-after children and young people)\n\nany contact with home-educated children\n\nduring occupational health checks for everyone who works in a clinical or social care setting, even if their role is not healthcare related.\n\nOffer people (or their family members or carers, as appropriate) access to online systems or apps to allow them to view and check their NHS vaccination records (or those of their child or the person they care for).\n\nProviders of online systems or apps should ensure that people automatically have access to their vaccination status as part of their electronic records as the default option.\n\nUse the NHS summary care record, or any other available vaccination records (including records held by the person), to opportunistically identify people who are eligible for vaccination.\n\nUnless a person has a documented (or reliable verbal) vaccine history, assume that they are not immunised, and plan a full course of immunisations (see the UKHSA [previously PHE] guidance on vaccination of individuals with uncertain or incomplete immunisation status).\n\nGP practices should ensure that there is a mechanism in place to check the vaccination status of people registered as temporary residents and offer any vaccinations needed.\n\nProviders should routinely use prompts and reminders from electronic medical records to opportunistically identify people who are eligible and due or overdue for vaccination.\n\nAdd prompts to the records of parents or carers (as appropriate) if children are overdue vaccinations.\n\nMidwives should offer vaccination to pregnant women during routine antenatal visits, as recommended by the Green book and the NHS routine UK immunisation schedule. If the midwife cannot administer the vaccine, they should signpost women to vaccination services, drop-in clinics or their GP practice.\n\nWhen uncertainties exist around contraindications and allergies, consult the Green book and seek expert help if needed.\n\nWhen people eligible for vaccination have been identified opportunistically:\n\nHealthcare professionals should:\n\n\n\nif possible, discuss any outstanding vaccinations with them (or their family members or carers, as appropriate) and offer vaccination immediately\n\notherwise, encourage them to book an appointment to discuss the vaccinations or an appointment for vaccination\n\nthink about referring a child's parents or carers to the health visitor or school nurse, as age appropriate.\n\n\n\nNon-healthcare practitioners should signpost them to vaccination services.See also recommendation\xa01.2.15.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on identifying people eligible for vaccination and opportunistic vaccination\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: identification and recording of vaccination eligibility and status\n\nevidence review\xa0C: reminders interventions to increase the uptake of routine vaccines\n\nevidence review\xa0D: interventions to increase the uptake of routine vaccines by improving access\n\nevidence review\xa0E: education interventions to increase the uptake of routine vaccines\n\nevidence review\xa0H: multicomponent interventions to increase the uptake of routine vaccines.\n\nLoading. Please wait.\n\n## Recording vaccination offers and administration\n\nWhen offering a vaccination, record in the GP record or other medical record whether it was accepted or declined or there was no response (see recommendation\xa01.3.20).\n\nThe person administering the vaccine should ensure that information is recorded accurately and consistently, regardless of where the vaccine is administered, and includes:\n\ndetails of consent to the vaccination (including if someone else has consented on the person's behalf, and that person's relationship to them)\n\nthe dose, batch number, expiry date, vaccine name and vaccine product name\n\nthe date, route and site of administration\n\nany reported adverse reactions\n\nwhether the vaccine was administered under Patient Specific Directions or Patient Group Directions. (See the NICE guideline on patient group directions.)\n\nProviders should ensure that clinical and patient-held records (including records held on behalf of children) are updated at the time of the vaccination. If the patient-held record is not available at the appointment, give the person a printed record of the vaccination and ensure that the patient-held record is updated at a subsequent healthcare appointment.\n\nProviders should use electronic health record templates with compulsory data fields to support accurate recording of vaccination offers and administration (see recommendations\xa01.2.15 and 1.2.16).\n\nProviders should ensure that vaccinations are reported promptly (within 5 working days, or in line with required standards if shorter) to GP practices and child health information services (CHIS) (if relevant).\n\nWhere commissioned locally, CHIS should send details of vaccinations administered outside of the GP practice to GP practices within 2\xa0weeks or as specified in the CHIS contract if shorter.\n\nProviders should ensure that the information they provide to GP practices and CHIS is clear and in a readily accessible format that minimises the need for manual re-entry of data.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on recording vaccination offers and administration\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: identification and recording of vaccination eligibility and status.\n\nLoading. Please wait.\n\n# Invitations, reminders and escalation of contact\n\nThese recommendations should be read together with the NICE guideline on flu vaccination: increasing uptake.\n\n## System organisation and accessibility issues\n\nNHS England public health commissioning teams and screening and immunisation teams should ensure that there is a coordinated system in place at the local level for providers to send out invitations and reminders.\n\nConsider sending invitations and reminders for different vaccinations together (for example, the pneumococcal vaccine with the flu vaccine).\n\nIf possible, ensure that the information, invitation and any subsequent reminders are given in a format and language appropriate for the person and their family members or carers (as appropriate).\n\nEnsure that the information, invitation and any subsequent reminders meet the person's communication needs (see NHS England's Accessible Information Standard). For more guidance on giving people information and discussing their preferences, see the NICE guidelines on patient experience in adult NHS services and shared decision making.\n\nGive people who have come from outside the UK:\n\ndetails of the NHS vaccine schedule, how it is delivered, where and by whom if they:\n\n\n\nhave started vaccinations before arrival and not completed them or\n\nare eligible for vaccination.\n\n\n\nhelp to access healthcare, if needed.Be aware that expectations of who delivers vaccine services may differ by cultural background.\n\nIf people need to provide consent for vaccination but need additional support with decision-making (such as people with learning disabilities) or if they may lack mental capacity, follow the recommendations on supporting decision-making in the NICE guideline on decision-making and mental capacity.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on system organisation and accessibility issues\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0C: reminders interventions to increase the uptake of routine vaccines\n\nevidence review\xa0E: education interventions to increase the uptake of routine vaccines\n\nevidence review\xa0I: interventions to increase vaccine uptake by targeting acceptability\n\nevidence review\xa0J: acceptability and effectiveness of interventions to increase routine vaccine uptake.\n\nLoading. Please wait.\n\n## Vaccinations for babies, infants and preschool-aged children, and adults\n\nNICE has produced the following visual summaries:\n\nVaccinations for young children and older people: invitations, reminders and escalation of contact\n\nVaccinations for pregnant women: invitations, reminders and escalation of contact.\n\nInvite people who are eligible for vaccination or their family members or carers (as appropriate) to book an appointment or attend an open access clinic. Do this opportunistically during consultations if possible, or by letter, email, phone call or text. Use the person's preferred method of communication for invitations if possible.\n\nPractitioners working in maternity services and other healthcare practitioners who have contact with pregnant women should ensure that pregnant women are invited for vaccination or signposted to vaccination services or drop-in clinics.\n\nEnsure that the following people (or their family members or carers, as appropriate) know how to get home visits for vaccination if they cannot attend vaccination clinics or other settings where vaccinations are available:\n\npeople who live in care homes or residential settings\n\npeople who are housebound\n\nbabies and children whose parents or carers are housebound.See also recommendation\xa01.3.6 and the NICE guideline on managing medicines in care homes.\n\nConsider sending the vaccination invitation and any subsequent reminders from a healthcare professional or service that is known to the person or their family members or carers, such as a school, GP practice, doctor, nurse, midwife or health visitor.\n\nEnsure that the vaccination invitation contains:\n\nThe vaccines being offered (named in full) and the targeted diseases.\n\nA statement that the NHS and the relevant provider (with the type of provider specified) recommends the vaccination.\n\nDetails on contacting a healthcare professional (for example, practice nurse, GP, school nurse or pharmacist) to discuss any concerns the person (or their family members or carers) might have (including about possible contraindications or allergies that could affect whether the person can have a vaccination).\n\nInstructions for how to book an appointment at a vaccination clinic, if relevant, or where and when drop-in clinics are held. If possible, include options for online booking.\n\nA reminder to bring any relevant patient-held records for updating.\n\nIf space allows, include the following in the vaccination invitation or provide links:\n\nInformation on the vaccines, including:\n\n\n\nthe potential severity of the targeted diseases\n\nthe risks and benefits of vaccination, including individual benefits (including to the baby for maternal pertussis vaccination) and population benefits (protecting other people in their community)\n\nif relevant, the importance of having all doses of a vaccination course\n\nif relevant, why some vaccines are given at specific ages (for example, the HPV [human papillomavirus] vaccine).\n\n\n\nInstructions for accessing additional videos and information (including interactive information and decision tools) from trusted sources such as the Oxford University's Vaccine Knowledge Project, NHS England and the World Health Organization. Include hyperlinks or QR codes if possible.\n\nInformation about what to expect at the appointment.\n\nEnsure that the parents or carers (as appropriate) of babies who are in neonatal care units when they are eligible for their vaccinations receive relevant information (see recommendations\xa01.3.11 and 1.3.12) and are made aware of when and how their baby's vaccinations will take place.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on initial invitations\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0C: reminders interventions to increase the uptake of routine vaccines\n\nevidence review\xa0E: education interventions to increase the uptake of routine vaccines\n\nevidence review\xa0H: multicomponent interventions to increase the uptake of routine vaccines.\n\nLoading. Please wait.\n\nProviders (such as GP practices) should identify people who do not respond to invitations or attend clinics, vaccination appointments or other settings where vaccinations are available and send a reminder. (See also recommendation\xa01.3.10.) Confirm that the person has received the reminder.\n\nAt a pregnant woman's first appointment after the 20‑week scan, antenatal care providers should check whether they have been offered and accepted vaccination against pertussis in this pregnancy. If not, ensure they receive offers of vaccination or reminders (as relevant) at subsequent antenatal appointments or during any contact with their GP, midwife, health visitor or any other healthcare provider.\n\nTalk to parents or carers (as appropriate) of children aged\xa05 or under who have not responded to a reminder if a vaccination delay is approaching:\n\nweeks, for immunisations for babies up to age 1\xa0year\n\nmonths, for immunisations for children aged 1\xa0year and over. Explore with them the reasons for their lack of response and try to address any issues they raise.\n\nFor pregnant women and older people who do not respond to reminders, consider more direct contact such as a phone call. Explore with them the reasons for their lack of response and try to address any issues they raise.\n\nConsider a multidisciplinary approach to address any issues raised in recommendations 1.3.16 and 1.3.17, involving other relevant health and social care practitioners such as health visitors, social workers or key workers, while respecting the person's decision if they refuse vaccination.\n\nConsider home visits for people who have difficulty travelling to vaccination services. Discuss immunisation and offer them or their children (as relevant) vaccinations there and then (or arrange a convenient time in the future).\n\nIf someone declines an offer of vaccination, record this with the reason why, if given, and make sure they know how to get a vaccination at a later date if they change their mind.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reminders and escalation of contact\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0C: reminders interventions to increase the uptake of routine vaccines\n\nevidence review\xa0D: interventions to increase the uptake of routine vaccines by improving access\n\nevidence review H: multicomponent interventions to increase the uptake of routine vaccines.\n\nLoading. Please wait.\n\nCommissioners should consider involving local authorities, health visitors, or the community or voluntary sector to ensure that people who are not registered with a GP practice are identified and have opportunities to access relevant vaccinations. This could include homeless people and other transient populations. See also recommendation 1.2.9 on opportunistic identification, box\xa02 and the NICE guideline on integrated health and social care for people experiencing homelessness.\n\nCommissioners should ensure that people who are not registered with a GP practice are aware that they are eligible for NHS vaccinations, and where and how to access them.\n\nCHIS should identify children who are eligible for vaccination but are not registered with a GP practice. Where commissioned, they should send invitations to parents and carers or ensure this cohort is highlighted to the service commissioner. This might include children from Traveller, Gypsy and Roma communities, newly arrived immigrants or asylum seekers.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on people who are not registered with a GP practice\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: reminders interventions to increase the uptake of routine vaccines.\n\nLoading. Please wait.\n\n## Vaccinations for school-aged children and young people\n\nWhen administering vaccinations to secondary school-aged children and young people, do this in schools if possible.\n\nNICE has produced a visual summary on vaccinations for school-aged children and young people: invitations, reminders and escalation of contact.\n\nSchool-aged immunisation providers and schools should work together to organise and carry out vaccinations for secondary school-aged children and young people.\n\nEnsure that schools are involved in sending invitations (including consent forms) for vaccinations on behalf of the providers to pupils who attend school. Make the format of the invitation accessible to parents and secondary school-aged children and young people.\n\nEnsure that the invitation, information and consent form are available in a digital format, with non-digital options available where needed.\n\nProviders should ensure that young people and their parents or carers (as appropriate) have reliable information about vaccines that covers risks and benefits to help them to make informed decisions. The information should include who can consent to vaccination (Gillick competence) as well as the information listed in recommendations\xa01.3.11 and 1.3.12 (as appropriate). See also the NICE guideline on babies, children and young people's experience of healthcare.\n\nProviders and schools should work together to ensure that school-based education about vaccines is available in an age-appropriate format to children and young people to increase their understanding about vaccinations.\n\nProviders should offer incentives, such as a ticket for a prize draw, that encourage the return of consent forms.\n\nIf a completed consent form is not returned, send a reminder.\n\nPhone the child or young person's parents or carers (as appropriate) to ask for verbal consent if they have not responded by the time preparations are being made for vaccination day. If contact cannot be made, involve other health and social care providers who may be involved with the family to help gain consent.\n\nBe aware that young people under\xa016 can give their own consent to vaccination if they are assessed to be Gillick competent. Include an assessment for capacity to consent in the absence of parental consent or if there has been parental refusal, in line with guidance on consent in the Green book and from professional bodies such as the General Medical Council's advice on making decisions.\n\nSchool-aged immunisation services should ensure that they have a policy in place to support school-aged immunisation teams in assessing Gillick competence. Include guidance on what action to take when a young person's vaccination preference is different from that of their parents or carers.\n\nCommissioners should ensure that school-aged immunisation services offer catch-up vaccination sessions to children and young people who are not up to date with their school-aged vaccination schedule.\n\nIf children and young people who are not up to date with their school-aged vaccinations miss the catch-up sessions, alternative provision should be made for them to be offered the vaccinations.\n\nWhere children and young people are not up to date with any vaccinations that are not part of the school-aged programme, signpost parents and carers (as appropriate) to their GP to ensure that the children and young people can be offered these vaccinations.\n\nCHIS should provide information to school nursing teams to help them identify children and young people who are not up to date with their preschool vaccinations.\n\nCommissioners of vaccination services for school-aged children should ensure that children and young people who do not attend schools where vaccinations are provided are invited for vaccination at another setting.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on vaccinations for school-aged children and young people\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0C: reminders interventions to increase the uptake of routine vaccines\n\nevidence review\xa0D: interventions to increase the uptake of routine vaccines by improving access\n\nevidence review\xa0J: acceptability and effectiveness of interventions to increase routine vaccine uptake.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Family members or carers\n\nPeople with legal responsibility for decision-making for a person who is eligible for vaccination but cannot make this decision for themselves. These include parents of babies, children and young people and may also include other family members or guardians or carers if they have this responsibility (for example, if they hold a lasting power of attorney in health and welfare for another adult). See the Green book: chapter 2 on consent for more details.\n\n## Housebound\n\nPeople who are unable to leave their home environment through physical or psychological illness. The decision about whether someone is classified as housebound should be made according to relevant local or national policies. This terminology is used to maintain consistency with NHS documents and websites.\n\n## Low vaccine uptake\n\nAn area or population in which uptake of a particular vaccine is lower than the national or regional average, as reported in the Public Health Outcomes Framework. This recommends a 95% vaccine coverage target for UK routine childhood vaccination programmes, with at least 90% coverage in each defined area. The performance indicators are set out in section 7A of the NHS public health functions agreement. See annex B of the NHS public health functions agreement 2019/2021.\n\n## Older people\n\nAdults who are eligible for routine vaccination on the UK schedule, excluding pregnancy-related vaccinations. At the time of publication (May\xa02022), the UK schedule had routine vaccinations for adults who are aged 65\xa0years and over, but this is expected to change in line with the reduction in age of eligibility for the shingles vaccination. Consult the Green book for information about current age limits and vaccinations for older people.\n\n## Pregnant women\n\nWomen who are pregnant as well as trans or non-binary people who are pregnant. This terminology is used to maintain consistency with NHS documents and websites.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Increasing vaccination uptake in populations with low uptake\n\nWhat are the most effective and acceptable interventions to increase uptake in populations or groups with low routine vaccine uptake in the UK?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on initial invitations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: barriers to, and facilitators for, vaccine uptake.\n\nLoading. Please wait.\n\n## Incentives aimed at individuals, family members and carers\n\nWhat is the effectiveness and acceptability of incentives to increase uptake of routine vaccines in the UK?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on vaccinations for school-aged children and young people\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: interventions to increase the uptake of routine vaccines by improving infrastructure.\n\nLoading. Please wait.\n\n## Quasi-mandation of vaccinations\n\nWhat is the effectiveness and acceptability of quasi-mandation to increase vaccine uptake of routine vaccines?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on vaccinations for school-aged children and young people\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: interventions to increase the uptake of routine vaccines by improving infrastructure.\n\nLoading. Please wait.\n\n## Tailoring Immunisation Programmes\n\nIs the use of the World Health Organization 'Tailoring Immunisation Programmes' approach an effective way of designing interventions to increase vaccine uptake in a UK context?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on vaccinations for school-aged children and young people\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: acceptability and effectiveness of interventions to increase routine vaccine uptake.\n\nLoading. Please wait.\n\n## Framing content in vaccination invitations\n\nWhat is the relative effectiveness and acceptability of different styles of phrasing content in a vaccination invitation in the UK?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on initial invitations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: education interventions to increase the uptake of routine vaccines.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Increasing vaccination uptake in older people\n\nWhat are the most effective and acceptable interventions to increase routine vaccine uptake in older people in the UK?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on initial invitations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: barriers to, and facilitators for, vaccine uptake.\n\nLoading. Please wait.\n\n## HPV vaccination for boys\n\nWhat are the most effective and acceptable strategies to increase HPV (human papillomavirus) vaccine uptake in boys in the UK?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on vaccinations for school-aged children and young people\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: barriers to, and facilitators for, vaccine uptake.\n\nLoading. Please wait.\n\n## Increasing pertussis vaccination uptake by pregnant women\n\nWhat are the most effective and acceptable interventions to increase pertussis vaccine uptake in pregnant women in the UK?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on initial invitations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: interventions to increase the uptake of routine vaccines for pregnant women.\n\nLoading. Please wait.\n\n## Provider incentives\n\nWhat is the effectiveness and acceptability of giving incentives to providers to increase immunisation rates in the UK?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on designing and raising awareness of payment schemes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: interventions to increase the uptake of routine vaccines by improving infrastructure.\n\nLoading. Please wait.\n\n## School-based versus GP-based catch-up campaigns\n\nWhat is the effectiveness and acceptability of school-based catch-up vaccination sessions compared with GP-based catch-up campaigns in the UK?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on vaccinations for school-aged children and young people\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: acceptability and effectiveness of interventions to increase routine vaccine uptake.\n\nLoading. Please wait.\n\n## Incentives for school-aged vaccinations\n\nWhat levels and types of incentives are effective and acceptable for increasing vaccination uptake in a school-aged population in the UK?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on vaccinations for school-aged children and young people\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: acceptability and effectiveness of interventions to increase routine vaccine uptake.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Named vaccination leads\n\nRecommendations 1.1.1 to 1.1.6\n\n## Why the committee made the recommendations\n\nThe committee recognised several key stages in the vaccination process, such as identifying people eligible for vaccination. But based on their experience, they agreed that without a named vaccination lead, vaccine-related tasks for each organisation that provides or organises vaccinations may not be prioritised and completed, given the many other conflicting demands on people's time. Having a named lead would solve this issue. Named commissioner leads would be expected to liaise with the provider vaccination services to ensure that the vaccination process runs smoothly. They would not necessarily carry out the functions themselves but would be responsible for making sure they happened by involving other people with the required skill sets.\n\nPeople who are housebound are less likely to be vaccinated because they cannot attend appointments or vaccination clinics. Having a named person in each GP practice to identify these people will help to ensure that they are vaccinated.\n\nThe committee were keen to promote opportunistic vaccinations as part of their overall strategy to increase uptake, and for this to take place in a range of settings (see recommendations in the section on identifying people eligible for vaccination and opportunistic vaccination). They recognised that it was not possible to vaccinate people in some non-healthcare settings, such as during home visits for social care. But these settings do provide opportunities to signpost people to vaccination services and having a named lead would help ensure that there is a strategy in place to do this.\n\nThe committee were also aware that in some places, such as supported living settings and care homes, there is not always a clear procedure about what should happen if a vaccine invitation is received. This could result in the residents missing out on vaccinations. Having policies in place to ensure these invites are responded to would help avoid this, whether this is in their home or a clinical setting. Other healthcare settings where vaccines are not routinely administered, such as hospitals or other secondary or tertiary care providers, could also be used for opportunistic identification. In these settings, the named lead could be any suitably trained healthcare professional, such as a nurse, doctor or pharmacist.\n\n## How the recommendations might affect practice\n\nThese recommendations are not expected to need significant additional resources. It is likely that the named vaccination leads in healthcare settings would be existing members of staff. There are likely to be some small costs for the reallocation and reorganisation of tasks to the named lead in each scenario, but all of the activities should already be part of usual practice, and the benefits of having a named lead to ensure these tasks are carried out is expected to outweigh these costs. Although checking for eligibility for vaccination is not always usual practice in non-healthcare settings, it is unlikely to be a resource-intensive task.\n\nMany GP practices already have a register of people who are housebound that the nominated lead could use. In practices that do not have a register, the lead could identify them by reviewing people who decline vaccination because they cannot attend the surgery and coding them appropriately. This is not expected to have a significant resource impact.\n\nReturn to recommendations\n\n# Designing and raising awareness of payment schemes\n\nRecommendations 1.1.7 to 1.1.8\n\n## Why the committee made the recommendations\n\nAlthough funding is already available for vaccination programmes, the committee agreed that in their experience, healthcare professionals and providers are not always aware of all the funding streams available to them, particularly if they change frequently or are only available for short periods of time. Therefore, it is important for commissioners to raise awareness of these funding options because access to more funding will help providers to develop their vaccination schemes, potentially increasing access to vaccinations. In addition, the committee wanted to raise awareness among healthcare providers about the need to submit data on vaccination uptake rates to enable them to take advantage of organisational incentives such as those provided by the Quality and Outcomes Framework for GPs.\n\nThere was some evidence that provider incentives could increase the uptake of routine vaccinations. However, this evidence comprised a small number of non-UK-based studies. Although organisational incentives for vaccination are currently in use in the UK, they are subject to change, and it is unclear what types and levels of incentives are most effective in the UK. The committee therefore included a recommendation for research on provider incentives.\n\nThe committee expressed concern that targets for some vaccinations may inadvertently result in those vaccinations being prioritised over other, non-targeted, vaccines. It is therefore important that commissioners consider the potential for unintended consequences when designing incentive schemes for providers. By highlighting these considerations, the committee thought that commissioners and providers should be able to develop ways to mitigate any reductions in the uptake of non-incentivised vaccinations that are detected using local uptake data. These could involve reminding professionals about the importance of other non-incentivised vaccinations.\n\n## How the recommendations might affect services\n\nRaising awareness about funding streams and payments for providers is unlikely to need any additional resources because it could be done as part of existing communications between commissioners and providers. Because the funding streams already exist, no additional resources to provide funding would be needed.\n\nMaking commissioners aware of potential unintended consequences of prioritising certain vaccinations when using incentives is unlikely to need additional resources. This could be communicated to commissioners during the process of designing incentive schemes.\n\nReturn to recommendations\n\n# Making vaccination services accessible and tailoring to local needs\n\nRecommendations 1.1.9 to 1.1.15\n\n## Why the committee made the recommendations\n\nBased on their experience and the qualitative evidence, the committee agreed that it is important for commissioners and providers to identify the needs of their local communities because this will help them to tailor their vaccination services to address these needs. It will also allow them to identify areas of low uptake where targeted interventions may be needed, such as allowing extra time for healthcare professionals to identify and contact people eligible for vaccination. Using a Joint Strategic Needs Assessment will make sure that the local community is involved in determining local needs and priorities.\n\nThe committee did not state a single threshold for identifying areas of low vaccine uptake because uptake can vary greatly between different vaccines, leading to the need for separate vaccine-specific thresholds. Also, there may be some areas that have high vaccine uptake overall but subpopulations with low uptake. However, they did include a definition of the term low vaccine uptake, which includes links to information about targets for specific vaccinations. Targeted interventions could also involve developing ways for people to access vaccinations more easily, although the specific interventions used will vary depending on the local area, the community and its culture.\n\nDeveloping these interventions using a system-wide approach to addressing uptake would make them as relevant to the local community as possible. This could include using services in the community, such as nurseries, schools and colleges, and involving community and faith leaders. By including people from different populations and organisations, it will be easier to develop effective interventions for particular groups with low vaccine uptake. The use of targeted interventions in areas of low uptake could potentially reduce some of the barriers to vaccination and increase vaccine uptake. This could also help to reduce inequalities between population groups and between areas of higher and lower vaccine uptake.\n\nAlthough the specific barriers to uptake will vary between population groups, the committee thought it was important to highlight some of the key barriers that were identified during guideline development (box 1). These barriers were chosen on the basis that they were raised frequently across the age groups covered by the guideline or highlighted by the committee during discussions. The list is not exhaustive (see evidence review B for more details and additional barriers) but is intended to raise awareness of some of the common issues that may prevent people from accessing or consenting to vaccinations. The committee also included a list of population groups that are known to have low levels of vaccine uptake (box 2). Although this list is not exhaustive, it should give providers an indication about which populations may need more consideration when developing vaccination programmes. The committee noted that although people from some minority ethnic family backgrounds, such as those in the Black Caribbean, Somali and Polish communities, often have lower vaccine uptake than White British communities, the communities with low vaccine uptake can vary by immunisation programme, as well as by area.\n\nEvidence showed that inconvenient times and locations for vaccinations were barriers to uptake, and that providing alternative locations improved uptake. The committee were also aware that difficulties with booking appointments can be a barrier to being vaccinated and that people have different needs when booking appointments. For example, some people may find online booking systems convenient and easy to use, whereas others may lack the equipment or skill to use them. Therefore, having a range of different booking options would make this process more accessible.\n\nThe committee agreed that offering vaccinations outside normal hours and having a range of settings would increase the number of people who are able to attend and access the services. However, they recognised that the specific needs will vary between different populations and that services need to be tailored to meet these needs. So they decided against recommending specific ways to increase access because public health teams and providers would know best how to meet local needs and understand local barriers to access. However, as part of this process, care would need to be taken to ensure that expanding the range of settings did not increase wastage of vaccines associated with unused stocks or lead to shortages of vaccines in some settings due to under-ordering to avoid wastage. GP practices, for example, would need to be able to plan their orders based on the numbers of eligible people.\n\nThe committee also highlighted the importance of involving the local community in making decisions over the accessibility of services because increased community engagement could help ensure that services meet local needs and make it easier for people to be vaccinated.\n\nThe evidence identified a range of barriers to vaccine uptake for specific populations, such as immigrants and the Traveller, Roma and Gypsy communities. This included problems with registering with a GP practice, which makes it harder for people to be identified as eligible and invited for vaccination, or for them to book vaccination appointments. The committee were aware that some providers may ask for specific information, such as immigration status and proof or address, at registration. Therefore, they decided it was important to highlight that this type of information is not needed, and that primary care providers should ensure that their patient registration systems follow the standards of best practice. This will remove unnecessary barriers to accessing vaccination services.\n\n## How the recommendations might affect services\n\nThe ability to design services based on local needs will mean that providers can address any barriers to vaccination specific to their communities, thereby providing the opportunity to increase vaccine uptake and address inequalities in these areas. The impact on practice will therefore vary between areas. If the targeted interventions result in increased vaccine uptake, they are likely to also have time-saving and cost-saving benefits in the longer term, such as reducing the workload needed to identify, contact and vaccinate people who do not initially get vaccinated.\n\nIdentifying local population needs and tailoring hours and locations of vaccination services to meet those needs is not expected to need significant additional resources. This is already expected in current practice, and these recommendations are aimed at making this identification and tailoring of services more consistent across the country.\n\nProviding multiple opportunities and locations for more convenient vaccination is likely to be associated with some additional resource use. However, some of the costs are likely to be offset by the significant savings and other benefits from avoiding disease outbreaks and their associated care costs, and saving practitioner time for chasing up people who have missed vaccination. However, some of the savings and other benefits may be from a different operational budget than the funding for these activities. Increasing the opportunities for vaccination may be particularly beneficial in some areas, such as rural areas, where there may be fewer GP practices and pharmacies and a greater distance to travel to access services. Although there may still be a cost associated with this recommendation, it is expected to be small and the benefits of providing more accessible vaccination locations are expected to outweigh the costs.\n\nProviding a range of accessible options for booking appointments is not expected to need additional resources, as most vaccine providers should already have accessible methods of contact. Having a range of booking options would be beneficial not only for vaccination but also for various healthcare needs. Therefore, any resource impact would be shared across these areas and have a broader benefit.\n\nOut-of-hours or weekend services for vaccination would be associated with a significant resource burden if provided on top of existing services solely for the purpose of delivering vaccinations. Combining them with existing out-of-hours provision will help to contain costs.\n\nReturn to recommendations\n\n# Audit and feedback\n\nRecommendations 1.1.16 to 1.1.18\n\n## Why the committee made the recommendations\n\nThe evidence from studies on the effects of audit and feedback was inconclusive and varied in quality due to limitations with the design of some studies. These studies frequently included additional interventions such as provider education or bonuses, which made the effects of audit and feedback harder to isolate. Some showed increased vaccine uptake whereas in others, the studies could not detect a difference in uptake between the interventions and control (usual care or another non-vaccine-related intervention). In particular, 1 study was identified that used a multicomponent provider intervention that included audits and feedback with provider reminders and education, and this showed greater vaccine uptake than usual care. This study provided support for the use of multiple interventions including audit and feedback to increase uptake. It also reflected the committee's experience of the benefits to providers and healthcare professionals of being aware of their current vaccination activity and how it compares with other similar providers.\n\nThe committee recommended provider education and the use of alerts to facilitate opportunistic vaccination by providers (see the rationales for training and education for health and social care practitioners and identifying people eligible for vaccination and opportunistic vaccination). They also agreed that feedback needs to be available regularly to help providers keep track of their progress. In addition, if providers make use of this data, it can help to develop practices for continuous improvement as well as providing opportunities to share examples of good practice or effective interventions with similar providers.\n\nWhile the guideline was in development, many vaccination initiatives were introduced that aimed to increase the uptake of COVID-19 vaccines or ensure the continued and increased uptake of routine vaccinations during the pandemic. It was too soon for these initiatives to be evaluated as part of the current guideline development process because there is currently little evidence available relating to the effectiveness of these new initiatives. The committee agreed that it was important that these interventions (and others that may be introduced later in the pandemic) be formally evaluated in the future so that any effective interventions that are considered to be transferable, particularly those that raise vaccination rates in areas of low uptake, can be applied to routine vaccination programmes.\n\n## How the recommendations might affect services\n\nThese recommendations are not expected to need significant additional resources. Feedback and review are already current practice in some areas and the data on vaccine uptake is already reported. There may be an additional cost associated with compiling these feedback reports. But this is expected to be small, given that the task would probably be within the remit of an existing job role in most organisations.\n\nEvaluating initiatives used to increase vaccine uptake during the coronavirus pandemic is not expected to need significant additional resources. This is because the data on vaccine uptake will probably have already been collected, and any costs associated with compiling this evidence are likely to be small. There is likely to be an administrative cost associated with evaluating this evidence, but it is not expected to be significant, and this evaluation is likely to be a one-off activity. However, repeat evaluations may be needed to assess the longer-term impacts of these initiatives on COVID‑19 vaccination rates and on the rates of vaccine uptake in routine vaccination programmes if they are applied to them. This could have some additional cost implications in the future.\n\nReturn to recommendations\n\n# Training and education for health and social care practitioners\n\nRecommendations 1.1.19 to 1.1.21\n\n## Why the committee made the recommendations\n\nThere was very limited evidence for the effect of provider education or information alone on vaccine uptake. However, this intervention was a component of several multicomponent studies that showed increased vaccine uptake. In particular, 1 study of multicomponent provider interventions that included education for practitioners showed an increase in vaccine uptake compared with usual care. Qualitative evidence also highlighted how education can help healthcare practitioners feel confident when discussing vaccination with people, and that some practitioners need training in how to administer vaccines.\n\nThe committee acknowledged that the UK Health Security Agency (UKHSA; previously Public Health England [PHE]) core curriculum for immunisation training for registered healthcare practitioners sets out content to be covered by practitioners who are administering vaccinations. However, they agreed that providers should be given the time to undertake this training and to revisit it as part of their continuing professional development because a lack of support and dedicated time could act as a barrier to completing it.\n\nHaving effective conversations about vaccination can be particularly helpful when trying to address vaccine hesitancy. It might include, for example, adapting what content to discuss to help address people's questions and concerns, or how to deliver and discuss the content. It can also include discussing sensitive issues around stigma, such as those that may be associated with HIV. In addition, the committee were aware that people with some allergies or conditions may think that they are unable to have a vaccination because they think it is contraindicated. But this is often not the case. If healthcare practitioners understand when a vaccine is contraindicated, or are able to seek further information or advice to determine this, and discuss these concerns with the person, fewer people may be prevented from being vaccinated. The committee recognised that there is a broad range of access needs and agreed that having an awareness of how to make suitable adjustments to overcome some specific individual barriers to vaccination would help improve access to vaccination for a range of people.\n\nThe committee also agreed that vaccine-related education is important for people, such as staff in GP practices and those who work in social care, who do not give vaccinations but are in contact with those eligible for it. Using their experience, the committee agreed that these people need a basic knowledge of immunisation practices and issues so that they can hold simple conversations about the benefits of vaccination and are able to signpost people to relevant sources of more detailed information. In comparison, healthcare staff who do not administer vaccines may need a greater understanding of these topics to enable them to hold useful conversations with people. Therefore, the content and depth of information provided to the people covered by this recommendation should vary depending on their specific role, and this should be considered when deciding what training to provide to different staff members. These recommendations are aimed at increasing staff confidence when discussing vaccinations, and at making every contact count to increase the opportunities for people to discuss and receive vaccinations.\n\n## How the recommendations might affect services\n\nThese recommendations are not expected to need significant additional resources. The lower intensity education for health and social care staff not directly involved in administering vaccines is likely to need some additional resources to compile the information. However, the content is generally freely available, and the costs associated with delivering it could be contained by providing materials (such as a booklet or accessible webpage) rather than delivering education in person. Delivering education materials in this way is not expected to have a significant resource impact, even in heterogeneous groups such as social care practitioners whose education packages may not necessarily include information on vaccination.\n\nHealthcare practitioners who administer vaccinations already have to complete mandatory training. Ensuring that there is time and resources for this training and for including training as part of continuing professional development is not expected to have a substantial impact because this is generally already current practice.\n\nReturn to recommendations\n\n# Appointments and consultations\n\nRecommendation 1.1.22\n\n## Why the committee made the recommendation\n\nThere are several stages in each vaccination appointment, including discussing any questions or concerns that a person has about vaccination, gaining consent, administering vaccines and completing the necessary documentation. Despite this, vaccination appointments can be relatively short. The evidence highlighted that a lack of time during consultations can lead to rushed or incomplete discussions about vaccinations and therefore be a barrier to uptake. So the committee decided that it was important to highlight each of the stages of a vaccination appointment and the need to allocate sufficient time for each one, although they were unable to say how long the appointment should be.\n\nProviding sufficient time for appointments may help to improve vaccination rates for people who have concerns by allowing them time to discuss safety and other issues with a trained healthcare provider. It also means that providers would have enough time to accurately record vaccinations. Having suitable literature available to support discussions will help people to make informed decisions. The choice of literature should be based on people's individual needs, such as whether it is needed in a different language or whether easy read materials are needed.\n\n## How the recommendation might affect services\n\nThis recommendation is not expected to have a substantial resource impact because although additional staff time can be costly, it is expected that only a relatively small proportion of people eligible for vaccination will need a longer appointment for the purposes of addressing specific concerns. Additionally, the activities that should be carried out during a vaccination appointment are already current practice, so it is not likely that the recommendations will result in longer appointments.\n\nReturn to recommendation\n\n# Using compatible systems and processes\n\nRecommendation 1.2.1\n\n## Why the committee made the recommendation\n\nThe committee were aware of issues about the compatibility of different systems used by different providers to record vaccination status. This can make it difficult to coordinate the updating of vaccination records between different systems. It can also be time-consuming if this cannot be done automatically. Improving the ability for data to be transferred between these systems would increase the accuracy and timeliness of vaccination record updates. Improved record sharing could also make it easier for healthcare professionals in a variety of settings to be able to opportunistically check the vaccination status of people who are consulting them for other reasons if the appropriate permissions are in place.\n\nThe committee recognised that updating these systems to improve compatibility could be a big, time consuming and expensive task. They noted that compatible processes could be used instead to try to overcome some of the problems discussed above. For example, processes could be put in place to ensure that providers are recording vaccination data in a way that can be easily understood by other providers and used to accurately update their records.\n\n## How the recommendation might affect practice\n\nAlthough updating systems used by different providers could be expensive and time consuming, it is not expected that these costs would fall on the individual trusts or providers, and costs could be contained by using compatible processes where possible.\n\nReturn to recommendation\n\n# Keeping records up to date\n\nRecommendations 1.2.2 to 1.2.8\n\n## Why the committee made the recommendations\n\nBased on their expertise and experience, the committee agreed that it was important to ensure that records at GP practices and child health information services (CHIS) are accurate and up to date to help identify people eligible for vaccination. Vaccines administered by other providers need adding to GP records. The committee agreed that a 2‑week time limit was a realistic timeframe for this work given the competing demands for time in GP practices. If GP practices use the bulk transfers of information about children who are not up to date with their vaccinations provided by CHIS, this will help keep their records up to date. The GP practices can also use this information to facilitate their targeting of unvaccinated children for vaccination invitations and reminders. Informing CHIS if a child remains unvaccinated after 3\xa0invitations means that they can provide additional follow-up.\n\nThe committee noted that discrepancies can occur between GP records and other sources of information, such as records from CHIS, pharmacies that provide vaccinations for older people and providers in any other settings. These can result in people not being identified as eligible for vaccination or being wrongly identified as eligible when they have already been vaccinated or have moved out of the area. Investigating and resolving any such discrepancies regularly should improve the identification and recording of eligibility and status. Using up-to-date clinical system templates should also help with accurate record keeping. The incorrect or inconsistent use of clinical coding is another source of discrepancies in vaccination records. Therefore, relevant SNOMED CT codes should help to reduce inconsistencies.\n\nWhen a person has been identified as eligible for vaccination, it is important that their GP practice can contact them easily to invite them to be vaccinated. Some of the studies using invitations and reminders interventions reported issues with out-of-date contact details or use of unsuitable types of reminders, such as text messages for people who do not own a mobile phone. The qualitative evidence showed that an inability to speak English relatively fluently or understand the spoken or written language is a barrier to vaccine uptake for some people because it can make it harder to register at a GP practice and book appointments, and to ask for or understand information about vaccinations. In addition, low literacy levels can prevent people from accessing written information and may occur with or without the language barriers mentioned above. By making it clear whether a person has specific language or literacy requirements, it is more likely that any communications they receive will be in a language and format that they can understand.\n\n## How the recommendations might affect practice\n\nThe resource use associated with ensuring that patient contact details are up to date is likely to be variable. For most of the population, it will be straightforward and there will be no cost impact. But more intensive methods will be needed for some people, such as those who have frequent changes of address or those who have no fixed address. However, collecting contact information is necessary not only for vaccine reminders but also for various healthcare needs, so any resource impact would be shared across these areas and have a broader benefit.\n\nRegular validation of vaccination records against other sources by GP practices will lead to an increase in workload initially. However, once the current records have been checked, this workload would be expected to drop to a lower level because fewer discrepancies would be found.\n\nThe other recommendations in this section are not expected to need significant additional resources. Some small administrative costs may be incurred from allocating time for these tasks, but the tasks themselves should already be being done so should not need additional resources.\n\nReturn to recommendations\n\n# Identifying people eligible for vaccination and opportunistic vaccination\n\nRecommendations 1.2.9 to 1.2.19\n\n## Why the committee made the recommendations\n\nBased on their expertise and experience, the committee agreed that as well as inviting people for vaccination routinely (see the recommendations on invitations, reminders and escalation of contact), opportunistic identification and vaccination are important parts of an integrated strategy to increase vaccine uptake in the general population. This was supported by evidence showing that opportunistic vaccination in some settings increased vaccine uptake.\n\nIn the absence of specific evidence about how and where to opportunistically identify people eligible for routine vaccinations, the committee based their recommendation on recommendation 1.3.1 in the NICE guideline on flu vaccination: increasing uptake. The committee added several settings, including those outside the healthcare system, and points of contact with the healthcare system where they agreed that people eligible for vaccination could be identified. They also included some specific groups that may need more specific approaches (such as people who misuse alcohol, are homeless, use drugs, are asylum seekers or are in prisons). Because these people may not be in routine contact with the healthcare system, special consideration is needed to assess their eligibility for vaccination. The committee also noted that looked-after children and young people and those who are educated at home or outside mainstream schooling are particularly at risk of missing vaccinations. The list is not intended to be exhaustive.\n\nThe committee were aware of several barriers to opportunistic vaccination. For example, the lack of an integrated record-keeping system makes it hard for people eligible for vaccination to be identified. The committee agreed that if people can easily check their immunisation status, or that of their child or the person they care for using online systems such as digital apps, this would help them to stay up to date with their vaccinations. However, the committee were aware that routine vaccination records are not automatically available even when a person has signed up to the NHS app or has requested access to their GP records. People may need to contact their GP practice to activate access to the vaccination records section of their GP record, whereas ideally these would be available by default. The NHS app currently shows COVID‑19 vaccinations and this functionality could be expanded to include routine vaccination status.\n\nNHS summary care records could also be used to identify people eligible for vaccination. However, these records are not accessible to all healthcare professionals and cannot be checked by non-healthcare staff. In these cases, the committee agreed that any other available vaccination record, such as patient-held records, could be used for opportunistic identification.\n\nThere are additional issues with identification if there are uncertainties about someone's eligibility for vaccination, such as when someone has potential contraindications or allergies. Using the Green book, seeking expert advice or consulting other additional information (such as the British HIV Association guidelines on the use of vaccines in HIV-positive adults 2015) will help ensure that people are not missing out on vaccinations unnecessarily.\n\nFurther issues with identification may occur when people have uncertain vaccination histories. For example, this could be because they have come from outside the UK or they have moved around a lot within the UK. The committee were aware of the UKHSA (previously PHE) guidance on vaccinating people with uncertain or incomplete immunisation status. It states that, unless there is a documented or reliable verbal vaccine history, people should be assumed to be not immunised and a full course of immunisations planned. The committee agreed with this approach because duplicating vaccinations is generally not harmful but remaining unvaccinated could leave people open to infection.\n\nThe committee also noted that, in their experience, it can be more difficult to ensure that people who are registered as temporary residents have their vaccination status checked. It is important that GP practices have a mechanism in place to identify these people and assess their eligibility for vaccination to ensure that they are not overlooked.\n\nThe evidence showed that reminders to the provider in electronic medical records were effective at increasing vaccine uptake. The committee therefore wanted to highlight their use as prompts for opportunistic conversations about due and overdue vaccinations. The provider could then offer immediate vaccination if possible. Adding prompts to the records of parents or carers of children who are overdue vaccinations can help start discussions about vaccination for the children.\n\nThere was no evidence on invitations or reminders specifically for pregnant women, but the committee were confident that the evidence of the effectiveness of reminders for the other age groups and life stages would also apply to this group (see the rationale section on initial invitations for more details). The Green book recommends pertussis vaccination for pregnant women between 16 and 32\xa0weeks, so the committee decided that it would be appropriate for midwives to opportunistically offer and remind women of this vaccination during routine antenatal visits.\n\nThe evidence showed that opportunistic vaccination increased uptake and was consistent with a making every contact count approach. Ideally, people eligible for vaccination would be able to discuss their outstanding vaccinations and be offered vaccination immediately. But the committee were aware that this may not be possible in all healthcare settings and would not be possible in non-healthcare settings, so alternative options are needed. Referring parents or carers to the health visitor or school nurse will not always be necessary, as the parent or carer may agree to vaccination or decide to book an appointment to discuss vaccinations. However, when referrals do take place, the services should be able to provide parents and carers with additional support and information about childhood vaccinations.\n\n## How the recommendations might affect practice\n\nUsing more opportunities to identify people eligible for vaccination may lead to an increase in the numbers of people who are vaccinated on the spot or signposted to vaccination services. Healthcare settings that are not normally involved in vaccination may start to identify people eligible for vaccination and administer vaccines. Vaccinations provided as part of the routine UK immunisation schedule have already been assessed to be cost effective, and therefore increasing the number of people vaccinated is also expected to be cost effective.\n\nUsing existing records to facilitate opportunistic vaccination is not expected to need significant additional resources because the mechanisms for sharing and accessing these records are already in place.\n\nOpportunistic identification, offers and vaccinations are not expected to need significant additional resources. Existing records can be used to check eligibility for opportunistic vaccination, and mechanisms for sharing and accessing these records are already in place. Opportunistic vaccination is not likely to incur additional resources, because it would only be offered at venues where there is already vaccine storage available and where practitioners are qualified to give vaccinations.\n\nWhere vaccinations cannot be given, practitioners would simply need to know what local services to signpost people to or where people should book appointments to discuss vaccination or be vaccinated.\n\nEnsuring automatic access to electronic records is not expected to need additional resources because the mechanisms for making these records available to patients through the NHS app are already in place, for example, COVID‑19 vaccination status.\n\nReturn to recommendations\n\n# Recording vaccination offers and administration\n\nRecommendations 1.2.20 to 1.2.26\n\n## Why the committee made the recommendations\n\nThe committee based these recommendations on information from the NHS England enhanced service specifications for GP contracts covering pneumococcal, pertussis and shingles vaccinations, and committee expertise. All of these specifications include a requirement to record vaccination offers, consent and details about the vaccine, including batch and site of administration, and adverse reactions. The committee included the dose of the vaccine, route and site of administration and details of consent on the basis of information for public health practitioners on immunisation in the Green book.\n\nRecording when vaccinations have been declined should ensure that people are not repeatedly offered unwanted vaccinations. Also recording the reason for the refusal could provide information for future discussions to try to address why the person declined vaccination and overcome any barriers. If this information is available at a population level, this could help public health teams locally or nationally when designing strategies to increase vaccine uptake by targeting key barriers for the general population or specific subgroups. Recording a lack of response will enable non-responders to be followed up.\n\nThe committee also agreed that updating patient-held records with information about new vaccinations will ensure that people are aware of their vaccination status (or the status of the people they care for) and are able to request or chase up vaccinations if they wish to. Because some people may not have their vaccination record with them at the time of vaccination, the committee thought it was important for a printout to be provided as a temporary measure until the main record can be updated. However, they agreed it was best to update the records when the vaccinations are administered where possible because it could not be guaranteed that the record would be updated accurately later.\n\nThe committee agreed that accurate and timely updating of clinical records after vaccination is essential. One method to ensure accuracy and consistency of patient records is the use of compulsory vaccination fields in electronic health records. Providers also need to promptly report vaccinations to primary care, if the vaccination is carried out elsewhere, and to child health information services (CHIS) (if relevant). Child health information services can play an additional role in helping ensure that GP-held vaccination records are up to date by regularly sending information about new vaccinations to GP practices, where this service is commissioned in the local area. The 2‑week time limit was based on committee consensus regarding a reasonable time period for this information to be relayed to the GP practice. However, the CHIS specification or local contracts may specify a different time period.\n\nThe committee noted that in some cases, the data supplied by other providers and CHIS needs to be reformatted before it can be added to patient records. This can be time consuming, therefore ensuring that the information is supplied in a format that is clear and readily accessible will help the GP practice.\n\n## How the recommendations might affect practice\n\nRecording offers and administration of vaccines is expected to be associated with some administrative costs to set up and record this information, but these costs are expected to be small. It should save staff time – and therefore future costs – when following up people and processing information.\n\nGP practices already update their records when vaccination notifications are reported from other providers, and having to do this within a certain timeframe is not expected to lead to additional work. Providers already report information on vaccinations to primary care and CHIS. If the information is reported in a clear and readily accessible format, this may save GP practices time in not having to chase up inaccessible or unclear reports.\n\nThe recommendations on what to record when vaccinations are carried out broadly reflect current practice, and the additional detail about vaccination offers is not expected to take much additional time to record.\n\nUsing compulsory data fields in electronic health record templates is not expected to need additional resources because this is already possible and is simple to implement with current systems.\n\nReturn to recommendations\n\n# System organisation and accessibility issues\n\nRecommendations 1.3.1 to 1.3.6\n\n## Why the committee made the recommendations\n\nThe committee agreed that several processes needed to be in place to ensure that invitations and reminders were effective. They agreed that encouraging cooperation between providers and the local healthcare system would avoid duplication of effort. For example, the child health information services department could be contracted at the local level to send out invitations for young children (primary and preschool) on behalf of GP practices.\n\nThe evidence showed that bundling flu and pneumococcal vaccination invitations and reminders together was more cost effective than targeting pneumococcal vaccination separately. The committee agreed that sending invitations and reminders for different vaccinations together could be an effective way to increase vaccination uptake and reduce the number of reminders and vaccination appointments needed in some cases. However, they noted that this might not be clinically appropriate or effective for all combinations of vaccinations.\n\nThe qualitative evidence highlighted that some people (including some immigrants and people from Traveller, Gypsy and Roma communities) experience language barriers, and some cannot read or write in their own language. This can prevent them from accessing information about vaccines and make it harder for them to navigate the UK healthcare system to obtain vaccinations. Providing invitations and reminders in a language and format that the person, their family member or carer (as appropriate) can understand should help to increase vaccine uptake.\n\nThe qualitative evidence highlighted that some people from abroad had difficulties registering with GP practices to access NHS services. Differences in vaccination schedules between countries can also cause confusion. The committee therefore agreed that giving people information about the UK vaccination schedule could help them determine their eligibility for vaccination on the UK schedule. The committee also recognised that information alone might be insufficient and that some people might need help to understand the information and access healthcare. For example, for pregnant women and children under the age of 5 this could include involving health visitors.\n\nThe committee were also aware that the people who administer vaccinations can vary between the UK and other countries, and this can make some people hesitant about vaccination. Giving people from other countries information about who administers vaccinations in the UK, and where this takes place, can reassure people about what is standard practice and potentially remove 1\xa0of the barriers to vaccination. Some people may need additional support to access vaccinations. This could be provided by health visitors for pregnant women and children under 5.\n\nThe committee discussed how consent can be a barrier to vaccination for some adults who need support with decision-making or who may lack the mental capacity to consent. Although there was no evidence for these populations, the committee thought it was important to promote equality by ensuring that all people are given the support necessary to make informed decisions on vaccination. They noted that the NICE guideline on decision-making and mental capacity provides healthcare professionals with guidance on what to consider when discussing consent for adult vaccinations.\n\n## How the recommendations might affect practice\n\nThese recommendations are not expected to need significant additional resources. They are either easily incorporated into current practice, are required by law, or are anticipated to have lower administration costs by combining services for multiple vaccinations.\n\nReturn to recommendations\n\n# Initial invitations\n\nRecommendations 1.3.7 to 1.3.13\n\n## Why the committee made the recommendations\n\nThe evidence showed that invitations or reminders were more effective than controls (mainly usual care, the format of which varied between different studies) at increasing vaccine uptake in all age groups (apart from pregnant women, see below) that have routine vaccinations. Reminders of different types were better than usual care at increasing vaccine uptake. However, in most cases the evidence did not show whether particular types of invitations or reminders were more effective than others. Evidence that did show a difference came from single trials with small numbers of participants. Therefore, the committee agreed that a variety of methods could be used to contact people eligible for vaccination, based on the evidence and the 2019 GP contract. The committee agreed that 1 of the recipients' preferred methods of contact should be used when sending out invitations and noted that invitations given face-to-face in other appointments (opportunistic invitations) were also likely to be effective.\n\nThere was no evidence on whether invitations were effective in increasing vaccine uptake among pregnant women, but the committee agreed that the advice that applies to invitations for the general population should apply for pregnant women. Pregnant women have regular contact with their midwives, as well as other healthcare practitioners such as health visitors, general practice nurses and GPs. Therefore, they could receive in-person invitations, be signposted to vaccination services or offered vaccination during these appointments.\n\nThe committee agreed that some people, such as people living in care homes or other residential settings and those who are housebound, may be unable to attend vaccination clinics or other settings where vaccinations are available and are therefore at risk of remaining unvaccinated. The committee agreed that it is important that these people or their family members or carers (as appropriate) can arrange home visits for vaccination.\n\nThe qualitative evidence showed that healthcare providers who have built relationships with people (or their parents or carers) are likely to be trusted and able to positively influence the decision to vaccinate. However, not everyone has regular contact with a particular provider, and medical records that would be used to generate invitations may not show who a person has most contact with. The committee were also aware that in some areas, standardised invitations from a more centralised service are used, which may be difficult to personalise. Therefore, the committee agreed that using the name of a provider or service that is known to the person in the invitation and any subsequent reminders might be useful.\n\nThere was some evidence that education or information slightly increased vaccine uptake compared with usual care or another control intervention when all the studies were analysed together. However, most of the individual studies did not show that these interventions were better. The qualitative evidence highlighted barriers to vaccination that could be addressed by providing information or education, but there was little detailed evidence to suggest how these barriers could be overcome successfully. Because of the limitations above and taking into account that educational interventions are more expensive and labour intensive than giving information, the committee recommended providing information instead. The committee agreed that it was helpful to provide this information with the invitations.\n\nThe committee were aware that the invitations may differ in size depending on their format and they therefore came up with a list of points the invitation should contain to be useful. They also recommended a second list of items to include if space allowed. Although additional information would be too detailed for some types of invitations, such as text messages, it would be helpful to include this information in other types of invites if possible, such as those sent by post or email.\n\nFor items that should be included:\n\nThe qualitative evidence showed that people did not necessarily link vaccinations to the prevention of specific diseases. For example, people did not always connect HPV (human papillomavirus) vaccination to the prevention of cervical cancer.\n\nThe qualitative evidence showed that many people trusted the NHS and that people were more likely to accept recommendations to be vaccinated from healthcare practitioners that they trusted.\n\nSome people may not attend vaccination appointments if they have not had their questions answered in advance. Providing contact details should make arranging this discussion easier.\n\nThe committee agreed that letting people know about drop-in clinics can help those who find it difficult to get to appointments. They also discussed how giving people hyperlinks to book directly could make it easier to book appointments.\n\nA reminder to bring any patient-held records enables providers to keep vaccination records up to date and means that people are aware of their current vaccination status.\n\nFor items that should be included if space allows:\n\nThe qualitative evidence showed that some people underestimate the severity of certain diseases (for example, measles and shingles), and improved understanding of these issues may help increase the belief in the necessity of the vaccine and motivate people to be vaccinated.\n\nThe committee agreed with the qualitative evidence that many people are worried about vaccine side effects and think they are being understated or hidden. Clearly explaining the benefits of vaccinations compared with the risk and severity of the of the illness in comparison with side effects could help encourage people to have vaccines. Explaining individual and population benefits may help persuade people in under-vaccinated areas understand the additional benefits of vaccination to their communities. Studies show that many people did not understand the need for maternal pertussis vaccination to protect the baby during pregnancy and were worried about adverse effects during the baby's development.\n\nMany people do not finish vaccination courses and do not understand why they should have boosters, so the committee agreed that an explanation of these issues is important to help people be properly protected.\n\nStudies showed that people did not necessarily understand why HPV vaccination was offered to young people before they were likely to be sexually active. Therefore, giving information about why a vaccination is given at a particular age may help to increase uptake.\n\nThe qualitative evidence showed that people wanted information about vaccines from reliable sources but were unsure where to look. Providing links to trusted sites could help answer any outstanding questions about vaccines or the vaccination process, and interactive tools could help with the decision-making process. In addition, evidence from 1 quantitative study showed an increase in pertussis vaccine uptake in pregnant women using an interactive tool compared with non-specific advice about vaccinations in general. The committee agreed that a variety of options would be best because, in their experience, different people prefer different formats of information and not everyone has access to a smartphone to be able to use QR codes.\n\nThe qualitative evidence showed that people found attending a vaccination appointment for the first time or during the COVID‑19 pandemic could be a stressful experience and that uncertainty about the process and safety was likely to be a barrier to attendance. Explaining the process and any COVID‑19-related safety measures could remove this barrier.\n\nIt is also important that the parents or carers of babies in neonatal units are given this information. As some of these vaccinations may take place in the hospital, rather than with their GP, it is important that parents and carers are aware of how and when their baby's vaccinations will take place.\n\nThe committee were interested in whether certain methods of framing information within invitations would be more effective at encouraging vaccine uptake than others (for example, gaining immunity to disease versus avoiding catching a disease). None of the identified studies looked at this directly and so the committee wrote a recommendation for research on framing content in vaccination invitations.\n\nThe committee noted that there was a shortage of evidence for interventions to increase the uptake of routine vaccinations in pregnant women (pertussis vaccination) and older people (shingles and pneumococcal vaccinations), with this being particularly pronounced for the former group. The committee therefore made a recommendation for research to try to stimulate more research about effective interventions to increase pertussis vaccination uptake for pregnant women and another recommendation for research for older people.\n\nFinally, the committee agreed that it is especially important to try to increase routine vaccine uptake in groups, communities or populations with low uptake. They noted that there was limited evidence for groups of particular interest: Travellers, Gypsy and Roma; looked-after children and children not in mainstream education; migrants, asylum seekers and religious groups; and that the evidence was mainly qualitative in nature. Therefore, the committee included a recommendation for research to stimulate research on effective interventions to increase uptake in these and other groups of people with low routine vaccine uptake.\n\n## How the recommendations might affect practice\n\nThese recommendations are not expected to need significant additional resources. The format and content of invitations, and who these invitations are addressed from, are expected to be easily incorporated into the current approach to invitations.\n\nEnsuring that people (or their family members or carers) who live in care homes or residential settings, or who are housebound, are aware of how to access home visits for vaccination is unlikely to need substantial additional resources, because access to home visits is already in the GP contract and is common practice for people who are unable to attend clinics.\n\nEnsuring that parents or carers of babies who are in neonatal care units receive the relevant information about vaccinations, including when and how their baby's vaccinations will take place, is not expected to need additional resources, as this information is readily available and communication with those parents or carers should already be established.\n\nReturn to recommendations\n\n# Reminders and escalation of contact\n\nRecommendations 1.3.14 to 1.3.20\n\n## Why the committee made the recommendations\n\nThe committee agreed that it is important to identify people who do not respond to invitations or do not attend scheduled clinics or vaccination appointments, because these people may respond to a reminder. In addition, some people may not have up-to-date contact details, for example if they have moved house recently, so it is important to check that they have received the invitation and reminder. This may mean using another method of contact in some cases, such as a phone call or text message.\n\nFor pregnant women, the Green book recommends vaccination between 16\xa0and 32\xa0weeks of pregnancy. Therefore, reminders can be provided at antenatal appointments after the 20‑week scan or when they have contact with a GP or other healthcare provider, such as health visitor.\n\nFor babies and young children whose parents or carers (as appropriate) have not responded to the reminder, the committee agreed that the follow-up needs to occur rapidly and needs a conversation. Delays may cause some parents to think it was acceptable to defer vaccination. This could lead to them delaying subsequent vaccinations, which would expose the child to a higher risk of getting the diseases targeted by the vaccines. The time limits recommended were based on committee consensus aimed at preventing delays. The limits were shortest for babies because they have vaccinations due at 2, 3 and 4\xa0months old and it is important that these are carried out in a timely manner as discussed above. Reminders for older people are less time sensitive because they can be vaccinated for shingles and pneumonia over a period of several years.\n\nThe committee acknowledged that invitations and reminders (or call-recall) activity is limited for certain vaccinations in the GP contract. However, they agreed that it was important to highlight the approaches and processes that were most effective at increasing vaccine uptake to promote best practice, based on the evidence. They also noted that the GP contract does not prevent people going beyond these requirements, and groups who are not covered by call-recall can be identified opportunistically.\n\nThere was qualitative evidence to show that if a person does not respond after being sent a reminder, an escalating system of contact can be effective in increasing uptake. The committee agreed that this approach matched their experience, and it was also supported by quantitative evidence from a study looking at an escalating reminders intervention that showed an increase in the number of people being vaccinated, with the intervention compared with usual care.\n\nThe committee agreed that initial vaccine invitations and reminders should use methods – such as a text or email – that are not labour intensive or costly. For people who continue not to respond, escalating reminders may initially involve a phone call from a GP receptionist, then from the practice nurse and finally from the GP, until the person is vaccinated or declines vaccination. However, this approach could be resource intensive and the evidence did not show that using escalating reminders was more effective than other forms of reminders. Despite this, the committee agreed that these more intensive methods of contact represented an appropriate use of NHS resources because the group of people needing to be contacted in this manner is likely to be relatively small and to consist of people in groups or communities with lower vaccination rates.\n\nAn economic analysis of the cost effectiveness of direct conversations with parents and carers of babies and toddlers who are behind on their vaccinations showed that the average cost per additional person vaccinated when using a direct contact intervention was estimated to be lower than the fee for the service that GPs receive for administering vaccines. On this basis, the committee agreed that the direct contact intervention would be a cost-effective use of resources. The committee also noted the very serious negative consequences of the diseases vaccinated against in babies and toddlers (and the high costs of treating those conditions) and were therefore confident that this would be an acceptable use of resources.\n\nThe committee agreed that when contact is made with a person who has not responded to an invitation or reminder to be vaccinated, it is important to try to understand the reasons behind the lack of response or delay in vaccination because this could enable any barriers to vaccination to be addressed. For example, if the person is concerned about vaccine safety and side effects, a conversation about this at the time of contact or a consultation with a nurse or GP may be able to encourage them to be vaccinated. In other cases, if access is a barrier to vaccination, then telling the person about out-of-hours clinics and other settings for vaccination may enable them or their children to be vaccinated.\n\nThe committee agreed that in some cases, a multidisciplinary approach could be helpful in overcoming barriers to vaccination. People such as social workers and health visitors may already be in direct contact with a person who has not responded to vaccination invitations and reminders and may therefore have more opportunities to discuss immunisation with them. Health visitors have multiple mandated contacts with the families of babies and young children under 2\xa0years as part of the Healthy Child Programme (2021). They could use these as opportunities to discuss, educate, signpost and support families to access immunisations if they were made aware of unvaccinated children. This could also include implementing local interventions such as 'was not brought' protocols if there are frequent missed appointments and a lack of response to invitations. This information could be supplied by child health information services directly to the health visitors, but there might need to be a local agreement for health visitors to take on this work.\n\nEvidence showed that providing vaccinations at home increased uptake compared with usual care. However, the committee were aware that home visits would be costly so they should be reserved for people who are unable to travel to vaccination clinics, appointments or other settings where vaccinations are available. Using these restrictions should ensure that the proportion of the population who would need home visits would be small because they would be offered only when all other routes to vaccination have been exhausted. This recommendation should help ensure that people who are housebound, for example, are vaccinated, and also improve access for other underserved populations, thereby reducing inequalities.\n\nThe committee agreed that it was important to record when people declined to be vaccinated so they were not offered vaccinations repeatedly, because this can be annoying and a waste of resources. However, they recognised that people can change their minds, so they wanted to make them aware that the offer of vaccination remains open if they wanted to take it up in the future.\n\n## How the recommendations might affect practice\n\nDirect conversations with parents and carers of babies and toddlers who are behind with their vaccinations are likely to have additional costs for staff time.\n\nIdentifying and providing additional reminders or offers of pertussis vaccination to pregnant women not already immunised is not expected to need additional resources, because these reminders can be given at existing antenatal appointments, and midwives already have a patient record in which vaccination status can be checked.\n\nEscalation of contact is likely to need additional resources because it is generally associated with more intensive tasks that need more staff time.\n\nHome vaccination visits would be associated with considerable additional resource use but the proportion of the population who would need them would be small because home visits would be offered only when all other routes to vaccination have been exhausted.\n\nReturn to recommendations\n\n# People who are not registered with a GP practice\n\nRecommendations 1.3.21 to 1.3.23\n\n## Why the committee made the recommendations\n\nThe committee were aware that some people such as some Travellers, Gypsy and Roma, homeless people, immigrants and asylum seekers are not registered with a GP practice and so will not receive vaccination invitations or reminders unless a different approach is taken to identify them. This is also reflected in the qualitative evidence, which showed that some Travellers, Gypsy and Roma and immigrants have difficulty registering with a GP practice and accessing healthcare from the NHS. The committee agreed that unless these people are made aware that they are eligible for NHS vaccinations and given help to access them, they are unlikely to be vaccinated. The committee agreed that local authorities, health visitors or community involvement could help to ensure that these people are not overlooked for vaccinations.\n\nChildren who are not registered with a GP practice may still be known to child health information services (CHIS). In these cases, where they are commissioned to, CHIS can send invitations to parents or supply this information to the service commissioner directly. CHIS can also include a message to encourage the parent or carer (as appropriate) to register the child with a GP practice. However, it is likely that some children will not be registered with either service and will need to be identified using alternative approaches (see recommendation 1.3.21).\n\n## How the recommendations might affect practice\n\nInvolving local authorities, health visitors or the community or voluntary sector in identifying people not registered with a GP practice and ensuring they have opportunities to access vaccination may have an impact on resource use, but the committee considered this to be an appropriate use of NHS resources. Outbreaks of vaccine-preventable diseases are very costly and have significant health consequences for the population, so it is worth the additional effort of identifying and vaccinating people not registered with a GP practice. Identifying people not registered with a GP practice is not only necessary for vaccination but for various healthcare needs, so any resource impact would be shared across these areas and have a broader benefit.\n\nRaising awareness about eligibility and how to access vaccination for people not registered with a GP practice is not expected to need additional resources. It is current practice to provide leaflets to new migrants about what vaccines are on the UK immunisation schedule, and where and how to access these. This information already exists and would be simple to pass on to people not registered with a GP practice once they have been identified.\n\nEnsuring that invitations are sent to parents or carers of children not registered with a GP practice is not expected to need significant additional resources because CHIS already have a register of children, whether they are registered with a GP practice or not, and this information can be passed on to those sending out invitations for vaccination.\n\nReturn to recommendations\n\n# Vaccinations for school-aged children and young people\n\nRecommendations 1.3.24 to 1.3.39\n\n## Why the committee made the recommendations\n\nThe committee agreed, based on their experience, that vaccinating school-aged children and young people at school was the most efficient and convenient way to vaccinate this population. But they recognised that this may not be possible in all cases because not all school-aged children and young people attend school.\n\nThe committee agreed, based on their experience, that although vaccination programmes for school-aged children and young people are unique enough to need a separate set of recommendations, the main steps of the process are the same as for the other age groups and life stages. They all involve an initial invitation for vaccination, a reminder and then an escalation of contact for people who do not respond. However, the invitations are sent by schools on behalf of the vaccination providers. The qualitative evidence highlighted logistical barriers that providers face with running vaccination sessions in schools and that these could be overcome with support from the schools involved. However, they noted that schools may not always prioritise vaccinations and that it is very important that providers have a good relationship with the school to facilitate sending invitations to eligible pupils and running the school-aged vaccination sessions.\n\nInvitations, information and consent forms are often provided in a digital format. Making non-digital options available will help parents, children and young people who are unable to access digital content to make informed decisions and will help reduce inequalities.\n\nThe evidence for young people aged 11\xa0to 18\xa0years eligible for HPV vaccination consistently highlighted that young people want to be involved in discussions about vaccination. The committee therefore agreed that information provided about the vaccinations needs to be aimed at both the parents or carers (as appropriate) and the young people themselves. The general contents of the information would be the same as for vaccinations for young children and adults but tailored to the relevant vaccinations for this age group. Although not discussed in the evidence, the committee decided that it was important for the information to also cover Gillick competence so that both parents and young people are fully aware of all the options for vaccine consent. They also agreed that sending the invitation for vaccination to the young people and secondary school-aged children as well as to the parents or carers would help them be involved in the process.\n\nThe committee agreed that school-based education is a key method of ensuring that children and young people understand the importance of vaccinations and can ask questions about their concerns. This was mentioned in the qualitative evidence as 1\xa0of the acceptable methods of giving young people information about vaccinations and is already standard practice in some schools. They agreed that this education should be age appropriate and may involve school nurses, depending on commissioned service specifications.\n\nThe committee agreed that 1 of the main barriers to school vaccinations is the low rate of return of consent forms. This means that school immunisation teams are unaware of whether parents or carers consent to their child being vaccinated and they have to spend time chasing up people who do not respond. One study indicated that a programme that incentivises the return of consent forms could increase the number of forms returned, and that most of these consent forms were about vaccination acceptance. The committee agreed that in their experience, for school-aged vaccinations, a positive consent form would lead to vaccination and therefore that this intervention was likely to increase the number of children and young people who are vaccinated. In addition, although some incentives, such as prize draws, will have an associated cost, this is expected to be offset by a reduction in the time and costs of nurses having to contact parents and carers of children and young people who have not returned their consent form.\n\nThe committee discussed the acceptability of incentivising other parts of the vaccination process. However, they decided that incentivising consent form return rather than vaccination is likely to be more acceptable, because it is encouraging decision-making rather than the vaccination itself. There was some concern over the ethics and effectiveness of the financial incentive used in the study because in some communities, such as faith schools, a money-based incentive could be perceived as gambling and be inappropriate and ineffective. As a result, the committee did not specify the exact type of incentive in the recommendation so that local providers can make their own decisions on what is most appropriate for their local community.\n\nThe committee agreed that a reminder should be sent out in cases where the consent form has not been returned. However, even with invitations and standard reminders, there will still be some young people who do not return a consent form and a more direct method of contact (a phone call) can be made before vaccination day or even on vaccination day if there is time. The committee discussed other ways to encourage families to return consent forms and thought that contact from other health and social care providers who already know the family, such as school nurses, could be helpful.\n\nIn addition, the committee noted that catch-up sessions would ensure that children and young people who are not up to date with their vaccinations have other opportunities to be vaccinated. These sessions are currently limited to children and young people who have missed school-aged vaccinations, but they could be expanded to provide opportunities to catch up on earlier preschool vaccinations. Where children or young people are unable to attend the school-aged catch-up sessions, for example because of sickness, exclusion or extended leave, alternative provisions are necessary to ensure that they can be offered their overdue vaccinations. This could involve signposting to GPs or other places where the vaccinations are available. There was a shortage of evidence for catch-up campaigns, with only a single study identified that provided results in favour of school-based catch-up sessions over referring pupils to GP practices in the UK. The committee took this evidence into account and used their clinical experience of the importance of catch-up sessions to make a recommendation on this topic. However, they also included a recommendation for research on school-based versus GP-based catch-up campaigns to increase the evidence base and to examine the acceptability of catch-up sessions in these settings. To help with identifying these children and young people, child health information services can provide vaccination histories to providers.\n\nThe committee agreed that it was important to highlight that young people under\xa016 may be able to consent to their own vaccinations if they are assessed to have the competence and understanding to appreciate what it involves. These young people are said to be Gillick competent.\n\nThe assessment of Gillick competence, and when it was appropriate for young people to be assessed for competence and allowed to consent to vaccination for themselves, was a key discussion point. The committee decided that if the consent form had not been returned, and it was not possible to contact parents or carers, young people should be assessed for Gillick competence. They also agreed that young people whose parents or carers had refused consent should be given the opportunity to be assessed for competence. They thought that this should be done at the earliest opportunity, which could include on the day of the vaccination session if possible. However, they recognised that at times this assessment might be difficult to carry out on vaccination day itself because of the potentially large numbers of young people involved. In these situations, there may be more capacity to carry out these assessments before catch-up vaccination sessions. Committee discussions also highlighted the need for school immunisation teams to feel supported if they are assessing for Gillick competence; in particular when young peoples' wishes differ from that of their parents or carers. Therefore, they thought it important for providers to have policies to support local teams with these decisions.\n\nThe committee made several recommendations for research that were linked to school-aged vaccinations or that came out of discussions relating to school-aged vaccinations. Although the committee made a recommendation for incentivising consent form return for school-aged vaccinations, this was based on evidence for a financial incentive for consent form return. It was unclear whether non-financial incentives would also be effective in this setting and what levels of financial or non-financial incentives would be effective. The committee wrote a recommendation for research on incentives for school-aged vaccinations. They were also interested in whether incentives would be effective and acceptable for other age groups or life stages and so they wrote a similar recommendation for research on incentives aimed at individuals, family members and carers.\n\nAnother potential method of increasing vaccine uptake in school-aged children and young people and the wider populations is using mandates. The evidence looked at mandating vaccinations or education to allow access to schools in the US. However, very few studies were identified that looked at the effectiveness of mandation, and the qualitative evidence about acceptability was mixed. The committee therefore made a recommendation for research on quasi-mandation of vaccinations.\n\nThere was limited quantitative and qualitative evidence for HPV vaccination in boys because routine HPV vaccination for boys has only recently been introduced in many countries, including the UK and US. The committee agreed that it is important to understand whether similar barriers and facilitators apply to HPV vaccination for boys as for girls and whether the same interventions are effective for them. They made a recommendation for research on HPV vaccination for boys to reflect this.\n\nFinally, the committee discussed whether using the World Health Organization 'Tailoring Immunisation Programmes' approach would be an effective way of designing interventions to increase vaccine uptake in a UK context. Some qualitative evidence was identified that used this approach, but it was unclear if it had been used to help design any of the interventions included in this guideline. The committee made a recommendation for research on Tailoring Immunisation Programmes.\n\nThe committee were aware that not all children and young people attend schools where vaccinations are available. These include those who do not attend school at all, such as those who are home educated, chronically unwell, have local authority tutoring, and those in faith or independent schools that do not routinely hold vaccination sessions, or those in young offender institutions. These children and young people could be at risk of not being vaccinated but it was unclear to the committee how they could be identified effectively using the current system. They therefore agreed that it would be best for commissioners of the vaccination services for school-aged children to ensure that systems are put in place to identify and vaccinate these people.\n\n## How the recommendations might affect practice\n\nThese strategies are already current practice in most schools and are unlikely to have a resource impact. Offering one-off vaccination days to vaccinate children at school is likely to be less resource intensive than contacting and booking appointments for children individually in other settings.\n\nInvitations and reminders for routinely offered school-aged vaccination programmes are not expected to have a substantial resource impact because the recommended activities are current practice in most schools that provide mass vaccination days. Providing a specification for the approach to these reminders is unlikely to have resource implications.\n\nEnsuring that school-based vaccination education is accessible to children and young people is not expected to have a substantial resource impact, because this information is readily available and could simply be distributed to children and young people during school hours.\n\nIf more providers offer an incentive for returning consent forms, this is likely to increase the number of forms returned, which may lead to an increase in vaccine uptake. Although some incentives, such as prize draws, will have an associated cost, this is expected to be offset by a reduction in the time and costs of nurses having to contact parents and carers of children and young people who have not returned their consent form. The NHS already uses incentives (such as prize draws) to obtain feedback for certain initiatives, so this is not a completely new approach. These incentives do not necessarily have to be expensive or complicated, and lower or zero cost incentives such as school-based perks (for example, being able to go to the front of the lunch queue) could be used instead to contain costs.\n\nInvolving other health and social care providers that are in contact with the family to help gain consent where contact cannot be made through the school is not expected to need significant additional resources, because this is likely to be for a smaller group, and those people should already be in contact with the family.\n\nPutting policies in place for assessing Gillick competence may increase the vaccination team's confidence in performing the assessment, thereby increasing the number of young people who are assessed for competence and allowed to consent to their own vaccination. This will help to reduce 1 of the barriers to vaccination and potentially increase vaccine uptake in this group.\n\nChild health information services already hold vaccination records of children and young people, so identifying those who are not up to date with preschool vaccinations and informing the school nursing teams is not expected to need significant additional resources.\n\nThis is not expected to need significant additional resources because local authorities already have a duty to know which children and young people do not attend schools where vaccinations are provided, and they have contact details for their parents or carers. Local authorities could therefore contact these people on behalf of vaccination providers to arrange vaccination in a suitable setting.\n\nReturn to recommendations", 'Context': 'Vaccinations provide personal and population-level protection against many diseases. High vaccine uptake rates create population-level protection, leading to herd immunity. This protects both immunised and non-immunised people. Examples of non-immunised people include those who are highly susceptible to disease such as newborn babies and older people, and people who cannot be vaccinated for medical reasons or for whom vaccines are contraindicated. By contrast, vaccines for some diseases such as shingles only protect those who receive them and provide minimal indirect protection to other people.\n\nThe UK routine vaccination schedule covers key vaccinations for different stages in life including childhood, adolescence, pregnancy and old age (currently 65\xa0years and older). Although vaccination coverage in general in the UK is relatively high, uptake varies between vaccines, areas and the age groups they are targeted at. For example, 5-in-1 coverage of children measured at 5 years was 95.2% in 2019/2020, whereas 83.9% of Year 9 girls completed the 2‑dose HPV (human papillomavirus) vaccination course in 2018/19. By contrast, from April 2018 to March 2019, shingles vaccine uptake for the 70‑year‑old routine cohort was only 31.9%, pneumococcal vaccine uptake for all people aged 65 and over was 69.2% and pertussis vaccine coverage in pregnant women was 68.8%.\n\nVaccination coverage needs to be actively maintained, and ideally increased, in the face of increasing vaccine scepticism and misinformation. In addition, certain population groups (such as Travellers, Gypsy and Roma, refugees and asylum seekers) have lower levels of vaccination than the general public. Additional or different actions may be needed to increase their vaccination rates.\n\nReasons for low uptake may include poor access to healthcare services; inaccurate claims about safety and effectiveness, which can lead to increased concerns and a reduction in the perceived need for vaccines; and insufficient capacity in the healthcare system to provide vaccinations. In addition, problems with the recording of vaccination status and poor identification of people who are eligible to be vaccinated may have contributed to low uptake.'}	https://www.nice.org.uk/guidance/ng218	This guideline aims to increase the uptake of all vaccines provided on the NHS routine UK immunisation schedule by everyone who is eligible. It supports the aims of the NHS Long Term Plan, which includes actions to improve immunisation coverage by GPs (including the changes to vaccinations and immunisations detailed in the 2021/2022 and 2022/23 GP contracts) and support a narrowing of health inequalities.
8f4ed2267aa120ff7c7b138dc97ae6ce8b322ce0	nice	Avelumab for maintenance treatment of locally advanced or metastatic urothelial cancer after platinum-based chemotherapy	Avelumab for maintenance treatment of locally advanced or metastatic urothelial cancer after platinum-based chemotherapy Evidence-based recommendations on avelumab for maintenance treatment of locally advanced or metastatic urothelial cancer after platinum-based chemotherapy in adults. # Recommendations Avelumab is recommended as an option for maintenance treatment of locally advanced or metastatic urothelial cancer that has not progressed after platinum-based chemotherapy in adults, only if: avelumab is stopped at 5 years of uninterrupted treatment or earlier if the disease progresses and the company provides avelumab according to the commercial arrangement. This recommendation is not intended to affect treatment with avelumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations There are no maintenance treatments routinely available for locally advanced or metastatic urothelial cancer that has responded to platinum-based chemotherapy. Clinical trial evidence shows that if people take avelumab it takes longer for their cancer to get worse, and they live longer than if they have best supportive care. Avelumab meets NICE's criteria to be considered a life-extending treatment at the end of life. This is because although there are different ways to estimate life expectancy, overall, it is likely that most people who would have been eligible for treatment with avelumab would live on average less than 24 months. The most likely cost-effectiveness estimates are within what NICE usually considers an acceptable use of NHS resources for end of life treatments. So avelumab is recommended, if it is stopped at 5 years or earlier if the disease progreses.# Information about avelumab # Marketing authorisation indication Avelumab (Bavencio, Merck Serono) is indicated 'as monotherapy for the first-line maintenance treatment of adult patients with locally advanced or metastatic urothelial cancer who are progression-free following platinum-based chemotherapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for avelumab. # Price The list price is £768.00 per 200 mg/10 ml concentrate for solution for infusion vials (excluding VAT; BNF online, accessed February 2022). The company has a commercial arrangement. This makes avelumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Merck Serono, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Metastatic urothelial cancer decreases quality of life Urothelial cancer causes a number of symptoms, including haematuria (blood in the urine) and increased frequency, urgency and pain associated with urination. The committee was aware that many people with locally advanced or metastatic urothelial cancer are older and may have comorbidities, which can affect treatment decisions. The patient experts explained that chemotherapy is associated with unpleasant side effects such as fatigue, nausea and vomiting and means people are at greater risk of infection. The committee recognised that locally advanced or metastatic urothelial cancer has a substantial effect on quality of life. ## There is unmet need for effective treatment options The main aim of treatment for locally advanced or metastatic urothelial cancer is to prevent disease progression, maintain health-related quality of life, provide relief from cancer symptoms and extend life. The patient experts explained that the side effects of chemotherapy can have a major negative effect on quality of life and regular hospital visits for treatment disrupts usual activities and affects their ability to work. The committee heard how people whose disease remains stable or responds to first-line chemotherapy must wait for disease progression before having further treatment. The clinical experts noted that maintenance treatments can prevent or delay the need for second-line treatment and there is a population who would benefit from maintenance therapy at this point in the treatment pathway. The committee concluded that there is an unmet need for effective treatment options for people with locally advanced or metastatic urothelial cancer that has not progressed after platinum-based chemotherapy. # Clinical evidence ## The JAVELIN Bladder 100 trial is generalisable to clinical practice in the UK The clinical effectiveness evidence for avelumab came from 1 phase 3, randomised, open-label, parallel, 2‑arm study. This included 700 adults with locally advanced or metastatic urothelial cancer that did not get worse during, or 4 to 10 weeks after, first-line platinum-based chemotherapy. People had either avelumab 10 mg/kg once every 2 weeks (n=350) or best supportive care alone (n=350). The study population included people who had a cisplatin- or carboplatin-based chemotherapy with gemcitabine. This aligns with current NICE recommendations on a platinum-based chemotherapy regimen. The committee agreed this reflected current UK clinical practice. It highlighted that a weight-based dose for avelumab was used in JAVELIN Bladder 100, whereas the licence specifies a fixed dose. It accepted that the fixed licensed dose would have similar clinical outcomes to the weight-based dose and so it was not necessary to adjust for differential efficacy. The company presented interim data from a cut-off date of October 2019. It considered this to be the final analyses because the trial had achieved its primary objectives. The committee concluded that JAVELIN Bladder 100 is generalisable to clinical practice in the UK. ## Avelumab and best supportive care improves overall survival compared with best supportive care alone The evidence from JAVELIN Bladder 100 had 2 co-primary populations: everyone in the trial and people with PD‑L1‑positive tumours. The committee noted there was a statistically significant improvement in overall survival for the whole trial population who had avelumab with best supportive care (median 21.4 months; 95% confidence interval 18.9 to 26.1 months). There was a 31% reduction in the risk of death compared with people who had best supportive care alone (median 14.3 months; 95% CI 12.9 to 17.9 months; hazard ratio 0.69; 95% CI 0.556 to 0.863; p=0.001). There was also a statistically significant improvement in overall survival for people with PD‑L1 positive tumours. This group had a 44% reduction in the risk of death (median not reached; 95% CI 20.3 months to not reached) compared with people who had best supportive care alone (median 17.1 months; 95% CI 13.5 to 23.7 months; HR 0.56; 95% CI 0.404 to 0.787, p<0.001). There was a 15% reduction in risk of death for people with PD‑L1 negative tumours. But these results were not statistically significant when comparing people having avelumab and best supportive care (median 18.8 months; 95% CI 13.3 to 22.5 months) with those having best supportive care alone (median 13.7 months; 95% CI 10.8 to 17.8 months; HR 0.85; 95% CI 0.615 to 1.181, p value not reported). The committee concluded avelumab and best supportive care improves overall survival compared with best supportive care alone but may not do so in people with PD‑L1 negative tumours. ## Avelumab and best supportive care improves progression-free survival compared with best supportive care alone There was a statistically significant improvement in progression-free survival (assessed by blinded independent central review) for all people having avelumab compared with best supportive care (median 3.7 months; 95% CI 3.5 to 5.5 months). The risk of progression or death reduced by 38% compared with people who had best supportive care alone (median 2.0 months; 95% CI 1.9 to 2.7 months; HR 0.62; 95% CI 0.519 to 0.751, p<0.0001). There was a statistically significant improvement in progression-free survival for the people with PD‑L1‑positive tumours. The risk of death reduced by 44% for people having avelumab and best supportive care (median 5.7 months; 95% CI 3.7 to 7.4 months) compared with people who had best supportive care alone (median 2.1 months; 95% CI 1.9 to 3.5 months; HR 0.56; 95% CI 0.431 to 0.728, p<0.0001). There was a 37% reduction in risk of death for people with PD‑L1 negative tumours having avelumab and best supportive care (median 3.0 months; 95% CI 2.0 to 3.7 months) compared with people who had best supportive care alone (median 1.9 months; 95% CI 1.9 to 2.0 months; HR 0.63; 95% CI 0.476 to 0.845, p value not reported). The committee agreed the results showed that avelumab and best supportive care improves progression-free survival compared with best supportive care alone. # Assumptions in the economic model ## The generalised gamma and log-normal models are both acceptable for extrapolating overall survival In the economic model, the company used parametric distributions to extrapolate data on overall and progression-free survival from JAVELIN Bladder 100. In its original submission the company stated that overall survival estimates were expected to be between 20% and 30% at 5 years and between 10% and 15% at 10 years for people having avelumab. For watchful waiting (people having best supportive care alone) overall survival was expected to be between 5% and 15%, and 10‑year overall survival between 2% and 7%. The company originally selected the generalised gamma curve to extrapolate both avelumab and watchful waiting overall survival in its base case because the 10‑year survival predictions were in line with clinical estimates. It stated that the generalised gamma was the only model that predicted 10‑year overall survival estimates in the region of clinical estimates for avelumab (10% to 14%). It noted the 5‑year (15%), and 10‑year (6.48%) generalised gamma estimates for watchful waiting were optimistic. But it noted the estimates for avelumab may be considered pessimistic, based on clinical expectations. It preferred to use the same parametric model for both treatment groups. The ERG considered this may overestimate overall survival for both avelumab and watchful waiting, because it predicted 5‑year and 10‑year survival estimates that were close to the upper end of clinical expectations. The ERG preferred the log-normal curve for watchful waiting because the 5‑year (10.71%) and 10‑year (2.90%) predictions were closer to the mid-point of clinical expectations and because it had the best statistical fit. In response to technical engagement, the company accepted that both the generalised gamma and log-normal curves were helpful for decision making. But it revised its base case to use the log-normal model, aligned with the ERG's preferred base case. Both the company and ERG stated that there was little to distinguish between each model. The committee agreed that there is little to distinguish between the extrapolations in terms of statistical fit. But changing the model reduced the mean life years for people who had not had avelumab from 35.4 months (generalised gamma) to 27.82 months (log-normal). At the second committee meeting, the company confirmed it would prefer the log-normal extrapolation model. However, the committee considered that it was reasonable to use the generalised gamma. It could be plausible that survival estimates for watchful waiting are at the upper end of clinical ranges. For this reason, the committee concluded that both models should be considered plausible for extrapolating overall survival data. ## Progression should be defined by blinded independent central review In the company's model, progression-free survival curves were fitted for 2 alternative definitions of progression: blinded independent central review and investigator-assessed progression. The company's original base-case analysis considered blinded independent central review defined progression because it was expected to give the most unbiased assessment of disease progression. The ERG noted that treatment decisions in clinical practice are more likely to be based on investigator-assessed progression. In response to technical engagement, the company provided feedback from 8 UK‑based oncologists who supported the ERG's preference for using investigator-assessed progression. The committee noted that in open-label trials, investigator-assessed progression has the potential for biased decisions. After an initial investigator assessment, all subsequent assessments of progression in JAVELIN Bladder 100 were based on blinded independent central review. This is consistent with greater internal validity as noted in NICE's guide to the methods of technology appraisal. The committee recalled that blinded independent central review defined progression was the preferred approach in many published technology appraisals. For this reason, it concluded that progression should be defined by blinded independent central review. ## Time to stopping treatment should reflect the trial (before the appeal) In its original economic model, the company assumed that 95% of people will stop treatment with avelumab at 2 years whether or not their disease has progressed, and all remaining people would stop treatment with avelumab at 5 years. The company also assumed that people would continue to benefit from avelumab for the remainder of their lifetime, even after stopping treatment. The committee noted that this did not reflect JAVELIN Bladder 100 and the summary of product characteristics does not include a stopping rule. Data from the trial showed that substantially more people were having treatment at 2 years than the 5% assumed in the company's model. But the exact figures are considered confidential by the company, so cannot be reported. The model captured the benefits these people had from continuing avelumab treatment, but the costs were not included. The clinical experts explained that stopping treatment after 2 years might be reasonable for some people for reasons such as fatigue from fortnightly hospital visits or the adverse effects of the treatment. The committee agreed, but it was not clear whether this would apply to people with urothelial cancer in general, or the population considered here of people whose disease has responded to chemotherapy and is continuing to respond to maintenance treatment. The clinical lead for the Cancer Drugs Fund explained that the company's original assumptions about stopping avelumab treatment could not be implemented in the NHS. But he noted that, for other immunotherapies, a rule to stop treatment at 2 years has been implemented in the NHS. The clinical and patient experts stated that they would accept a similar stopping rule if this would enable access to avelumab, if the alternative was for avelumab to be not recommended in the NHS. This was confirmed by 2 patient organisations in response to consultation. The committee was aware that the company had not provided a scenario analysis when all patients stopped having treatment at 2 years. It was concerned that it would be difficult for patients to accept that they would no longer be able to have treatment after 2 years if they were free from disease, and they may fear losing treatment benefit. Also, people whose disease had not progressed before needing to stop avelumab would not be able to have another immunotherapy in the NHS. The committee noted that other NICE technology appraisals of avelumab have preferred no stopping rules. The committee would prefer the model to base time to stopping treatment on the trial data. But, it was also concerned that because people cannot have further immunotherapy, treatment in the NHS may continue beyond radiographical progression. One clinical expert noted that they would prefer to continue avelumab until symptomatic progression. The committee therefore asked the company to provide the progression-free survival and time to stopping treatment curves presented on the same graph to assess the relationship between the 2 in the trial. After consultation, the company confirmed that their initial assumption around treatment duration was not intended to be a stopping rule but to reflect the likely treatment duration of people in clinical practice. It proposed a 2‑year stopping rule based on expectations that in clinical practice people will stop treatment by then. It noted this was in line with immunotherapies for other indications. The committee recalled that there were many people in JAVELIN Bladder 100 whose disease had not progressed at 2 years, but a slightly lower number were still having treatment after 2 years. It acknowledged that some of these people may stop having avelumab for other reasons than disease progression. The committee was aware of other examples when decisions about including or excluding stopping rules had been applied for immunotherapies after platinum-based chemotherapy in urothelial cancer. In these technology appraisals, a stopping rule was included in the trial, or the committee was able to generalise these results to other treatments in the same class used in the same populations and settings. It considered that there was no similar evidence here to support a stopping rule, since JAVELIN Bladder 100 did not include one and the setting and population in this technology appraisal was different to others in this disease area. The committee concluded that time to stopping treatment should reflect the trial evidence and a stopping rule should not be included in the model. The committee considered this issue further after the appeal (see section 3.18). ## Waning of treatment effect should not be included in the model (before the appeal) Related to the assumptions about stopping treatment, the company originally assumed a lifetime treatment benefit for avelumab in its base case, even after stopping treatment. The company and ERG provided several scenario analyses in which the treatment effect for avelumab was capped at different time points. The clinical experts explained that for immunotherapies, it is common for the treatment benefit to continue when treatment stops. But the committee agreed that it was implausible that the treatment effect for avelumab would continue for a person's lifetime after stopping treatment. It noted that in other technology appraisals of immunotherapies, a treatment cap between 2 and 5 years had been applied when a stopping rule had been applied. After consultation, the company proposed that waning of treatment benefit should be applied at 5 years. Any treatment benefit would stop 3 years after stopping treatment, aligned with its proposed 2‑year stopping rule. The ERG noted that the true duration of benefit after stopping treatment is unclear. It provided several scenario analyses varying the duration of continued benefit. These varied from no benefit after stopping treatment, to 5 years after stopping treatment, which was included in other technology appraisals of immunotherapies for metastatic urothelial cancer. It also provided a gradual waning of treatment effect in line with the company's original scenario analysis. The committee noted that there is substantial uncertainty about the most appropriate treatment benefit capping assumptions. It concluded that since a stopping rule had not been accepted, a waning of treatment effect should not be included in the model. ## The SACT dataset does not reflect the maintenance setting in which avelumab would be used in clinical practice The company model included the costs of subsequent treatments after progression based on JAVELIN Bladder 100, adjusted to reflect the treatments available in UK clinical practice. The ERG noted that the proportion of people having subsequent treatments in the trial would likely to be higher than that seen in clinical practice. People in the trial had more stable disease and so were considered fitter than those in clinical practice and were monitored more closely. So, they were more likely to have subsequent treatment after progression. The company provided estimates from the systematic anti-cancer therapy (SACT) dataset. This showed that 41.9% of people in UK clinical practice have a second-line therapy after first-line platinum-based chemotherapy. This was lower than the proportion in JAVELIN Bladder 100. The clinical experts explained that only people with stable disease would have been eligible to be included in JAVELIN Bladder 100. This was because people whose disease progressed during, or very shortly after, first-line chemotherapy were not eligible. As a result, the number having subsequent treatments in JAVELIN Bladder 100 would have only included people who had stable disease (and therefore may be considered fitter and more likely to have subsequent treatment). This was not directly comparable with those in the SACT dataset, which includes people whose disease has progressed during or immediately after chemotherapy. The SACT dataset was collected before NICE recommendations that increased the treatment options in metastatic urothelial cancer to include immunotherapies. Also, the hazard ratios and incremental cost-effectiveness ratios (ICERs) that the cost-effectiveness results were based on came directly from those in JAVELIN Bladder 100. The committee agreed that the data used to inform the proportion of people having subsequent treatment in the model should come from JAVELIN Bladder 100. It concluded that the SACT dataset does not reflect the maintenance setting in which avelumab would be used in clinical practice. ## The costs of subsequent treatments in the model should reflect the treatments used in JAVELIN Bladder 100 Some people had immunotherapies after disease progression on avelumab in JAVELIN Bladder 100. In the economic model, the company removed the cost of these immunotherapy treatments to reflect NHS clinical practice. The clinical experts confirmed that in clinical practice people would not have a second-line immunotherapy after disease progression on avelumab. The committee recognised that in the NHS people would not have further immunotherapy after avelumab. However, it considered that people may have had some benefit from immunotherapy treatment after avelumab, but that the model had not been adjusted to account for this. It was aware of discussions from NICE's technology appraisal guidance on pembrolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy. These concluded that it was inconsistent to include the potential benefits of subsequent immunotherapy treatment without the costs, so both should either be included or excluded. So, the committee concluded that the costs of immunotherapies used after disease progression on avelumab should be included in the model. ## It is not appropriate to pool health-state utilities across treatment arms The company submission stated that overall health status and health-related quality of life were similar between both arms of JAVELIN Bladder 100. So the company used pooled utility values to inform the model. However, it also provided health-state utility data for each arm of the study, split by before progression and after progression states. The ERG noted that utilities before progression were slightly higher in the avelumab with best supportive care arm compared with best supportive care alone. But values after progression were lower for avelumab with best supportive care compared with best supportive care alone. The committee noted that people who had best supportive care in JAVELIN Bladder 100 would also have immunotherapies or chemotherapy if their disease progressed. The committee considered that this might explain the difference in utility values for people who had avelumab with best supportive care or best supportive care alone. The clinical experts explained that lower utility after progression on avelumab was clinically plausible because people would be having less effective chemotherapy treatment, and this may affect their health-related quality of life. The clinical experts stated that it would be reasonable to include health-state utilities from each arm of the trial. After consultation, the company maintained its preference for using pooled health-state utilities. It noted that pooled values have previously been accepted in NICE's technology appraisal guidance on pembrolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy. However, the committee noted that in that appraisal the same treatments were available to people in both study groups whose disease progressed. The company also suggested that the difference in utilities before and after progression from JAVELIN Bladder 100 might be explained by fewer observations of people after progression in the avelumab arm of the trial. But the committee considered the data was still robust enough to allow conclusions to be drawn. The ERG noted that it was reasonable to consider the effect of treatment-specific utilities on cost-effectiveness estimates, if any uncertainty might be introduced by combining health-state utilities across treatment arms. It provided a scenario analyses exploring this uncertainty. Using pooled data for the health-state utilities slightly increased the ICER for avelumab. The committee considered the views of the company and clinical experts and the ERG. It concluded that, on balance, it was not appropriate to pool health-state utilities across treatment arms. # End of life (before the appeal) ## Avelumab extends life by at least 3 months The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The committee agreed based on the evidence that was available and the views of the clinical experts that the overall survival gain with avelumab would likely be more than 3 months. The data from the company's model suggested there was an increase in mean overall survival of 12 months (median 6.9 months). The committee agreed that avelumab meets the criterion for a life-extending treatment because it increases overall survival by more than 3 months. ## Avelumab does not meet the short life expectancy criterion and so is not considered to be a life-extending treatment at the end of life The company confirmed that mean estimates were not available from JAVELIN Bladder 100, but the median overall survival for people who had best supportive care alone was 14.3 months. It noted that people in the trial would generally be fitter than in UK clinical practice. The company's original base case predicted a mean overall survival of 35.4 months and a median of 15.9 months for people having best supportive care. The ERG's base case predicted a mean overall survival of 27.82 months and a median of 15.6 months. The committee noted that mean estimates are very rarely available from clinical trial data directly. In situations such as this, the options available will usually involve alternative measures of survival, such as landmark survival times or using a restricted mean survival time. The alternative is to use extrapolation models to estimate the mean. It acknowledged that this involves assumptions and uncertainty. The economic model was based on the results from JAVELIN Bladder 100, which the company considered included people who were fitter than those in clinical practice. The mean estimates of overall survival were higher than 24 months and the cost-effectiveness analyses are based on mean survival estimates. Most survival distributions will have a skewed distribution where the mean is often higher than the median. The skew can be more pronounced with immunotherapies (that people in the comparator arm have when their disease progresses). This is because of the small number of people whose disease sustains a durable response to treatment. This is a key benefit of these therapies, and the cost-effectiveness estimates are normally very sensitive to this specific effect of these drugs. It is important for the committee to consider the mean survival since using mean life years is a key part of the NICE methods for assessing cost effectiveness. The committee also recognised the value in looking at 2‑year landmark survival. It noted that overall survival extrapolations from the economic model predicted 37% (generalised gamma) and 35% (log-normal) of people who did not have avelumab were likely to live longer than 2 years. It considered that this did not suggest that only a very small number of people are expected to survive beyond 2 years. After consultation, the company highlighted 2 NICE technology appraisals that had documented median overall survival in the sections of the guidance considering end of life criteria. In both NICE's technology appraisal guidance on pembrolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy and isatuximab with pomalidomide and dexamethasone for treating relapsed and refractory multiple myeloma, median overall survival was less than 24 months. The committee noted that in these 2 examples, data available in the committee papers shows that the mean overall survival was also less than 24 months. The same was true in NICE's technology appraisal guidance on inotuzumab ozogamicin for treating relapsed or refractory B-cell acute lymphoblastic leukaemia mentioned by a patient organisation in their consultation response. The clinical expert submission received at technical engagement stated that median overall survival in JAVELIN Bladder 100 was taken from the time of randomisation. Randomisation happened within 4 to 10 weeks after 4 to 6 cycles of chemotherapy. The committee considered what this meant for interpreting overall survival estimates. In clinical practice, chemotherapy is given for 4 to 6 cycles, with 3 weeks between each cycle. Measuring survival from starting chemotherapy would add an estimated extra 4 to 7 months to the survival outcomes. This would mean the median values from JAVELIN Bladder 100 would be more than 20 months and the mean survival from the modelling estimates more than 30 months. However, the committee considered that the important point is that from the time of randomisation, only people whose cancer responded well to chemotherapy remained in the study. At the first meeting, the committee was concerned that the overall survival values from existing clinical trials and estimates provided by the clinical experts may not accurately reflect people who are eligible for maintenance treatment with avelumab. It considered that these estimates might include people whose cancer had not responded well to chemotherapy and so have a short prognosis and therefore would not be eligible for maintenance treatment. After consultation, the company provided several sources of median survival data for people with advanced or metastatic urothelial cancer, although only 1 related specifically to people whose disease had responded well to chemotherapy. These showed that median survival estimates ranged from 9.3 to 18 months. The company also submitted feedback from 8 clinicians who said that overall survival for people whose disease responds to chemotherapy was between 12 and 18 months. A patient organisation also provided similar estimates from 2 clinicians. The committee recognised that there was potential value in real-world evidence to help inform its decision making and noted that these corresponded with the median estimate from the trial. But it was concerned about the differences between median overall survival and the mean estimates produced in the model. It considered that the best estimate of expected survival came from modelling mean life expectancy based on the trial, because the cost-effectiveness results are based on mean quality-adjusted life years and costs. The committee concluded that the short life expectancy criterion had not been met based on the extrapolations of JAVELIN Bladder 100 from the point of randomisation. Therefore avelumab could not be considered a life-extending treatment at the end of life. The committee considered this issue further after the appeal (see section 3.19). # Cost-effectiveness estimates (before the appeal) ## The ICER using the committee's preferred assumptions is substantially higher than £20,000 per QALY gained so avelumab cannot be recommended for routine use NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The company's deterministic base-case ICERs, compared with watchful waiting, were above the higher end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). Because of confidential discounts for subsequent therapies, the cost-effectiveness results cannot be reported here. The committee agreed that its preferred assumptions included: -verall survival extrapolated using either the generalised gamma or log-normal model (see section 3.6) progression assessed by blinded independent central review (see section 3.7) the proportion of people having treatment after progression based on JAVELIN Bladder 100 (see section 3.10) including costs of immunotherapies for people having avelumab whose disease had progressed (see section 3.11) no stopping rule and no waning of treatment benefit (see section 3.8 and section 3.9) health-state utilities before and after disease progression based on each arm of JAVELIN Bladder 100 (see section 3.12).The cumulative effect of the committee's preferred assumptions increased the company's base case significantly above what is normally considered a cost-effective use of NHS resources. The ICER was £72,933 per QALY gained (including the discount for avelumab). The ICER was higher than this when confidential discounts for subsequent treatments were included. The committee therefore concluded that avelumab could not be recommended for routine use in the NHS. # Cancer Drugs Fund ## Avelumab does not meet the criteria to be included in the Cancer Drugs Fund Having concluded that avelumab could not be recommended for routine use, the committee considered if it could be recommended within the Cancer Drugs Fund. It discussed the new arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The most plausible ICER including the committee's preferred assumptions was significantly above the range normally considered a cost-effective use of NHS resources and so there was no plausible potential for routine use. The committee noted that there are no planned or ongoing studies that could address the uncertainties identified. It concluded that avelumab did not meet the criteria for inclusion in the Cancer Drugs Fund. # After the appeal ## The committee has considered the appeal points upheld by the appeal panel and the company's revised patient access scheme At the third appraisal committee meeting, the committee considered the appeal panel's decision to uphold 2 appeal points and refer these back to the appraisal committee for further consideration. These were: The committee should either consider the application of a stopping rule for avelumab or should explicitly detail the rationale for why a stopping rule is either methodologically problematic or practically difficult (in contrast to NICE technology appraisal guidance on atezolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy and pembrolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy ). The committee should appraise the technology on the basis that the NICE end of life criteria applies.The committee considered these points and updated analyses including a revised patient access scheme. ## The population and setting in this appraisal are different from TA525 and TA692 The committee reconsidered its decision that a 2‑year stopping rule should not be included in the model (see section 3.9). The appeal panel had said that there was no obligation for the committee to apply a stopping rule but that the committee should fully explain its rationale for not doing so. The committee recalled that TA525 and TA692, where stopping rules had been applied, were in the second-line setting. It was also aware that there was a stopping rule in the key pembrolizumab trial (TA692), but not the atezolizumab trial (TA525). The committee recognised that the initial guidance recommending pembrolizumab for use in the Cancer Drugs Fund with a stopping rule was issued before the appraisal of atezolizumab. Given the overlapping populations, settings and mode of action of the technologies, the committee appraising atezolizumab found the proposed 2‑year stopping rule acceptable. In addition, that committee recorded in its considerations that it "also recognised that NICE guidance for other immunotherapies for metastatic urothelial carcinoma and other cancers include 2‑year stopping rules". The committee considered that there were key differences between those appraisals and the appraisal of avelumab: The setting for this appraisal is maintenance treatment, when platinum-based chemotherapy has controlled the disease, rather than when there has been disease progression as for pembrolizumab and atezolizumab. The population in this appraisal includes people whose cancer has responded well to platinum-based chemotherapy, whereas the second-line population would include some people with cancer that had not responded to chemotherapy or had progressed very quickly. The population in this appraisal may have cancer that also responds differently to immunotherapy. In JAVELIN Bladder 100, a substantially higher proportion of people were having treatment at 2 years (the exact figures are considered confidential by the company, so cannot be reported). Just under 10% of people were still on pembrolizumab and atezolizumab treatment at 2 years, irrespective of whether the trials included a stopping rule. So a stopping rule for avelumab would potentially affect a higher proportion of people. There is more experience now of using immunotherapies beyond 2 years in clinical practice than at the time of the appraisals of pembrolizumab and atezolizumab. TA525 notes clinical concern about using immunotherapies beyond 2 years, but clinical experts suggest that these concerns have reduced. For these reasons, the committee considered that stopping treatment at 2 years for people whose disease has responded to chemotherapy and is continuing to respond to maintenance treatment was distinct from stopping treatment at 2 years in the second-line setting. The committee concluded that the population and setting in this appraisal are different from TA525 and TA692. ## A 5-year stopping rule is acceptable in this appraisal The committee was also not confident that a 2-year stopping rule could be applied without risking significant harm to people. The clinical and patient experts stated that people would accept a stopping rule if it was explained to them at the start of treatment and if the mechanism of action of immunotherapies was also explained. But the committee was concerned what effect stopping treatment would have on these people. It queried whether there was any evidence that stopping treatment in a maintenance setting would not result in increasing numbers of people whose disease relapses. The company stated that there was no evidence in the maintenance setting, but there was evidence in other settings and indications. This has showed that there is a continued benefit from immunotherapy after treatment is stopped. The committee was aware of a trial in people with non-small-cell lung cancer that showed that stopping treatment with immunotherapy after 1 year resulted in worse outcomes compared with people who stayed on treatment. It was also aware of emerging long-term follow up from pembrolizumab trials showing a significant proportion of people whose cancer relapsed after stopping treatment at 2 years. Although the clinical expert broadly agreed with the company, they noted that the optimal length of treatment was still uncertain. As such, trials were planned to look at different treatment durations. The committee noted that accepting a stopping rule would increase the uncertainty in the model and would need additional assumptions, on how long reduced risk of disease progression would continue after stopping avelumab and how treatment effect waning should be applied. However, it accepted that it had been possible to adapt the models in other appraisals, so these challenges did not prevent a stopping rule. In response to the committee's concerns, the company presented a scenario which modelled stopping treatment at 5 years. The extrapolation suggested that the proportion of people still on avelumab treatment at 5 years would be less than 10%. The committee noted that this was similar to the proportion of people on treatment at 2 years in the atezolizumab and pembrolizumab trials in TA525 and TA692. The company also argued that the proportion of people on treatment at 5 years in clinical practice is likely to be lower than that in the extrapolation data. The clinical expert agreed that they would expect few people to be on treatment at 5 years. The committee accepted that a 5‑year stopping rule would address some of its concerns regarding a 2‑year stopping rule since most people would have stopped treatment by this time. The committee concluded that it is acceptable to include a 5‑year stopping rule in this appraisal. ## A treatment effect cap at 1 year should be included in the model Having accepted the inclusion of a 5‑year stopping rule, the committee discussed at what point any treatment benefit would stop. The company had originally proposed a lifetime treatment benefit, which the committee agreed was implausible (see section 3.9). After the appeal, the company provided scenario analyses varying the duration of continued benefit from 1 to 3 years after stopping avelumab. The committee considered that there was no evidence that a treatment benefit would continue for 3 years after stopping treatment. However, it agreed that the benefits of avelumab would not end immediately on stopping treatment. So it considered a treatment effect cap at 1 year was plausible, despite a lack of evidence to support this. The committee concluded that, although the treatment effect duration was uncertain, a treatment effect cap at 1 year after stopping avelumab should be included in the model. ## Avelumab meets the short life expectancy criterion and is a life-extending treatment at the end of life The committee reconsidered its decision that avelumab does not meet the short life expectancy criterion (see section 3.14). It firmly believed that the best estimate of life expectancy came from the mean survival for the eligible patient population, based on the decision model submitted by the company. This is because the model should reflect all relevant, quality-assessed evidence on the costs and effects of the different comparator treatments. Also, the mean is the most suitable statistic reflecting the totality of evidence, whereas the median does not take into account the outcomes of 50% of people. Using mean survival is also consistent with cost-effectiveness results, which are based on mean quality-adjusted life years and costs. However, the committee accepted that the NICE methods guide does not specifically state how this criterion should be assessed. It noted that the appeal panel had a different interpretation of the NICE methods guide and considered that the model and the decision about usual life expectancy are standalone considerations. The appeal panel concluded that the totality of evidence should be considered when assessing whether avelumab meets the short life expectancy criterion, including mean and median survival estimates and clinical opinion. The panel concluded that NICE stakeholders would consider it unreasonable to state that life expectancy for this population was normally more than 24 months, given that the modelled mean life expectancy indicated that most people (65%) did not survive after 24 months. At the committee meeting after the appeal, the clinical expert reiterated that that overall survival for people whose disease responds to chemotherapy was less than 24 months. The committee accepted the appeal panel's conclusion that the short life expectancy criterion was met. The committee therefore concluded that avelumab meets the criteria to be considered a life-extending treatment at the end of life. ## The ICER with a 5 year stopping rule and 1 year treatment effect cap is within the range usually considered cost effective for end of life treatments After the appeal, the company revised its patient access scheme and submitted revised cost-effectiveness estimates. The company accepted the committee's preferred assumptions (see section 3.15), except around a stopping rule. The company's base case with a 2‑year stopping rule and treatment effect cap at 3 years resulted in an ICER of less than £50,000 per QALY gained. The committee also considered the company's analyses including a 5‑year stopping rule and a treatment effect cap at 1 year. The ICER for this scenario, including the revised patient access scheme and the confidential discounts for subsequent treatments was within the range usually considered a cost-effective use of NHS resources for end of life treatments. The committee therefore recommended avelumab for routine use in the NHS for the maintenance treatment of locally advanced or metastatic urothelial cancer after platinum-based chemotherapy. It is only recommended only if treatment is stopped at 5 years of uninterrupted treatment or earlier if the disease progresses. # Innovation ## The treatment benefit from avelumab has been adequately incorporated into the model The committee considered whether avelumab was innovative. It noted that maintenance treatment after platinum-based chemotherapy is a step-change compared with current treatment options. Avelumab is not a novel compound because it is available as a treatment option for other types of cancer. The company stated that innovation should be considered separately for each indication. The committee agreed with the company that, in this case, the innovation is in using avelumab as maintenance treatment for people whose disease had not progressed 4 to 10 weeks after having first-line chemotherapy. The company considered that avelumab was innovative because there is an unmet need for people with metastatic urothelial cancer and there are no other treatment options for disease that has not progressed. The committee considered that the benefits of avelumab, related to improvements in length and quality of life, have already been incorporated into the model. It concluded that the treatment benefit from avelumab for this indication has been adequately incorporated into the model. # Other factors No equality or social value judgement issues were identified.	{'Recommendations': "Avelumab is recommended as an option for maintenance treatment of locally advanced or metastatic urothelial cancer that has not progressed after platinum-based chemotherapy in adults, only if:\n\navelumab is stopped at 5\xa0years of uninterrupted treatment or earlier if the disease progresses and\n\nthe company provides avelumab according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with avelumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThere are no maintenance treatments routinely available for locally advanced or metastatic urothelial cancer that has responded to platinum-based chemotherapy. Clinical trial evidence shows that if people take avelumab it takes longer for their cancer to get worse, and they live longer than if they have best supportive care.\n\nAvelumab meets NICE's criteria to be considered a life-extending treatment at the end of life. This is because although there are different ways to estimate life expectancy, overall, it is likely that most people who would have been eligible for treatment with avelumab would live on average less than 24\xa0months. The most likely cost-effectiveness estimates are within what NICE usually considers an acceptable use of NHS resources for end of life treatments. So avelumab is recommended, if it is stopped at 5\xa0years or earlier if the disease progreses.", 'Information about avelumab': "# Marketing authorisation indication\n\nAvelumab (Bavencio, Merck Serono) is indicated 'as monotherapy for the first-line maintenance treatment of adult patients with locally advanced or metastatic urothelial cancer who are progression-free following platinum-based chemotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for avelumab.\n\n# Price\n\nThe list price is £768.00 per 200\xa0mg/10\xa0ml concentrate for solution for infusion vials (excluding VAT; BNF online, accessed February\xa02022).\n\nThe company has a commercial arrangement. This makes avelumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': 'The appraisal committee considered evidence submitted by Merck Serono, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Metastatic urothelial cancer decreases quality of life\n\nUrothelial cancer causes a number of symptoms, including haematuria (blood in the urine) and increased frequency, urgency and pain associated with urination. The committee was aware that many people with locally advanced or metastatic urothelial cancer are older and may have comorbidities, which can affect treatment decisions. The patient experts explained that chemotherapy is associated with unpleasant side effects such as fatigue, nausea and vomiting and means people are at greater risk of infection. The committee recognised that locally advanced or metastatic urothelial cancer has a substantial effect on quality of life.\n\n## There is unmet need for effective treatment options\n\nThe main aim of treatment for locally advanced or metastatic urothelial cancer is to prevent disease progression, maintain health-related quality of life, provide relief from cancer symptoms and extend life. The patient experts explained that the side effects of chemotherapy can have a major negative effect on quality of life and regular hospital visits for treatment disrupts usual activities and affects their ability to work. The committee heard how people whose disease remains stable or responds to first-line chemotherapy must wait for disease progression before having further treatment. The clinical experts noted that maintenance treatments can prevent or delay the need for second-line treatment and there is a population who would benefit from maintenance therapy at this point in the treatment pathway. The committee concluded that there is an unmet need for effective treatment options for people with locally advanced or metastatic urothelial cancer that has not progressed after platinum-based chemotherapy.\n\n# Clinical evidence\n\n## The JAVELIN Bladder\xa0100 trial is generalisable to clinical practice in the UK\n\nThe clinical effectiveness evidence for avelumab came from 1 phase\xa03, randomised, open-label, parallel, 2‑arm study. This included 700\xa0adults with locally advanced or metastatic urothelial cancer that did not get worse during, or 4\xa0to 10\xa0weeks after, first-line platinum-based chemotherapy. People had either avelumab 10\xa0mg/kg once every 2\xa0weeks (n=350) or best supportive care alone (n=350). The study population included people who had a cisplatin- or carboplatin-based chemotherapy with gemcitabine. This aligns with current NICE recommendations on a platinum-based chemotherapy regimen. The committee agreed this reflected current UK clinical practice. It highlighted that a weight-based dose for avelumab was used in JAVELIN Bladder\xa0100, whereas the licence specifies a fixed dose. It accepted that the fixed licensed dose would have similar clinical outcomes to the weight-based dose and so it was not necessary to adjust for differential efficacy. The company presented interim data from a cut-off date of October\xa02019. It considered this to be the final analyses because the trial had achieved its primary objectives. The committee concluded that JAVELIN Bladder\xa0100 is generalisable to clinical practice in the UK.\n\n## Avelumab and best supportive care improves overall survival compared with best supportive care alone\n\nThe evidence from JAVELIN Bladder\xa0100 had 2 co-primary populations: everyone in the trial and people with PD‑L1‑positive tumours. The committee noted there was a statistically significant improvement in overall survival for the whole trial population who had avelumab with best supportive care (median 21.4\xa0months; 95% confidence interval [CI] 18.9 to 26.1\xa0months). There was a 31% reduction in the risk of death compared with people who had best supportive care alone (median 14.3\xa0months; 95% CI 12.9 to 17.9\xa0months; hazard ratio [HR] 0.69; 95% CI 0.556 to 0.863; p=0.001). There was also a statistically significant improvement in overall survival for people with PD‑L1 positive tumours. This group had a 44% reduction in the risk of death (median not reached; 95% CI 20.3\xa0months to not reached) compared with people who had best supportive care alone (median 17.1\xa0months; 95% CI 13.5 to 23.7\xa0months; HR 0.56; 95% CI 0.404 to 0.787, p<0.001). There was a 15% reduction in risk of death for people with PD‑L1 negative tumours. But these results were not statistically significant when comparing people having avelumab and best supportive care (median 18.8\xa0months; 95% CI 13.3 to 22.5\xa0months) with those having best supportive care alone (median 13.7\xa0months; 95% CI 10.8 to 17.8\xa0months; HR 0.85; 95% CI 0.615 to 1.181, p value not reported). The committee concluded avelumab and best supportive care improves overall survival compared with best supportive care alone but may not do so in people with PD‑L1 negative tumours.\n\n## Avelumab and best supportive care improves progression-free survival compared with best supportive care alone\n\nThere was a statistically significant improvement in progression-free survival (assessed by blinded independent central review) for all people having avelumab compared with best supportive care (median 3.7\xa0months; 95% CI 3.5 to 5.5\xa0months). The risk of progression or death reduced by 38% compared with people who had best supportive care alone (median 2.0\xa0months; 95% CI 1.9 to 2.7\xa0months; HR 0.62; 95% CI 0.519 to 0.751, p<0.0001). There was a statistically significant improvement in progression-free survival for the people with PD‑L1‑positive tumours. The risk of death reduced by 44% for people having avelumab and best supportive care (median 5.7\xa0months; 95% CI 3.7 to 7.4\xa0months) compared with people who had best supportive care alone (median 2.1\xa0months; 95% CI 1.9 to 3.5\xa0months; HR 0.56; 95% CI 0.431 to 0.728, p<0.0001). There was a 37% reduction in risk of death for people with PD‑L1 negative tumours having avelumab and best supportive care (median 3.0\xa0months; 95% CI 2.0 to 3.7\xa0months) compared with people who had best supportive care alone (median 1.9\xa0months; 95% CI 1.9 to 2.0\xa0months; HR 0.63; 95% CI 0.476 to 0.845, p\xa0value not reported). The committee agreed the results showed that avelumab and best supportive care improves progression-free survival compared with best supportive care alone.\n\n# Assumptions in the economic model\n\n## The generalised gamma and log-normal models are both acceptable for extrapolating overall survival\n\nIn the economic model, the company used parametric distributions to extrapolate data on overall and progression-free survival from JAVELIN Bladder\xa0100. In its original submission the company stated that overall survival estimates were expected to be between 20% and 30% at 5\xa0years and between 10% and 15% at 10\xa0years for people having avelumab. For watchful waiting (people having best supportive care alone) overall survival was expected to be between 5% and 15%, and 10‑year overall survival between 2% and 7%. The company originally selected the generalised gamma curve to extrapolate both avelumab and watchful waiting overall survival in its base case because the 10‑year survival predictions were in line with clinical estimates. It stated that the generalised gamma was the only model that predicted 10‑year overall survival estimates in the region of clinical estimates for avelumab (10% to 14%). It noted the 5‑year (15%), and 10‑year (6.48%) generalised gamma estimates for watchful waiting were optimistic. But it noted the estimates for avelumab may be considered pessimistic, based on clinical expectations. It preferred to use the same parametric model for both treatment groups. The ERG considered this may overestimate overall survival for both avelumab and watchful waiting, because it predicted 5‑year and 10‑year survival estimates that were close to the upper end of clinical expectations. The ERG preferred the log-normal curve for watchful waiting because the 5‑year (10.71%) and 10‑year (2.90%) predictions were closer to the mid-point of clinical expectations and because it had the best statistical fit. In response to technical engagement, the company accepted that both the generalised gamma and log-normal curves were helpful for decision making. But it revised its base case to use the log-normal model, aligned with the ERG\'s preferred base case. Both the company and ERG stated that there was little to distinguish between each model. The committee agreed that there is little to distinguish between the extrapolations in terms of statistical fit. But changing the model reduced the mean life years for people who had not had avelumab from 35.4\xa0months (generalised gamma) to 27.82\xa0months (log-normal). At the second committee meeting, the company confirmed it would prefer the log-normal extrapolation model. However, the committee considered that it was reasonable to use the generalised gamma. It could be plausible that survival estimates for watchful waiting are at the upper end of clinical ranges. For this reason, the committee concluded that both models should be considered plausible for extrapolating overall survival data.\n\n## Progression should be defined by blinded independent central review\n\nIn the company\'s model, progression-free survival curves were fitted for 2 alternative definitions of progression: blinded independent central review and investigator-assessed progression. The company\'s original base-case analysis considered blinded independent central review defined progression because it was expected to give the most unbiased assessment of disease progression. The ERG noted that treatment decisions in clinical practice are more likely to be based on investigator-assessed progression. In response to technical engagement, the company provided feedback from 8\xa0UK‑based oncologists who supported the ERG\'s preference for using investigator-assessed progression. The committee noted that in open-label trials, investigator-assessed progression has the potential for biased decisions. After an initial investigator assessment, all subsequent assessments of progression in JAVELIN Bladder\xa0100 were based on blinded independent central review. This is consistent with greater internal validity as noted in NICE\'s guide to the methods of technology appraisal. The committee recalled that blinded independent central review defined progression was the preferred approach in many published technology appraisals. For this reason, it concluded that progression should be defined by blinded independent central review.\n\n## Time to stopping treatment should reflect the trial (before the appeal)\n\nIn its original economic model, the company assumed that 95% of people will stop treatment with avelumab at 2\xa0years whether or not their disease has progressed, and all remaining people would stop treatment with avelumab at 5\xa0years. The company also assumed that people would continue to benefit from avelumab for the remainder of their lifetime, even after stopping treatment. The committee noted that this did not reflect JAVELIN Bladder\xa0100 and the summary of product characteristics does not include a stopping rule. Data from the trial showed that substantially more people were having treatment at 2\xa0years than the 5% assumed in the company\'s model. But the exact figures are considered confidential by the company, so cannot be reported. The model captured the benefits these people had from continuing avelumab treatment, but the costs were not included. The clinical experts explained that stopping treatment after 2\xa0years might be reasonable for some people for reasons such as fatigue from fortnightly hospital visits or the adverse effects of the treatment. The committee agreed, but it was not clear whether this would apply to people with urothelial cancer in general, or the population considered here of people whose disease has responded to chemotherapy and is continuing to respond to maintenance treatment. The clinical lead for the Cancer Drugs Fund explained that the company\'s original assumptions about stopping avelumab treatment could not be implemented in the NHS. But he noted that, for other immunotherapies, a rule to stop treatment at 2\xa0years has been implemented in the NHS. The clinical and patient experts stated that they would accept a similar stopping rule if this would enable access to avelumab, if the alternative was for avelumab to be not recommended in the NHS. This was confirmed by 2\xa0patient organisations in response to consultation. The committee was aware that the company had not provided a scenario analysis when all patients stopped having treatment at 2\xa0years. It was concerned that it would be difficult for patients to accept that they would no longer be able to have treatment after 2\xa0years if they were free from disease, and they may fear losing treatment benefit. Also, people whose disease had not progressed before needing to stop avelumab would not be able to have another immunotherapy in the NHS. The committee noted that other NICE technology appraisals of avelumab have preferred no stopping rules. The committee would prefer the model to base time to stopping treatment on the trial data. But, it was also concerned that because people cannot have further immunotherapy, treatment in the NHS may continue beyond radiographical progression. One clinical expert noted that they would prefer to continue avelumab until symptomatic progression. The committee therefore asked the company to provide the progression-free survival and time to stopping treatment curves presented on the same graph to assess the relationship between the 2 in the trial. After consultation, the company confirmed that their initial assumption around treatment duration was not intended to be a stopping rule but to reflect the likely treatment duration of people in clinical practice. It proposed a 2‑year stopping rule based on expectations that in clinical practice people will stop treatment by then. It noted this was in line with immunotherapies for other indications. The committee recalled that there were many people in JAVELIN Bladder\xa0100 whose disease had not progressed at 2\xa0years, but a slightly lower number were still having treatment after 2\xa0years. It acknowledged that some of these people may stop having avelumab for other reasons than disease progression. The committee was aware of other examples when decisions about including or excluding stopping rules had been applied for immunotherapies after platinum-based chemotherapy in urothelial cancer. In these technology appraisals, a stopping rule was included in the trial, or the committee was able to generalise these results to other treatments in the same class used in the same populations and settings. It considered that there was no similar evidence here to support a stopping rule, since JAVELIN Bladder\xa0100 did not include one and the setting and population in this technology appraisal was different to others in this disease area. The committee concluded that time to stopping treatment should reflect the trial evidence and a stopping rule should not be included in the model. The committee considered this issue further after the appeal (see section\xa03.18).\n\n## Waning of treatment effect should not be included in the model (before the appeal)\n\nRelated to the assumptions about stopping treatment, the company originally assumed a lifetime treatment benefit for avelumab in its base case, even after stopping treatment. The company and ERG provided several scenario analyses in which the treatment effect for avelumab was capped at different time points. The clinical experts explained that for immunotherapies, it is common for the treatment benefit to continue when treatment stops. But the committee agreed that it was implausible that the treatment effect for avelumab would continue for a person\'s lifetime after stopping treatment. It noted that in other technology appraisals of immunotherapies, a treatment cap between 2\xa0and 5\xa0years had been applied when a stopping rule had been applied. After consultation, the company proposed that waning of treatment benefit should be applied at 5\xa0years. Any treatment benefit would stop 3\xa0years after stopping treatment, aligned with its proposed 2‑year stopping rule. The ERG noted that the true duration of benefit after stopping treatment is unclear. It provided several scenario analyses varying the duration of continued benefit. These varied from no benefit after stopping treatment, to 5\xa0years after stopping treatment, which was included in other technology appraisals of immunotherapies for metastatic urothelial cancer. It also provided a gradual waning of treatment effect in line with the company\'s original scenario analysis. The committee noted that there is substantial uncertainty about the most appropriate treatment benefit capping assumptions. It concluded that since a stopping rule had not been accepted, a waning of treatment effect should not be included in the model.\n\n## The SACT dataset does not reflect the maintenance setting in which avelumab would be used in clinical practice\n\nThe company model included the costs of subsequent treatments after progression based on JAVELIN Bladder\xa0100, adjusted to reflect the treatments available in UK clinical practice. The ERG noted that the proportion of people having subsequent treatments in the trial would likely to be higher than that seen in clinical practice. People in the trial had more stable disease and so were considered fitter than those in clinical practice and were monitored more closely. So, they were more likely to have subsequent treatment after progression. The company provided estimates from the systematic anti-cancer therapy (SACT) dataset. This showed that 41.9% of people in UK clinical practice have a second-line therapy after first-line platinum-based chemotherapy. This was lower than the proportion in JAVELIN Bladder\xa0100. The clinical experts explained that only people with stable disease would have been eligible to be included in JAVELIN Bladder\xa0100. This was because people whose disease progressed during, or very shortly after, first-line chemotherapy were not eligible. As a result, the number having subsequent treatments in JAVELIN Bladder\xa0100 would have only included people who had stable disease (and therefore may be considered fitter and more likely to have subsequent treatment). This was not directly comparable with those in the SACT dataset, which includes people whose disease has progressed during or immediately after chemotherapy. The SACT dataset was collected before NICE recommendations that increased the treatment options in metastatic urothelial cancer to include immunotherapies. Also, the hazard ratios and incremental cost-effectiveness ratios (ICERs) that the cost-effectiveness results were based on came directly from those in JAVELIN Bladder\xa0100. The committee agreed that the data used to inform the proportion of people having subsequent treatment in the model should come from JAVELIN Bladder\xa0100. It concluded that the SACT dataset does not reflect the maintenance setting in which avelumab would be used in clinical practice.\n\n## The costs of subsequent treatments in the model should reflect the treatments used in JAVELIN Bladder\xa0100\n\nSome people had immunotherapies after disease progression on avelumab in JAVELIN Bladder\xa0100. In the economic model, the company removed the cost of these immunotherapy treatments to reflect NHS clinical practice. The clinical experts confirmed that in clinical practice people would not have a second-line immunotherapy after disease progression on avelumab. The committee recognised that in the NHS people would not have further immunotherapy after avelumab. However, it considered that people may have had some benefit from immunotherapy treatment after avelumab, but that the model had not been adjusted to account for this. It was aware of discussions from NICE\'s technology appraisal guidance on pembrolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy. These concluded that it was inconsistent to include the potential benefits of subsequent immunotherapy treatment without the costs, so both should either be included or excluded. So, the committee concluded that the costs of immunotherapies used after disease progression on avelumab should be included in the model.\n\n## It is not appropriate to pool health-state utilities across treatment arms\n\nThe company submission stated that overall health status and health-related quality of life were similar between both arms of JAVELIN Bladder\xa0100. So the company used pooled utility values to inform the model. However, it also provided health-state utility data for each arm of the study, split by before progression and after progression states. The ERG noted that utilities before progression were slightly higher in the avelumab with best supportive care arm compared with best supportive care alone. But values after progression were lower for avelumab with best supportive care compared with best supportive care alone. The committee noted that people who had best supportive care in JAVELIN Bladder\xa0100 would also have immunotherapies or chemotherapy if their disease progressed. The committee considered that this might explain the difference in utility values for people who had avelumab with best supportive care or best supportive care alone. The clinical experts explained that lower utility after progression on avelumab was clinically plausible because people would be having less effective chemotherapy treatment, and this may affect their health-related quality of life. The clinical experts stated that it would be reasonable to include health-state utilities from each arm of the trial. After consultation, the company maintained its preference for using pooled health-state utilities. It noted that pooled values have previously been accepted in NICE\'s technology appraisal guidance on pembrolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy. However, the committee noted that in that appraisal the same treatments were available to people in both study groups whose disease progressed. The company also suggested that the difference in utilities before and after progression from JAVELIN Bladder\xa0100 might be explained by fewer observations of people after progression in the avelumab arm of the trial. But the committee considered the data was still robust enough to allow conclusions to be drawn. The ERG noted that it was reasonable to consider the effect of treatment-specific utilities on cost-effectiveness estimates, if any uncertainty might be introduced by combining health-state utilities across treatment arms. It provided a scenario analyses exploring this uncertainty. Using pooled data for the health-state utilities slightly increased the ICER for avelumab. The committee considered the views of the company and clinical experts and the ERG. It concluded that, on balance, it was not appropriate to pool health-state utilities across treatment arms.\n\n# End of life (before the appeal)\n\n## Avelumab extends life by at least 3\xa0months\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE\'s guide to the methods of technology appraisal. The committee agreed based on the evidence that was available and the views of the clinical experts that the overall survival gain with avelumab would likely be more than 3\xa0months. The data from the company\'s model suggested there was an increase in mean overall survival of 12\xa0months (median 6.9\xa0months). The committee agreed that avelumab meets the criterion for a life-extending treatment because it increases overall survival by more than 3\xa0months.\n\n## Avelumab does not meet the short life expectancy criterion and so is not considered to be a life-extending treatment at the end of life\n\nThe company confirmed that mean estimates were not available from JAVELIN Bladder\xa0100, but the median overall survival for people who had best supportive care alone was 14.3\xa0months. It noted that people in the trial would generally be fitter than in UK clinical practice. The company\'s original base case predicted a mean overall survival of 35.4\xa0months and a median of 15.9\xa0months for people having best supportive care. The ERG\'s base case predicted a mean overall survival of 27.82\xa0months and a median of 15.6\xa0months. The committee noted that mean estimates are very rarely available from clinical trial data directly. In situations such as this, the options available will usually involve alternative measures of survival, such as landmark survival times or using a restricted mean survival time. The alternative is to use extrapolation models to estimate the mean. It acknowledged that this involves assumptions and uncertainty. The economic model was based on the results from JAVELIN Bladder\xa0100, which the company considered included people who were fitter than those in clinical practice. The mean estimates of overall survival were higher than 24\xa0months and the cost-effectiveness analyses are based on mean survival estimates. Most survival distributions will have a skewed distribution where the mean is often higher than the median. The skew can be more pronounced with immunotherapies (that people in the comparator arm have when their disease progresses). This is because of the small number of people whose disease sustains a durable response to treatment. This is a key benefit of these therapies, and the cost-effectiveness estimates are normally very sensitive to this specific effect of these drugs. It is important for the committee to consider the mean survival since using mean life years is a key part of the NICE methods for assessing cost effectiveness. The committee also recognised the value in looking at 2‑year landmark survival. It noted that overall survival extrapolations from the economic model predicted 37% (generalised gamma) and 35% (log-normal) of people who did not have avelumab were likely to live longer than 2\xa0years. It considered that this did not suggest that only a very small number of people are expected to survive beyond 2\xa0years. After consultation, the company highlighted 2 NICE technology appraisals that had documented median overall survival in the sections of the guidance considering end of life criteria. In both NICE\'s technology appraisal guidance on pembrolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy and isatuximab with pomalidomide and dexamethasone for treating relapsed and refractory multiple myeloma, median overall survival was less than 24\xa0months. The committee noted that in these 2 examples, data available in the committee papers shows that the mean overall survival was also less than 24\xa0months. The same was true in NICE\'s technology appraisal guidance on inotuzumab ozogamicin for treating relapsed or refractory B-cell acute lymphoblastic leukaemia mentioned by a patient organisation in their consultation response. The clinical expert submission received at technical engagement stated that median overall survival in JAVELIN Bladder\xa0100 was taken from the time of randomisation. Randomisation happened within 4\xa0to 10\xa0weeks after 4\xa0to 6\xa0cycles of chemotherapy. The committee considered what this meant for interpreting overall survival estimates. In clinical practice, chemotherapy is given for 4\xa0to 6\xa0cycles, with 3\xa0weeks between each cycle. Measuring survival from starting chemotherapy would add an estimated extra 4\xa0to 7\xa0months to the survival outcomes. This would mean the median values from JAVELIN Bladder\xa0100 would be more than 20\xa0months and the mean survival from the modelling estimates more than 30\xa0months. However, the committee considered that the important point is that from the time of randomisation, only people whose cancer responded well to chemotherapy remained in the study. At the first meeting, the committee was concerned that the overall survival values from existing clinical trials and estimates provided by the clinical experts may not accurately reflect people who are eligible for maintenance treatment with avelumab. It considered that these estimates might include people whose cancer had not responded well to chemotherapy and so have a short prognosis and therefore would not be eligible for maintenance treatment. After consultation, the company provided several sources of median survival data for people with advanced or metastatic urothelial cancer, although only 1 related specifically to people whose disease had responded well to chemotherapy. These showed that median survival estimates ranged from 9.3\xa0to 18\xa0months. The company also submitted feedback from 8\xa0clinicians who said that overall survival for people whose disease responds to chemotherapy was between 12 and 18\xa0months. A patient organisation also provided similar estimates from 2 clinicians. The committee recognised that there was potential value in real-world evidence to help inform its decision making and noted that these corresponded with the median estimate from the trial. But it was concerned about the differences between median overall survival and the mean estimates produced in the model. It considered that the best estimate of expected survival came from modelling mean life expectancy based on the trial, because the cost-effectiveness results are based on mean quality-adjusted life years and costs. The committee concluded that the short life expectancy criterion had not been met based on the extrapolations of JAVELIN Bladder\xa0100 from the point of randomisation. Therefore avelumab could not be considered a life-extending treatment at the end of life. The committee considered this issue further after the appeal (see section\xa03.19).\n\n# Cost-effectiveness estimates (before the appeal)\n\n## The ICER using the committee\'s preferred assumptions is substantially higher than £20,000 per QALY gained so avelumab cannot be recommended for routine use\n\nNICE\'s guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The company\'s deterministic base-case ICERs, compared with watchful waiting, were above the higher end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). Because of confidential discounts for subsequent therapies, the cost-effectiveness results cannot be reported here. The committee agreed that its preferred assumptions included:\n\noverall survival extrapolated using either the generalised gamma or log-normal model (see section\xa03.6)\n\nprogression assessed by blinded independent central review (see section\xa03.7)\n\nthe proportion of people having treatment after progression based on JAVELIN Bladder\xa0100 (see section\xa03.10)\n\nincluding costs of immunotherapies for people having avelumab whose disease had progressed (see section\xa03.11)\n\nno stopping rule and no waning of treatment benefit (see section\xa03.8 and section\xa03.9)\n\nhealth-state utilities before and after disease progression based on each arm of JAVELIN Bladder\xa0100 (see section\xa03.12).The cumulative effect of the committee\'s preferred assumptions increased the company\'s base case significantly above what is normally considered a cost-effective use of NHS resources. The ICER was £72,933 per QALY gained (including the discount for avelumab). The ICER was higher than this when confidential discounts for subsequent treatments were included. The committee therefore concluded that avelumab could not be recommended for routine use in the NHS.\n\n# Cancer Drugs Fund\n\n## Avelumab does not meet the criteria to be included in the Cancer Drugs Fund\n\nHaving concluded that avelumab could not be recommended for routine use, the committee considered if it could be recommended within the Cancer Drugs Fund. It discussed the new arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE\'s Cancer Drugs Fund methods guide (addendum). The most plausible ICER including the committee\'s preferred assumptions was significantly above the range normally considered a cost-effective use of NHS resources and so there was no plausible potential for routine use. The committee noted that there are no planned or ongoing studies that could address the uncertainties identified. It concluded that avelumab did not meet the criteria for inclusion in the Cancer Drugs Fund.\n\n# After the appeal\n\n## The committee has considered the appeal points upheld by the appeal panel and the company\'s revised patient access scheme\n\nAt the third appraisal committee meeting, the committee considered the appeal panel\'s decision to uphold 2\xa0appeal points and refer these back to the appraisal committee for further consideration. These were:\n\nThe committee should either consider the application of a stopping rule for avelumab or should explicitly detail the rationale for why a stopping rule is either methodologically problematic or practically difficult (in contrast to NICE technology appraisal guidance on atezolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy [TA525] and pembrolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy [TA692]).\n\nThe committee should appraise the technology on the basis that the NICE end of life criteria applies.The committee considered these points and updated analyses including a revised patient access scheme.\n\n## The population and setting in this appraisal are different from TA525 and TA692\n\nThe committee reconsidered its decision that a 2‑year stopping rule should not be included in the model (see section\xa03.9). The appeal panel had said that there was no obligation for the committee to apply a stopping rule but that the committee should fully explain its rationale for not doing so. The committee recalled that TA525 and TA692, where stopping rules had been applied, were in the second-line setting. It was also aware that there was a stopping rule in the key pembrolizumab trial (TA692), but not the atezolizumab trial (TA525). The committee recognised that the initial guidance recommending pembrolizumab for use in the Cancer Drugs Fund with a stopping rule was issued before the appraisal of atezolizumab. Given the overlapping populations, settings and mode of action of the technologies, the committee appraising atezolizumab found the proposed 2‑year stopping rule acceptable. In addition, that committee recorded in its considerations that it "also recognised that NICE guidance for other immunotherapies for metastatic urothelial carcinoma and other cancers include 2‑year stopping rules". The committee considered that there were key differences between those appraisals and the appraisal of avelumab:\n\nThe setting for this appraisal is maintenance treatment, when platinum-based chemotherapy has controlled the disease, rather than when there has been disease progression as for pembrolizumab and atezolizumab.\n\nThe population in this appraisal includes people whose cancer has responded well to platinum-based chemotherapy, whereas the second-line population would include some people with cancer that had not responded to chemotherapy or had progressed very quickly. The population in this appraisal may have cancer that also responds differently to immunotherapy.\n\nIn JAVELIN Bladder\xa0100, a substantially higher proportion of people were having treatment at 2\xa0years (the exact figures are considered confidential by the company, so cannot be reported). Just under 10% of people were still on pembrolizumab and atezolizumab treatment at 2\xa0years, irrespective of whether the trials included a stopping rule. So a stopping rule for avelumab would potentially affect a higher proportion of people.\n\nThere is more experience now of using immunotherapies beyond 2\xa0years in clinical practice than at the time of the appraisals of pembrolizumab and atezolizumab. TA525 notes clinical concern about using immunotherapies beyond 2\xa0years, but clinical experts suggest that these concerns have reduced. For these reasons, the committee considered that stopping treatment at 2\xa0years for people whose disease has responded to chemotherapy and is continuing to respond to maintenance treatment was distinct from stopping treatment at 2\xa0years in the second-line setting. The committee concluded that the population and setting in this appraisal are different from TA525 and TA692.\n\n## A 5-year stopping rule is acceptable in this appraisal\n\nThe committee was also not confident that a 2-year stopping rule could be applied without risking significant harm to people. The clinical and patient experts stated that people would accept a stopping rule if it was explained to them at the start of treatment and if the mechanism of action of immunotherapies was also explained. But the committee was concerned what effect stopping treatment would have on these people. It queried whether there was any evidence that stopping treatment in a maintenance setting would not result in increasing numbers of people whose disease relapses. The company stated that there was no evidence in the maintenance setting, but there was evidence in other settings and indications. This has showed that there is a continued benefit from immunotherapy after treatment is stopped. The committee was aware of a trial in people with non-small-cell lung cancer that showed that stopping treatment with immunotherapy after 1\xa0year resulted in worse outcomes compared with people who stayed on treatment. It was also aware of emerging long-term follow up from pembrolizumab trials showing a significant proportion of people whose cancer relapsed after stopping treatment at 2\xa0years. Although the clinical expert broadly agreed with the company, they noted that the optimal length of treatment was still uncertain. As such, trials were planned to look at different treatment durations. The committee noted that accepting a stopping rule would increase the uncertainty in the model and would need additional assumptions, on how long reduced risk of disease progression would continue after stopping avelumab and how treatment effect waning should be applied. However, it accepted that it had been possible to adapt the models in other appraisals, so these challenges did not prevent a stopping rule. In response to the committee\'s concerns, the company presented a scenario which modelled stopping treatment at 5\xa0years. The extrapolation suggested that the proportion of people still on avelumab treatment at 5\xa0years would be less than 10%. The committee noted that this was similar to the proportion of people on treatment at 2\xa0years in the atezolizumab and pembrolizumab trials in TA525 and TA692. The company also argued that the proportion of people on treatment at 5\xa0years in clinical practice is likely to be lower than that in the extrapolation data. The clinical expert agreed that they would expect few people to be on treatment at 5\xa0years. The committee accepted that a 5‑year stopping rule would address some of its concerns regarding a 2‑year stopping rule since most people would have stopped treatment by this time. The committee concluded that it is acceptable to include a 5‑year stopping rule in this appraisal.\n\n## A treatment effect cap at 1 year should be included in the model\n\nHaving accepted the inclusion of a 5‑year stopping rule, the committee discussed at what point any treatment benefit would stop. The company had originally proposed a lifetime treatment benefit, which the committee agreed was implausible (see section\xa03.9). After the appeal, the company provided scenario analyses varying the duration of continued benefit from 1 to 3\xa0years after stopping avelumab. The committee considered that there was no evidence that a treatment benefit would continue for 3\xa0years after stopping treatment. However, it agreed that the benefits of avelumab would not end immediately on stopping treatment. So it considered a treatment effect cap at 1\xa0year was plausible, despite a lack of evidence to support this. The committee concluded that, although the treatment effect duration was uncertain, a treatment effect cap at 1\xa0year after stopping avelumab should be included in the model.\n\n## Avelumab meets the short life expectancy criterion and is a life-extending treatment at the end of life\n\nThe committee reconsidered its decision that avelumab does not meet the short life expectancy criterion (see section\xa03.14). It firmly believed that the best estimate of life expectancy came from the mean survival for the eligible patient population, based on the decision model submitted by the company. This is because the model should reflect all relevant, quality-assessed evidence on the costs and effects of the different comparator treatments. Also, the mean is the most suitable statistic reflecting the totality of evidence, whereas the median does not take into account the outcomes of 50% of people. Using mean survival is also consistent with cost-effectiveness results, which are based on mean quality-adjusted life years and costs. However, the committee accepted that the NICE methods guide does not specifically state how this criterion should be assessed. It noted that the appeal panel had a different interpretation of the NICE methods guide and considered that the model and the decision about usual life expectancy are standalone considerations. The appeal panel concluded that the totality of evidence should be considered when assessing whether avelumab meets the short life expectancy criterion, including mean and median survival estimates and clinical opinion. The panel concluded that NICE stakeholders would consider it unreasonable to state that life expectancy for this population was normally more than 24\xa0months, given that the modelled mean life expectancy indicated that most people (65%) did not survive after 24\xa0months. At the committee meeting after the appeal, the clinical expert reiterated that that overall survival for people whose disease responds to chemotherapy was less than 24\xa0months. The committee accepted the appeal panel\'s conclusion that the short life expectancy criterion was met. The committee therefore concluded that avelumab meets the criteria to be considered a life-extending treatment at the end of life.\n\n## The ICER with a 5 year stopping rule and 1 year treatment effect cap is within the range usually considered cost effective for end of life treatments\n\nAfter the appeal, the company revised its patient access scheme and submitted revised cost-effectiveness estimates. The company accepted the committee\'s preferred assumptions (see section\xa03.15), except around a stopping rule. The company\'s base case with a 2‑year stopping rule and treatment effect cap at 3\xa0years resulted in an ICER of less than £50,000 per QALY gained. The committee also considered the company\'s analyses including a 5‑year stopping rule and a treatment effect cap at 1\xa0year. The ICER for this scenario, including the revised patient access scheme and the confidential discounts for subsequent treatments was within the range usually considered a cost-effective use of NHS resources for end of life treatments. The committee therefore recommended avelumab for routine use in the NHS for the maintenance treatment of locally advanced or metastatic urothelial cancer after platinum-based chemotherapy. It is only recommended only if treatment is stopped at 5\xa0years of uninterrupted treatment or earlier if the disease progresses.\n\n# Innovation\n\n## The treatment benefit from avelumab has been adequately incorporated into the model\n\nThe committee considered whether avelumab was innovative. It noted that maintenance treatment after platinum-based chemotherapy is a step-change compared with current treatment options. Avelumab is not a novel compound because it is available as a treatment option for other types of cancer. The company stated that innovation should be considered separately for each indication. The committee agreed with the company that, in this case, the innovation is in using avelumab as maintenance treatment for people whose disease had not progressed 4\xa0to\xa010\xa0weeks after having first-line chemotherapy. The company considered that avelumab was innovative because there is an unmet need for people with metastatic urothelial cancer and there are no other treatment options for disease that has not progressed. The committee considered that the benefits of avelumab, related to improvements in length and quality of life, have already been incorporated into the model. It concluded that the treatment benefit from avelumab for this indication has been adequately incorporated into the model.\n\n# Other factors\n\nNo equality or social value judgement issues were identified.'}	https://www.nice.org.uk/guidance/ta788	Evidence-based recommendations on avelumab for maintenance treatment of locally advanced or metastatic urothelial cancer after platinum-based chemotherapy in adults.
aef5705de6b46c919aa77ea6825a93ff358533cb	nice	Liposuction for chronic lymphoedema	Liposuction for chronic lymphoedema Evidence-based recommendations on liposuction for chronic lymphoedema in adults. This involves using suction to remove fluid and fat through punctures in the skin. # Recommendations Evidence on the efficacy and safety of liposuction for chronic lymphoedema is adequate. The evidence on safety shows that the potential risks include venous thromboembolism, fat embolism, and fluid overload. This procedure can be used provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page. For auditing the outcomes of this procedure, the main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Patient selection must be done by a multidisciplinary team with expertise in managing lymphoedema. The procedure should only be done in specialist centres by clinicians with training and expertise in liposuction for lymphoedema following agreed perioperative protocols.# The condition, current treatments and procedure # The condition Lymphoedema is the abnormal accumulation of subcutaneous fluid and sometimes fat in body tissues. It leads to chronic swelling that can cause disability, pain, and cosmetic issues. Any part of the body can be affected, but the condition is most common in the arms and legs. Lymphoedema can be complicated by recurrent infection (cellulitis), which further damages the lymphatic vessels and aggravates the condition. Primary lymphoedema results from a range of conditions that affect how the lymphatic system develops and functions. Secondary lymphoedema results from damage to the lymphatic system or removal of lymph nodes by surgery, radiation, infection, or injury. Liposuction may be particularly appropriate for select people with primary lymphoedema and for people with cancer-related lymphoedema. # Current treatments The current conservative treatment for lymphoedema is decongestive lymphatic therapy. This involves compression bandaging, skin care and exercise. For some people, manual lymphatic drainage massage that stimulates lymph to move away from the affected limb may also be helpful. Once decongestive lymphatic therapy sessions are stopped, the person is fitted with a custom-made compression garment, which is worn every day for life. These techniques aim to reduce the pain and discomfort associated with lymphoedema. In severe and chronic cases, in people with lymphoedema that does not respond to conservative treatment, liposuction can be used. Procedures to restore lymphatic flow from the limb, such as lymphovenous anastomosis or lymph node transfer, are less commonly used and are usually reserved for earlier-stage lymphoedema. # The procedure Liposuction for chronic lymphoedema is usually done under general anaesthesia, but using regional nerve blockade is also possible. A tourniquet is applied to the proximal limb. A few small incisions are made in the limb. Cannulas, connected to a vacuum pump, are inserted into the incisions and oedematous adipose tissue is removed by vacuum aspiration. Liposuction is done around and all the way along the limb up to the distal border of the tourniquet. The tourniquet is then removed; the proximal limb, which is unable to be controlled by tourniquet, is infused with tumescent solution; and the fat and fluid from this area are aspirated. Immediately after liposuction, a compression bandage is applied to the limb to control any bleeding and to prevent post-surgical oedema. Antibiotics and prophylaxis against venous thromboembolism are typically prescribed before and after the operation. After the procedure, a custom-made compression garment must be worn for life to maintain the volume reduction. This garment needs to be revised multiple times until the oedema volume has been reduced as much as possible and a steady state has been reached, but must be worn for life.	{'Recommendations': "Evidence on the efficacy and safety of liposuction for chronic lymphoedema is adequate. The evidence on safety shows that the potential risks include venous thromboembolism, fat embolism, and fluid overload. This procedure can be used provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nFor auditing the outcomes of this procedure, the main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nPatient selection must be done by a multidisciplinary team with expertise in managing lymphoedema.\n\nThe procedure should only be done in specialist centres by clinicians with training and expertise in liposuction for lymphoedema following agreed perioperative protocols.", 'The condition, current treatments and procedure': '# The condition\n\nLymphoedema is the abnormal accumulation of subcutaneous fluid and sometimes fat in body tissues. It leads to chronic swelling that can cause disability, pain, and cosmetic issues. Any part of the body can be affected, but the condition is most common in the arms and legs. Lymphoedema can be complicated by recurrent infection (cellulitis), which further damages the lymphatic vessels and aggravates the condition. Primary lymphoedema results from a range of conditions that affect how the lymphatic system develops and functions. Secondary lymphoedema results from damage to the lymphatic system or removal of lymph nodes by surgery, radiation, infection, or injury. Liposuction may be particularly appropriate for select people with primary lymphoedema and for people with cancer-related lymphoedema.\n\n# Current treatments\n\nThe current conservative treatment for lymphoedema is decongestive lymphatic therapy. This involves compression bandaging, skin care and exercise. For some people, manual lymphatic drainage massage that stimulates lymph to move away from the affected limb may also be helpful. Once decongestive lymphatic therapy sessions are stopped, the person is fitted with a custom-made compression garment, which is worn every day for life. These techniques aim to reduce the pain and discomfort associated with lymphoedema. In severe and chronic cases, in people with lymphoedema that does not respond to conservative treatment, liposuction can be used. Procedures to restore lymphatic flow from the limb, such as lymphovenous anastomosis or lymph node transfer, are less commonly used and are usually reserved for earlier-stage lymphoedema.\n\n# The procedure\n\nLiposuction for chronic lymphoedema is usually done under general anaesthesia, but using regional nerve blockade is also possible. A tourniquet is applied to the proximal limb. A few small incisions are made in the limb. Cannulas, connected to a vacuum pump, are inserted into the incisions and oedematous adipose tissue is removed by vacuum aspiration. Liposuction is done around and all the way along the limb up to the distal border of the tourniquet. The tourniquet is then removed; the proximal limb, which is unable to be controlled by tourniquet, is infused with tumescent solution; and the fat and fluid from this area are aspirated. Immediately after liposuction, a compression bandage is applied to the limb to control any bleeding and to prevent post-surgical oedema. Antibiotics and prophylaxis against venous thromboembolism are typically prescribed before and after the operation. After the procedure, a custom-made compression garment must be worn for life to maintain the volume reduction. This garment needs to be revised multiple times until the oedema volume has been reduced as much as possible and a steady state has been reached, but must be worn for life.'}	https://www.nice.org.uk/guidance/ipg723	Evidence-based recommendations on liposuction for chronic lymphoedema in adults. This involves using suction to remove fluid and fat through punctures in the skin.
647f75b05513df4379b9c083cd63bd6575947dfa	nice	Epilepsies in children, young people and adults	Epilepsies in children, young people and adults This guideline covers diagnosing and managing epilepsy in children, young people and adults in primary and secondary care, and referral to tertiary services. It aims to improve diagnosis and treatment for different seizure types and epilepsy syndromes, and reduce the risks for people with epilepsy. # Diagnosis and assessment of epilepsy People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Referral after a first seizure or remission and assessing risk of a second seizure ## Referral after a first seizure For recommendations on immediate guidance and referral for children under 2 years with suspected or confirmed infantile spasms, see the section on infantile spasms syndrome. Refer children, young people and adults urgently (for an appointment within 2 weeks) for an assessment after a first suspected seizure: For adults, refer to a clinician with expertise in assessing first seizures and diagnosing epilepsy. For children and young people, refer to a paediatrician with expertise in assessing first seizures and diagnosing epilepsy. ## Referral after remission Refer children, young people and adults urgently (for an appointment within 2 weeks) for an assessment if they have a seizure recurrence after a period of remission. ## Assessing the risk of a second seizure When a child, young person or adult presents with a first seizure, carry out an individualised assessment of their risk of a second seizure. In adults, assessment should include checking for the following modifiable factors that may increase the risk of a second seizure: an underlying mental health problem (such as depression, anxiety, psychosis and alcohol or substance misuse) vascular risk factors (for example, diabetes, hypertension, atrial fibrillation) sepsis. Be aware that children presenting with a first afebrile seizure (seizure without a fever) are at an increased risk of further afebrile seizures, especially within 6 to 12 months, compared with children with a febrile seizure (seizure with a fever). Be aware that children presenting with complicated febrile seizures (febrile seizures that last longer than 10 minutes or febrile seizures associated with other features, such as weakness, on one side of the body) may be at higher risk of epilepsy, especially if other predisposing risk factors for epilepsy are present. Using a person-centred approach, discuss with the person, and their family and carers if appropriate, their individualised risks for further seizures. This should include any mental, physical and social factors identified as possible risk factors and how these may be modified. ## Information and support after a first seizure After a first seizure, give the person, and their family and carers if appropriate, information about: how to recognise a further seizure first aid and initial safety guidance in case of another seizure (see safety issues in box 1) any changes they can make to reduce their risk of another seizure who they should contact if they have a further seizure while awaiting their appointment for assessment and diagnosis. After a first afebrile seizure in a child, explain to their parents or carers how to self-refer the child urgently if they have a further seizure. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral after a first seizure or remission and assessing risk of a second seizure . Full details of the evidence and the committee's discussion are in: evidence review 1: prediction of second seizure evidence review 2: modifiable risk factors for a second seizure. Loading. Please wait. # Specialist assessment and diagnosis See also NICE's guideline on transient loss of consciousness ('blackouts') in over 16s for recommendations on initial assessment of people after a suspected transient loss of consciousness. In particular, see the recommendations on performing electrocardiogram (ECG) in the section on obtaining patient history, physical examination and tests and on features suggestive of epileptic seizures in the section on suspected epilepsy. Take a detailed history from the child, young person or adult after a first suspected seizure, and from their families and carers if appropriate, and carry out a physical examination. If possible, use eyewitness accounts and video footage of the seizure to inform the assessment. Evaluate people after a first suspected seizure with a 12-lead ECG to help identify cardiac-related conditions that could mimic an epileptic seizure. Be aware that metabolic disturbance, including hypoglycaemia, can result in seizures. Offer brain neuroimaging tests if an underlying structural cause is suspected (see also the section on neuroimaging). ## Electroencephalogram (EEG) If the person's history and examination suggests an epileptic seizure, and a diagnosis of epilepsy is suspected, consider a routine EEG carried out while awake to support diagnosis and provide information about seizure type or epilepsy syndrome. Do not use EEG to exclude a diagnosis of epilepsy. If an EEG is requested after a first seizure, perform it as soon as possible (ideally within 72 hours after the seizure). When offering an EEG, discuss the benefits and risks of provoking manoeuvres during EEG, such as hyperventilation and photic stimulation, with the person and their family or carers if appropriate. If agreed, include provoking manoeuvres during routine EEG to assess a suspected first seizure. If routine EEG is normal, consider a sleep-deprived EEG if agreed with the person, and their family or carers if appropriate, after discussing the benefits and risks. If routine and sleep-deprived EEG results are normal and diagnostic uncertainty persists, consider ambulatory EEG (for up to 48 hours). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on specialist assessment and diagnosis . Full details of the evidence and the committee's discussion are in evidence review 3: diagnosis of epilepsies. Loading. Please wait. # Neuroimaging ## Initial imaging scans Offer an MRI scan to children, young people and adults diagnosed with epilepsy, unless they have idiopathic generalised epilepsy or self-limited epilepsy with centrotemporal spikes. The MRI should be carried out: within 6 weeks of the MRI referral and following regionally agreed epilepsy MRI protocols. If MRI is contraindicated, consider a CT scan for children, young people and adults with epilepsy. When offering an MRI or CT scan, discuss the risks and benefits with the person with epilepsy (and their families and carers, as appropriate), especially if a general anaesthetic or sedation is needed for the scan. ## Reporting and reviewing scans Ensure that MRI scans are reported by a radiologist with expertise in paediatric or adult neuroradiology, as appropriate. If seizures are ongoing despite treatment, and diagnosis remains unclear, consider an additional review of MRI scans by a specialist in paediatric or adult neuroradiology within a tertiary centre. ## Repeat scanning Consider an additional MRI scan for children, young people and adults with epilepsy, if: the original scan was suboptimal there are new features to their epilepsy they have idiopathic generalised epilepsy or self-limited epilepsy with centrotemporal spikes that has not responded to first-line treatment surgery is being considered. ## Scanning in acute situations Do not carry out a CT scan for people with established epilepsy presenting at an emergency department after a typical seizure, unless there are other concerns. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on neuroimaging . Full details of the evidence and the committee's discussion are in: evidence review A: magnetic resonance imaging scan to detect relevant abnormalities in people with epilepsy evidence review B: computed tomography scan performance in people with epilepsy. Loading. Please wait. # Genetic testing Discuss with a neurologist or geneticist any uncertainties about whether to offer genetic testing or which tests to offer to a person with epilepsy. When making decisions about which tests to offer, refer to the NHS National Genomic Test Directory for rare and inherited disease for information on genetic tests commissioned by the NHS in England. Before carrying out genetic tests: discuss the purpose of testing and the possible implications of the results with the person with epilepsy, and their family and carers if appropriate -btain informed consent with appropriate genetic counselling in line with the NHS Genomic Medicine Service. Consider whole-genome sequencing for people with epilepsy of unknown cause who: were aged under 2 years when epilepsy started or have clinical features suggestive of a specific genetic epilepsy syndrome (for example, Dravet syndrome) or have additional clinical features such as: a learning disability autism spectrum disorder a structural abnormality (for example, dysmorphism or congenital malformation) unexplained cognitive or memory decline.See also the eligibility criteria that accompany the NHS National Genomic Test Directory. Consider whole-genome sequencing for people with epilepsy of unknown cause who were aged between 2 and 3 years when epilepsy started, if clinically agreed by a specialist multidisciplinary team. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on genetic testing . Full details of the evidence and the committee's discussion are in evidence review C: effectiveness of genetic testing in determining the aetiology of epilepsy. Loading. Please wait. # Antibody testing Consider antibody testing in discussion with a neurologist for people with new-onset epilepsy if autoimmune encephalitis is suspected. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on antibody testing . Full details of the evidence and the committee's discussion are in evidence review D: antibody testing in epilepsy. Loading. Please wait.# Information and support For information and support before diagnosis, see the section on information and support after a first seizure. When providing information to people with epilepsy and their families or carers, follow: the recommendations on communication and information in NICE's guidelines on patient experience in adult NHS services or babies, children and young people's experience of healthcare and NICE's guideline on shared decision making. Provide tailored information and support to people with epilepsy, and their families or carers if appropriate, according to their individual needs and circumstances. Include children and young people in discussions about their information and support needs, and provide information appropriate to their developmental age. Take into account the information and support needs of people with epilepsy who are older, have a learning disability or have other complex needs, for example: give longer appointments to allow more time for discussion provide information in different formats, such as easy read, large print or audio versions involve family members or carers or an advocate if the person wishes share information with those involved in the care of older people or people with learning disabilities if appropriate.See also the section on general principles of care in NICE's guideline on challenging behaviour and learning disabilities and the section on overarching principles in NICE's guideline on care and support of people growing older with learning disabilities. Give people with epilepsy, and their families and carers if appropriate, details of local and national epilepsy information and support groups. Support people to self-manage their epilepsy and make informed choices by discussing the following issues with them during their first appointment: triggers that may provoke seizures medications for epilepsy, the importance of adherence to medication and possible side effects reducing epilepsy-related risks, including sudden unexpected death in epilepsy (SUDEP) impact on daily activities, including driving their epilepsy syndrome or seizure types.The discussion may be reiterated at an information and care-planning session with an epilepsy specialist nurse (see also the section on epilepsy specialist nurses). Provide the person with epilepsy, and their family or carers if appropriate, with a copy of their care plan, which includes details of their care and support as discussed and agreed with the person, and their family or carers if appropriate. Repeat information for people with epilepsy, and their families or carers if appropriate, at subsequent appointments according to their individual needs and circumstances. Provide information and support at routine appointments with the person's GP, specialist or epilepsy specialist nurse, as needed, and also at dedicated information and care-planning appointments with an epilepsy specialist nurse (see the section on epilepsy specialist nurses). Consider providing a framework for discussions before appointments that includes issues commonly raised by people with epilepsy or that may be of concern to the person. Offer people with epilepsy, and their families and carers if appropriate, opportunities at each appointment to discuss issues that concern them including, but not limited to, the topics in box 1. Activities of daily living Safety issues, including activities that should be adapted or avoided, for example, showering rather than having baths, cooking safely, caring for babies and young children safely, and avoiding working at heights. Safety issues for children and young people, including supervised swimming and water sports, not climbing above their height without supervision. Potential impact on lifestyle and social life and any experiences of social exclusion. Driving, including Driver and Vehicle Licensing Agency (DVLA) regulations. Employment and education, including concerns and rights related to employment and education. Carers Physical and emotional demands of caring for and supporting a person with epilepsy. Information and support for carers, including assessing carers needs (see also NICE's guideline on supporting adult carers). Cognition Concerns about the impact of epilepsy and antiseizure medication on cognitive function, including memory, attention, concentration, educational attainment and performance in the workplace. Medication Adherence to antiseizure medication and how to improve this (see also NICE's guidelines on medicines adherence and medicines optimisation). Experiences of side effects from medication and coping strategies. Explaining changes to medication. Mental health Emotional health and psychological wellbeing, for example, experience of depression, anxiety or low mood (see also NICE's guidelines on depression in adults with a chronic physical health problem, depression in children and young people and mental health problems in people with learning disabilities). Neurobehavioural disorders commonly associated with epilepsy, including autism and attention deficit hyperactivity disorder. Stigmatisation of epilepsy. Reproductive health and pregnancy Support and information on contraception and pregnancy for women and their partners to enable them to make informed decisions. Support for changes in medications and the potential interactions with contraception. Teratogenicity of antiseizure medications. Pre-conception planning, including the use of folic acid and reducing epilepsy-related risk during pregnancy. Planning the birth. Postnatal care and breastfeeding. See also the section on antiseizure medications for women and girls and follow the Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on antiepileptic drugs in pregnancy. SUDEP Concerns of people with epilepsy and their families and carers about sudden unexpected death in epilepsy (SUDEP). Information about SUDEP, including risk factors for SUDEP and how to reduce the risks. Availability of SUDEP counselling. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support . Full details of the evidence and the committee's discussion are in: evidence review 4: information and support evidence review O: effectiveness of a nurse specialist in the management of epilepsy. Loading. Please wait.# Referral to tertiary specialist services Ensure that all children, young people and adults with suspected or confirmed epilepsy have access to a tertiary epilepsy service, if needed, via their specialist. Take into account that people with suspected or confirmed epilepsy and a learning disability, physical disability or mental health problem may need additional specialist support to manage their epilepsy. Support them to access a tertiary epilepsy service if needed. Refer people with epilepsy to a tertiary epilepsy service, to be seen within 4 weeks, if any of the following apply: uncertainty about the diagnosis or cause of epilepsy, the seizure type or epilepsy syndrome the person has an epilepsy syndrome likely to be drug resistant, their seizures are drug resistant or their treatment is associated with intolerable side effects further assessment and treatment approaches are indicated, such as: video electroencephalogram (EEG) telemetry, neuropsychology or neuropsychiatry, specialised neuroimaging, specialised treatments (for example, medication that can only be prescribed by a tertiary epilepsy service or a ketogenic diet), epilepsy surgery or vagus nerve stimulation the person is eligible for and wishes to participate in a clinical trial or research study. Refer children with suspected or confirmed epilepsy to a tertiary paediatric epilepsy service to be seen within 2 weeks, if they: are aged under 3 years are aged under 4 years and have myoclonic seizures (see recommendation 5.4.1 in the section on myoclonic seizures) have a unilateral structural lesion are showing deterioration in their behaviour, speech or learning. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral to tertiary specialist services . Full details of the evidence and the committee's discussion are in evidence review N: criteria for referral to specialist services. Loading. Please wait.# Principles of treatment, safety, monitoring and withdrawal # Treatment with antiseizure medications See also the section on antiseizure medications for women and girls for special considerations for this group. Develop an individualised antiseizure medication treatment strategy with the person, and their family and carers if appropriate, taking into account: sex age seizure type epilepsy syndrome whether treatment is needed risks and benefits of antiseizure medications, including their importance in reducing the risk of epilepsy-related death possible interactions with any other medicines taken any comorbidities the preferences of the person, and their family or carers if appropriate personal circumstances, such as education, employment, likelihood of pregnancy, driving, alcohol use, travel how and when antiseizure medicines need to be taken.See also NICE's guidelines on shared decision making and decision making and mental capacity. Take into account any particular issues for older people starting an antiseizure medication, especially those with comorbidities, for example: check for possible interactions with other medicines they are taking use a tailored approach to dosage and titration, usually starting at a lower dose and increasing slowly check if the person would benefit from an approach that takes into account multimorbidity; for more information, see NICE's guideline on multimorbidity. Use a single antiseizure medication (monotherapy) to treat epilepsy whenever possible. Review the diagnosis of epilepsy if seizures continue despite an optimal dose of a first-line antiseizure medication. If first-line monotherapy is unsuccessful and epilepsy diagnosis remains confirmed, try monotherapy with another antiseizure medication, using caution during the changeover period: Increase the dose of the second medicine slowly while maintaining the dose of the first medicine. If the second medicine is successful, slowly taper off the dose of the first medicine. If the second medicine is unsuccessful, slowly taper off the dose of the second medicine and consider an alternative. If monotherapy is unsuccessful, consider trying an add-on treatment. When starting an add-on treatment, carefully titrate the additional medicine and review treatment frequently, including monitoring for adverse effects such as sedation. If trials of add-on treatment do not result in a reduction in seizures, use the regimen that provides the best balance between effectiveness and tolerability of side effects. Discuss with the person, and their family and carers as appropriate, the benefits of taking as few medicines as possible to maintain seizure freedom or control. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatment with antiseizure medications . Full details of the evidence and the committee's discussion are in the following evidence reviews: evidence review E: monotherapy for generalised tonic-clonic and focal onset seizures evidence review F: add-on therapy for generalised tonic-clonic and focal onset seizures evidence review G: effectiveness of antiseizure therapies in the treatment of absence seizures evidence review H: effectiveness of antiseizure therapies in the treatment of myoclonic seizures evidence review I: effectiveness of antiseizure therapies in the treatment of tonic or atonic seizures/drop attacks evidence review J: effectiveness of antiseizure therapies in the treatment of idiopathic generalised epilepsies, including juvenile myoclonic epilepsy evidence review K: effectiveness of antiseizure therapies in the treatment of Dravet syndrome evidence review L: effectiveness of antiseizure therapies in the treatment of Lennox-Gastaut syndrome evidence review P: effectiveness of antiseizure therapies for infantile spasms evidence review Q: effectiveness of antiseizure medications for self-limited epilepsy with centrotemporal spikes evidence review R: effectiveness of antiseizure therapies for epilepsy with myoclonic-atonic seizures (Doose syndrome). Loading. Please wait. # When to start antiseizure medication Start treatment with an antiseizure medication once the diagnosis of epilepsy is confirmed. Consider starting treatment after a first unprovoked seizure if any of the following apply: an examination identifies signs of neurological deficit the electroencephalogram (EEG) shows unequivocal epileptic activity after a discussion of the risk of further seizures, the person or their family or carers consider the risk unacceptable brain imaging shows a structural abnormality. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on when to start antiseizure medication . Full details of the evidence and the committee's discussion are in the following evidence reviews: evidence review E: monotherapy for generalised tonic-clonic and focal onset seizures evidence review F: add-on therapy for generalised tonic-clonic and focal onset seizures evidence review G: effectiveness of antiseizure therapies in the treatment of absence seizures evidence review H: effectiveness of antiseizure therapies in the treatment of myoclonic seizures evidence review I: effectiveness of antiseizure therapies in the treatment of tonic or atonic seizures/drop attacks evidence review J: effectiveness of antiseizure therapies in the treatment of idiopathic generalised epilepsies, including juvenile myoclonic epilepsy evidence review K: effectiveness of antiseizure therapies in the treatment of Dravet syndrome evidence review L: effectiveness of antiseizure therapies in the treatment of Lennox-Gastaut syndrome evidence review P: effectiveness of antiseizure therapies for infantile spasms evidence review Q: effectiveness of antiseizure medications for self-limited epilepsy with centrotemporal spikes evidence review R: effectiveness of antiseizure therapies for epilepsy with myoclonic-atonic seizures (Doose syndrome). Loading. Please wait. # Safety considerations See the section on antiseizure medications for women and girls for additional safety considerations for this group. Follow Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on switching between different manufacturers' products of a particular antiseizure medication. Be aware that phenytoin is associated with an increased risk of serious skin reactions in people of Han Chinese or Thai family background. Be aware that carbamazepine and potentially medicines with a similar chemical structure (such as oxcarbazepine and eslicarbazepine acetate) are associated with an increased risk of serious skin reactions in people of Han Chinese, Thai, European or Japanese family background. Be aware that long-term treatment with some antiseizure medications (such as carbamazepine, phenytoin, primidone and sodium valproate) is associated with decreased bone mineral density and increased risk of osteomalacia. Follow the MHRA safety advice on antiepileptics: adverse effects on bone and consider vitamin D and calcium supplementation for people at risk. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on safety considerations . Full details of the evidence and the committee's discussion are in the following evidence reviews: evidence review E: monotherapy for generalised tonic-clonic and focal onset seizures evidence review F: add-on therapy for generalised tonic-clonic and focal onset seizures evidence review G: effectiveness of antiseizure therapies in the treatment of absence seizures evidence review H: effectiveness of antiseizure therapies in the treatment of myoclonic seizures evidence review I: effectiveness of antiseizure therapies in the treatment of tonic or atonic seizures/drop attacks evidence review J: effectiveness of antiseizure therapies in the treatment of idiopathic generalised epilepsies, including juvenile myoclonic epilepsy evidence review K: effectiveness of antiseizure therapies in the treatment of Dravet syndrome evidence review L: effectiveness of antiseizure therapies in the treatment of Lennox-Gastaut syndrome evidence review P: effectiveness of antiseizure therapies for infantile spasms evidence review Q: Effectiveness of antiseizure medications for self-limited epilepsy with centrotemporal spikes evidence review R: effectiveness of antiseizure therapies for epilepsy with myoclonic-atonic seizures (Doose syndrome). Loading. Please wait. # Antiseizure medications for women and girls Give women and girls with epilepsy information and support that is tailored to their age-specific and developmental needs. Review regularly information provided about: contraception folic acid supplementation conception pregnancy breastfeeding caring for children menopause. Discuss with women and girls with epilepsy who are able to have children (including young girls who are likely to need treatment when they are able to have children), and their families or carers if appropriate, the risks to an unborn child of taking antiseizure medications during pregnancy, such as congenital malformations, neurodevelopmental impairments and fetal growth restriction. Assess the risks and benefits of treatment with individual antiseizure medications when prescribing antiseizure medications for women and girls who are able to have children, now or in the future. Take into account the latest data on the risks to the unborn child and be aware that there are important uncertainties about the risks, particularly with newer drugs. Follow the MHRA safety advice on antiepileptic drugs in pregnancy. Specifically, discuss the risks to the unborn child of using sodium valproate during pregnancy, including the increased risk with higher doses and polytherapy. Follow the MHRA safety advice on valproate use by women and girls. Be aware that some antiseizure medications, for example, carbamazepine, oxcarbazepine, phenytoin and topiramate, can impair the effectiveness of hormonal contraceptives. Refer to the summary of product characteristics (SPC) and BNF or BNF for children for individual drug advice on the interactions between antiseizure medications and contraception. Be aware that oestrogen-containing hormonal contraceptives and hormone replacement therapy can impair the effectiveness of lamotrigine. Explain that breastfeeding for most women and girls taking antiseizure medications is generally safe and should be encouraged. Support each mother to choose a feeding method that bests suits her and her family. Prescribers should consult individual drug advice in the SPC and the BNF or BNF for children when prescribing antiseizure medications for women and girls who are breastfeeding. Decisions about antiseizure therapy and breastfeeding should be made between the woman or girl and the prescriber, and take into account the benefits of breastfeeding alongside the potential risks of the medication affecting the child. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on antiseizure medications for women and girls . Full details of the evidence and the committee's discussion are in evidence review 6: safety of antiseizure medications in women and girls. Loading. Please wait. # Monitoring and review Arrange regular (at least annual) monitoring reviews for adults with epilepsy and any of the following: a learning disability drug-resistant epilepsy a high risk of sudden unexpected death in epilepsy (SUDEP; see the section on reducing the risk of epilepsy-related death) a serious comorbidity, such as complex psychosocial, cognitive or mental health problems who are taking antiseizure medications associated with long-term side effects or drug interactions who are able to get pregnant and are taking valproate or any other high-risk teratogenic antiseizure medication (see also the MHRA safety advice on antiepileptic drugs in pregnancy). See also, the section on epilepsy specialist nurses for epilepsy specialist nurse sessions for adults with ongoing seizures. Discuss monitoring reviews with children and young people with epilepsy and their families and carers if appropriate, and agree a frequency for regular reviews that is: individually tailored to the child or young person's needs, preferences and the nature of their epilepsy and at least every 12 months. See also the section on infantile spasms syndrome for recommendations on additional monitoring reviews for children with infantile spasms. See the section on epilepsy specialist nurses for recommendations on epilepsy specialist nurse sessions for children and young people with ongoing seizures. Consider monitoring antiseizure medication levels in people with epilepsy and any of the following: uncontrolled seizures side effects from their medication a specific clinical condition needing closer supervision (such as pregnancy or renal failure) poor adherence to medication. Explain to people with epilepsy and, if appropriate, their families and carers, that they can ask for a review of their care if they have concerns, need support or their care needs change, for example, to support medicines withdrawal, pregnancy planning or to review treatment if seizures recur. Provide contact details and information on how to access epilepsy services. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring and review . Full details of the evidence and the committee's discussion are in: evidence review 7: monitoring evidence review O: effectiveness of a nurse specialist in the management of epilepsy. Loading. Please wait. # Support and monitoring for women planning pregnancy or who are pregnant Refer women and girls with epilepsy who are planning pregnancy or are pregnant to an epilepsy specialist team for a review of their antiseizure medication options. Ensure information about the care of women and girls during pregnancy is shared between the epilepsy specialist team, a specialist obstetric team and primary care. Explain to women and girls who are pregnant or are planning pregnancy the importance of adherence to their antiseizure medications and that they should not stop their medication without medical supervision (see also recommendation 4.6.1 on referral). Discuss the relative benefits and risks of adjusting medication with the woman or girl planning pregnancy to enable her to make informed decisions. This should include discussing the balance between the risks of poorly controlled seizures and the risks to the baby when antiseizure medicines are taken in pregnancy or while breastfeeding. Consider more frequent monitoring reviews for women and girls with epilepsy who are pregnant and are prescribed antiseizure medication, if they: have a learning disability are aged under 16 years have active epilepsy (a seizure within the past 12 months) have bilateral tonic-clonic seizures have modifiable risk factors for SUDEP (see recommendation 10.1.2). Consider monitoring antiseizure medication levels in women or girls with epilepsy who are planning pregnancy and are considered to be at risk of their seizures worsening. When starting monitoring in women or girls planning pregnancy, obtain a baseline (pre-conception) concentration of antiseizure medications (for example, carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital and phenytoin) and check adherence to their medication. For women or girls with epilepsy who are pregnant or planning a pregnancy and taking carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital or phenytoin, monitor and adjust dosages following the MHRA safety advice on antiepileptic drugs in pregnancy. If monitoring of antiseizure medications levels is carried out in pregnancy, discuss the results with the woman or girl with epilepsy to inform choices about any adjustments to doses. If dosing of antiseizure medications is changed during pregnancy, discuss and make an antenatal plan with the woman or girl to return her medications to pre-conception dosages. Antiseizure medications should begin to return to pre-conception dosages in the first few days after the birth. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on support and monitoring for women planning pregnancy or who are pregnant . Full details of the evidence and the committee's discussion are in: evidence review 7: monitoring evidence review O: effectiveness of a nurse specialist in the management of epilepsy. Loading. Please wait. # Discontinuing antiseizure medication For further guidance on managing withdrawal of benzodiazepines and gabapentinoids in adults, see the section on withdrawing a medicine in NICE's guideline on medicines associated with dependence or withdrawal symptoms. Discuss the benefits and risks of discontinuing antiseizure medication with the person with epilepsy, and their family and carers as appropriate, as part of an ongoing assessment of their treatment at any appointment or review. Provide information about the risks and benefits in an accessible format. After a person has been seizure-free for 2 years, carry out an individualised assessment to determine the risk of seizure recurrence if antiseizure medications are discontinued. This should be carried out by an epilepsy specialist if there is any doubt or concern about the risks. When deciding whether to discontinue antiseizure medications, discuss with the person with epilepsy, and their family or carers if appropriate: their individualised risk assessment, including their risk of seizures recurring and, if appropriate, the risk of SUDEP the person's preferences and lifestyle, including the implications for driving if relevant. If a decision is made to discontinue antiseizure medication, agree a plan with the person, and their family or carers if appropriate, based on the person's risk and preferences. The plan should include reducing their antiseizure medications gradually: For most medicines, this would typically be over at least 3 months. For benzodiazepines and barbiturates, this would typically be over a longer period to reduce the risk of drug-related withdrawal symptoms. For people with epilepsy taking multiple antiseizure medications, discontinue their medications one at a time. If seizures recur during or after discontinuation, reverse the last dose reduction and seek guidance from the epilepsy specialist, in line with the agreed plan. After epilepsy surgery, discontinue antiseizure medications under the guidance of the epilepsy surgery centre. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on discontinuing antiseizure medication . Full details of the evidence and the committee's discussion are in evidence review M: discontinuation of pharmacological treatment. Loading. Please wait.# Treating epileptic seizures in children, young people and adults # Generalised tonic-clonic seizures For more information on treatment in women and girls, see the section on antiseizure medications for women and girls. Follow the Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy. December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section. ## Monotherapy Offer sodium valproate as first-line monotherapy for generalised tonic-clonic seizures in: boys and men girls aged under 10 years and who are unlikely to need treatment when they are old enough to have children women who are unable to have children. Offer lamotrigine or levetiracetam as first-line monotherapy for generalised tonic-clonic seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children). If the first choice is unsuccessful, offer the other of these options.In April 2022, these were off-label uses of lamotrigine in children under 13 years and levetiracetam in adults and children. See NICE's information on prescribing medicines. If first-line monotherapy with sodium valproate is unsuccessful for generalised tonic-clonic seizures, offer lamotrigine or levetiracetam as second-line monotherapy treatment. If the first choice is unsuccessful, try the other of these options.In April 2022, these were off-label uses of lamotrigine in children under 13 years and levetiracetam in adults and children. See NICE's information on prescribing medicines. Do not offer sodium valproate monotherapy for generalised tonic-clonic seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children), unless: -ther treatment options are unsuccessful the risks and benefits have been fully discussed, including the risks to an unborn child the likelihood of pregnancy has been taken into account and a pregnancy prevention programme put in place, if appropriate.Follow the MHRA safety advice on valproate use by women and girls. ## Add-on treatment For guidance on safe prescribing and managing withdrawal of clobazam in adults, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. If monotherapy is unsuccessful in people with generalised tonic-clonic seizures, consider 1 of the following first-line add-on treatment options: clobazam lamotrigine levetiracetam perampanel sodium valproate, except in women and girls able to have children topiramate. If the first choice is unsuccessful, consider the other first-line add-on options.In April 2022, these were off-label uses of clobazam as add-on therapy in children under 6 months, lamotrigine in children under 2 years, levetiracetam in children under 12 years, perampanel in children under 7 years, and topiramate in children under 2 years. See NICE's information on prescribing medicines. If first-line add-on treatments tried are unsuccessful in people with generalised tonic-clonic seizures, consider 1 of the following second-line add-on treatment options: brivaracetam lacosamide phenobarbital primidone zonisamide. If the first choice is unsuccessful, consider the other second-line add-on options.In April 2022, these were off-label uses of brivaracetam in adults and children, lacosamide in children under 4 years, and zonisamide in adults and children. See NICE's information on prescribing medicines. Do not offer sodium valproate as an add-on treatment for generalised tonic-clonic seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children), unless: -ther treatment options are unsuccessful the risks and benefits have been fully discussed, including the risks to an unborn child the likelihood of pregnancy has been taken into account and a pregnancy prevention programme put in place, if appropriate.Follow the MHRA safety advice on valproate use by women and girls. ## Other treatment considerations Be aware that the following antiseizure medications may exacerbate seizures in people with absence or myoclonic seizures, including in juvenile myoclonic epilepsy: carbamazepine gabapentin lamotrigine (for myoclonic seizures) -xcarbazepine phenytoin pregabalin tiagabine vigabatrin. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on generalised tonic-clonic seizures . Full details of the evidence and the committee's discussion are in: evidence review E: monotherapy for generalised tonic-clonic and focal onset seizures evidence review F: add-on therapy for generalised tonic-clonic and focal onset seizures. Loading. Please wait. # Focal seizures with or without evolution to bilateral tonic-clonic seizures For more information on treatment in women and girls, see the section on antiseizure medications for women and girls. Follow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy. December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section. ## Monotherapy Consider lamotrigine or levetiracetam as first-line monotherapy for people with focal seizures. If the first choice is unsuccessful, consider the other of these options.In April 2022, these were off-label uses of lamotrigine in children under 13 years, and levetiracetam in children and young people under 16 years. See NICE's information on prescribing medicines. If first-line monotherapies are unsuccessful in people with focal seizures, consider 1 of the following second-line monotherapy options: carbamazepine -xcarbazepine zonisamide. If the first choice is unsuccessful, consider the other second-line monotherapy options.In April 2022, these were off-label uses of oxcarbazepine in children under 6 years, and zonisamide in children. See NICE's information on prescribing medicines. If second-line monotherapies tried are unsuccessful in people with focal seizures, consider lacosamide as third-line monotherapy. In April 2022, this was an off-label use of lacosamide in children under 4 years. See NICE's information on prescribing medicines. ## Add-on treatment For guidance on safe prescribing of pregabalin in adults, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. If monotherapy is unsuccessful in people with focal seizures, consider 1 of the following first-line add-on treatment options: carbamazepine lacosamide lamotrigine levetiracetam -xcarbazepine topiramate zonisamide. If the first choice is unsuccessful, consider the other first-line add-on options.In April 2022, these were off-label uses of lacosamide in children under 4 years, lamotrigine in children under 2 years, levetiracetam in children under 4 years, oxcarbazepine in children under 6 years, topiramate in children under 2 years, and zonisamide in children under 6 years. See NICE's information on prescribing medicines. If first-line add-on treatments tried are unsuccessful in people with focal seizures, consider 1 of the following second-line add-on treatment options: brivaracetam cenobamate (in line with NICE's technology appraisal guidance on cenobamate for treating focal onset seizures in epilepsy) eslicarbazepine acetate perampanel pregabalin sodium valproate, except in women and girls able to have children. If the first choice is unsuccessful, consider the other second-line add-on options.In April 2022, these were off-label uses of brivaracetam in children under 4 years, eslicarbazepine acetate in children under 6 years, perampanel in children under 4 years, and pregabalin in children. See NICE's information on prescribing medicines. If second-line add-on treatments tried are unsuccessful in people with focal seizures, consider 1 of the following third-line add-on treatment options: phenobarbital phenytoin tiagabine vigabatrin. If the first choice is unsuccessful, consider the other third-line add-on options.In April 2022, this was an off-label use of tiagabine in children under 12 years. See NICE's information on prescribing medicines. Do not offer sodium valproate as an add-on treatment for focal seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children), unless: -ther treatment options are unsuccessful the risks and benefits have been fully discussed, including the risks to an unborn child the likelihood of pregnancy has been taken into account and a pregnancy prevention programme put in place, if appropriate.Follow the MHRA safety advice on valproate use by women and girls. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on focal seizures with or without evolution to bilateral tonic-clonic seizures . Full details of the evidence and the committee's discussion are in: evidence review E: monotherapy for generalised tonic-clonic and focal onset seizures evidence review F: add-on therapy for generalised tonic-clonic and focal onset seizures. Loading. Please wait. # Absence seizures For more information on treatment in women and girls, see the section on antiseizure medications for women and girls. Follow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy. December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section. ## Absence seizures (including childhood absence epilepsy) Offer ethosuximide as first-line treatment for absence seizures. If first-line treatment is unsuccessful, offer sodium valproate as second-line monotherapy or add-on treatment for absence seizures in: boys of all ages girls aged under 10 years and who are unlikely to need treatment when they are old enough to have children women who are unable to have children. If second-line treatment is unsuccessful for absence seizures, consider lamotrigine or levetiracetam as a third-line monotherapy or add-on treatment options. If the first choice is unsuccessful, consider the other of these options.In April 2022, these were off-label uses of lamotrigine in children under 2 years and levetiracetam in adults and children. See NICE's information on prescribing medicines. Be aware that the following antiseizure medications may exacerbate seizures in people with absence seizures: carbamazepine gabapentin -xcarbazepine phenobarbital phenytoin pregabalin tiagabine vigabatrin. ## Absence seizures with other seizure types Consider sodium valproate as first-line treatment for absence seizures with other seizure types (or at risk of these) in: boys and men girls aged under 10 years and who are unlikely to need treatment when they are old enough to have children women who are unable to have children. Consider lamotrigine or levetiracetam as first-line treatment options in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children) with absence seizures and other seizure types (or at risk of these). If the first choice is unsuccessful, consider the other of these options.In April 2022, these were off-label uses of levetiracetam as monotherapy for adults and children, and as an add-on therapy for children under 12 years. See NICE's information on prescribing medicines. Do not offer sodium valproate for absence seizures with other seizure types (or at risk of these) in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children), unless: -ther treatment options are unsuccessful the risks and benefits have been fully discussed, including the risks to an unborn child the likelihood of pregnancy has been taken into account and a pregnancy prevention programme put in place, if appropriate.Follow the MHRA safety advice on valproate use by women and girls. If first-line treatments tried are unsuccessful for absence seizures and other seizure types (or at risk of these), consider: lamotrigine or levetiracetam as a second-line monotherapy or add-on treatment options or ethosuximide as a second-line add-on treatment.If the first choice is unsuccessful, consider the other second-line options.In April 2022, these were off-label uses of lamotrigine in children under 2 years, and levetiracetam in adults and children. See NICE's information on prescribing medicines. Be aware that the following antiseizure medications may exacerbate seizures in people with absence seizures and other seizure types (or at risk of these): carbamazepine gabapentin -xcarbazepine phenobarbital phenytoin pregabalin tiagabine vigabatrin. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on absence seizures . Full details of the evidence and the committee's discussion are in evidence review G: effectiveness of antiseizure therapies in the treatment of absence seizures. Loading. Please wait. # Myoclonic seizures For more information on treatment in women and girls, see the section on antiseizure medications for women and girls. Follow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy. December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section. ## Specialist involvement If a child under 4 years has myoclonic seizures, either seek guidance on treatment from or refer to a tertiary paediatric neurologist. ## First-line treatment Offer sodium valproate as first-line treatment for myoclonic seizures in: boys and men girls aged under 10 years and who are unlikely to need treatment when they are old enough to have children women who are unable to have children. Offer levetiracetam as first-line treatment for myoclonic seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children). In April 2022, this was an off-label use of levetiracetam. See NICE's information on prescribing medicines. ## Second- and third-line treatments For guidance on safe prescribing and managing withdrawal of clobazam and clonazepam in adults, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. If sodium valproate is unsuccessful as first-line treatment for myoclonic seizures, offer levetiracetam as a second-line monotherapy or add-on treatment.In April 2022, these were off-label uses of levetiracetam as monotherapy for adults and children, and as an add-on therapy for children under 12 years. See NICE's information on prescribing medicines. If levetiracetam is unsuccessful for myoclonic seizures, consider 1 of the following as monotherapy or add-on treatment options: brivaracetam clobazam clonazepam lamotrigine phenobarbital piracetam topiramate zonisamide.If the first choice is unsuccessful, consider any other of these options.In April 2022, these were off-label uses for brivaracetam in adults and children, clobazam as monotherapy in adults and children, clobazam as add-on therapy in children under 6 months, clonazepam solution in children, lamotrigine as monotherapy for children under 13 years and add-on therapy for children under 2 years, piracetam in children, topiramate in adults and children, and zonisamide in adults and children. See NICE's information on prescribing medicines. Do not offer sodium valproate for myoclonic seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children), unless: -ther treatment options are unsuccessful the risks and benefits have been fully discussed, including the risks to an unborn child the likelihood of pregnancy has been taken into account and a pregnancy prevention programme put in place, if appropriate.Follow the MHRA safety advice on valproate use by women and girls. ## Other treatment considerations Be aware that lamotrigine can occasionally exacerbate myoclonic seizures. Do not use any of the following antiseizure medications in people with myoclonic seizures because they may exacerbate seizures: carbamazepine gabapentin -xcarbazepine phenytoin pregabalin tiagabine vigabatrin. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on myoclonic seizures . Full details of the evidence and the committee's discussion are in evidence review H: effectiveness of antiseizure therapies in the treatment of myoclonic seizures. Loading. Please wait. # Tonic or atonic seizures For more information on treatment in women and girls, see the section on antiseizure medications for women and girls. Follow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy. December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section. ## Specialist involvement Ensure that people with a diagnosis of tonic or atonic seizures are assessed by a neurologist with expertise in epilepsy to: diagnose the syndrome if possible and advise on investigation and treatment. ## First-line treatment Offer sodium valproate as first-line treatment for tonic or atonic seizures in: boys and men girls aged under 10 years and who are unlikely to need treatment when they are old enough to have children women who are unable to have children. Consider lamotrigine as first-line treatment for tonic or atonic seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children).In April 2022, this was an off-label use of lamotrigine in children under 13 years. See NICE's information on prescribing medicines. ## Second- and third-line treatments For guidance on safe prescribing and managing withdrawal of clobazam in adults, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. If sodium valproate is unsuccessful as first-line treatment for tonic or atonic seizures, consider lamotrigine as a second-line monotherapy or add-on treatment.In April 2022, this was an off-label use of lamotrigine as monotherapy in children under 13 years and add-on therapy in children under 2 years. See NICE's information on prescribing medicines. If lamotrigine is unsuccessful for treating tonic or atonic seizures, consider 1 of the following as monotherapy or add-on treatment options: clobazam rufinamide topiramate.If the first choice is unsuccessful, consider any other of these options.In April 2022, these were off-label uses for clobazam as monotherapy in adults and children, clobazam as add-on therapy in children under 6 months, rufinamide, and topiramate as monotherapy in children under 6 years, and topiramate as add-on therapy in children under 2 years. See NICE's information on prescribing medicines. Do not offer sodium valproate for tonic or atonic seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children), unless: -ther treatment options are unsuccessful the risks and benefits have been fully discussed, including the risks to an unborn child the likelihood of pregnancy has been taken into account and a pregnancy prevention programme put in place, if appropriate.Follow the MHRA safety advice on valproate use by women and girls. ## Further treatment options If third-line treatment is unsuccessful for tonic or atonic seizures in children, consider a ketogenic diet as an add-on treatment under the supervision of a ketogenic diet team. If all other treatment options for tonic or atonic seizures are unsuccessful, consider felbamate as an add-on treatment under the supervision of a neurologist with expertise in epilepsy.In April 2022, felbamate was not licensed for use in the UK. See NICE's information on prescribing medicines. ## Other treatment considerations Be aware that the following antiseizure medications may exacerbate seizures in people with tonic or atonic seizures: carbamazepine gabapentin -xcarbazepine pregabalin tiagabine vigabatrin. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on tonic or atonic seizures . Full details of the evidence and the committee's discussion are in evidence review I: effectiveness of antiseizure therapies in the treatment of tonic or atonic seizures/drop attacks. Loading. Please wait. # Idiopathic generalised epilepsies For more information on treatment in women and girls, see the section on antiseizure medications for women and girls. Follow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy. December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section. ## First-line treatment Offer sodium valproate as first-line treatment for idiopathic generalised epilepsies in: boys and men girls aged under 10 years and who are unlikely to need treatment when they are old enough to have children women who are unable to have children. Offer lamotrigine or levetiracetam as first-line treatment for idiopathic generalised epilepsies in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children). If the first choice is unsuccessful, offer the other of these options.In April 2022, these were off-label uses of lamotrigine in children under 13 years, and levetiracetam in adults and children. See NICE's information on prescribing medicines. ## Second-line treatment If first-line treatments are unsuccessful for idiopathic generalised epilepsies, consider lamotrigine or levetiracetam as a second-line monotherapy or add-on treatment options. If the first choice is unsuccessful, consider the other of these options.In April 2022, these were off-label uses of lamotrigine as monotherapy in children under 13 years and add-on therapy for children under 2 years, and levetiracetam as monotherapy in adults and children and add-on therapy for children under 12 years. See NICE's information on prescribing medicines. If second-line treatments tried are unsuccessful for idiopathic generalised epilepsies, consider perampanel or topiramate as third-line add-on treatment options. If the first choice is unsuccessful, consider the other of these options.In April 2022, this was an off-label use of perampanel for children under 7 years. See NICE's information on prescribing medicines. Do not offer sodium valproate for idiopathic generalised epilepsies in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children), unless: -ther treatment options are unsuccessful the risks and benefits have been fully discussed, including the risks to an unborn child the likelihood of pregnancy has been taken into account and a pregnancy prevention programme put in place, if appropriate.Follow the MHRA safety advice on valproate use by women and girls. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on idiopathic generalised epilepsies . Full details of the evidence and the committee's discussion are in evidence review J: effectiveness of antiseizure therapies in the treatment of idiopathic generalised epilepsies, including juvenile myoclonic epilepsy. Loading. Please wait.# Treating childhood-onset epilepsies Antiseizure medications for childhood-onset epilepsy syndromes are considered off-label unless they are authorised for the specific syndrome. # Dravet syndrome For more information on treatment in women and girls, see the section on antiseizure medications for women and girls. Follow the Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy. December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section. For guidance on safe prescribing and managing withdrawal of clobazam in adults, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. ## Specialist involvement Ensure that people with Dravet syndrome have an adult or paediatric neurologist with expertise in epilepsy involved in their care. ## First-line treatment Consider sodium valproate as first-line treatment for people with Dravet syndrome. Be aware that sodium valproate should be used with caution in women and girls, but it is recommended as first-line treatment for Dravet syndrome because of the severity of the syndrome and the lack of evidence for other effective first-line treatment options. If sodium valproate first-line monotherapy is started or continued for Dravet syndrome in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children): discuss the potential risks and benefits of treatment, including the risks to an unborn child take into account the likelihood of pregnancy and put in place a pregnancy prevention programme, if appropriate.Follow the MHRA safety advice on valproate use by women and girls. If sodium valproate alone is unsuccessful as first-line monotherapy for Dravet syndrome, consider triple therapy with stiripentol and clobazam as first-line add-on therapy. Carefully titrate the additional drugs and review treatment frequently, including monitoring for adverse effects such as sedation. In April 2022, these were off-label uses of clobazam as add-on therapy in children under 6 months, and stiripentol when it is started in adults over 18 years. See NICE's information on prescribing medicines. ## Second-line treatment If triple therapy is unsuccessful for Dravet syndrome and the child is over 2 years, consider cannabidiol in combination with clobazam as a second-line add-on treatment option in line with NICE's technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Dravet syndrome. ## Further treatment options If triple therapy is unsuccessful for Dravet syndrome in a child aged under 2 years or second-line treatment is unsuccessful in a child aged over 2 years, consider 1 of the following add-on options under the supervision of a ketogenic diet team or a neurologist with expertise in epilepsy, as appropriate: ketogenic diet levetiracetam topiramate.If the first choice is unsuccessful, consider the other add-on options.In April 2022, these were off-label uses of levetiracetam and topiramate. See NICE's information on prescribing medicines. If all other treatment options for Dravet syndrome are unsuccessful, consider potassium bromide under the guidance of a neurologist with expertise in epilepsy.In April 2022, potassium bromide was not licensed for use in the UK. See NICE's information on prescribing medicines. ## Other treatment considerations Be aware that the following medications may exacerbate seizures in people with Dravet syndrome: carbamazepine gabapentin lacosamide lamotrigine -xcarbazepine phenobarbital pregabalin tiagabine vigabatrin.NICE has produced technology appraisal guidance on fenfluramine for treating seizures associated with Dravet syndrome. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on Dravet syndrome . Full details of the evidence and the committee's discussion are in evidence review K: effectiveness of antiseizure therapies in the treatment of Dravet syndrome. Loading. Please wait. # Lennox–Gastaut syndrome For more information on treatment in women and girls, see the section on antiseizure medications for women and girls. Follow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy. December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section. ## Specialist involvement Ensure that people with Lennox–Gastaut syndrome have an adult or paediatric neurologist with expertise in epilepsy involved in their care. ## First-line treatment Consider sodium valproate as first-line treatment for people with Lennox–Gastaut syndrome. Be aware that sodium valproate should be used with caution in women and girls, but it is recommended as first-line treatment for Lennox–Gastaut syndrome because of the severity of the syndrome and the lack of evidence for other effective first-line treatment options. If sodium valproate treatment is started or continued for Lennox–Gastaut syndrome in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children): discuss the risks and benefits of treatment, including the risks to an unborn child take into account the likelihood of pregnancy and put in place a pregnancy prevention programme, if appropriate.Follow the MHRA safety advice on valproate use by women and girls. ## Second-line treatment If first-line treatment is unsuccessful, consider lamotrigine as a second-line monotherapy or add-on treatment for people with Lennox–Gastaut syndrome.In April 2022, this use of lamotrigine was off-label as monotherapy in children under 13 years and add-on therapy for children under 2 years. See NICE's information on prescribing medicines. ## Third-line treatment For guidance on safe prescribing and managing withdrawal of clobazam in adults, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. If second-line treatment is unsuccessful, consider the following as third-line add-on treatment options for people with Lennox–Gastaut syndrome: cannabidiol in combination with clobazam if the child is over 2 years, in line with NICE's technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Lennox–Gastaut syndrome clobazam rufinamide topiramate. In April 2022, these were off-label uses of clobazam as add-on therapy in children under 6 months, rufinamide in children under 1 year, and topiramate in children under 2 years. See NICE's information on prescribing medicines. ## Starting an add-on treatment When starting an add-on treatment in people with Lennox–Gastaut syndrome, carefully titrate the additional medicine and review treatment frequently, including monitoring for adverse effects such as sedation. ## Further treatment options If seizures continue with third-line treatments for Lennox–Gastaut syndrome, consider a ketogenic diet as an add-on treatment under the supervision of a ketogenic diet team. If all other treatment options for Lennox–Gastaut syndrome are unsuccessful, consider felbamate as add-on treatment under the supervision of a neurologist with expertise in epilepsy. In April 2022, felbamate was not licensed for use in the UK. See NICE's information on prescribing medicines. ## Other treatment considerations Be aware that the following medications may exacerbate seizures in people with Lennox–Gastaut syndrome: carbamazepine gabapentin lacosamide lamotrigine -xcarbazepine phenobarbital pregabalin tiagabine vigabatrin. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on Lennox–Gastaut syndrome . Full details of the evidence and the committee's discussion are in evidence review L: effectiveness of antiseizure therapies in the treatment of Lennox-Gastaut syndrome. Loading. Please wait. # Infantile spasms syndrome ## Specialist involvement If a child under 2 years has suspected or confirmed infantile spasms, within 24 hours seek guidance from, and refer the child urgently to, a tertiary paediatric neurologist to ensure rapid assessment, including a sleep electroencephalogram (EEG), and rapid treatment to stop spasms. ## Monitoring Review children under 2 years with infantile spasms at least weekly during treatment and repeat sleep EEG at 2 weeks after starting treatment. When infantile spasms have stopped, review children monthly and repeat sleep EEG if spasms recur or there are clinical concerns. ## First-line treatment Offer combination therapy with high-dose oral prednisolone and vigabatrin as first-line treatment for infantile spasms that are not due to tuberous sclerosis, unless the child is at high risk of steroid-related side effects. In April 2022, this was an off-label use of vigabatrin in combination with prednisolone. See NICE's information on prescribing medicines. Consider vigabatrin alone as first-line treatment for infantile spasms in children at high risk of steroid-related side effects. Offer vigabatrin alone as first-line treatment for infantile spasms due to tuberous sclerosis. If vigabatrin is ineffective after 1 week, add high-dose oral prednisolone.In April 2022, this was an off-label use of vigabatrin in combination with prednisolone. See NICE's information on prescribing medicines. Before starting oral prednisolone for infantile spasms: discuss the possible side effects of steroid treatment with parents and carers test whether the child has antibodies to the varicella zoster virus give the parents and carers a steroid card and information about when to seek medical help for side effects. When using oral prednisolone to treat infantile spasms, follow the advice in the BNF for children on prednisolone dosages. Monitor blood pressure and urinary glucose weekly during treatment. When using vigabatrin to treat infantile spasms, increase the dose as outlined in the BNF for children on vigabatrin. Discuss further dose increases with a tertiary paediatric neurologist if the spasms do not stop (clinically and on EEG). ## Second-line treatment If first-line treatment for infantile spasms is unsuccessful, discuss further treatment with a tertiary paediatric epilepsy specialist. Consider the following as a second-line monotherapy or add-on treatment options for infantile spasms, guided by a ketogenic diet team or tertiary paediatric epilepsy specialist, as appropriate: ketogenic diet levetiracetam nitrazepam sodium valproate topiramate.If the first choice is unsuccessful, consider the other second-line options.In April 2022, these were off-label uses of levetiracetam, nitrazepam and topiramate. See NICE's information on prescribing medicines. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on infantile spasms syndrome . Full details of the evidence and the committee's discussion are in evidence review P: effectiveness of antiseizure therapies for infantile spasms. Loading. Please wait. # Self-limited epilepsy with centrotemporal spikes For more information on treatment in women and girls, see the section on antiseizure medications for women and girls. Follow the MHRA safety advice on antiepileptic drugs in pregnancy. ## Discussing starting treatment Discuss with children and young people with self-limited epilepsy with centrotemporal spikes, and their families or carers as appropriate, whether they wish to start treatment. In particular, discuss: frequency and severity of seizures possible hazards of ongoing seizures (including the small risk of death) possible side effects of treatment. ## First-line treatment Consider lamotrigine or levetiracetam as first-line treatment for self-limited epilepsy with centrotemporal spikes. If either lamotrigine or levetiracetam is unsuccessful, try the other of these options.In April 2022, these were off-label uses of lamotrigine in children under 13 years, and levetiracetam in children under 16 years. See NICE's information on prescribing medicines. ## Second-line treatment If first-line treatments for self-limited epilepsy with centrotemporal spikes are unsuccessful, consider the following as second-line monotherapy treatment options: carbamazepine -xcarbazepine zonisamide.If the first choice is unsuccessful, consider the other second-line monotherapy options.In April 2022, these were off-label uses for oxcarbazepine in children under 6 years, and zonisamide in adults and children. See NICE's information on prescribing medicines. ## Third-line treatment If second-line treatments tried are unsuccessful for self-limited epilepsy with centrotemporal spikes, consider sulthiame as monotherapy or add-on treatment, but only after discussion with a tertiary paediatric neurologist.In April 2022, sulthiame was not licensed for use in the UK. See NICE's information on prescribing medicines. ## Other treatment considerations Be aware that carbamazepine, oxcarbazepine and lamotrigine may rarely exacerbate seizures or the development of another epilepsy syndrome, or affect cognitive performance, in a small number of children and young people with self-limited epilepsy with centrotemporal spikes. If there is concern about the school performance of a child or young person having antiseizure medication, seek guidance from an epilepsy specialist and consider: sleep electroencephalogram (EEG) to exclude exacerbation of epileptic activity (electrical status epilepticus during sleep) and neuropsychology assessment to review academic performance. If a child or young person having antiseizure medication treatment develops other seizure types, consider a sleep EEG to exclude exacerbation of epileptic activity (developmental epileptic encephalopathy with spike-wave activation in sleep). Offer follow up at a frequency and with a healthcare professional appropriate to the child or young person's individual needs. Discuss discontinuing treatment if a child or young person with self-limited epilepsy with centrotemporal spikes is seizure-free for at least 2 years or at age 14 years. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on self-limited epilepsy with centrotemporal spikes . Full details of the evidence and the committee's discussion are in evidence review Q: effectiveness of antiseizure medications for self-limited epilepsy with centrotemporal spikes. Loading. Please wait. # Epilepsy with myoclonic-atonic seizures (Doose syndrome) For more information on treatment in women and girls, see the section on antiseizure medications for women and girls. Follow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy. December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section. ## Specialist involvement Discuss the treatment and management of epilepsy with myoclonic-atonic seizures in children with a tertiary paediatric neurologist. ## First-line treatment Consider levetiracetam or sodium valproate as first-line treatments for epilepsy with myoclonic-atonic seizures. If either levetiracetam or sodium valproate is unsuccessful, try the other of these options.In April 2022, this was an off-label use of levetiracetam. See NICE's information on prescribing medicines. If sodium valproate is started or continued for epilepsy with myoclonic-atonic seizures in girls or women able to have children (including young girls who are likely to need treatment when they are old enough to have children): discuss the risks and benefits of treatment, including the risks to an unborn child take into account the likelihood of pregnancy and put in place a pregnancy prevention programme, if appropriate.Follow the MHRA safety advice on valproate use by women and girls. ## Second-line treatment If first-line treatments for epilepsy with myoclonic-atonic seizures are unsuccessful, consider a ketogenic diet as a second-line monotherapy or add-on treatment, under the supervision of a ketogenic diet team. ## Third-line treatment For guidance on safe prescribing and managing withdrawal of clobazam in adults, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. If second-line treatment for epilepsy with myoclonic-atonic seizures is unsuccessful, consider the following as third-line monotherapy or add-on treatment options: clobazam ethosuximide topiramate zonisamide.If the first choice is unsuccessful, consider the other third-line options.In April 2022, these were off-label uses of clobazam as monotherapy in adults and children, and add-on therapy in children under 6 months, and topiramate and zonisamide in adults and children. See NICE's information on prescribing medicines. ## Other treatment considerations Do not use any of the following medications because they may exacerbate seizures in people with epilepsy with myoclonic-atonic seizures: carbamazepine gabapentin -xcarbazepine phenytoin pregabalin vigabatrin. ## Discontinuing medication Consider discontinuing antiseizure medication treatment in children with epilepsy with myoclonic-atonic seizures who are seizure-free for 2 years. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on epilepsy with myoclonic-atonic seizures (Doose syndrome) . Full details of the evidence and the committee's discussion are in evidence review R: effectiveness of antiseizure therapies for epilepsy with myoclonic-atonic seizures (Doose syndrome). Loading. Please wait.# Treating status epilepticus, repeated or cluster seizures, and prolonged seizures # Status epilepticus ## Initial treatment for generalised convulsive status epilepticus Provide resuscitation and immediate emergency treatment for children, young people and adults who have convulsive status epilepticus (seizures lasting 5 minutes or more). If the person with convulsive status epilepticus has an individualised emergency management plan that is immediately available, administer medication as detailed in the plan. If the person with convulsive status epilepticus does not have an individualised emergency management plan immediately available: give a benzodiazepine (buccal midazolam or rectal diazepam) immediately as first-line treatment in the community or use intravenous lorazepam if intravenous access and resuscitation facilities are immediately available. Be aware of the possible underlying causes of status epilepticus, including hypoglycaemia, eclampsia and alcohol withdrawal, which may need to be treated with additional medication. Be alert to non-adherence to antiseizure medication, which can also be a cause of status epilepticus. Be aware that non-epileptic seizures (dissociative seizures) can be similar in presentation to convulsive status epilepticus. ## Management if initial treatment is unsuccessful If convulsive status epilepticus does not respond to the first dose of benzodiazepine: call emergency services in the community or seek expert guidance in hospital. Continue to follow the person's individualised emergency management plan, if this is immediately available, or give a second dose of benzodiazepine if the seizure does not stop within 5 to 10 minutes of the first dose. If convulsive status epilepticus does not respond to 2 doses of a benzodiazepine, give any of the following medicines intravenously as a second-line treatment: levetiracetam phenytoin sodium valproate. Take into account that levetiracetam may be quicker to administer and have fewer adverse effects than the alternative options.In April 2022, this was an off-label use of levetiracetam. See NICE's information on prescribing medicines. Follow the Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on valproate use by women and girls. If convulsive status epilepticus does not respond to a second-line treatment, consider trying an alternative second-line treatment option under expert guidance. If convulsive status epilepticus does not respond to the second-line treatment options tried, consider the following third-line options under expert guidance: phenobarbital or general anaesthesia. After an episode of convulsive status epilepticus, agree an emergency management plan with the person if they do not already have one and there is concern that status epilepticus may recur. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on status epilepticus . Full details of the evidence and the committee's discussion are in evidence review 9: antiseizure medication for status epilepticus. Loading. Please wait. # Repeated seizures or cluster seizures Manage repeated or cluster seizures (typically 3 or more self-terminating seizures in 24 hours) as a medical emergency. If a person has repeated or cluster seizures: follow their individualised emergency management plan, if this is immediately available or consider giving a benzodiazepine, such as clobazam or midazolam, immediately if they do not have an individualised emergency management plan immediately available. Seek expert guidance if the person has further episodes of repeated or cluster seizures. Agree an individualised emergency management plan with the person after repeated or cluster seizures if they do not have one already and there is concern that repeated or cluster seizures may recur. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on repeated or cluster seizures . Full details of the evidence and the committee's discussion are in evidence review 10: antiseizure medications for repetitive/cluster seizures: monotherapy and add-on therapies. Loading. Please wait. # Prolonged seizures For convulsive seizures that continue for 5 minutes or more, follow the recommendations in the section on status epilepticus. Manage prolonged convulsive seizures (any convulsive seizure that continues for more than 2 minutes longer than a person's usual seizure) as a medical emergency. If a person has a prolonged convulsive seizure: follow their individualised emergency management plan if this is immediately available or consider giving a benzodiazepine, such as midazolam or clobazam, immediately if they do not have an individualised emergency management plan immediately available. After a prolonged convulsive seizure, agree an emergency management plan with the person if they do not already have one and there is concern that prolonged convulsive seizures may recur. After a prolonged non-convulsive seizure (a non-convulsive seizure that continues for more than 2 minutes longer than a person's usual seizure), agree an emergency management plan with the person if they do not already have one and there is concern that prolonged non-convulsive seizures may recur. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prolonged seizures . Full details of the evidence and the committee's discussion are in evidence review 11: antiseizure medication for prolonged seizures: monotherapy. Loading. Please wait.# Non-pharmacological treatments # Ketogenic diet Consider a ketogenic diet under the guidance of a tertiary epilepsy specialist, in people with: certain childhood-onset epilepsy syndromes (see also the section on treating childhood-onset epilepsies), for example: glucose transporter type 1 deficiency syndrome (GLUT1 deficiency syndrome) epilepsy associated with pyruvate dehydrogenase deficiency infantile spasms syndrome epilepsy with myoclonic-atonic seizures (Doose syndrome) Dravet syndrome Lennox–Gastaut syndrome drug-resistant epilepsy if other treatment options have been unsuccessful or are not appropriate. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on ketogenic diet . Full details of the evidence and the committee's discussion are in evidence review 12: ketogenic diets for drug-resistant epilepsy. Loading. Please wait. # Resective epilepsy surgery ## Referral for resective epilepsy surgery assessment Discuss the options for assessment for resective epilepsy surgery with people who have drug-resistant epilepsy, and their families or carers if appropriate. Explain what the process of surgical assessment involves as well as the benefits and risks associated with surgical procedures. Refer people with drug-resistant epilepsy, including those without identified MRI abnormalities, for consideration of assessment for resective epilepsy surgery: For adults, this should be to a tertiary epilepsy service. For children and young people, this should be to a tertiary paediatric neurology service for consideration of referral to a children's epilepsy service surgery centre. For people with MRI abnormalities that indicate a high risk of drug-resistant epilepsy, consider early referral to a tertiary epilepsy service for assessment, including an evaluation for resective epilepsy surgery if appropriate. Examples of specific lesions seen on MRI may include, but are not limited to, the following: hippocampal sclerosis malformations of cortical development epilepsy-associated low-grade tumours hypothalamic hamartomas neuronal migrational disorders tuberous sclerosis complex vascular malformations, including Sturge–Weber syndrome cerebral contusions from previous head injury. Do not exclude people with learning disabilities or underlying genetic abnormalities from referral for resective epilepsy surgery assessment if it is indicated. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on resective epilepsy surgery . Full details of the evidence and the committee's discussion are in evidence review 13: referral and surgical interventions. Loading. Please wait. # Vagus nerve stimulation If resective epilepsy surgery is not suitable for a person with drug-resistant seizures, consider vagus nerve stimulation as an add-on treatment to antiseizure medication. See also NICE's interventional procedures guidance on vagus nerve stimulation for refractory epilepsy in children. Discuss with the person with epilepsy, and their family or carers if appropriate, the benefits and risks of vagus nerve stimulation before making a shared decision about having this procedure. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on vagus nerve stimulation . Full details of the evidence and the committee's discussion are in evidence review 14: vagus nerve stimulation. Loading. Please wait.# Psychological, neurobehavioural, cognitive and developmental comorbidities in epilepsy # Providing coordinated care Be aware that there is a higher prevalence of mental health difficulties, learning disabilities, neurodevelopmental comorbidities (for example, attention deficit hyperactivity disorder and autism spectrum disorder) and dementia, and a higher risk of suicide in people with epilepsy compared with the general population. Provide coordinated care for people with epilepsy who have a mental health condition or learning disability using a multidisciplinary team approach. Be aware that children and young people with a complex childhood epilepsy syndrome can have developmental difficulties and cognitive impairment, and may need additional support from a multidisciplinary team. Ensure effective communication and liaison between healthcare professionals across the relevant services involved in the care of people with epilepsy and a mental health condition to agree and plan care across services. For people with epilepsy who have a learning disability, a mental health problem or challenging behaviour, or who have dementia, follow the recommendations on coordinating care in NICE's guidelines on mental health problems in people with learning disabilities, challenging behaviour and learning disabilities and dementia. # Support and treatment Recognise that a diagnosis of epilepsy can have a significant adverse impact on a person's mental health and that people with epilepsy may feel socially excluded and stigmatised. Review neurodevelopment, cognitive function, mental health, social and emotional wellbeing, and learning disabilities as part of the routine management for people with epilepsy. Offer assessment and provide mental health support and treatment for people with epilepsy and depression in line with NICE's guidelines on depression in adults with a chronic physical health problem and depression in children and young people. Be alert to anxiety, other mental health difficulties and the risk of suicide in people diagnosed with epilepsy. If mental health difficulties are suspected, consider referral and follow the recommendations in NICE's guidelines on: attention deficit hyperactivity disorder autism spectrum disorders in under 19s autism spectrum disorder in adults common mental health problems mental health problems in people with learning disabilities generalised anxiety disorder and panic disorder in adults psychosis and schizophrenia in adults psychosis and schizophrenia in children and young people. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychological, neurobehavioural, cognitive and developmental comorbidities in epilepsy . Full details of the evidence and the committee's discussion are in: evidence review 15: prevalence of psychological disorders in people with epilepsies evidence review 16: psychological treatments for people with epilepsies. Loading. Please wait.# Reducing the risk of epilepsy-related death including sudden unexpected death in epilepsy # Risk factors Be aware that epilepsy is associated with an increased risk of premature death, including a risk of sudden unexpected death in epilepsy (SUDEP). Be aware that potentially modifiable risk factors for SUDEP include: non-adherence to medication alcohol and drug misuse having focal to bilateral tonic-clonic seizures or generalised tonic-clonic seizures having uncontrolled seizures living alone sleeping alone without supervision. Be aware that the risk of epilepsy-related death is increased in people with: previous brain injury previous central nervous system infection metastatic cancer previous stroke abnormal neurological examination findings. Discuss with people with epilepsy, and their families and carers if appropriate, their individual risk of epilepsy-related death, including SUDEP, from the time of diagnosis onwards. For young children, this discussion should be with the child's parents or carers. Discussion should include: supporting them to understand the risks of epilepsy-related death, including SUDEP exploring and agreeing ways to reduce the risks. Discuss the risk of SUDEP with people who have seizures during sleep and, if appropriate, include their families and carers. Provide information on minimising risks, including taking their medication as prescribed. # Interventions Discuss the possibility of introducing or increasing night-time supervision, for example, a parent or carer may wish to use a night monitor for people with epilepsy who have seizures during sleep and have been assessed to be at higher risk of epilepsy-related death. Support people with epilepsy to take their medications as prescribed to reduce seizures. Explain that uncontrolled seizures increase the risk of epilepsy-related death, particularly for people with generalised tonic-clonic seizures or focal to bilateral tonic-clonic seizures. Follow the recommendations in NICE's guideline on medicines adherence. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reducing the risk of epilepsy-related death including sudden unexpected death in epilepsy . Full details of the evidence and the committee's discussion are in the following evidence reviews: evidence review 17: prediction of death, including SUDEP, in people with epilepsy evidence review 18: modifiable risk factors for epilepsy related mortality evidence review 19: reducing the risk of seizure-related mortality, including SUDEP. Loading. Please wait.# Service provision and transition # Epilepsy specialist nurses Ensure that all children, young people and adults with epilepsy have access to an epilepsy specialist nurse who: has a central role in providing information, education and support (see box 1 for information that should be covered) supports epilepsy specialists and healthcare professionals in primary and secondary care, and in educational, respite and social care settings is a point of contact for, and facilitates access to, other community and multi-agency services. Offer people with epilepsy an information and care-planning session with an epilepsy specialist nurse that includes emotional wellbeing and self-management strategies promoting inclusion and participation. For people with epilepsy who continue to have seizures, offer epilepsy specialist nurse sessions: at least twice a year and after A&E department visits. Consider epilepsy specialist nurse-led group sessions for education and information giving in young people and adults with epilepsy. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on epilepsy specialist nurses . Full details of the evidence and the committee's discussion are in evidence review O: effectiveness of a nurse specialist in the management of epilepsy. Loading. Please wait. # Transition from children's to adults' epilepsy services Involve young people with epilepsy in planning for their transition from children's to adult epilepsy services in line with the NICE guideline on transition from children's to adults' services for young people using health or social care services. Ensure transition from children's to adults' epilepsy services is individually tailored to the young person with epilepsy. Begin planning transition early for young people who have complex or additional health and social care needs, for example young people whose seizures are not yet controlled or those with learning disabilities. During transition of young people with epilepsy to adult services, the paediatric and adult multidisciplinary teams should jointly review the person's diagnosis and management plan, taking a person-centred approach that involves the young person, and their family or carers as appropriate, in planning and decisions about their care. Ensure that information about the young person's management plan and support for transition to adult services is discussed with the young person with epilepsy and shared in an accessible format that meets their needs and uses language they understand. Repeat this information at different time points to establish that the young person understands their care plan and the support that will be provided. When discussing transition to adult epilepsy services with the young person, cover any issues of concern to the person, including, but not limited to, the following: activities of daily living, including driving and sports adherence to antiseizure medication comorbidities, such as low mood or impaired memory continuing in education or work emotional health and psychological wellbeing living independently possible effects of epilepsy and antiseizure medication on neurodevelopment, cognition and behaviour risks associated with alcohol and illicit drugs safety and risk (including sudden unexpected death in epilepsy ) reproductive health, including contraception, pregnancy and teratogenicity sleep disturbance social aspects of epilepsy, including considering if or when to disclose epilepsy status and managing the impact of possible assumed limitations stigmatisation of epilepsy. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on transition from children's to adults' epilepsy services . Full details of the evidence and the committee's discussion are in evidence review 20: transition from paediatric to adult epilepsy services. Loading. Please wait.# Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. The definitions for the epilepsy syndromes and seizure types are based on the International League Against Epilepsy's proposed new definitions and framework for classifying epilepsy. # Drug-resistant epilepsy Epilepsy in which seizures persist and seizure freedom is very unlikely to be attained with further manipulation of antiseizure medication. Defined by the International League Against Epilepsy as 'failure of adequate trials of 2 tolerated and appropriately chosen and used antiseizure medication schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom'. # MRI protocols An MRI scan produces sets of images of the brain, or 'sequences', each with a particular appearance. An epilepsy MRI protocol is made up of a group of sequences, put together to improve the sensitivity and specificity in demonstrating possible structural abnormalities of the brain that cause epilepsy. The use of a regionally agreed, standardised protocol aims to maximise diagnostic quality and deliver consistency in scan quality. # Suboptimal MRI An MRI scan would be deemed suboptimal if: it gives an inappropriate or inadequate set of sequences image quality is poor, for example, because of patient movement. # Tertiary epilepsy service A service provided by epilepsy specialists who are adult or paediatric neurologists who undertake continuing professional development in the investigation, diagnosis and management of complex epilepsy. It offers: Access to additional specialist assessments, including: neuropsychology neuropsychiatry specialised neuroimaging, including 3T MRI specialised neurophysiology, including video electroencephalogram (EEG) telemetry. Specialised assessment and management of particular patient groups, including: people with learning disability pregnant women people transitioning between services -lder people with epilepsy. Access to: specialised non-surgical treatments, for example, cannabidiol, ketogenic diet genetic diagnosis and counselling specialised assessment for surgery vagus nerve stimulation participation in relevant clinical trials and research studies. # Unprovoked seizure A seizure that is not caused by a particular event such as a fever, head injury or consumption of alcohol or drugs. # Unsuccessful treatment Treatment is unsuccessful if it does not reduce or stop seizures, or if side effects are intolerable for the person with epilepsy.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Antibody testing What immunomodulation strategies are effective in people with defined autoimmune epilepsy syndromes? For a short explanation of why the committee made this recommendation for research, see the rationale section on antibody testing . Full details of the evidence and the committee's discussion are in evidence review D: antibody testing in epilepsy. Loading. Please wait. ## Complex epilepsy syndromes What antiseizure therapies (alternative or add-on) are effective in the treatment of complex epilepsy syndromes (that is, Dravet syndrome, Lennox–Gastaut syndrome, infantile spams syndrome and epilepsy with myoclonic-atonic seizures ) when first-line therapy is unsuccessful or not tolerated? For a short explanation of why the committee made this recommendation for research, see the rationale section on Dravet syndrome . Full details of the evidence and the committee's discussion are in evidence review K: effectiveness of antiseizure therapies in the treatment of Dravet syndrome. Loading. Please wait. For a short explanation of why the committee made this recommendation for research, see the rationale section on Lennox–Gastaut syndrome . Full details of the evidence and the committee's discussion are in evidence review L: effectiveness of antiseizure therapies in the treatment of Lennox-Gastaut syndrome. Loading. Please wait. For a short explanation of why the committee made this recommendation for research, see the rationale section on infantile spasms syndrome . Full details of the evidence and the committee's discussion are in evidence review P: effectiveness of antiseizure therapies for infantile spasms. Loading. Please wait. For a short explanation of why the committee made this recommendation for research, see the rationale section on epilepsy with myoclonic-atonic seizures (Doose syndrome) . Full details of the evidence and the committee's discussion are in evidence review R: effectiveness of antiseizure therapies for epilepsy with myoclonic-atonic seizures (Doose syndrome). Loading. Please wait. ## Risk prediction tool for all-cause epilepsy-related death Development of a risk prediction tool to detect all-cause mortality including sudden unexpected death in epilepsy (SUDEP) in people with epilepsy or those who have had a single seizure, and an external validation of a risk prediction tool to detect the probability of epilepsy-related death. For a short explanation of why the committee made this recommendation for research, see the rationale section on reducing the risk of epilepsy-related death including SUDEP . Full details of the evidence and the committee's discussion are in evidence review 17: prediction of death, including SUDEP, in people with epilepsy. Loading. Please wait. ## Vagus nerve stimulation What is the effectiveness of vagus nerve stimulation in treating epilepsy (including people with learning disabilities as a subgroup)? For a short explanation of why the committee made this recommendation for research, see the rationale section on vagus nerve stimulation . Full details of the evidence and the committee's discussion are in evidence review 14: vagus nerve stimulation. Loading. Please wait. ## Psychological treatments What is the cost effectiveness of providing tailored psychological treatments for people with epilepsy? For a short explanation of why the committee made this recommendation for research, see the rationale section on psychological, neurobehavioural, cognitive and developmental comorbidities in epilepsy . Full details of the evidence and the committee's discussion are in in evidence review 16: psychological treatments for people with epilepsies. Loading. Please wait. ## Monitoring antiseizure medications in women and girls What is the clinical and cost effectiveness of therapeutic drug monitoring in girls, young women and women with epilepsy? For a short explanation of why the committee made this recommendation for research, see the rationale section on support and monitoring for women planning pregnancy or who are pregnant . Full details of the evidence and the committee's discussion are in evidence review 8: therapeutic drug monitoring in women and girls. Loading. Please wait. # Other recommendations for research ## Digital health technologies What is the clinical and cost effectiveness of digital health technologies in people with epilepsy? For a short explanation of why the committee made this recommendation for research, see the rationale section on new technologies . Full details of the evidence and the committee's discussion are in evidence review 5: new technologies. Loading. Please wait. ## Antiseizure medication for repeated or cluster seizures What antiseizure medications (monotherapy or add-on) are effective in the treatment of repeated or cluster seizures? For a short explanation of why the committee made this recommendation for research, see the rationale section on repeated or cluster seizures . Full details of the evidence and the committee's discussion are in evidence review 10: antiseizure medications for repetitive/cluster seizures: monotherapy and add-on therapies. Loading. Please wait. ## Risk prediction tool for second seizure Development of a risk prediction tool for second seizures in people with a single seizure, and an external validation of a risk prediction tool to detect the probability of a second seizure in people with a single seizure at baseline. For a short explanation of why the committee made this recommendation for research, see the rationale section on referral after a first seizure or remission and assessing risk of a second seizure . Full details of the evidence and the committee's discussion are in evidence review 1: prediction of second seizure. Loading. Please wait. ## Ketogenic diets What is the short-term and long-term clinical and cost effectiveness of ketogenic diets in adults and children with drug-resistant epilepsy, and what factors affect the long-term maintenance and tolerability of ketogenic diets? For a short explanation of why the committee made this recommendation for research, see the rationale section on ketogenic diet . Full details of the evidence and the committee's discussion are in evidence review 12: ketogenic diets for drug-resistant epilepsy. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Referral after a first seizure or remission and assessing risk of a second seizure Recommendations 1.1.1 to 1.1.9 ## Why the committee made the recommendations ## Referral after a first seizure The committee agreed that people presenting with a suspected first seizure should be referred urgently to ensure that a specialist is involved early in diagnosing epilepsy. Diagnosing epilepsy can be complex and involving a specialist can help avoid misdiagnosis and ensure that the person receives the right care and support. ## Assessing the risk of a second seizure The evidence suggested that adults having a first seizure who have a mental health condition are almost 3 times more likely to have a second seizure when compared with the general population. The risk was even higher for people with sepsis, who are 4.5 times more likely to have a second seizure than people who do not have sepsis. The committee agreed that these are significant risk factors that could be modified to try to prevent second seizures. Evidence for vascular risk factors did not show a difference in risk. However, based on their knowledge and experience, the committee agreed that conditions such as diabetes, hypertension and atrial fibrillation are important risk factors for seizures in adults that may also be modified. In children, the committee acknowledged that there was a lack of clarity in the evidence for risk associated with higher or lower temperature. A seizure because of a high temperature does not necessarily predispose a child to more seizures, but they agreed that increased temperature is important to take into consideration. Febrile seizures tend not to predispose to a second afebrile seizure. However, afebrile seizures may be associated with an increased risk of a second seizure. The committee agreed that parents and carers should be given information about the potential risk and how to self-refer should the child have a second seizure. Safety guidance should also be given so that parents and carers can take precautions to minimise the risk of injury. The risk factors identified in the studies are not the only factors that affect a person's chances of having a second seizure. For this reason, the committee decided that assessment should include identifying any potential mental, physical and social risk factors, which should then be discussed with the person and their family or carers. The committee discussed the evidence for prediction tools for a second seizure, but did not recommend using any of these tools because they were considered to carry the potential for harm. The evidence suggested that the tools had a poor capacity to discriminate between people at low and high risk of second seizure. Therefore, the committee made a recommendation for research on developing and testing a risk prediction tool for second seizure. ## How the recommendations might affect practice These recommendations are likely to mean a change in clinical practice for how adults are cared for after a first seizure. In current practice, only about 25% of adults are fully assessed for modifiable risk factors. Assessment includes checking for underlying mental health problems, vascular risk factors and sepsis. Although the recommendations for adults will result in a change in clinical practice, the assessment does not take long and is not expected to result in a substantial resource impact. A small increase in costs is likely for additional staff time to assess people presenting with a first seizure. The recommendation made for children reflects current practice so the committee agreed there should be no substantial resource impact. Return to recommendations # Specialist assessment and diagnosis Recommendations 1.2.1 to 1.2.10 ## Why the committee made the recommendations In assessing the evidence for individual tests to diagnose epilepsy, the committee agreed that a diagnostic test would need to give the lowest possible level of false-positive and false-negative results. False-positive results may result in unnecessary treatment and anxiety, whereas false-negative results may result in people with epilepsy remaining undiagnosed and untreated. Given the seriousness of these harms, the committee agreed that a 10% rate for false negatives and a 10% rate for false positives were the highest acceptable rates (equating to a minimally acceptable value of 0.9 for both sensitivity and specificity). Most tests evaluated in the review did not meet this threshold. Clinical history and examination provided by a specialist in epilepsy demonstrated levels of sensitivity and specificity for detecting epilepsy that were above the agreed threshold. Although the evidence was restricted to adults, the committee were confident that this could also be applied to diagnosis in children and young people. Witness reports and review of video footage were included as useful additional features of the clinical history. The evidence did not show sufficient diagnostic accuracy to warrant the use of witness reports or video footage independently, but the committee agreed that they increase the accuracy of expert clinical diagnosis. The committee agreed, based on their knowledge and experience, that a positive electrocardiogram (ECG) can identify cardiac causes of seizure-like symptoms, and a negative ECG can support a further investigation of suspected epilepsy. Similarly, they agreed that the assessment of metabolic disturbances, such as hypoglycaemia can help to exclude alternative causes of a first seizure. Although none of the imaging modalities were sufficiently accurate for use as diagnostic tools, the committee agreed that neuroimaging should be used to investigate potential structural causes of epilepsy. The evidence showed low sensitivity for routine interictal EEG, suggesting that many people with epilepsy will not demonstrate interictal EEG abnormalities. The committee therefore agreed that a negative routine interictal EEG should not be used to exclude an epilepsy diagnosis. However, the specificity was high enough for a positive EEG finding to support a provisional diagnosis of epilepsy. Most people without epilepsy will not have EEG abnormalities, so a person with a positive finding on EEG is more likely to have epilepsy than not. The committee agreed that routine EEG should therefore be considered to help support clinical diagnoses of epilepsy. The committee also agreed, based on clinical knowledge and experience, that EEG would provide more accurate results if done as soon as possible (ideally within 72 hours) after the seizure. Some evidence also suggested that provoking manoeuvres or longer-term EEG (for example, during a period of sleep or ambulatory EEG over 48 hours) could slightly increase sensitivity. Although this small increase in sensitivity would be insufficient to exclude diagnoses if EEG findings are negative, it might help to further support the overall clinical diagnosis of epilepsy. The committee agreed that provoking manoeuvres during an EEG or, for example, sleep deprivation to capture sleep EEG, could be offered if agreed with the person being tested (or their family or carers). If routine and sleep-deprived EEG are normal, the committee agreed that longer-term monitoring with ambulatory EEG could be considered for some people. This may be particularly indicated in people who are thought to have a focal epilepsy. The committee highlighted the potential harms of these methods and agreed that the risks and benefits should be fully discussed with the person and their families or carers before performing the relevant EEG test. ## How the recommendations might affect practice No impact on practice is expected, because these recommendations do not substantially change current practice. Return to recommendations # Neuroimaging Recommendations 1.3.1 to 1.3.7 ## Why the committee made the recommendations Neuroimaging may help to identify the cause of epilepsy, inform prognosis and can give information to plan appropriate management. However, the committee agreed that it is unnecessary for people with epilepsy that is not associated with structural brain abnormalities, such as idiopathic generalised epilepsy or self-limited epilepsy with centrotemporal spikes. Based on the evidence and their experience, the committee agreed that MRI is the investigation of choice for people with epilepsy. The evidence for different protocols was not reviewed, so based on awareness of the wider literature, the committee decided that regionally agreed epilepsy protocols should be followed, using sequences available on most modern MRI scanners, to capture enough detail. The committee stressed the importance of carrying out scans early to inform timely management choices, and discussed variation in current practice, with some people having to wait several weeks. They agreed that imaging should take place as soon as possible and specified a wait of no longer than 6 weeks from referral for the MRI, in line with the pledge on waiting times for diagnostic tests in the Handbook to the NHS Constitution for England. The committee acknowledged that there may be situations when MRI is not suitable and CT should be offered instead, for example, if a person has severe claustrophobia or a non-MRI conditional pacemaker. Successful interpretation of MRI findings depends on the reader's proficiency, so the committee agreed, based on their experience, that scans should be reported by a radiologist with expertise in neuroradiology. Tertiary neuroradiology centres have expertise in performing and interpreting MRI scans, so further review by these specialist centres may be warranted if the diagnosis is in doubt or the person has drug-resistant epilepsy. Based on their experience, the committee agreed on certain situations for which repeat MRI in people with an established epilepsy diagnosis may be important. For example, to look for change in lesions in people with new symptoms, such as rapid cognitive decline or unexplained increase in seizure frequency. Repeat MRI may also be used to help locate the areas of the brain responsible for seizures if surgery is being considered. Based on their experience and expertise, the committee agreed that a CT scan can help determine whether a new-onset seizure is caused by an acute neurological lesion or illness in those with acute symptomatic seizures. However, being aware that people with an established diagnosis of epilepsy who present to an emergency department with a seizure often have a CT scan, the committee emphasised that this is not needed for those who have a typical seizure if there are no other clinical concerns. ## How the recommendations might affect practice The use of neuroimaging varies in current practice, and is not routinely used in all settings. The recommendations will reduce variation in current practice. There may be an increase in the number of people who have neuroimaging. However, with the use of regionally agreed protocols, the detection of abnormalities may avoid the need for more scans in the future. Return to recommendations # Genetic testing Recommendations 1.4.1 to 1.4.5 ## Why the committee made the recommendations The committee agreed that a discussion with a neurologist or geneticist may be needed to advise on who to test and which type of test to use if there are uncertainties. Access to genetic testing varies but is likely to increase. The committee noted that the NHS National Genomic Test Directory for rare and inherited disease lists the genetic tests for epilepsy that are nationally commissioned by the NHS in England, and when they should be performed. A genetic diagnosis can provide information about treatment options, related medical problems and prognosis. It can also inform genetic counselling for the person and their family members. The committee discussed the importance of genetic counselling to ensure that people, and their families or carers if appropriate, are supported to understand the possible results of testing and what they might mean for them and their family. Results can reveal information about the person who is being tested, but also their family members, which may have emotional and social consequences. The committee agreed that a full discussion of the purpose and implications of genetic testing is needed before testing, so that the person, and their family or carers if appropriate, can make decisions about testing and give informed consent. Informed consent needs to be documented and it involves a full discussion about the benefits and possible limitations and risks of genetic testing, as well as consent to share information, where appropriate, about the results to advise the person's relatives. The evidence did not support genetic testing for all people with epilepsy, so the committee took a pragmatic approach and agreed that testing should be considered in situations most likely to yield positive diagnostic results. The committee agreed that there was not enough evidence to recommend genetic testing at a specific point in the clinical pathway. People whose epilepsy started at an early age (under 2 years) and people whose epilepsy is associated with developmental disorders or certain clinical features are more likely to have epilepsy with a genetic cause. Therefore, based on their knowledge and experience, the committee agreed that whole-genome sequencing would be best targeted to this population. This is in line with the eligibility criteria that accompany the NHS National Genomic Test Directory (clinical indication R59: early-onset or syndromic epilepsy). The diagnostic yield of genetic testing in people with epilepsy of unknown cause with onset between 2 and 3 years is affected by factors such as co-occurring conditions and MRI and EEG findings. The committee noted that a genetic diagnosis in this group of people can have a significant positive impact on outcomes and management, therefore, based on their knowledge and experience and as specified by the NHS National Genomic Test Directory, they agreed that whole-genome sequencing should be carried out if agreed by a specialist multidisciplinary team. ## How the recommendations might affect practice The use of genetic testing varies in current practice, and it is not routinely carried out even when a genetic cause is suspected. The recommendations clarify when genetic testing should be considered, which will reduce variation in current practice. There may be an increase in the number of people who have a genetic test and who are referred for genetic counselling. However, with the use of whole-genome sequencing, there may also be a reduction in the number of people having unnecessary tests that do not provide additional information on their diagnosis. Return to recommendations # Antibody testing Recommendation 1.5.1 ## Why the committee made the recommendation The evidence for antibody testing was limited and did not support routine antibody testing for people with epilepsy. However, the committee discussed antibody testing in the context of suspected autoimmune encephalitis in people with new-onset epilepsy because it is recognised that people with autoimmune encephalitis can present with seizures or status epilepticus with encephalopathy. Although not part of the evidence review, the committee was aware that treatment guided by antibody testing (immunotherapy) may improve outcomes in these people compared with standard antiseizure medication. There is emerging evidence on 'autoimmune epilepsy', but the committee agreed that further research is needed to assess which immunomodulation strategies are effective in people with defined autoimmune epilepsy syndromes. The committee agreed that further research is needed and developed a recommendation for research on immunomodulation strategies for people with autoimmune epilepsy syndromes to help inform future guidance. ## How the recommendation might affect practice Suspected autoimmune encephalitis is relatively rare and antibody testing is already current practice, so the recommendation reinforces current best practice. Return to recommendation # Information and support Recommendations 2.1.1 to 2.1.11 ## Why the committee made the recommendations The evidence showed that there are gaps in current practice in communication and in the information and support available to people with epilepsy. The committee agreed that tailored information should be provided to people with epilepsy, and their parents and carers if appropriate, to enable them to be fully informed and involved in decisions about their care. The evidence reported that some people with epilepsy and some parents and carers felt that information was withheld, making it difficult to be fully involved in their care. It also showed that children and young people wanted to be involved but sometimes struggled to understand information inappropriate for their age, including information about sudden unexpected death in epilepsy (SUDEP). The committee stressed the importance of providing age-appropriate information to enable children to be involved in discussions about their care. Extra support and time in consultations for people with learning disabilities or complex needs, such as other comorbidities, were also highlighted by the committee. The committee highlighted the important role that epilepsy specialist nurses play in information giving. This was supported by the evidence and recommendations on epilepsy specialist nurses. The evidence showed that parents and carers struggled to find help from sources other than their doctor. The committee acknowledged that information on where and how people with epilepsy can access information and support for activities of daily living, such as local and national support groups, should be provided. The committee stressed the importance of providing key information for self-managing epilepsy during the first appointment. Medicines adherence, mitigating epilepsy-related risk and avoiding potential provoking factors for seizures were identified as key topics from the evidence to enable the person to self-manage their epilepsy and maintain everyday activities. Based on their experience, the committee also included activities of daily living, including driving, as a key topic for discussion because it is commonly raised as a concern at the first appointment. The committee agreed that this key information should be repeated at subsequent appointments. The committee recognised that people with epilepsy may have a range of worries and anxieties that may change over time, and that opportunities should be provided to discuss these at each appointment. They agreed on some topics that are often of concern to people with epilepsy and their families and carers, based on their experience and themes identified in the evidence, which could be used to help provide a framework for discussions. ## How the recommendations might affect practice The recommendations reflect current practice so the committee agreed there should be no substantial resource impact. Return to recommendations # New technologies ## Why the committee did not make any recommendations No evidence was found on using digital health technologies, so the committee agreed that no recommendation could be made. The committee noted that people are already using devices, such as night monitors and alarms, as self-management tools, but that evidence is lacking to support this use, and these are not currently offered by the NHS. Based on their experience, the committee acknowledged that some monitoring tools may offer benefit to people with epilepsy. There is a trend towards the use of digital health technologies and the committee were keen to encourage more research in this emerging and potentially important area. A recommendation for research on digital health technologies was developed to help determine their clinical and cost effectiveness for people with epilepsy in the hope that these interventions could lead to improvements in self-management. Return to recommendation for research # Referral to tertiary specialist services Recommendations 3.1.1 to 3.1.4 ## Why the committee made the recommendations There was a lack of evidence on referral to specialist services, so the committee based their recommendations on their clinical experience and expertise, and also used the NHS England 2019 guidance for referral pathways to specialist services for adults as a reference. Children, young people and adults may need access to tertiary services at certain times during their care and these services should be available to everyone who needs them through their specialist. However, the committee acknowledged that some groups may need extra tertiary support to manage their epilepsy, even if they are already receiving care from other specialists for another condition. The committee noted that people with a learning disability or mental health problem may struggle to access tertiary services and may need help to get appropriate referrals. They may also need additional support to attend appointments, such as having a family member or carer accompany them. With the number of referrals increasing, the committee agreed that clearer and more specific criteria for referral would help to ensure that people who will benefit most from specialist services are prioritised. The proposed criteria aim to ensure that people with epilepsy that is difficult to diagnose or manage receive the specialist care and treatment they need, including consideration for clinical trials. The committee recommended, based on their knowledge and expertise, that people with epilepsy meeting these criteria should be seen within 4 weeks. The committee agreed that these are people with substantial health needs, so prompt referral could have a significant positive impact on their prognosis. This is in line with current clinical practice and consistent with the previous version of the guideline, so it is not expected to have an impact on resources. The committee agreed to retain and update the recommendation from the previous guideline because it was important to continue to guide clinicians to improve care and to reduce variation in service provision and outcomes between services. The committee also discussed particular groups of children that should be prioritised for more urgent referral within 2 weeks. This was based on the committee's knowledge and experience, and on the probability that treatment from a tertiary paediatric epilepsy service would significantly benefit children meeting these criteria. They agreed that all children under 3 years should be referred to tertiary services without delay, because of the risk of developmental problems with some paediatric syndromes with onset before this age. Children with myoclonic seizures presenting aged up to 4 years should be referred because myoclonic seizures may start after 3 years and could indicate an underlying neurodegenerative disorder that may be treatable. Children with a unilateral structural lesion should be prioritised for immediate referral because this is likely to lead to difficulties in seizure management and surgery may need to be considered early. The presence of deterioration in the child's behaviour, speech or learning (such as loss of previously acquired developmental milestones), particularly in the absence of an established diagnosis, should also be a priority for prompt investigation in tertiary services. ## How the recommendations might affect practice The recommendations will not change current practice, but will reinforce current best practice. Return to recommendations # Treatment with antiseizure medications Recommendations 4.1.1 to 4.1.9 ## Why the committee made the recommendations These recommendations are based on the committee's informal consensus on principles for the use of antiseizure medications for treating all epilepsy syndromes and seizure types. They are based on recommendations from the previous version of the guideline and have been retained and updated because the committee agreed it was important to include them to guide clinicians to improve care. The committee agreed on some general factors to consider once the diagnosis of epilepsy is confirmed to ensure that the best treatment is started, balancing the risks and benefits of the medicine with the lifestyle and choices of the person. For example, if a person is starting university and the most effective medication can affect cognitive performance, they may wish to choose a different option without these side effects. For some people, their seizure type may mean that a medicine that is faster-acting to reduce seizures might be a priority. These factors should be discussed with the person with epilepsy (and their families and carers if appropriate) in all settings where antiseizure medications may be prescribed and managed, including primary, secondary and tertiary care. The committee agreed on some particular issues that should additionally be taken into account when giving antiseizure medications in older people. This group presents with specific considerations because of differences in clinical presentation and aetiology when compared with younger people, particularly those with co-occurring conditions. Treatment can be more difficult because of drug interactions, therefore other medications the person may be taking should be taken into account. Additionally, care is needed in choosing the adequate initial dose and subsequent titration. The committee noted that following the NICE guideline on multimorbidity, which covers care optimisation in people with multiple long-term conditions, may benefit people with epilepsy and 1 or more mental or physical health condition. The committee agreed that an antiseizure medication treatment strategy should take account of these factors and the special considerations for antiseizure medications in women and girls. The committee agreed that a shared decision should be made with the person to agree their individualised antiseizure medication treatment strategy. The committee agreed on some principles if seizures continue after monotherapy treatment, which included reviewing the diagnosis and trying monotherapy with another antiseizure medication to ensure that the most effective treatment strategy is being used. The committee agreed that, when starting an alternative antiseizure medication, the dose of the new antiseizure medication should be slowly increased while the existing antiseizure medication is tapered off because this can reduce the risk of drug-related withdrawal symptoms of the first medication and clinicians can monitor the correct dose of the second medication. If alternative antiseizure medications prove to be unsuccessful, an add-on treatment should be considered. Because of the possible interactions between antiseizure medications, for example sodium valproate and lamotrigine, the committee agreed that add-on therapies should be carefully titrated and people should be monitored for adverse effects and their medicines reviewed frequently. The committee highlighted the importance of using the regimen that provides the best balance in terms of effectiveness and tolerability of side effects, and that the benefits of rationalising medications (using a single medicine if possible and what to consider if this monotherapy is unsuccessful) should be discussed with the person with epilepsy (and their families and carers if appropriate) to ensure people are not taking more medicines than is necessary to reduce the impact of side effects. ## How the recommendations might affect practice The recommendations will not change current practice, but will reinforce current best practice. Return to recommendations # When to start antiseizure medication Recommendations 4.2.1 and 4.2.2 ## Why the committee made the recommendations These recommendations are based on the committee's informal consensus on when to start treatment with antiseizure medication for all epilepsy syndromes and seizure types. The committee agreed that treatment with antiseizure medication after a first unprovoked seizure should not be offered routinely. However, they agreed that some clinical features should prompt early treatment after a first unprovoked seizure, such as if an examination shows the person has a neurological deficit or the EEG shows unequivocal epileptic activity, which may indicate that the risk of recurrence is high. In some circumstances, for example if there is a risk of loss of employment, further seizures may be unacceptable, so the person or their family or carers may choose to start early treatment. A structural brain abnormality indicates that the brain is damaged, therefore prompt treatment may stop further seizures. ## How the recommendations might affect practice The recommendations will not change current practice, but will reinforce current best practice. Return to recommendations # Safety considerations Recommendations 4.3.1 to 4.3.4 ## Why the committee made the recommendations These recommendations are based on the committee's informal consensus on safety considerations for starting antiseizure medication to treat all epilepsy syndromes and seizure types with antiseizure medication. Antiseizure medications differ significantly in their characteristics, therefore the risk of switching between different manufacturer's products, different generic products or branded originator and generic products needs to be taken into account. The committee agreed that Medicines and Healthcare products Regulatory Agency (MHRA) advice on switching between different manufacturer's products needs to be followed. In line with the BNF, the committee agreed clinicians should be aware of the risks of serious complications associated with phenytoin for people of Han Chinese or Thai family background, and the risks of serious complications associated with carbamazepine and potentially medicines with a similar chemical structure (such as oxcarbazepine and eslicarbazepine acetate) for people of Han Chinese, Thai, European or Japanese family background. In line with the MHRA, the committee noted the antiseizure medicines most commonly reported to cause decreased bone mineral density and increased risk of osteomalacia. The committee agreed that appropriate supplementation should be considered for those at risk. ## How the recommendations might affect practice The recommendations will not change current practice, but will reinforce current best practice. Return to recommendations # Antiseizure medications for women and girls Recommendations 4.4.1 to 4.4.8 ## Why the committee made the recommendations The guideline committee wanted to ensure that women and girls with epilepsy had access to appropriate support and information about contraception, conception, pregnancy, breastfeeding and caring for children, and menopause. They stressed the importance of having regular reviews with women and girls to ensure they had access to further information and treatment as their circumstances change. The committee referred to the MHRA's Public Assessment Report of antiepileptic drugs: review of safety of use during pregnancy to inform the recommendations. In the absence of evidence, the committee made consensus recommendations for women and girls with epilepsy who were breastfeeding. They agreed women and girls should be supported to breastfeed if they wish, because the benefits of breastfeeding outweigh the small risk of the drug affecting the child. ## Impact of the recommendations on practice Women and girls with epilepsy do not currently have their concerns addressed adequately. Services providing reviews and support are thought to be under-commissioned at the present time and so the recommendations are likely to have an impact on practice with an increase in regular reviews. The MHRA safety advice may encourage women who are on antiseizure medications other than lamotrigine and levetiracetam to reconsider their treatment options. Return to recommendations # Monitoring and review Recommendations 4.5.1 to 4.5.4 ## Why the committee made the recommendations Monitoring reviews are essential to reassess the clinical management plans of people with epilepsy as their needs change. Evidence comparing regular scheduled reviews with patient-initiated ad-hoc reviews did not suggest any differences in benefit or harm between these approaches. The committee discussed that patient-initiated review could help to ensure timely management of changes in a person's needs and support their sense of ownership of managing their epilepsy. However, it would have disadvantages for people with less independence or capacity to make decisions, and could lead to loss of contact with services, with potentially serious consequences. It might also be unsuitable for people with a serious or complex condition, for whom failing to contact services could be particularly harmful. The committee agreed that patient-initiated review should be available to all people with epilepsy, but that regular reviews should be provided to groups that are less suited to a patient-initiated approach. Based on their experience, the committee agreed that groups scheduled for regular reviews should include people with reduced capacity for decision making, people with serious or complex epilepsy, those with serious comorbidities, and children and young people. They also identified people taking antiseizure medication associated with long-term side effects or drug interactions as a priority to check for any adverse effects. Long-term side effects may include adverse effects on blood parameters or bone health, or changes in lipid metabolism. Enzyme-inducing medications in particular are associated with reduced bone density. Regular review for women and girls who are able to have children and are taking valproate or other high-risk teratogenic medication was also recommended to allow a discussion of their treatment options and any plans for pregnancy. The committee commented that regular review is current practice for children and young people, typically with 2 reviews a year and at least once every 12 months. The evidence comparing therapeutic drug monitoring with clinical review suggested there is little difference in benefit between these approaches. Based on their experience, the committee agreed that for most people with epilepsy, therapeutic drug monitoring is unnecessary, but that certain groups might gain particular benefit from it. These groups include people who need accurate titration of their medicine levels, such as those with side effects, whose seizures are not controlled with treatment and those in whom adherence is less assured. They also include people at particular risk from their medication, because of either the intrinsic nature of the medication or the increased risks of the medication in people with comorbidities or who are pregnant (for example, to monitor for changes in lamotrigine plasma levels during pregnancy and after birth). ## How the recommendations might affect practice The recommendations may change practice because regular review is currently standard practice for all people with epilepsy. There was some concern that specialist nurse services would need to be developed to coordinate patient-initiated reviews. However, the committee agreed that demand on services is likely to be manageable, provided that regular reviews are maintained for groups that might have additional need for coordination. Restricting therapeutic drug monitoring to a few specific groups will not place any extra burden on providers, and might even slightly reduce it. Return to recommendations # Support and monitoring for women planning pregnancy or who are pregnant Recommendations 4.6.1 to 4.6.10 ## Why the committee made the recommendations The committee acknowledged the potential importance of drug monitoring in pregnancy. However, the available evidence was limited to a single study. The committee agreed that the evidence was inconclusive, so the group based the recommendations on their own experience and guidance from the MHRA about monitoring levels of carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital or phenytoin if used in pregnancy. The committee noted that on-site testing is often available at tertiary epilepsy centres for some antiseizure medications, including carbamazepine, phenytoin and phenobarbital. They acknowledged that phenytoin and phenobarbital are not usually taken by girls and women who are planning pregnancy. The committee also agreed that pre-conception monitoring of antiseizure medication levels should be considered in women and girls at risk of their seizures worsening during pregnancy and made a recommendation based on committee consensus. The committee highlighted the importance of obtaining pre-conception levels of antiseizure medication as a baseline level to compare and titrate against when monitoring drug levels during pregnancy. The committee expressed the need for robust evidence in this area and therefore suggested a recommendation for research on monitoring antiseizure medications in women and girls. ## How the recommendations might affect practice The committee noted that currently there would be some women with epilepsy who are planning pregnancy or who are pregnant who are not having their antiseizure medications monitored. The recommendations are in line with MHRA safety advice on monitoring in pregnancy, and may result in some increases in drug monitoring compared with current practice. Return to recommendations # Discontinuing antiseizure medication Recommendations 4.7.1 to 4.7.7 ## Why the committee made the recommendations Decisions about stopping antiseizure medication are nuanced, based on the person's preferences and their individual risk of seizure recurrence. Although there was some evidence for independent risk factors associated with seizure recurrence, the committee agreed that the recommendations should be broader than listing risk factors, which could be misleading in isolation. Ongoing risk and benefit assessment is important to take account of the evolving needs of the person with epilepsy. Based on their knowledge and experience, the committee agreed that an individualised assessment of the risk of seizure recurrence should be carried out in those who have been 2 years without seizures. The committee stressed the importance of having a discussion with the person, and their family or carer if appropriate, about their personal preferences and the person's individual risk of seizure recurrence, in particular taking into account the type of epilepsy, so that the person is able to make an informed decision about their care. For example, stopping antiseizure medication in people with certain epileptic syndromes, such as juvenile myoclonic epilepsy, structural abnormalities or with co-existing neurodegenerative and other neurological conditions will pose a significant risk of seizure recurrence. The committee agreed that guidance should be sought if there are doubts or concerns about the risks and benefits of discontinuing antiseizure medications. Because of the complexity and wide variation of epilepsy surgery techniques, the committee agreed that those who have undergone epilepsy surgery should have antiseizure medications discontinued under the guidance of the epilepsy surgery centre. The committee highlighted the importance of stopping antiseizure medications slowly, especially benzodiazepines and barbiturates, because of the possibility of drug-related withdrawal symptoms. They also agreed that epilepsy specialist guidance would be needed if seizures recur. ## How the recommendations might affect practice The recommendations will not change current practice, but will reinforce current best practice. Return to recommendations # Generalised tonic-clonic seizures Recommendations 5.1.1 to 5.1.8 ## Why the committee made the recommendations Generalised tonic-clonic seizures rapidly involve both sides of the brain. During such seizures, consciousness is lost and muscles will stiffen before jerking rhythmically. The evidence showed that, for time to treatment failure, no drugs performed better than sodium valproate, with sodium valproate showing clear benefits over lacosamide, phenobarbital, carbamazepine and topiramate. There was no clear difference between sodium valproate and all other drugs for remission or time to first seizure. The committee agreed that sodium valproate should be offered as first-line treatment, but because of the risks to unborn babies associated with sodium valproate use in pregnancy, they highlighted that it should not be used in women and girls who are able to have children unless other treatments are unsuccessful and the MHRA safety advice is followed. The evidence suggested that, after sodium valproate, lamotrigine and levetiracetam had the next best time until treatment failure. For this reason, the committee recommended them as first-line monotherapy options for women and girls who can have children and second-line monotherapy options when sodium valproate is unsuccessful as first-line monotherapy. The committee discussed the evidence on adverse events and their importance in making choices about drug treatment. However, these were reported inconsistently across the studies making comparisons between drugs difficult. The committee also agreed that for most drugs, adverse events could be managed by careful titration and dosage changes. From the evidence, it was difficult to determine the most effective add-on drug for generalised tonic-clonic seizures that have failed to respond to monotherapy. Therefore, a number of drugs were recommended as potential first-line add-on treatments. There was evidence that lamotrigine, levetiracetam, perampanel and topiramate performed better than placebo for achieving a 50% response rate. No evidence was identified for clobazam and sodium valproate, but the committee agreed to include them based on their experience and current use in practice. There was also some evidence that levetiracetam and perampanel were more effective than placebo at achieving seizure freedom, but there was a lot of uncertainty around these results. The evidence also suggested that brivaracetam might be more effective than placebo at achieving more than 50% reduction in seizure frequency, and lacosamide was less effective than levetiracetam for the same outcome. The committee therefore recommended both brivaracetam and lacosamide, as well as phenobarbital, primidone and zonisamide, based on their experience and knowledge of current practice, as possible second-line add-on treatments. The committee stressed again that women and girls able to have children should not be offered sodium valproate as a first-line add-on. The committee highlighted that clinicians should take into account that some drugs used in clinical practice can exacerbate seizures in those with absence or myoclonic seizures, including in juvenile myoclonic epilepsy. In line with the MHRA, the committee emphasised that long-term treatment with primidone and sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk. ## How the recommendations might affect practice The recommendations will reinforce current practice. Return to recommendations # Focal seizures with or without evolution to bilateral tonic-clonic seizures Recommendations 5.2.1 to 5.2.7 ## Why the committee made the recommendations Focal-onset seizures originate in 1 area on 1 side of the brain and the person may have full or partial awareness. Symptoms vary widely depending on the area of the brain they originate from. The evidence showed that lamotrigine and levetiracetam were continued for longer than other drugs for treating focal epilepsy, suggesting that they may be more effective and better tolerated. However, the evidence also suggested they were not more effective than other drugs in terms of remission at 6 and 12 months, and the evidence for time to first seizure suggested they were less effective than carbamazepine. The committee discussed the evidence on adverse events and their importance in making choices about drug treatment. The evidence suggested that lamotrigine, levetiracetam and gabapentin may have more tolerable adverse events than other drugs. However, adverse events were reported inconsistently across the studies making comparisons between drugs difficult. The committee also agreed that for most drugs, adverse events could be managed by careful titration and dosage changes. The committee agreed that lamotrigine and levetiracetam should be considered as first-line monotherapy options, and this was supported by economic modelling. They agreed that if these treatments were unsuccessful, carbamazepine, oxcarbazepine or zonisamide could be considered for second-line monotherapy. The evidence was weaker for lacosamide, so this was included as a third-line option. From the evidence, it was difficult to determine the most effective add-on treatment for people with focal epilepsy that has failed to respond to monotherapy. The evidence showed that a number of antiseizure medications are effective compared with placebo for more than 50% reduction in seizure frequency rate: brivaracetam, carbamazepine, eslicarbazepine acetate, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, topiramate and zonisamide. Medications with the strongest evidence for this outcome were recommended as first-line options. The committee agreed the use of cenobamate as an add-on treatment, after at least 1 other add-on antiseizure medication has been unsuccessful, in line with NICE's technology appraisal guidance on cenobamate for treating focal onset seizures in epilepsy. As with the evidence for monotherapy, the evidence on adverse events with add-on therapy was inconsistent and the committee were not able to use it to inform the recommendations. Although the evidence was less clear, the committee agreed that, based on their experience, sodium valproate can also be an effective option. Because of the risks to unborn babies associated with sodium valproate use in pregnancy, the committee highlighted that it should not be used in women and girls who are able to have children unless other treatments are unsuccessful and the MHRA safety advice is followed. There was a lack of evidence for other antiseizure medications, but based on the committee's experience, phenobarbital, phenytoin and vigabatrin were recommended only when the previous treatments are not tolerated or are unsuccessful, for example because of the risk of particular adverse effects. The committee noted that, in line with guidance from the MHRA, clinicians should be aware of the risks of serious complications associated with phenytoin for people of Han Chinese or Thai family background, and the risks of serious complications associated with carbamazepine, and potentially medicines with a similar chemical structure (such as oxcarbazepine and eslicarbazepine acetate) for people of Han Chinese, Thai, European or Japanese family background. In addition, in line with the MHRA, the committee emphasised that long-term treatment with carbamazepine, phenytoin and sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk. ## How the recommendations might affect practice The recommendations will reinforce current practice. Previous NICE guidance recommended lamotrigine and carbamazepine for first-line monotherapy, with restrictions on the use of levetiracetam owing to costs. Levetiracetam is now significantly cheaper and widely prescribed in the NHS. These recommendations may lead to a small increase in the use of levetiracetam, but this will not lead to a significant increase in costs. All drugs recommended as add-on treatments are already widely used. Gabapentin and clobazam are no longer recommended, which may lead to a small decrease in the use of these drugs. However, these drugs are not widely used and are likely to be continued in people who are already using them successfully. Return to recommendations # Absence seizures Recommendations 5.3.1 to 5.3.9 ## Why the committee made the recommendations Absence seizures are a form of generalised epileptic seizure, characterised by a lack of awareness, stopping moving or talking and staring blankly. They can occur in isolation, but can also be associated epilepsy syndromes, such as childhood absence epilepsy, juvenile absence epilepsy and juvenile myoclonic epilepsy. The evidence identified was only on children and young people; however, the committee agreed that it was appropriate to extrapolate from this evidence to the adult population because of the similar pathophysiology in children, young people and adults. The limited evidence suggested that ethosuximide may improve outcomes for absence seizures (including childhood absence epilepsy). It also suggested that ethosuximide may increase the likelihood of remission, which is the main objective of treatment for people with these seizures. The committee agreed that, despite a lack of robust evidence, their expertise and experience supported the use of ethosuximide as first-line treatment for absence seizures. The committee noted that ethosuximide treatment may lead to improved cognitive outcomes and is already well established in clinical practice. The committee agreed that sodium valproate should be offered as second-line monotherapy or add-on treatment for absence seizures because the evidence suggested that it may increase the likelihood of remission and it appears to be associated with fewer adverse events than other drugs reviewed. The committee acknowledged that sodium valproate should be used with caution in women and girls, only if the risks and benefits have been thoroughly discussed, other treatments are unsuccessful and MHRA safety advice is followed. However, they agreed that sodium valproate should be considered because absence seizures are usually self-limiting, so treatment is likely to be discontinued or an alternative sought if seizures continue beyond puberty. In line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk. The evidence also suggested that lamotrigine and levetiracetam were effective in treating absence seizures. However, the evidence was limited and the committee agreed that these medications should only be considered as third-line monotherapy or add-on treatments. The committee agreed that although other antiseizure medications are used in clinical practice and may benefit some people, it should be highlighted that some can exacerbate seizures. The evidence showed that sodium valproate is associated with a higher likelihood of remission and is well tolerated, so the committee agreed that it should be considered as first-line treatment for absence seizures with other seizure types (or at risk of other seizure types). However, because of the risks to unborn babies associated with sodium valproate use in pregnancy, the committee decided that it should not be offered as first-line treatment for women and girls able to have children who experience absence seizures in addition to other seizure types. In addition, in line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk. The evidence also indicated that lamotrigine and levetiracetam are effective, so the committee agreed that these could be considered as first-line options for women and girls able to have children and as second-line monotherapy or add-on treatment options for men, boys and women unable to have children. The evidence on ethosuximide suggested that it may improve outcomes for absence seizures and increase the likelihood of remission, so the committee agreed that it could also be a possible second-line add-on treatment. Because ethosuximide only controls absence seizures, the committee noted that it should not be used as monotherapy treatment for absence seizures with other seizure types. The committee agreed it is important to stress that for some women and girls who are able to have children, sodium valproate may still be an option, but only if the risks and benefits have been thoroughly discussed, other treatments are unsuccessful and safety advice from the MHRA is followed. This should be a shared decision taken by the person with epilepsy and their healthcare professional. The committee agreed that although other antiseizure medications are used in clinical practice and may benefit some people, it should be highlighted that some can exacerbate seizures. ## How the recommendations might affect practice The recommendations will not change current practice, but will reinforce current best practice. Return to recommendations # Myoclonic seizures Recommendations 5.4.1 to 5.4.8 ## Why the committee made the recommendations There was very limited evidence on first-line treatment for myoclonic seizures, so the committee used their clinical expertise and expert opinion to inform the recommendations. The onset of myoclonic seizures before the age of 4 years may indicate an underlying neurodegenerative disorder, therefore the committee agreed that these children should be referred to a tertiary paediatric neurologist. Myoclonic seizures are classified as generalised seizures. Because no evidence was identified on monotherapy or first-line treatments for myoclonic seizures, the committee agreed that it was appropriate to extrapolate from the evidence reviewed on generalised tonic-clonic seizures. Based on this, the committee agreed that sodium valproate is the most effective treatment option for myoclonic seizures compared with other antiseizure medications. However, because of the risks to unborn babies associated with sodium valproate use during pregnancy, the committee agreed that it was important to make separate recommendations for women and girls who are able to have children. In addition, in line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk. There was some evidence that levetiracetam, when used as an add-on treatment, is effective in controlling seizures, so the committee agreed that it should be offered as the first-line treatment in women and girls who are able to have children, and for younger girls with epilepsy likely to continue beyond puberty. Based on this evidence, the committee agreed that levetiracetam should also be offered as a second-line add-on or monotherapy treatment for men and boys if sodium valproate is unsuccessful. The committee agreed it is important to stress that for some women and girls who are able to have children, sodium valproate may still be an option, but only if the risks and benefits have been thoroughly discussed, other treatments are unsuccessful and safety advice from the MHRA is followed. This should be a shared decision taken by the person with epilepsy and their healthcare professional. In the absence of robust evidence, the committee discussed their experience and knowledge of other antiseizure medications for myoclonic seizures and agreed that brivaracetam, clobazam, clonazepam, lamotrigine, phenobarbital, piracetam, topiramate and zonisamide may be effective as third-line treatments if second-line monotherapy or add-on treatment is not sufficient to stop seizures. The committee noted that doctors should use their knowledge and experience to determine which treatment is most appropriate for the person with myoclonic seizures, taking into account clinical factors and the person's preferences and choice. They noted that although lamotrigine is used in clinical practice and may benefit some people, it can sometimes exacerbate myoclonic seizures. The committee wanted to make clear that carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine and vigabatrin should not be used because they are known to increase the frequency of myoclonic seizures. ## How the recommendations might affect practice The recommendations will not change current practice, but will reinforce current best practice. Return to recommendations # Tonic or atonic seizures Recommendations 5.5.1 to 5.5.9 ## Why the committee made the recommendations Tonic or atonic seizures are events that may cause a person to suddenly drop to the floor. These may be the result of atonic (generalised loss of tone) or tonic (sustained generalised body stiffening) seizures. Although these are characteristic of Lennox–Gastaut syndrome, they are also seen in other epilepsy syndromes and aetiologies. They often result in injury and can therefore have a significant impact on quality of life. Because of the complexities associated with the treatment of tonic or atonic seizures and the range of syndromes of which they can be a feature, the committee agreed that a neurologist with expertise in epilepsy should assess people with these seizures in order to provide accurate diagnoses if possible and advise on further investigations as well as treatment. Tonic or atonic seizures are classified as generalised seizures. Because no evidence was identified on monotherapy or first-line treatments for tonic or atonic seizures, the committee agreed that it was appropriate to extrapolate from the evidence on generalised tonic-clonic seizures. Based on this, the committee agreed that sodium valproate is the most effective treatment option for tonic or atonic seizures compared with other antiseizure medications. However, because of the risks to unborn babies associated with sodium valproate use during pregnancy, the committee agreed that it was important to make separate recommendations for women and girls who are able to have children. In addition, in line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk. There was some evidence that lamotrigine, when used as an add-on therapy, is effective in controlling tonic and atonic seizures or drop attacks, so the committee agreed that it could be considered as first-line treatment for women and girls who are able to have children and as a second-line monotherapy or add-on treatment for boys and men, and women and girls unable to have children. However, the committee also agreed that for some women and girls who are able to have children, sodium valproate may still be an option, but only if the risks and benefits have been thoroughly discussed, other treatments are unsuccessful and safety advice from the MHRA is followed. This should be a shared decision taken by the person with epilepsy and their healthcare professional. The evidence indicated that clobazam, rufinamide and topiramate can also be effective in the management of tonic and atonic seizures and the committee recommended that any of these antiseizure medications could be used as a third-line monotherapy or add-on treatment. In the absence of clear cost-effectiveness evidence of superiority between the different options, the committee agreed that clinicians should use their knowledge and experience to determine which treatment is most appropriate for the person with epilepsy, taking into account clinical factors and the person's preference. Evidence was identified for a number of other treatment options; however, the low quality and absence of direct comparisons meant that it was difficult for the committee to prioritise 1 treatment over another. The committee agreed that a ketogenic diet can be considered as an add-on treatment and, if this is unsuccessful, felbamate may also be an option as an add-on treatment. However, these treatments should only be used under the supervision of a ketogenic diet team or a neurologist with expertise in epilepsy, respectively, because of the complex nature of the epilepsy. The committee agreed that although other antiseizure medications are used in clinical practice and may benefit some people, it should be highlighted that some can exacerbate seizures. ## How the recommendations might affect practice The recommendations are not likely to change current practice, but should reinforce best practice. Return to recommendations # Idiopathic generalised epilepsies Recommendations 5.6.1 to 5.6.5 ## Why the committee made the recommendations Idiopathic generalised epilepsies are 1 of the most common forms of epilepsy. These are well defined, and onset is usually in adolescence, although it can begin in childhood. Seizures will continue into middle age, after which there is some evidence that these will remit, but is not possible to predict in which people this will occur. Many have a good prognosis for seizure control with antiseizure medications and treatment goal is seizure freedom. The evidence showed that sodium valproate is the most effective treatment for idiopathic generalised epilepsies compared with other antiseizure medications. However, because of the risks to unborn babies associated with sodium valproate use during pregnancy, the committee agreed that it was important to make separate recommendations for women and girls who are able to have children. In addition, in line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk. The evidence showed that both lamotrigine and levetiracetam were effective at reducing seizures, and the committee agreed that they should be options for first-line treatment in women and girls who are able to have children, and for younger girls with epilepsy likely to continue beyond puberty. The committee agreed it was important to stress that for some women and girls who are able to have children, sodium valproate may still be an option, but only if the risks and benefits have been thoroughly discussed, other treatments are unsuccessful and safety advice from the MHRA is followed. This should be a shared decision taken by the person with epilepsy and their healthcare professional. There was some evidence that levetiracetam is of benefit as add-on therapy compared with placebo. The evidence also showed that lamotrigine was associated with fewer side effects leading to treatment stopping and better health-related quality of life than sodium valproate. Therefore, the committee agreed that these medications could be considered as monotherapy or add-on treatment if first-line treatment is unsuccessful. The included studies did not show a clinically important benefit for topiramate when compared with placebo or valproate; however, the committee noted that this drug is useful in clinical practice. The evidence showed that add-on perampanel is effective for reducing seizures and therefore, based on their expert opinion and the evidence reviewed respectively, the committee agreed that these drugs should be available as a third-line add-on treatment option. ## How the recommendations might affect practice The committee agreed these recommendations will reinforce current best practice. Return to recommendations # Dravet syndrome Recommendations 6.1.1 to 6.1.8 ## Why the committee made the recommendations Onset of Dravet syndrome is usually in the first year of life. Children present with prolonged febrile seizures, which may need admission to an intensive care unit. Dravet syndrome can be difficult to diagnose in the first year of life; therefore, the committee emphasised that these recommendations only apply once the diagnosis has been confirmed and discussed with a paediatric neurologist. Dravet syndrome is complex to treat and the response to treatment is variable. Based on their experience and expertise, the committee agreed that the involvement of a neurologist with expertise in epilepsy is needed to guide the care of people with Dravet syndrome. There was no evidence for first-line treatments, so the committee based their recommendations on clinical experience and expert opinion. The committee agreed that sodium valproate can be effective at reducing seizures in people with Dravet syndrome because it is successfully used in current practice to treat generalised epilepsies, including Dravet syndrome. The committee acknowledged that sodium valproate should be used with caution in women and girls, only after the risks and benefits have been thoroughly discussed and in line with safety advice from the MHRA. However, they agreed that sodium valproate should be considered as first-line treatment for all people with Dravet syndrome, because there are few effective treatment options and treatment is often started at a young age (under 2 years). In line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk. The evidence suggested that triple therapy with sodium valproate, clobazam and stiripentol was effective at reducing seizures in children and young people whose seizures were previously treated unsuccessfully with clobazam and sodium valproate in combination. Although the evidence was limited, the committee agreed that it supported this as first-line add-on therapy. The committee also highlighted that careful titration of doses and regular review are important because of possible adverse effects such as sedation. The committee agreed that the NICE technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Dravet syndrome supports the use of this combination as a second-line treatment option. There was an absence of evidence to guide further treatment if seizures continue. The committee recommended further treatment options based on their experience and expert opinion, and agreed that these should be considered only under the supervision of a neurologist with expertise in epilepsy or a ketogenic diet team, as appropriate. The use of potassium bromide is unusual in practice, but the committee noted that for some people with Dravet syndrome, it can be effective. The committee were aware of ongoing trials, but agreed that further research on treating Dravet syndrome when first-line therapy is unsuccessful or not tolerated would be beneficial and they developed a recommendation for research on complex epilepsy syndromes to help inform future guidance. ## How the recommendations might affect practice The recommendations will not change current practice, but will reinforce best practice. Return to recommendations # Lennox–Gastaut syndrome Recommendations 6.2.1 to 6.2.9 ## Why the committee made the recommendations Lennox–Gastaut syndrome is a severe developmental and epileptic encephalopathy with onset in childhood. It can be difficult to diagnose, so children may be started on antiseizure medication before a final diagnosis is established. Lennox–Gastaut syndrome is complex to treat and the response to treatment is variable. Based on their experience and expertise, the committee agreed that the involvement of a neurologist with expertise in epilepsy is needed to guide the care of people with Lennox–Gastaut syndrome. There was no evidence for first-line treatments, so the committee based the recommendations on clinical experience and expert opinion. The committee agreed that sodium valproate can be effective in suppressing seizures in people with Lennox–Gastaut syndrome because it is successfully used in current practice to treat generalised epilepsy, including Lennox–Gastaut syndrome. They acknowledged that sodium valproate should be used with caution in women and girls, and only if the risks and benefits have been thoroughly discussed and safety advice from the MHRA is followed. However, they agreed that it should be considered as first-line treatment for all people with Lennox–Gastaut syndrome because there are few effective treatment options and treatment is often started at a young age (under 2 years). In line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk. The evidence showed that when used as an add-on treatment, lamotrigine is effective for reducing seizures and drop attacks, therefore the committee agreed that it could be used as second-line therapy, as either an add-on or monotherapy treatment if treatment was not successful or first-line therapy is not tolerated. If used as an add-on therapy, the committee recommended lower initial doses and caution in titration, in line with the BNF. This is because of interactions between sodium valproate and lamotrigine. There was some evidence that clobazam, rufinamide and topiramate were of benefit in reducing seizure frequency and drop attacks when used as add-on therapy compared with a placebo. In addition, the NICE technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Lennox–Gastaut syndrome supports the use of this combination as a further treatment option. Therefore, the committee agreed that any of these treatment options could be considered as an add-on treatment if first- and second-line therapy are not tolerated or if seizures continue. There was an absence of robust evidence to guide further treatment if seizures continue. The committee discussed possible alternative treatment options and, based on their expert opinion and knowledge, agreed that a ketogenic diet or felbamate could be considered, but only under the supervision of a ketogenic diet team or neurologist with expertise in epilepsy, respectively. The committee noted that although other drugs are used in clinical practice and may benefit some people with Lennox–Gastaut syndrome, it should be highlighted that they can exacerbate seizures in some people. Given the paucity of published drug trial data in this population, the committee decided to prioritise a recommendation for research on complex epilepsy syndromes including the effectiveness of antiseizure therapies in people with Lennox–Gastaut syndrome when first-line therapy is unsuccessful or not tolerated. ## How the recommendations might affect practice The recommendations are not likely to change current practice, but should reinforce best practice. Return to recommendations # Infantile spasms syndrome Recommendations 6.3.1 to 6.3.11 ## Why the committee made the recommendations Infantile spasms are a severe developmental and epileptic encephalopathy that need urgent care. Based on experience and expertise, the committee agreed that guidance should be sought immediately from a tertiary paediatric neurologist, followed by referral if needed. If untreated, long-term risks of infantile spasms include poor neurodevelopmental outcomes, which could be a serious safety concern. Based on their experience and expertise, the committee stressed that prompt diagnosis and treatment is associated with an improved prognosis. Based on best practice and monitoring strategies used in the studies included in the review, the committee agreed that these children should be monitored both during and after treatment for the relapse of spasms and the emergence of other seizure types, as well as for possible side effects related to treatment. The evidence suggested that first-line treatment combining steroids with vigabatrin is more effective than either steroids or vigabatrin alone in stopping spasms. There was no clear evidence about whether oral or injectable steroids were better, but the committee agreed that oral steroids would be easier to use. Based on their expert opinion, the committee agreed that steroids may not be suitable for all children under 2 years and that vigabatrin alone should be considered for those at high risk from the side effects of steroid treatment, such as those with neurological impairments and other comorbidities. There was evidence that vigabatrin alone is effective for children with infantile spasms associated with tuberous sclerosis, so the committee agreed that it should be used as first-line treatment in these children, with high-dose oral prednisolone added on if vigabatrin is ineffective after 1 week. The committee agreed that there should be a discussion between parents and carers of children under 2 years taking steroids and their healthcare professional, and that information should be given about possible side effects, such as the increased risk of infection, high blood pressure and high blood sugar levels. Information should include, for example, how to reduce exposure to infections such as chickenpox and what to do if the child may have been exposed. The evidence showed that higher doses of both vigabatrin and oral steroids gave improved freedom from spasms, so the committee agreed that dosages should be increased in line with the guidance in the BNF for children. Based on their expert opinion, the committee agreed that it may be necessary to go above the specified doses of vigabatrin if the spasms do not stop, but this should be carried out with specialist supervision. There was an absence of robust evidence to guide second-line treatments. The committee agreed possible options based on expert opinion and experience, which should be guided and supervised by a tertiary paediatric neurologist experienced in the care of these children. The committee agreed to prioritise a recommendation for research on complex epilepsy syndromes including the effectiveness of antiseizure therapies for infantile spasms when first-line therapy is unsuccessful, because there is no controlled trial data to support evidence-based therapy decisions when first-line treatment fails to stop the spasms. ## How the recommendations might affect practice The recommendations will not change current practice, but will reinforce best practice. Return to recommendations # Self-limited epilepsy with centrotemporal spikes Recommendations 6.4.1 to 6.4.8 ## Why the committee made the recommendations Children will grow out of self-limited epilepsy with centrotemporal spikes by their early teens. Some only have infrequent seizures, which have little impact on wellbeing. Therefore, not all children and young people and their families will choose antiseizure medication treatment. The committee acknowledged the importance of discussing the balance of risks and benefits of treatment compared with no treatment, with the child or young person and their family or carers, and agreed on some important factors that should form part of a full discussion about treatment. They also agreed that the risk of sudden unexpected death in epilepsy (SUDEP) should be discussed, and reassurance given that this is very rare. The committee members were confident, based on their experience and knowledge, that current practice using antiseizure medications is effective at controlling seizures in children and young people with self-limited epilepsy with centrotemporal spikes. There was a lack of evidence on antiseizure medications for self-limited epilepsy with centrotemporal spikes, but because these children and young people usually have focal seizures, the committee agreed to use the evidence on monotherapy for treating focal seizures to inform the recommendations for first- and second-line treatments. This evidence showed that lamotrigine and levetiracetam were continued for longer than other drugs for treating focal epilepsy, suggesting that they may be more effective and better tolerated. However, the evidence also suggested they were not more effective than other drugs in terms of remission at 6 and 12 months, and the evidence for time to first seizure suggested they were less effective than carbamazepine. The evidence on focal seizures suggested that lamotrigine, levetiracetam and gabapentin may have more tolerable adverse events than other drugs. However, adverse events were reported inconsistently across the studies making comparisons between drugs difficult. The committee also agreed that, for most drugs, adverse events could be managed by careful titration and dosage changes. Based on the evidence for focal seizures, the committee agreed that lamotrigine and levetiracetam should be considered as first-line treatment options, and carbamazepine, oxcarbazepine or zonisamide as second-line monotherapy treatments. The committee noted that, in line with guidance from the MHRA, clinicians should be aware of the risks of serious complications associated with carbamazepine and potentially medicines with a similar chemical structure (such as oxcarbazepine and eslicarbazepine acetate) for people of Han Chinese, Thai, European or Japanese family background. In addition, in line with the MHRA, the committee emphasised that long-term treatment with carbamazepine can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk. The evidence on self-limited epilepsy with centrotemporal spikes showed that sulthiame is effective for reducing seizures, and so the committee agreed that it should also be available. However, the evidence was limited in quantity and sulthiame is not currently licensed in the UK, so the committee decided that it should be considered as a third-line treatment if licensed options are unsuccessful, and only in consultation with a tertiary paediatric neurologist. The committee noted that in their experience, carbamazepine, oxcarbazepine and lamotrigine are sometimes associated with increased seizures or the development of another epilepsy syndrome. The committee recognised that only a small number of children are likely to be affected by these problems, but agreed that any change should prompt a sleep electroencephalogram (EEG) to exclude developmental epileptic encephalopathy with spike-wave activation in sleep, which may indicate an atypical form of self-limited epilepsy with centrotemporal spikes. The committee agreed that poor school performance should also prompt a neuropsychology assessment. Based on their experience, the committee agreed that these children and young people will have varied needs for review, for example, depending on frequency of seizures and choice of treatment. Regular reviews are important to prevent children and young people continuing on unnecessary treatment and allow discussion of stopping treatment. The committee agreed that this should usually happen when the child has been seizure-free for 2 years or at age 14 years. ## How the recommendations might affect practice The recommendations are not likely to change current practice, but should reinforce best practice. Return to recommendations # Epilepsy with myoclonic-atonic seizures (Doose syndrome) Recommendations 6.5.1 to 6.5.7 ## Why the committee made the recommendations Epilepsy with myoclonic-atonic seizures is a rare condition in young children. Successful treatment depends on accurate diagnosis, so based on their experience and expertise, the committee agreed that a tertiary paediatric neurologist should advise on management. No evidence was identified on treating epilepsy with myoclonic-atonic seizures. Based on their experience, the committee agreed that levetiracetam and sodium valproate should be considered as first-line treatment options because they are used effectively in current practice to treat generalised epilepsy, including epilepsy with myoclonic-atonic seizures. The committee acknowledged that sodium valproate should be used with caution in women and girls, only after the risks and benefits have been thoroughly discussed, other treatments are unsuccessful and MHRA safety advice is followed. However, they agreed that sodium valproate should be considered as a first-line treatment option for girls and women with epilepsy with myoclonic-atonic seizures, with regular review of the risks and benefits, because there are few effective treatment options available, treatment is often started at a young age and most children will outgrow their seizures by their teenage years. In line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk. The committee were aware of studies that showed benefits of a ketogenic diet in these children, and based on this knowledge and their experience, agreed that this should be considered as a second-line add-on or alternative treatment, under the supervision of a ketogenic diet team. In the absence of evidence, the committee discussed their experience and knowledge of other antiseizure medications for epilepsy with myoclonic-atonic seizures. They agreed that clobazam, ethosuximide, topiramate and zonisamide may be effective. However, these medicines are less commonly used than the first-line treatments, so the committee decided that they could be considered only if first- and second-line options are unsuccessful. The committee wanted to make it clear that carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin and vigabatrin should not be used for epilepsy with myoclonic-atonic seizures, because they are known to increase the frequency of seizures in this type of epilepsy. Children can grow out of epilepsy with myoclonic-atonic seizures, so the committee discussed discontinuing treatment. Based on their experience, they agreed that this should be considered if the child is seizure-free for 2 years. The committee agreed that further research is needed on treating epilepsy with myoclonic-atonic seizures when first-line therapy is unsuccessful or not tolerated and developed a recommendation for research on complex epilepsy syndromes to help inform future guidance. ## How the recommendations might affect practice The recommendations are not likely to change practice. Return to recommendations # Status epilepticus Recommendations 7.1.1 to 7.1.12 ## Why the committee made the recommendations Convulsive status epilepticus is a medical emergency that needs immediate treatment with antiseizure medication. The committee noted the importance of an agreed, individualised emergency management plan for people with epilepsy that should be followed for people experiencing status epilepticus. The management plan should include details of any emergency medicine that has been prescribed, who is trained to use it and when to give it. The evidence showed an overall benefit for benzodiazepines, but no clear evidence to support a particular drug. The committee agreed that the speed of delivery is more important than the type of benzodiazepine, and that the route of administration is likely to depend on whether the drug is being given in the community or in a hospital. In community settings, medicines are usually given in buccal or rectal forms because intravenous access is not available. The committee discussed that intravenous lorazepam is routinely given in hospitals and agreed that it should be the first-choice treatment in this setting because of its rapid action and because it causes less respiratory depression and sedation than other drugs. Buccal midazolam is currently used in the community, and based on their experience and the evidence, the committee agreed that it should remain as the first choice, with rectal diazepam as an alternative if agreed, based on previous use or if buccal midazolam is unavailable. The committee agreed that the evidence for further antiseizure medication, if seizures continue after 2 doses of a benzodiazepine, showed a benefit for the intravenous administration of levetiracetam, phenytoin or valproate, but did not favour 1 specific medication over the others. However, based on their experience, the committee agreed that levetiracetam can be quicker to prepare, easier to administer and may be associated with fewer adverse effects than the alternative options, so it is likely to become the preferred second-line treatment. However, because the evidence showed no difference in efficacy, the committee agreed that phenytoin or valproate can also be considered. If status epilepticus does not respond to 1 of these medications, the committee agreed that another second-line medication should be considered. A small amount of evidence showed benefit for general anaesthesia and phenobarbital if status epilepticus continues after second-line treatment. The committee agreed that these should be considered as third-line treatment options, but cautioned that guidance should be sought from an expert in administering these drugs. The committee discussed concerns that some causes of status epilepticus may need additional treatment and agreed that awareness of the different circumstances that can cause status epilepticus should be promoted. They also highlighted the need to differentiate non-epileptic attacks from convulsive status epilepticus. ## How the recommendations might affect practice The committee agreed that the recommendations reflect current practice and are not likely to involve a significant change in practice or have a substantial resource impact. Return to recommendations # Repeated or cluster seizures Recommendations 7.2.1 to 7.2.4 ## Why the committee made the recommendations The committee discussed the limited evidence available for repeated or clusters of seizures. There was some evidence that benzodiazepines are effective, and the committee agreed that they should be an option. Clobazam and midazolam were given as examples, reflecting the committee's experience and knowledge of current practice. Rectal diazepam is not preferred owing to the route of administration. The committee agreed that further research using clear, consistent definitions for repeated or cluster seizures are needed and developed a recommendation for research on antiseizure medication for repeated or cluster seizures to inform future guidance. ## How the recommendations might affect practice The committee agreed that the recommendations reflect current practice and are not likely to involve a significant change in practice or have a substantial resource impact. Return to recommendations # Prolonged seizures Recommendations 7.3.1 to 7.3.4 ## Why the committee made the recommendations No evidence was found on treating prolonged convulsive seizures, defined as seizures that last less than 5 minutes but are more than 2 minutes longer than the person's usual seizures. The committee noted that the definition of prolonged convulsive seizures used to include those longer than 5 minutes, because status epilepticus was defined as seizures that persist for 30 minutes. The International League Against Epilepsy (ILAE) proposed a new definition of status epilepticus meaning that all seizures lasting longer than 5 minutes constitute status epilepticus. The committee noted that prolonged convulsive seizures should be managed as an emergency. Based on their experience and knowledge, they agreed that benzodiazepines should be a treatment option and that midazolam is often used in current practice. ## How the recommendations might affect practice The committee agreed that the recommendations reflect current practice and are not likely to involve a significant change in practice or have a substantial resource impact. Return to recommendations # Ketogenic diet Recommendation 8.1.1 ## Why the committee made the recommendation The committee were unable to ascertain clear benefits for ketogenic diets in either adults or children with drug-resistant epilepsy from the evidence available. The committee were also mindful of the potential long-term health drawbacks of ketogenic diets, as well as the high-cost implication of providing ketogenic diets. However, from their experience and knowledge, the committee were also aware that benefits are sometimes seen in clinical practice for a small number of people with drug-resistant epilepsy, including children with certain childhood epilepsy syndromes. The committee decided against recommending ketogenic diets routinely, but did not wish to remove them completely as an option for specialist consideration in people with few further treatment options. They highlighted the need for high-quality clinical data in this area and agreed that a recommendation for research for children and adults on the effectiveness and long-term tolerability of ketogenic diets would help to inform future guidance. ## How the recommendation might affect practice Ketogenic diets are not routinely offered and so the recommendations are unlikely to have an impact on current practice. Return to recommendation # Resective epilepsy surgery Recommendations 8.2.1 to 8.2.4 ## Why the committee made the recommendations: The evidence on surgical interventions showed that resective epilepsy surgery is the most clinically effective treatment for children, young people and adults with drug-resistant focal epilepsy. This was based on the evidence showing better quality of life and lower rates of recurrence after surgery compared with medical care. The committee also considered the relative harms of surgery, such as higher rates of postoperative cognitive deficits and other adverse events. The benefits of surgery were agreed to outweigh these harms, because in many cases, the cognitive effects did not cause significant dysfunction in everyday life, and many of the other adverse events (perioperative infection, bleeding and postoperative changes in mood) were self-limiting. In addition, the committee noted that the risk of harm from surgery needed to be balanced against the risks of ongoing seizures, which include injury, head injury and sudden unexpected death in epilepsy (SUDEP). The committee accepted that the risk of harm may increase as the surgical complexity increases, but agreed that the overall balance in favour of a benefit is likely to apply across most types of epilepsy surgery for both children and adults. Original health economic modelling was undertaken to assess the cost effectiveness of resective epilepsy surgery in adults. However, insufficient data were available to model cost effectiveness in children. The results of the analysis indicated that resective epilepsy surgery was cost effective in adults. Overall, the committee concluded that resective epilepsy surgery was also highly likely to be cost effective for children because they typically have better outcomes after surgery than adults, and the benefits of surgery are experienced for longer. The committee did note that the cost of assessment for resective epilepsy surgery may be higher in children, but these costs would likely be offset by later savings in the form of fewer outpatient appointments and the benefits observed from resective epilepsy surgery. No evidence was found on the most effective criteria for referral. However, the committee agreed that because benefits from surgery would outweigh harms across all the populations considered, including improvement in seizure control, potential seizure freedom, better quality of life and reduced risk of epilepsy-related death, all people with drug-resistant epilepsy would benefit from a referral to a tertiary centre for consideration of resective surgery, including those without identified MRI abnormalities. The committee also discussed whether there were other groups that might benefit from a referral for consideration of surgery. The committee agreed, by consensus, that people with specific MRI abnormalities that might indicate future resistance to antiseizure medication, should be referred to a tertiary centre at diagnosis, rather than waiting until treatment is unsuccessful. In addition, the committee discussed that, in their experience, people with genetic abnormalities or learning disabilities can sometimes be excluded from referral to a tertiary centre for consideration of surgery. This may happen because it is thought that surgery is not suitable for them, or they might be erroneously considered unable to cope with surgical assessment. The committee agreed they should have treatment in the same way as other people with epilepsy and be referred if indicated. ## How the recommendations might affect practice Only a proportion of people with drug-resistant epilepsy are referred for resective surgery currently, because of relatively low levels of epilepsy surgical treatment provision, as well as lengthy waiting times for presurgical assessments. Therefore, referral of all people with drug-resistant epilepsy to surgical centres will probably lead to an increase in presurgical investigations and surgical procedures. This may necessitate the need for more epilepsy surgical training and a greater investment in epilepsy surgery programmes. Referral of people whose epilepsy is not drug resistant might increase the burden on tertiary centres, but the number of people in these groups is likely to be relatively small. Return to recommendations # Vagus nerve stimulation Recommendations 8.3.1 and 8.3.2 ## Why the committee made the recommendations There was no long-term robust evidence on vagus nerve stimulation in epilepsy. The committee noted that there is variation in current use, but that it tends to be offered when antiseizure medications have failed to control seizures and epilepsy surgery is not suitable or has not been successful. There was no evidence to suggest that use of vagus nerve stimulation should stop for this small group with complex needs and few management options. The committee agreed that the benefits and harms should be discussed with the person because the intervention does not work in all people and is not a risk-free procedure. NICE has published interventional procedures guidance on the use of vagus nerve stimulation in children with refractory epilepsy. The committee agreed that more research is needed in this area and drafted a recommendation for research on the effectiveness of vagus nerve stimulation. ## How the recommendations might affect practice The use of vagus nerve stimulation in practice is currently quite varied. It tends to be a palliative procedure for people with epilepsy that is resistant to treatment and who are not candidates for surgery. The recommendations are not expected to lead to a large change in current practice. Return to recommendations # Psychological, neurobehavioural, cognitive and developmental comorbidities in epilepsy Recommendations 9.1.1 to 9.1.5 and 9.2.1 to 9.2.4 ## Why the committee made the recommendations The committee felt it was important to address the higher prevalence of mental health comorbidities, learning disabilities and dementia in people with epilepsy. They also acknowledged the gap in communication and knowledge between the different specialities involved in managing epilepsy and these comorbidities, and thus the need for joint multidisciplinary working relationships. The committee highlighted the importance of active and ongoing liaison between the different specialist teams and people with epilepsy (and their families and carers if appropriate) to ensure the adequate support and treatment is in place. The committee agreed the recommendations reflected current good practice. There is variability in the evidence in terms of the different types of psychological interventions, the healthcare professionals who delivered the therapies and the characteristics of people included in the studies. The analyses showed that the differences in psychological treatments and populations did not affect the epilepsy-related quality-of-life outcome significantly, but the committee acknowledged that making recommendations for specific subgroups of people for specific interventions would not be possible from the pooled evidence. The committee also agreed that the clinical evidence for children and young people was extremely limited and very uncertain. However, the committee acknowledged the importance of recognising neurodevelopmental comorbidities in children, particularly those with complex syndromes that may need additional support from the multidisciplinary team. Coupled with the lack of health economic evidence, it was not possible to make recommendations for tailored psychological interventions with any confidence. The committee noted the need for health economic research in this area. People with epilepsy are at higher risk of experiencing depression. Anxiety is also associated with epilepsy, along with psychosis to a lesser degree. The increased risk of dying from suicide was also noted. The committee highlighted that healthcare professionals should be alert to these psychological comorbidities and check for them in people with epilepsy as part of regular review. The committee agreed to refer to existing NICE guidance on depression. They also agreed to make a recommendation for research on the cost effectiveness of tailored psychological therapy for people with epilepsy. ## How the recommendations might affect practice The recommendations on providing coordinated care do not reflect routine practice, and therefore will involve a change of practice for the majority of providers. The guideline committee acknowledged the lack of psychological therapies available to people with epilepsy in current practice, especially children and young people. Although some centres have access to neuropsychology services, this varies across the country and there are often long waiting lists. An improvement in access to psychological services for people with epilepsy and depression or anxiety may result from highlighting existing NICE guidance. No significant resource impact is expected as a consequence of the recommendations on support and treatment. Return to recommendations # Reducing the risk of epilepsy-related death including sudden unexpected death in epilepsy Recommendations 10.1.1 to 10.1.5 and 10.2.1 and 10.2.2 ## Why the committee made the recommendations There was a lack of evidence for tools predicting sudden unexpected death in epilepsy (SUDEP) and other causes of epilepsy-related death. Sparse data for the SUDEP-7 and SUDEP-7 revised tools suggested good accuracy, but the level of imprecision was very high because of the small number of SUDEP events recorded. Similarly, although there was some evidence for 3 tools for predicting all-cause mortality, it was from a single study with insufficient data to make recommendations. The committee agreed that more research is needed and that this should focus on the development of a tool, as well as its validation (see the recommendation for research on risk prediction tool for all-cause epilepsy-related death). The new tool should not focus entirely on SUDEP but should look at other causes of epilepsy-related death, such as suicide, injury and drowning. Large national or international registries recording SUDEP, all causes of death and a wide range of risk factors are needed to produce data of sufficient detail to inform a useful tool. These would need to collect data over a long period of time to provide useful numbers of outcomes. The committee also acknowledged that the SUDEP-7 tool showed some promise, despite the uncertainties in the data, and agreed that further larger-scale validation studies of SUDEP-7 should be conducted in the shorter term. The committee agreed it was important to highlight the increased risk of premature death, including SUDEP, for people with epilepsy. The lifetime risk of SUDEP is estimated to be between 7% and 12%. This risk is increased in people with severe drug-resistant epilepsy, and is particularly high among those with uncontrolled tonic-clonic seizures. To help prevent premature death, people with epilepsy and their families or carers should be supported to understand their individualised risk as well as what they can do to reduce the risk of SUDEP. Based on the evidence and their experience in clinical practice, the committee decided to highlight non-adherence to medication, alcohol and drug misuse, living alone, sleeping alone without supervision, and generalised tonic-clonic, focal to bilateral tonic-clonic and uncontrolled seizures, as important risk factors. Non-adherence to medications may also cause the person to experience more seizures and increase their risk of physical injury and premature death. The committee acknowledged that the type of seizures the person has and how often they have them can be modified through medication, significantly reducing the risk of death from seizures. The evidence showed that living alone or sleeping without supervision increased a person's risk of dying. By modifying these risk factors with support from family, carers and clinicians, a person can directly reduce their risk of premature death or SUDEP. The committee did acknowledge that it may not be possible to provide night-time supervision to adults living independently. They highlighted the use of monitors and alarms to prevent risk in children living with their parents. The committee also acknowledged that it may not be possible to remove all risk related to epilepsy. The evidence demonstrated that several comorbidities could contribute to the risk of epilepsy-related death. Therefore, the committee agreed that from a person's clinical history, a person's individual risk of premature death including SUDEP should be assessed and should include a history of abnormal neurological findings, neurological conditions and cancer. The committee noted that other risk factors may increase the risk of premature death in a person with epilepsy, and that these should also be discussed with the person to help them fully understand their individual risk. There was a lack of evidence for interventions to reduce seizure-related death including SUDEP. The committee agreed that the evidence on supervising people with nocturnal seizures was not of sufficient quantity or quality to warrant making a recommendation. However, based on their clinical experience and expertise, the committee agreed it was important to discuss risk factors with people who have nocturnal seizures to minimise the risk of seizures and promote safe practice (such as adherence to medication and improving sleep hygiene) as much as possible. Although limited, the evidence for nocturnal supervision did show some benefit, and based on their knowledge and experience, the committee agreed that this might be discussed alongside other support and information on minimising risks, for example if a carer wishes to use a night monitor or a parent wishes to sleep in the same room as a child. The committee agreed that every effort should be made to reduce epilepsy-related risk, particularly the risk of mortality, and emphasised the importance of supporting people with epilepsy to take their medications as prescribed to reduce seizures. Although this applies to all people with epilepsy, the committee noted that this is particularly the case for people with generalised tonic-clonic seizures and focal to bilateral tonic-clonic seizures, because these seizure types are associated with higher risk. ## How the recommendations might affect practice The committee highlighted that there is variation in the information currently discussed about the risk of premature death including SUDEP. The recommendations will have an impact on clinical practice by focusing on specific modifiable risk factors and working with people to reduce risk and prevent premature death. The recommendations will create a framework for discussions between healthcare professionals and the person with epilepsy and their families and carers to help inform decisions. The recommendation on night-time supervision reflects current good practice and is unlikely to change current practice. Return to recommendations # Epilepsy specialist nurses Recommendations 11.1.1 to 11.1.4 ## Why the committee made the recommendations The clinical evidence on epilepsy specialist nurses was limited in quality and quantity, and the committee acknowledged that research in this area can be challenging because of limited funding and difficulties conducting high-quality randomised studies, given that epilepsy specialist nurses are already embedded in many services. However, because there was economic evidence of cost savings both long term and within the first year, the committee agreed that people with epilepsy should have access to an epilepsy specialist nurse. Epilepsy specialist nurses are already embedded in practice and the committee agreed that they play a vital role in supporting other healthcare professionals in primary, secondary and tertiary care, as well as educational and social care settings. They are specialised in supporting children, young people and adults with all aspects of living with epilepsy, providing support with information giving, advice on administering medications, care planning, management of side effects and the impact of epilepsy on daily activities. In addition, epilepsy specialist nurses may identify problems that had been previously unnoticed, such as long-standing side effects of antiseizure medications. The committee used the evidence to determine the common features of clinically and cost-effective epilepsy specialist nurse interventions. Based on the clinical evidence, they agreed that interventions should include emotional wellbeing and self-management strategies to support improvements to day-to-day living and health. Based on economic evidence and their own expertise, the committee agreed that people's needs for information and care planning may vary over time and more contact may be needed when seizures are ongoing. The economic evidence showed that epilepsy specialist nurse-led interventions are likely to be cost saving and cost effective when delivered twice a year to people with epilepsy and after attending an emergency department. The committee recommended this approach for people with ongoing seizures or after an emergency department visit. Although it was a wider population (approximately 300,000 people in England) to that explored in the economic analyses, they are much more likely to be in regular contact with healthcare services, with a quarter of this group making at least 1 emergency department visit per year. Nearly all will have some sort of outpatient appointment in a hospital setting, often with an epilepsy specialist nurse where these are available. Therefore, a large number of these epilepsy specialist nurse appointments will already be taking place or will replace appointments with other healthcare practitioners. Although there will be additional total healthcare appointments as a result of these recommendations, the increase would be much smaller in this group than for all people with epilepsy, and costs would be potentially regained within the first year. ## How the recommendations might affect practice The recommendations reflect current practice available in some services, but there is variation in epilepsy specialist nurses' involvement across different settings. Some services may need to make changes to practice, such as hiring epilepsy specialist nurses or changing how they work, but this should lead to a number of advantages, including improved patient satisfaction and emotional wellbeing, greater consistency in provision and care, improved access to epilepsy specialist nurses and potentially cost savings. The involvement of an epilepsy specialist nurse is likely to result in cost savings by reducing the overall use of healthcare services especially in terms of reduced emergency department visits and the subsequent length of hospital stay. Return to recommendations # Transition from children's to adults' epilepsy services Recommendations 11.2.1 to 11.2.6 ## Why the committee made the recommendations The committee acknowledged that many of the recommendations in the NICE guideline on transition from children's to adults' services for young people using health or social care services are directly applicable to young people with epilepsy and their families or carers. So, they reviewed the evidence on identified themes specific to people with epilepsy that are not covered by that guideline. The committee noted that a young person's transition should be tailored to their needs and that this should be recognised by both paediatric and adult services. The committee discussed the value of reviewing diagnosis and management at transition and agreed that this should involve both paediatric and adult multidisciplinary teams working together with the young person and their family or carers. The evidence found that young people who engaged with a multidisciplinary team felt more confident and able to communicate their needs, so the committee stressed that planning and decision making should be patient-centred, with young people and their families and carers (if appropriate) fully involved in discussions about their transition and ongoing care. The committee acknowledged that transition can be a distressing time for young people with epilepsy and their families and carers. The evidence showed a lack of clarity in communication and the information given to young people and their families and carers at transition, for example they lacked clear information about the risks of SUDEP and unplanned pregnancy. The committee agreed that clear and balanced information is vital during transition and, based on their experience, listed some key areas that should be covered in discussions. In particular, stigma around epilepsy was highlighted as an important topic to raise so as to give the young person the opportunity to discuss their experiences and for support to be provided. The evidence showed that stigma can have a significant impact on young people's everyday activities, educational achievement and engagement with healthcare professionals. The evidence also suggested that repeating information at intervals during transition would help young people understand and retain key information. Based on the evidence and their experience, the committee highlighted the importance of providing information in a suitable format for the person, using language they understand and that is appropriate for their developmental age, and avoiding technical terms. The evidence showed that young people with epilepsy and a learning disability, and their parents, often struggled with transition, and had difficulty finding information and understanding the changes in service provision. They noted that transition was often not planned or happened much later than for young people without learning disabilities. Young people with learning disabilities may have complex needs, and transition to adult services may need more planning and involve other specialties, such as a learning disabilities multidisciplinary team and child and adolescent mental health services. Based on their experience, the committee agreed that it would be beneficial to start transition planning earlier than usual for young people with complex health or social care needs, including people whose seizures were not fully controlled by their treatment or those with a learning disability, to allow time for care packages to be set up. They agreed that the timeframe would depend on individual circumstances. ## How the recommendations might affect practice The recommendations reflect current best practice so the committee agreed there should be no resource impact. Return to recommendations# Context Epilepsy is one of the most common serious neurological disorders, affecting around 50 million people worldwide and about 533,000 in England and Wales. Of these, around 112,000 are children and young people. The incidence of epilepsy is estimated to be 50 per 100,000 per year and the prevalence of active epilepsy in the UK is estimated to be 5 to 10 people per 1,000. Epilepsy is also a common cause of people attending A&E departments. Epileptic seizures can result in injury, and may also be associated with mortality, for example, because of sudden unexpected death in epilepsy (SUDEP). Most people with active epilepsy (60% to 70%) have their seizures satisfactorily controlled with antiseizure medications. Other treatment options may include surgery, vagus nerve stimulation, and psychological and dietary therapies. Optimal management improves health and wellbeing, including reducing the impact of epilepsy on social activities, education and career choices, and reduces the risk of SUDEP. The original NICE guideline on epilepsy (2004) stated that the annual estimated cost of established epilepsy was £2 billion (direct and indirect costs). However, newer and more expensive antiseizure medications are now being prescribed. With an increase in treatment costs likely in coming years, it is essential to ensure that antiseizure medications with proven clinical and cost effectiveness are identified. The 2004 NICE guideline on epilepsies, the 2004 NICE technology appraisal guidance and the subsequent 2012 pharmacological review on newer drugs for epilepsy, failed to show a difference in effectiveness between newer and older antiseizure medications, or between the newer drugs (as monotherapy) for seizure control. The International League Against Epilepsy has proposed new definitions and a framework for classifying epilepsy, and diagnosis and investigation have become more focused on aetiology. This guideline update reflects this and considers new evidence on managing epilepsies.	{'Diagnosis and assessment of epilepsy': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Referral after a first seizure or remission and assessing risk of a second seizure\n\n## Referral after a first seizure\n\nFor recommendations on immediate guidance and referral for children under 2\xa0years with suspected or confirmed infantile spasms, see the section on infantile spasms syndrome.\n\nRefer children, young people and adults urgently (for an appointment within 2\xa0weeks) for an assessment after a first suspected seizure:\n\nFor adults, refer to a clinician with expertise in assessing first seizures and diagnosing epilepsy.\n\nFor children and young people, refer to a paediatrician with expertise in assessing first seizures and diagnosing epilepsy.\n\n## Referral after remission\n\nRefer children, young people and adults urgently (for an appointment within 2\xa0weeks) for an assessment if they have a seizure recurrence after a period of remission.\n\n## Assessing the risk of a second seizure\n\nWhen a child, young person or adult presents with a first seizure, carry out an individualised assessment of their risk of a second seizure.\n\nIn adults, assessment should include checking for the following modifiable factors that may increase the risk of a second seizure:\n\nan underlying mental health problem (such as depression, anxiety, psychosis and alcohol or substance misuse)\n\nvascular risk factors (for example, diabetes, hypertension, atrial fibrillation)\n\nsepsis.\n\nBe aware that children presenting with a first afebrile seizure (seizure without a fever) are at an increased risk of further afebrile seizures, especially within 6 to 12\xa0months, compared with children with a febrile seizure (seizure with a fever).\n\nBe aware that children presenting with complicated febrile seizures (febrile seizures that last longer than 10\xa0minutes or febrile seizures associated with other features, such as weakness, on one side of the body) may be at higher risk of epilepsy, especially if other predisposing risk factors for epilepsy are present.\n\nUsing a person-centred approach, discuss with the person, and their family and carers if appropriate, their individualised risks for further seizures. This should include any mental, physical and social factors identified as possible risk factors and how these may be modified.\n\n## Information and support after a first seizure\n\nAfter a first seizure, give the person, and their family and carers if appropriate, information about:\n\nhow to recognise a further seizure\n\nfirst aid and initial safety guidance in case of another seizure (see safety issues in box\xa01)\n\nany changes they can make to reduce their risk of another seizure\n\nwho they should contact if they have a further seizure while awaiting their appointment for assessment and diagnosis.\n\nAfter a first afebrile seizure in a child, explain to their parents or carers how to self-refer the child urgently if they have a further seizure.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral after a first seizure or remission and assessing risk of a second seizure\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 1: prediction of second seizure\n\nevidence review 2: modifiable risk factors for a second seizure.\n\nLoading. Please wait.\n\n# Specialist assessment and diagnosis\n\nSee also NICE's guideline on transient loss of consciousness ('blackouts') in over 16s for recommendations on initial assessment of people after a suspected transient loss of consciousness. In particular, see the recommendations on performing electrocardiogram (ECG) in the section on obtaining patient history, physical examination and tests and on features suggestive of epileptic seizures in the section on suspected epilepsy.\n\nTake a detailed history from the child, young person or adult after a first suspected seizure, and from their families and carers if appropriate, and carry out a physical examination. If possible, use eyewitness accounts and video footage of the seizure to inform the assessment.\n\nEvaluate people after a first suspected seizure with a 12-lead ECG to help identify cardiac-related conditions that could mimic an epileptic seizure.\n\nBe aware that metabolic disturbance, including hypoglycaemia, can result in seizures.\n\nOffer brain neuroimaging tests if an underlying structural cause is suspected (see also the section on neuroimaging).\n\n## Electroencephalogram (EEG)\n\nIf the person's history and examination suggests an epileptic seizure, and a diagnosis of epilepsy is suspected, consider a routine EEG carried out while awake to support diagnosis and provide information about seizure type or epilepsy syndrome.\n\nDo not use EEG to exclude a diagnosis of epilepsy.\n\nIf an EEG is requested after a first seizure, perform it as soon as possible (ideally within 72\xa0hours after the seizure).\n\nWhen offering an EEG, discuss the benefits and risks of provoking manoeuvres during EEG, such as hyperventilation and photic stimulation, with the person and their family or carers if appropriate. If agreed, include provoking manoeuvres during routine EEG to assess a suspected first seizure.\n\nIf routine EEG is normal, consider a sleep-deprived EEG if agreed with the person, and their family or carers if appropriate, after discussing the benefits and risks.\n\nIf routine and sleep-deprived EEG results are normal and diagnostic uncertainty persists, consider ambulatory EEG (for up to 48\xa0hours).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on specialist assessment and diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa03: diagnosis of epilepsies.\n\nLoading. Please wait.\n\n# Neuroimaging\n\n## Initial imaging scans\n\nOffer an MRI scan to children, young people and adults diagnosed with epilepsy, unless they have idiopathic generalised epilepsy or self-limited epilepsy with centrotemporal spikes. The MRI should be carried out:\n\nwithin 6 weeks of the MRI referral and\n\nfollowing regionally agreed epilepsy MRI protocols.\n\nIf MRI is contraindicated, consider a CT scan for children, young people and adults with epilepsy.\n\nWhen offering an MRI or CT scan, discuss the risks and benefits with the person with epilepsy (and their families and carers, as appropriate), especially if a general anaesthetic or sedation is needed for the scan.\n\n## Reporting and reviewing scans\n\nEnsure that MRI scans are reported by a radiologist with expertise in paediatric or adult neuroradiology, as appropriate.\n\nIf seizures are ongoing despite treatment, and diagnosis remains unclear, consider an additional review of MRI scans by a specialist in paediatric or adult neuroradiology within a tertiary centre.\n\n## Repeat scanning\n\nConsider an additional MRI scan for children, young people and adults with epilepsy, if:\n\nthe original scan was suboptimal\n\nthere are new features to their epilepsy\n\nthey have idiopathic generalised epilepsy or self-limited epilepsy with centrotemporal spikes that has not responded to first-line treatment\n\nsurgery is being considered.\n\n## Scanning in acute situations\n\nDo not carry out a CT scan for people with established epilepsy presenting at an emergency department after a typical seizure, unless there are other concerns.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on neuroimaging\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: magnetic resonance imaging scan to detect relevant abnormalities in people with epilepsy\n\nevidence review B: computed tomography scan performance in people with epilepsy.\n\nLoading. Please wait.\n\n# Genetic testing\n\nDiscuss with a neurologist or geneticist any uncertainties about whether to offer genetic testing or which tests to offer to a person with epilepsy.\n\nWhen making decisions about which tests to offer, refer to the NHS National Genomic Test Directory for rare and inherited disease for information on genetic tests commissioned by the NHS in England.\n\nBefore carrying out genetic tests:\n\ndiscuss the purpose of testing and the possible implications of the results with the person with epilepsy, and their family and carers if appropriate\n\nobtain informed consent with appropriate genetic counselling in line with the NHS Genomic Medicine Service.\n\nConsider whole-genome sequencing for people with epilepsy of unknown cause who:\n\nwere aged under 2 years when epilepsy started or\n\nhave clinical features suggestive of a specific genetic epilepsy syndrome (for example, Dravet syndrome) or\n\nhave additional clinical features such as:\n\n\n\na learning disability\n\nautism spectrum disorder\n\na structural abnormality (for example, dysmorphism or congenital malformation)\n\nunexplained cognitive or memory decline.See also the eligibility criteria that accompany the NHS National Genomic Test Directory.\n\n\n\nConsider whole-genome sequencing for people with epilepsy of unknown cause who were aged between 2 and 3\xa0years when epilepsy started, if clinically agreed by a specialist multidisciplinary team.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on genetic testing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: effectiveness of genetic testing in determining the aetiology of epilepsy.\n\nLoading. Please wait.\n\n# Antibody testing\n\nConsider antibody testing in discussion with a neurologist for people with new-onset epilepsy if autoimmune encephalitis is suspected.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on antibody testing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: antibody testing in epilepsy.\n\nLoading. Please wait.", 'Information and support': "For information and support before diagnosis, see the section on information and support after a first seizure.\n\nWhen providing information to people with epilepsy and their families or carers, follow:\n\nthe recommendations on communication and information in NICE's guidelines on patient experience in adult NHS services or babies, children and young people's experience of healthcare\xa0and\n\nNICE's guideline on shared decision making.\n\nProvide tailored information and support to people with epilepsy, and their families or carers if appropriate, according to their individual needs and circumstances.\n\nInclude children and young people in discussions about their information and support needs, and provide information appropriate to their developmental age.\n\nTake into account the information and support needs of people with epilepsy who are older, have a learning disability or have other complex needs, for example:\n\ngive longer appointments to allow more time for discussion\n\nprovide information in different formats, such as easy read, large print or audio versions\n\ninvolve family members or carers or an advocate if the person wishes\n\nshare information with those involved in the care of older people or people with learning disabilities if appropriate.See also the section on general principles of care in NICE's guideline on challenging behaviour and learning disabilities and the section on overarching principles in NICE's guideline on care and support of people growing older with learning disabilities.\n\nGive people with epilepsy, and their families and carers if appropriate, details of local and national epilepsy information and support groups.\n\nSupport people to self-manage their epilepsy and make informed choices by discussing the following issues with them during their first appointment:\n\ntriggers that may provoke seizures\n\nmedications for epilepsy, the importance of adherence to medication and possible side effects\n\nreducing epilepsy-related risks, including sudden unexpected death in epilepsy (SUDEP)\n\nimpact on daily activities, including driving\n\ntheir epilepsy syndrome or seizure types.The discussion may be reiterated at an information and care-planning session with an epilepsy specialist nurse (see also the section on epilepsy specialist nurses).\n\nProvide the person with epilepsy, and their family or carers if appropriate, with a copy of their care plan, which includes details of their care and support as discussed and agreed with the person, and their family or carers if appropriate.\n\nRepeat information for people with epilepsy, and their families or carers if appropriate, at subsequent appointments according to their individual needs and circumstances.\n\nProvide information and support at routine appointments with the person's GP, specialist or epilepsy specialist nurse, as needed, and also at dedicated information and care-planning appointments with an epilepsy specialist nurse (see the section on epilepsy specialist nurses).\n\nConsider providing a framework for discussions before appointments that includes issues commonly raised by people with epilepsy or that may be of concern to the person.\n\nOffer people with epilepsy, and their families and carers if appropriate, opportunities at each appointment to discuss issues that concern them including, but not limited to, the topics in box\xa01.\n\nActivities of daily living\n\nSafety issues, including activities that should be adapted or avoided, for example, showering rather than having baths, cooking safely, caring for babies and young children safely, and avoiding working at heights.\n\nSafety issues for children and young people, including supervised swimming and water sports, not climbing above their height without supervision.\n\nPotential impact on lifestyle and social life and any experiences of social exclusion.\n\nDriving, including Driver and Vehicle Licensing Agency (DVLA) regulations.\n\nEmployment and education, including concerns and rights related to employment and education.\n\nCarers\n\nPhysical and emotional demands of caring for and supporting a person with epilepsy.\n\nInformation and support for carers, including assessing carers needs (see also NICE's guideline on supporting adult carers).\n\nCognition\n\nConcerns about the impact of epilepsy and antiseizure medication on cognitive function, including memory, attention, concentration, educational attainment and performance in the workplace.\n\nMedication\n\nAdherence to antiseizure medication and how to improve this (see also NICE's guidelines on medicines adherence and medicines optimisation).\n\nExperiences of side effects from medication and coping strategies.\n\nExplaining changes to medication.\n\nMental health\n\nEmotional health and psychological wellbeing, for example, experience of depression, anxiety or low mood (see also NICE's guidelines on depression in adults with a chronic physical health problem, depression in children and young people and mental health problems in people with learning disabilities).\n\nNeurobehavioural disorders commonly associated with epilepsy, including autism and attention deficit hyperactivity disorder.\n\nStigmatisation of epilepsy.\n\nReproductive health and pregnancy\n\nSupport and information on contraception and pregnancy for women and their partners to enable them to make informed decisions.\n\nSupport for changes in medications and the potential interactions with contraception.\n\nTeratogenicity of antiseizure medications.\n\nPre-conception planning, including the use of folic acid and reducing epilepsy-related risk during pregnancy.\n\nPlanning the birth.\n\nPostnatal care and breastfeeding.\n\nSee also the section on antiseizure medications for women and girls and follow the Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on antiepileptic drugs in pregnancy.\n\nSUDEP\n\nConcerns of people with epilepsy and their families and carers about sudden unexpected death in epilepsy (SUDEP).\n\nInformation about SUDEP, including risk factors for SUDEP and how to reduce the risks.\n\nAvailability of SUDEP counselling.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 4: information and support\n\nevidence review O: effectiveness of a nurse specialist in the management of epilepsy.\n\nLoading. Please wait.", 'Referral to tertiary specialist services': "Ensure that all children, young people and adults with suspected or confirmed epilepsy have access to a tertiary epilepsy service, if needed, via their specialist.\n\nTake into account that people with suspected or confirmed epilepsy and a learning disability, physical disability or mental health problem may need additional specialist support to manage their epilepsy. Support them to access a tertiary epilepsy service if needed.\n\nRefer people with epilepsy to a tertiary epilepsy service, to be seen within 4\xa0weeks, if any of the following apply:\n\nuncertainty about the diagnosis or cause of epilepsy, the seizure type or epilepsy syndrome\n\nthe person has an epilepsy syndrome likely to be drug resistant, their seizures are drug resistant or their treatment is associated with intolerable side effects\n\nfurther assessment and treatment approaches are indicated, such as: video electroencephalogram (EEG) telemetry, neuropsychology or neuropsychiatry, specialised neuroimaging, specialised treatments (for example, medication that can only be prescribed by a tertiary epilepsy service or a ketogenic diet), epilepsy surgery or vagus nerve stimulation\n\nthe person is eligible for and wishes to participate in a clinical trial or research study.\n\nRefer children with suspected or confirmed epilepsy to a tertiary paediatric epilepsy service to be seen within 2\xa0weeks, if they:\n\nare aged under 3\xa0years\n\nare aged under 4\xa0years and have myoclonic seizures (see recommendation 5.4.1 in the section on myoclonic seizures)\n\nhave a unilateral structural lesion\n\nare showing deterioration in their behaviour, speech or learning.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral to tertiary specialist services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: criteria for referral to specialist services.\n\nLoading. Please wait.", 'Principles of treatment, safety, monitoring and withdrawal': "# Treatment with antiseizure medications\n\nSee also the section on antiseizure medications for women and girls for special considerations for this group.\n\nDevelop an individualised antiseizure medication treatment strategy with the person, and their family and carers if appropriate, taking into account:\n\nsex\n\nage\n\nseizure type\n\nepilepsy syndrome\n\nwhether treatment is needed\n\nrisks and benefits of antiseizure medications, including their importance in reducing the risk of epilepsy-related death\n\npossible interactions with any other medicines taken\n\nany comorbidities\n\nthe preferences of the person, and their family or carers if appropriate\n\npersonal circumstances, such as education, employment, likelihood of pregnancy, driving, alcohol use, travel\n\nhow and when antiseizure medicines need to be taken.See also NICE's guidelines on shared decision making and decision making and mental capacity.\n\nTake into account any particular issues for older people starting an antiseizure medication, especially those with comorbidities, for example:\n\ncheck for possible interactions with other medicines they are taking\n\nuse a tailored approach to dosage and titration, usually starting at a lower dose and increasing slowly\n\ncheck if the person would benefit from an approach that takes into account multimorbidity; for more information, see NICE's guideline on multimorbidity.\n\nUse a single antiseizure medication (monotherapy) to treat epilepsy whenever possible.\n\nReview the diagnosis of epilepsy if seizures continue despite an optimal dose of a first-line antiseizure medication.\n\nIf first-line monotherapy is unsuccessful and epilepsy diagnosis remains confirmed, try monotherapy with another antiseizure medication, using caution during the changeover period:\n\nIncrease the dose of the second medicine slowly while maintaining the dose of the first medicine.\n\nIf the second medicine is successful, slowly taper off the dose of the first medicine.\n\nIf the second medicine is unsuccessful, slowly taper off the dose of the second medicine and consider an alternative.\n\nIf monotherapy is unsuccessful, consider trying an add-on treatment.\n\nWhen starting an add-on treatment, carefully titrate the additional medicine and review treatment frequently, including monitoring for adverse effects such as sedation.\n\nIf trials of add-on treatment do not result in a reduction in seizures, use the regimen that provides the best balance between effectiveness and tolerability of side effects.\n\nDiscuss with the person, and their family and carers as appropriate, the benefits of taking as few medicines as possible to maintain seizure freedom or control.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatment with antiseizure medications\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nevidence review\xa0E: monotherapy for generalised tonic-clonic and focal onset seizures\n\nevidence review\xa0F: add-on therapy for generalised tonic-clonic and focal onset seizures\n\nevidence review\xa0G: effectiveness of antiseizure therapies in the treatment of absence seizures\n\nevidence review\xa0H: effectiveness of antiseizure therapies in the treatment of myoclonic seizures\n\nevidence review\xa0I: effectiveness of antiseizure therapies in the treatment of tonic or atonic seizures/drop attacks\n\nevidence review\xa0J: effectiveness of antiseizure therapies in the treatment of idiopathic generalised epilepsies, including juvenile myoclonic epilepsy\n\nevidence review\xa0K: effectiveness of antiseizure therapies in the treatment of Dravet syndrome\n\nevidence review\xa0L: effectiveness of antiseizure therapies in the treatment of Lennox-Gastaut syndrome\n\nevidence review\xa0P: effectiveness of antiseizure therapies for infantile spasms\n\nevidence review\xa0Q: effectiveness of antiseizure medications for self-limited epilepsy with centrotemporal spikes\n\nevidence review\xa0R: effectiveness of antiseizure therapies for epilepsy with myoclonic-atonic seizures (Doose syndrome).\n\nLoading. Please wait.\n\n# When to start antiseizure medication\n\nStart treatment with an antiseizure medication once the diagnosis of epilepsy is confirmed.\n\nConsider starting treatment after a first unprovoked seizure if any of the following apply:\n\nan examination identifies signs of neurological deficit\n\nthe electroencephalogram (EEG) shows unequivocal epileptic activity\n\nafter a discussion of the risk of further seizures, the person or their family or carers consider the risk unacceptable\n\nbrain imaging shows a structural abnormality.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on when to start antiseizure medication\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nevidence review E: monotherapy for generalised tonic-clonic and focal onset seizures\n\nevidence review\xa0F: add-on therapy for generalised tonic-clonic and focal onset seizures\n\nevidence review\xa0G: effectiveness of antiseizure therapies in the treatment of absence seizures\n\nevidence review\xa0H: effectiveness of antiseizure therapies in the treatment of myoclonic seizures\n\nevidence review\xa0I: effectiveness of antiseizure therapies in the treatment of tonic or atonic seizures/drop attacks\n\nevidence review\xa0J: effectiveness of antiseizure therapies in the treatment of idiopathic generalised epilepsies, including juvenile myoclonic epilepsy\n\nevidence review\xa0K: effectiveness of antiseizure therapies in the treatment of Dravet syndrome\n\nevidence review\xa0L: effectiveness of antiseizure therapies in the treatment of Lennox-Gastaut syndrome\n\nevidence review\xa0P: effectiveness of antiseizure therapies for infantile spasms\n\nevidence review\xa0Q: effectiveness of antiseizure medications for self-limited epilepsy with centrotemporal spikes\n\nevidence review\xa0R: effectiveness of antiseizure therapies for epilepsy with myoclonic-atonic seizures (Doose syndrome).\n\nLoading. Please wait.\n\n# Safety considerations\n\nSee the section on antiseizure medications for women and girls for additional safety considerations for this group.\n\nFollow Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on switching between different manufacturers' products of a particular antiseizure medication.\n\nBe aware that phenytoin is associated with an increased risk of serious skin reactions in people of Han Chinese or Thai family background.\n\nBe aware that carbamazepine and potentially medicines with a similar chemical structure (such as oxcarbazepine and eslicarbazepine acetate) are associated with an increased risk of serious skin reactions in people of Han Chinese, Thai, European or Japanese family background.\n\nBe aware that long-term treatment with some antiseizure medications (such as carbamazepine, phenytoin, primidone and sodium valproate) is associated with decreased bone mineral density and increased risk of osteomalacia. Follow the MHRA safety advice on antiepileptics: adverse effects on bone and consider vitamin\xa0D and calcium supplementation for people at risk.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on safety considerations\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nevidence review\xa0E: monotherapy for generalised tonic-clonic and focal onset seizures\n\nevidence review\xa0F: add-on therapy for generalised tonic-clonic and focal onset seizures\n\nevidence review\xa0G: effectiveness of antiseizure therapies in the treatment of absence seizures\n\nevidence review\xa0H: effectiveness of antiseizure therapies in the treatment of myoclonic seizures\n\nevidence review\xa0I: effectiveness of antiseizure therapies in the treatment of tonic or atonic seizures/drop attacks\n\nevidence review\xa0J: effectiveness of antiseizure therapies in the treatment of idiopathic generalised epilepsies, including juvenile myoclonic epilepsy\n\nevidence review\xa0K: effectiveness of antiseizure therapies in the treatment of Dravet syndrome\n\nevidence review\xa0L: effectiveness of antiseizure therapies in the treatment of Lennox-Gastaut syndrome\n\nevidence review\xa0P: effectiveness of antiseizure therapies for infantile spasms\n\nevidence review\xa0Q: Effectiveness of antiseizure medications for self-limited epilepsy with centrotemporal spikes\n\nevidence review\xa0R: effectiveness of antiseizure therapies for epilepsy with myoclonic-atonic seizures (Doose syndrome).\n\nLoading. Please wait.\n\n# Antiseizure medications for women and girls\n\nGive women and girls with epilepsy information and support that is tailored to their age-specific and developmental needs. Review regularly information provided about:\n\ncontraception\n\nfolic acid supplementation\n\nconception\n\npregnancy\n\nbreastfeeding\n\ncaring for children\n\nmenopause.\n\nDiscuss with women and girls with epilepsy who are able to have children (including young girls who are likely to need treatment when they are able to have children), and their families or carers if appropriate, the risks to an unborn child of taking antiseizure medications during pregnancy, such as congenital malformations, neurodevelopmental impairments and fetal growth restriction.\n\nAssess the risks and benefits of treatment with individual antiseizure medications when prescribing antiseizure medications for women and girls who are able to have children, now or in the future. Take into account the latest data on the risks to the unborn child and be aware that there are important uncertainties about the risks, particularly with newer drugs. Follow the MHRA safety advice on antiepileptic drugs in pregnancy.\n\nSpecifically, discuss the risks to the unborn child of using sodium valproate during pregnancy, including the increased risk with higher doses and polytherapy. Follow the MHRA safety advice on valproate use by women and girls.\n\nBe aware that some antiseizure medications, for example, carbamazepine, oxcarbazepine, phenytoin and topiramate, can impair the effectiveness of hormonal contraceptives. Refer to the summary of product characteristics (SPC) and BNF or BNF for children for individual drug advice on the interactions between antiseizure medications and contraception.\n\nBe aware that oestrogen-containing hormonal contraceptives and hormone replacement therapy can impair the effectiveness of lamotrigine.\n\nExplain that breastfeeding for most women and girls taking antiseizure medications is generally safe and should be encouraged. Support each mother to choose a feeding method that bests suits her and her family.\n\nPrescribers should consult individual drug advice in the SPC and the BNF or BNF for children when prescribing antiseizure medications for women and girls who are breastfeeding. Decisions about antiseizure therapy and breastfeeding should be made between the woman or girl and the prescriber, and take into account the benefits of breastfeeding alongside the potential risks of the medication affecting the child.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on antiseizure medications for women and girls\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa06: safety of antiseizure medications in women and girls.\n\nLoading. Please wait.\n\n# Monitoring and review\n\nArrange regular (at least annual) monitoring reviews for adults with epilepsy and any of the following:\n\na learning disability\n\ndrug-resistant epilepsy\n\na high risk of sudden unexpected death in epilepsy (SUDEP; see the section on reducing the risk of epilepsy-related death)\n\na serious comorbidity, such as complex psychosocial, cognitive or mental health problems\n\nwho are taking antiseizure medications associated with long-term side effects or drug interactions\n\nwho are able to get pregnant and are taking valproate or any other high-risk teratogenic antiseizure medication (see also the MHRA safety advice on antiepileptic drugs in pregnancy). See also, the section on epilepsy specialist nurses for epilepsy specialist nurse sessions for adults with ongoing seizures.\n\nDiscuss monitoring reviews with children and young people with epilepsy and their families and carers if appropriate, and agree a frequency for regular reviews that is:\n\nindividually tailored to the child or young person's needs, preferences and the nature of their epilepsy and\n\nat least every 12 months. See also the section on infantile spasms syndrome for recommendations on additional monitoring reviews for children with infantile spasms. See the section on epilepsy specialist nurses for recommendations on epilepsy specialist nurse sessions for children and young people with ongoing seizures.\n\nConsider monitoring antiseizure medication levels in people with epilepsy and any of the following:\n\nuncontrolled seizures\n\nside effects from their medication\n\na specific clinical condition needing closer supervision (such as pregnancy or renal failure)\n\npoor adherence to medication.\n\nExplain to people with epilepsy and, if appropriate, their families and carers, that they can ask for a review of their care if they have concerns, need support or their care needs change, for example, to support medicines withdrawal, pregnancy planning or to review treatment if seizures recur. Provide contact details and information on how to access epilepsy services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring and review\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 7: monitoring\n\nevidence review O: effectiveness of a nurse specialist in the management of epilepsy.\n\nLoading. Please wait.\n\n# Support and monitoring for women planning pregnancy or who are pregnant\n\nRefer women and girls with epilepsy who are planning pregnancy or are pregnant to an epilepsy specialist team for a review of their antiseizure medication options.\n\nEnsure information about the care of women and girls during pregnancy is shared between the epilepsy specialist team, a specialist obstetric team and primary care.\n\nExplain to women and girls who are pregnant or are planning pregnancy the importance of adherence to their antiseizure medications and that they should not stop their medication without medical supervision (see also recommendation 4.6.1 on referral).\n\nDiscuss the relative benefits and risks of adjusting medication with the woman or girl planning pregnancy to enable her to make informed decisions. This should include discussing the balance between the risks of poorly controlled seizures and the risks to the baby when antiseizure medicines are taken in pregnancy or while breastfeeding.\n\nConsider more frequent monitoring reviews for women and girls with epilepsy who are pregnant and are prescribed antiseizure medication, if they:\n\nhave a learning disability\n\nare aged under 16\xa0years\n\nhave active epilepsy (a seizure within the past 12\xa0months)\n\nhave bilateral tonic-clonic seizures\n\nhave modifiable risk factors for SUDEP (see recommendation 10.1.2).\n\nConsider monitoring antiseizure medication levels in women or girls with epilepsy who are planning pregnancy and are considered to be at risk of their seizures worsening.\n\nWhen starting monitoring in women or girls planning pregnancy, obtain a baseline (pre-conception) concentration of antiseizure medications (for example, carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital and phenytoin) and check adherence to their medication.\n\nFor women or girls with epilepsy who are pregnant or planning a pregnancy and taking carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital or phenytoin, monitor and adjust dosages following the MHRA safety advice on antiepileptic drugs in pregnancy.\n\nIf monitoring of antiseizure medications levels is carried out in pregnancy, discuss the results with the woman or girl with epilepsy to inform choices about any adjustments to doses.\n\nIf dosing of antiseizure medications is changed during pregnancy, discuss and make an antenatal plan with the woman or girl to return her medications to pre-conception dosages. Antiseizure medications should begin to return to pre-conception dosages in the first few days after the birth.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on support and monitoring for women planning pregnancy or who are pregnant\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 7: monitoring\n\nevidence review O: effectiveness of a nurse specialist in the management of epilepsy.\n\nLoading. Please wait.\n\n# Discontinuing antiseizure medication\n\nFor further guidance on managing withdrawal of benzodiazepines and gabapentinoids in adults, see the section on withdrawing a medicine in NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nDiscuss the benefits and risks of discontinuing antiseizure medication with the person with epilepsy, and their family and carers as appropriate, as part of an ongoing assessment of their treatment at any appointment or review. Provide information about the risks and benefits in an accessible format.\n\nAfter a person has been seizure-free for 2\xa0years, carry out an individualised assessment to determine the risk of seizure recurrence if antiseizure medications are discontinued. This should be carried out by an epilepsy specialist if there is any doubt or concern about the risks.\n\nWhen deciding whether to discontinue antiseizure medications, discuss with the person with epilepsy, and their family or carers if appropriate:\n\ntheir individualised risk assessment, including their risk of seizures recurring and, if appropriate, the risk of SUDEP\n\nthe person's preferences and lifestyle, including the implications for driving if relevant.\n\nIf a decision is made to discontinue antiseizure medication, agree a plan with the person, and their family or carers if appropriate, based on the person's risk and preferences. The plan should include reducing their antiseizure medications gradually:\n\nFor most medicines, this would typically be over at least 3 months.\n\nFor benzodiazepines and barbiturates, this would typically be over a longer period to reduce the risk of drug-related withdrawal symptoms.\n\nFor people with epilepsy taking multiple antiseizure medications, discontinue their medications one at a time.\n\nIf seizures recur during or after discontinuation, reverse the last dose reduction and seek guidance from the epilepsy specialist, in line with the agreed plan.\n\nAfter epilepsy surgery, discontinue antiseizure medications under the guidance of the epilepsy surgery centre.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on discontinuing antiseizure medication\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: discontinuation of pharmacological treatment.\n\nLoading. Please wait.", 'Treating epileptic seizures in children, young people and adults': "# Generalised tonic-clonic seizures\n\nFor more information on treatment in women and girls, see the section on antiseizure medications for women and girls.\n\nFollow the Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy.\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section.\n\n## Monotherapy\n\nOffer sodium valproate as first-line monotherapy for generalised tonic-clonic seizures in:\n\nboys and men\n\ngirls aged under 10\xa0years and who are unlikely to need treatment when they are old enough to have children\n\nwomen who are unable to have children.\n\nOffer lamotrigine or levetiracetam as first-line monotherapy for generalised tonic-clonic seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children). If the first choice is unsuccessful, offer the other of these options.In April 2022, these were off-label uses of lamotrigine in children under 13\xa0years and levetiracetam in adults and children. See NICE's information on prescribing medicines.\n\nIf first-line monotherapy with sodium valproate is unsuccessful for generalised tonic-clonic seizures, offer lamotrigine or levetiracetam as second-line monotherapy treatment. If the first choice is unsuccessful, try the other of these options.In April 2022, these were off-label uses of lamotrigine in children under 13\xa0years and levetiracetam in adults and children. See NICE's information on prescribing medicines.\n\nDo not offer sodium valproate monotherapy for generalised tonic-clonic seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children), unless:\n\nother treatment options are unsuccessful\n\nthe risks and benefits have been fully discussed, including the risks to an unborn child\n\nthe likelihood of pregnancy has been taken into account and a pregnancy prevention programme put in place, if appropriate.Follow the MHRA safety advice on valproate use by women and girls.\n\n## Add-on treatment\n\nFor guidance on safe prescribing and managing withdrawal of clobazam in adults, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nIf monotherapy is unsuccessful in people with generalised tonic-clonic seizures, consider 1\xa0of the following first-line add-on treatment options:\n\nclobazam\n\nlamotrigine\n\nlevetiracetam\n\nperampanel\n\nsodium valproate, except in women and girls able to have children\n\ntopiramate. If the first choice is unsuccessful, consider the other first-line add-on options.In April 2022, these were off-label uses of clobazam as add-on therapy in children under 6\xa0months, lamotrigine in children under 2\xa0years, levetiracetam in children under 12\xa0years, perampanel in children under 7 years, and topiramate in children under 2\xa0years. See NICE's information on prescribing medicines.\n\nIf first-line add-on treatments tried are unsuccessful in people with generalised tonic-clonic seizures, consider 1\xa0of the following second-line add-on treatment options:\n\nbrivaracetam\n\nlacosamide\n\nphenobarbital\n\nprimidone\n\nzonisamide. If the first choice is unsuccessful, consider the other second-line add-on options.In April 2022, these were off-label uses of brivaracetam in adults and children, lacosamide in children under 4\xa0years, and zonisamide in adults and children. See NICE's information on prescribing medicines.\n\nDo not offer sodium valproate as an add-on treatment for generalised tonic-clonic seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children), unless:\n\nother treatment options are unsuccessful\n\nthe risks and benefits have been fully discussed, including the risks to an unborn child\n\nthe likelihood of pregnancy has been taken into account and a pregnancy prevention programme put in place, if appropriate.Follow the MHRA safety advice on valproate use by women and girls.\n\n## Other treatment considerations\n\nBe aware that the following antiseizure medications may exacerbate seizures in people with absence or myoclonic seizures, including in juvenile myoclonic epilepsy:\n\ncarbamazepine\n\ngabapentin\n\nlamotrigine (for myoclonic seizures)\n\noxcarbazepine\n\nphenytoin\n\npregabalin\n\ntiagabine\n\nvigabatrin.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on generalised tonic-clonic seizures\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review E: monotherapy for generalised tonic-clonic and focal onset seizures\n\nevidence review F: add-on therapy for generalised tonic-clonic and focal onset seizures.\n\nLoading. Please wait.\n\n# Focal seizures with or without evolution to bilateral tonic-clonic seizures\n\nFor more information on treatment in women and girls, see the section on antiseizure medications for women and girls.\n\nFollow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy.\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section.\n\n## Monotherapy\n\nConsider lamotrigine or levetiracetam as first-line monotherapy for people with focal seizures. If the first choice is unsuccessful, consider the other of these options.In April 2022, these were off-label uses of lamotrigine in children under 13\xa0years, and levetiracetam in children and young people under 16\xa0years. See NICE's information on prescribing medicines.\n\nIf first-line monotherapies are unsuccessful in people with focal seizures, consider 1 of the following second-line monotherapy options:\n\ncarbamazepine\n\noxcarbazepine\n\nzonisamide. If the first choice is unsuccessful, consider the other second-line monotherapy options.In April 2022, these were off-label uses of oxcarbazepine in children under 6\xa0years, and zonisamide in children. See NICE's information on prescribing medicines.\n\nIf second-line monotherapies tried are unsuccessful in people with focal seizures, consider lacosamide as third-line monotherapy. In April 2022, this was an off-label use of lacosamide in children under 4\xa0years. See NICE's information on prescribing medicines.\n\n## Add-on treatment\n\nFor guidance on safe prescribing of pregabalin in adults, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nIf monotherapy is unsuccessful in people with focal seizures, consider 1 of the following first-line add-on treatment options:\n\ncarbamazepine\n\nlacosamide\n\nlamotrigine\n\nlevetiracetam\n\noxcarbazepine\n\ntopiramate\n\nzonisamide. If the first choice is unsuccessful, consider the other first-line add-on options.In April 2022, these were off-label uses of lacosamide in children under 4\xa0years, lamotrigine in children under 2\xa0years, levetiracetam in children under 4 years, oxcarbazepine in children under 6\xa0years, topiramate in children under 2\xa0years, and zonisamide in children under 6\xa0years. See NICE's information on prescribing medicines.\n\nIf first-line add-on treatments tried are unsuccessful in people with focal seizures, consider 1 of the following second-line add-on treatment options:\n\nbrivaracetam\n\ncenobamate (in line with NICE's technology appraisal guidance on cenobamate for treating focal onset seizures in epilepsy)\n\neslicarbazepine acetate\n\nperampanel\n\npregabalin\n\nsodium valproate, except in women and girls able to have children. If the first choice is unsuccessful, consider the other second-line add-on options.In April 2022, these were off-label uses of brivaracetam in children under 4\xa0years, eslicarbazepine acetate in children under 6\xa0years, perampanel in children under 4\xa0years, and pregabalin in children. See NICE's information on prescribing medicines.\n\nIf second-line add-on treatments tried are unsuccessful in people with focal seizures, consider 1 of the following third-line add-on treatment options:\n\nphenobarbital\n\nphenytoin\n\ntiagabine\n\nvigabatrin. If the first choice is unsuccessful, consider the other third-line add-on options.In April 2022, this was an off-label use of tiagabine in children under 12\xa0years. See NICE's information on prescribing medicines.\n\nDo not offer sodium valproate as an add-on treatment for focal seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children), unless:\n\nother treatment options are unsuccessful\n\nthe risks and benefits have been fully discussed, including the risks to an unborn child\n\nthe likelihood of pregnancy has been taken into account and a pregnancy prevention programme put in place, if appropriate.Follow the MHRA safety advice on valproate use by women and girls.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on focal seizures with or without evolution to bilateral tonic-clonic seizures\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review E: monotherapy for generalised tonic-clonic and focal onset seizures\n\nevidence review F: add-on therapy for generalised tonic-clonic and focal onset seizures.\n\nLoading. Please wait.\n\n# Absence seizures\n\nFor more information on treatment in women and girls, see the section on antiseizure medications for women and girls.\n\nFollow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy.\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section.\n\n## Absence seizures (including childhood absence epilepsy)\n\nOffer ethosuximide as first-line treatment for absence seizures.\n\nIf first-line treatment is unsuccessful, offer sodium valproate as second-line monotherapy or add-on treatment for absence seizures in:\n\nboys of all ages\n\ngirls aged under 10\xa0years and who are unlikely to need treatment when they are old enough to have children\n\nwomen who are unable to have children.\n\nIf second-line treatment is unsuccessful for absence seizures, consider lamotrigine or levetiracetam as a third-line monotherapy or add-on treatment options. If the first choice is unsuccessful, consider the other of these options.In April 2022, these were off-label uses of lamotrigine in children under 2\xa0years and levetiracetam in adults and children. See NICE's information on prescribing medicines.\n\nBe aware that the following antiseizure medications may exacerbate seizures in people with absence seizures:\n\ncarbamazepine\n\ngabapentin\n\noxcarbazepine\n\nphenobarbital\n\nphenytoin\n\npregabalin\n\ntiagabine\n\nvigabatrin.\n\n## Absence seizures with other seizure types\n\nConsider sodium valproate as first-line treatment for absence seizures with other seizure types (or at risk of these) in:\n\nboys and men\n\ngirls aged under 10\xa0years and who are unlikely to need treatment when they are old enough to have children\n\nwomen who are unable to have children.\n\nConsider lamotrigine or levetiracetam as first-line treatment options in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children) with absence seizures and other seizure types (or at risk of these). If the first choice is unsuccessful, consider the other of these options.In April 2022, these were off-label uses of levetiracetam as monotherapy for adults and children, and as an add-on therapy for children under 12\xa0years. See NICE's information on prescribing medicines.\n\nDo not offer sodium valproate for absence seizures with other seizure types (or at risk of these) in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children), unless:\n\nother treatment options are unsuccessful\n\nthe risks and benefits have been fully discussed, including the risks to an unborn child\n\nthe likelihood of pregnancy has been taken into account and a pregnancy prevention programme put in place, if appropriate.Follow the MHRA safety advice on valproate use by women and girls.\n\nIf first-line treatments tried are unsuccessful for absence seizures and other seizure types (or at risk of these), consider:\n\nlamotrigine or levetiracetam as a second-line monotherapy or add-on treatment options or\n\nethosuximide as a second-line add-on treatment.If the first choice is unsuccessful, consider the other second-line options.In April 2022, these were off-label uses of lamotrigine in children under 2\xa0years, and levetiracetam in adults and children. See NICE's information on prescribing medicines.\n\nBe aware that the following antiseizure medications may exacerbate seizures in people with absence seizures and other seizure types (or at risk of these):\n\ncarbamazepine\n\ngabapentin\n\noxcarbazepine\n\nphenobarbital\n\nphenytoin\n\npregabalin\n\ntiagabine\n\nvigabatrin.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on absence seizures\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: effectiveness of antiseizure therapies in the treatment of absence seizures.\n\nLoading. Please wait.\n\n# Myoclonic seizures\n\nFor more information on treatment in women and girls, see the section on antiseizure medications for women and girls.\n\nFollow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy.\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section.\n\n## Specialist involvement\n\nIf a child under 4\xa0years has myoclonic seizures, either seek guidance on treatment from or refer to a tertiary paediatric neurologist.\n\n## First-line treatment\n\nOffer sodium valproate as first-line treatment for myoclonic seizures in:\n\nboys and men\n\ngirls aged under 10\xa0years and who are unlikely to need treatment when they are old enough to have children\n\nwomen who are unable to have children.\n\nOffer levetiracetam as first-line treatment for myoclonic seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children). In April 2022, this was an off-label use of levetiracetam. See NICE's information on prescribing medicines.\n\n## Second- and third-line treatments\n\nFor guidance on safe prescribing and managing withdrawal of clobazam and clonazepam in adults, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nIf sodium valproate is unsuccessful as first-line treatment for myoclonic seizures, offer levetiracetam as a second-line monotherapy or add-on treatment.In April 2022, these were off-label uses of levetiracetam as monotherapy for adults and children, and as an add-on therapy for children under 12\xa0years. See NICE's information on prescribing medicines.\n\nIf levetiracetam is unsuccessful for myoclonic seizures, consider 1 of the following as monotherapy or add-on treatment options:\n\nbrivaracetam\n\nclobazam\n\nclonazepam\n\nlamotrigine\n\nphenobarbital\n\npiracetam\n\ntopiramate\n\nzonisamide.If the first choice is unsuccessful, consider any other of these options.In April 2022, these were off-label uses for brivaracetam in adults and children, clobazam as monotherapy in adults and children, clobazam as add-on therapy in children under 6\xa0months, clonazepam solution in children, lamotrigine as monotherapy for children under 13\xa0years and add-on therapy for children under 2\xa0years, piracetam in children, topiramate in adults and children, and zonisamide in adults and children. See NICE's information on prescribing medicines.\n\nDo not offer sodium valproate for myoclonic seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children), unless:\n\nother treatment options are unsuccessful\n\nthe risks and benefits have been fully discussed, including the risks to an unborn child\n\nthe likelihood of pregnancy has been taken into account and a pregnancy prevention programme put in place, if appropriate.Follow the MHRA safety advice on valproate use by women and girls.\n\n## Other treatment considerations\n\nBe aware that lamotrigine can occasionally exacerbate myoclonic seizures.\n\nDo not use any of the following antiseizure medications in people with myoclonic seizures because they may exacerbate seizures:\n\ncarbamazepine\n\ngabapentin\n\noxcarbazepine\n\nphenytoin\n\npregabalin\n\ntiagabine\n\nvigabatrin.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on myoclonic seizures\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: effectiveness of antiseizure therapies in the treatment of myoclonic seizures.\n\nLoading. Please wait.\n\n# Tonic or atonic seizures\n\nFor more information on treatment in women and girls, see the section on antiseizure medications for women and girls.\n\nFollow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy.\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section.\n\n## Specialist involvement\n\nEnsure that people with a diagnosis of tonic or atonic seizures are assessed by a neurologist with expertise in epilepsy to:\n\ndiagnose the syndrome if possible and\n\nadvise on investigation and treatment.\n\n## First-line treatment\n\nOffer sodium valproate as first-line treatment for tonic or atonic seizures in:\n\nboys and men\n\ngirls aged under 10\xa0years and who are unlikely to need treatment when they are old enough to have children\n\nwomen who are unable to have children.\n\nConsider lamotrigine as first-line treatment for tonic or atonic seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children).In April 2022, this was an off-label use of lamotrigine in children under 13\xa0years. See NICE's information on prescribing medicines.\n\n## Second- and third-line treatments\n\nFor guidance on safe prescribing and managing withdrawal of clobazam in adults, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nIf sodium valproate is unsuccessful as first-line treatment for tonic or atonic seizures, consider lamotrigine as a second-line monotherapy or add-on treatment.In April 2022, this was an off-label use of lamotrigine as monotherapy in children under 13\xa0years and add-on therapy in children under 2\xa0years. See NICE's information on prescribing medicines.\n\nIf lamotrigine is unsuccessful for treating tonic or atonic seizures, consider 1 of the following as monotherapy or add-on treatment options:\n\nclobazam\n\nrufinamide\n\ntopiramate.If the first choice is unsuccessful, consider any other of these options.In April 2022, these were off-label uses for clobazam as monotherapy in adults and children, clobazam as add-on therapy in children under 6\xa0months, rufinamide, and topiramate as monotherapy in children under 6\xa0years, and topiramate as add-on therapy in children under 2\xa0years. See NICE's information on prescribing medicines.\n\nDo not offer sodium valproate for tonic or atonic seizures in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children), unless:\n\nother treatment options are unsuccessful\n\nthe risks and benefits have been fully discussed, including the risks to an unborn child\n\nthe likelihood of pregnancy has been taken into account and a pregnancy prevention programme put in place, if appropriate.Follow the MHRA safety advice on valproate use by women and girls.\n\n## Further treatment options\n\nIf third-line treatment is unsuccessful for tonic or atonic seizures in children, consider a ketogenic diet as an add-on treatment under the supervision of a ketogenic diet team.\n\nIf all other treatment options for tonic or atonic seizures are unsuccessful, consider felbamate as an add-on treatment under the supervision of a neurologist with expertise in epilepsy.In April 2022, felbamate was not licensed for use in the UK. See NICE's information on prescribing medicines.\n\n## Other treatment considerations\n\nBe aware that the following antiseizure medications may exacerbate seizures in people with tonic or atonic seizures:\n\ncarbamazepine\n\ngabapentin\n\noxcarbazepine\n\npregabalin\n\ntiagabine\n\nvigabatrin.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on tonic or atonic seizures\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: effectiveness of antiseizure therapies in the treatment of tonic or atonic seizures/drop attacks.\n\nLoading. Please wait.\n\n# Idiopathic generalised epilepsies\n\nFor more information on treatment in women and girls, see the section on antiseizure medications for women and girls.\n\nFollow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy.\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section.\n\n## First-line treatment\n\nOffer sodium valproate as first-line treatment for idiopathic generalised epilepsies in:\n\nboys and men\n\ngirls aged under 10\xa0years and who are unlikely to need treatment when they are old enough to have children\n\nwomen who are unable to have children.\n\nOffer lamotrigine or levetiracetam as first-line treatment for idiopathic generalised epilepsies in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children). If the first choice is unsuccessful, offer the other of these options.In April 2022, these were off-label uses of lamotrigine in children under 13\xa0years, and levetiracetam in adults and children. See NICE's information on prescribing medicines.\n\n## Second-line treatment\n\nIf first-line treatments are unsuccessful for idiopathic generalised epilepsies, consider lamotrigine or levetiracetam as a second-line monotherapy or add-on treatment options. If the first choice is unsuccessful, consider the other of these options.In April 2022, these were off-label uses of lamotrigine as monotherapy in children under 13\xa0years and add-on therapy for children under 2\xa0years, and levetiracetam as monotherapy in adults and children and add-on therapy for children under 12\xa0years. See NICE's information on prescribing medicines.\n\nIf second-line treatments tried are unsuccessful for idiopathic generalised epilepsies, consider perampanel or topiramate as third-line add-on treatment options. If the first choice is unsuccessful, consider the other of these options.In April 2022, this was an off-label use of perampanel for children under 7\xa0years. See NICE's information on prescribing medicines.\n\nDo not offer sodium valproate for idiopathic generalised epilepsies in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children), unless:\n\nother treatment options are unsuccessful\n\nthe risks and benefits have been fully discussed, including the risks to an unborn child\n\nthe likelihood of pregnancy has been taken into account and a pregnancy prevention programme put in place, if appropriate.Follow the MHRA safety advice on valproate use by women and girls.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on idiopathic generalised epilepsies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: effectiveness of antiseizure therapies in the treatment of idiopathic generalised epilepsies, including juvenile myoclonic epilepsy.\n\nLoading. Please wait.", 'Treating childhood-onset epilepsies': "Antiseizure medications for childhood-onset epilepsy syndromes are considered off-label unless they are authorised for the specific syndrome.\n\n# Dravet syndrome\n\nFor more information on treatment in women and girls, see the section on antiseizure medications for women and girls.\n\nFollow the Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy.\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section.\n\nFor guidance on safe prescribing and managing withdrawal of clobazam in adults, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\n## Specialist involvement\n\nEnsure that people with Dravet syndrome have an adult or paediatric neurologist with expertise in epilepsy involved in their care.\n\n## First-line treatment\n\nConsider sodium valproate as first-line treatment for people with Dravet syndrome. Be aware that sodium valproate should be used with caution in women and girls, but it is recommended as first-line treatment for Dravet syndrome because of the severity of the syndrome and the lack of evidence for other effective first-line treatment options.\n\nIf sodium valproate first-line monotherapy is started or continued for Dravet syndrome in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children):\n\ndiscuss the potential risks and benefits of treatment, including the risks to an unborn child\n\ntake into account the likelihood of pregnancy and put in place a pregnancy prevention programme, if appropriate.Follow the MHRA safety advice on valproate use by women and girls.\n\nIf sodium valproate alone is unsuccessful as first-line monotherapy for Dravet syndrome, consider triple therapy with stiripentol and clobazam as first-line add-on therapy. Carefully titrate the additional drugs and review treatment frequently, including monitoring for adverse effects such as sedation. In April 2022, these were off-label uses of clobazam as add-on therapy in children under 6\xa0months, and stiripentol when it is started in adults over 18\xa0years. See NICE's information on prescribing medicines.\n\n## Second-line treatment\n\nIf triple therapy is unsuccessful for Dravet syndrome and the child is over 2\xa0years, consider cannabidiol in combination with clobazam as a second-line add-on treatment option in line with NICE's technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Dravet syndrome.\n\n## Further treatment options\n\nIf triple therapy is unsuccessful for Dravet syndrome in a child aged under 2\xa0years or second-line treatment is unsuccessful in a child aged over 2\xa0years, consider 1 of the following add-on options under the supervision of a ketogenic diet team or a neurologist with expertise in epilepsy, as appropriate:\n\nketogenic diet\n\nlevetiracetam\n\ntopiramate.If the first choice is unsuccessful, consider the other add-on options.In April 2022, these were off-label uses of levetiracetam and topiramate. See NICE's information on prescribing medicines.\n\nIf all other treatment options for Dravet syndrome are unsuccessful, consider potassium bromide under the guidance of a neurologist with expertise in epilepsy.In April 2022, potassium bromide was not licensed for use in the UK. See NICE's information on prescribing medicines.\n\n## Other treatment considerations\n\nBe aware that the following medications may exacerbate seizures in people with Dravet syndrome:\n\ncarbamazepine\n\ngabapentin\n\nlacosamide\n\nlamotrigine\n\noxcarbazepine\n\nphenobarbital\n\npregabalin\n\ntiagabine\n\nvigabatrin.NICE has produced technology appraisal guidance on fenfluramine for treating seizures associated with Dravet syndrome.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on Dravet syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: effectiveness of antiseizure therapies in the treatment of Dravet syndrome.\n\nLoading. Please wait.\n\n# Lennox–Gastaut syndrome\n\nFor more information on treatment in women and girls, see the section on antiseizure medications for women and girls.\n\nFollow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy.\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section.\n\n## Specialist involvement\n\nEnsure that people with Lennox–Gastaut syndrome have an adult or paediatric neurologist with expertise in epilepsy involved in their care.\n\n## First-line treatment\n\nConsider sodium valproate as first-line treatment for people with Lennox–Gastaut syndrome. Be aware that sodium valproate should be used with caution in women and girls, but it is recommended as first-line treatment for Lennox–Gastaut syndrome because of the severity of the syndrome and the lack of evidence for other effective first-line treatment options.\n\nIf sodium valproate treatment is started or continued for Lennox–Gastaut syndrome in women and girls able to have children (including young girls who are likely to need treatment when they are old enough to have children):\n\ndiscuss the risks and benefits of treatment, including the risks to an unborn child\n\ntake into account the likelihood of pregnancy and put in place a pregnancy prevention programme, if appropriate.Follow the MHRA safety advice on valproate use by women and girls.\n\n## Second-line treatment\n\nIf first-line treatment is unsuccessful, consider lamotrigine as a second-line monotherapy or add-on treatment for people with Lennox–Gastaut syndrome.In April 2022, this use of lamotrigine was off-label as monotherapy in children under 13\xa0years and add-on therapy for children under 2\xa0years. See NICE's information on prescribing medicines.\n\n## Third-line treatment\n\nFor guidance on safe prescribing and managing withdrawal of clobazam in adults, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nIf second-line treatment is unsuccessful, consider the following as third-line add-on treatment options for people with Lennox–Gastaut syndrome:\n\ncannabidiol in combination with clobazam if the child is over 2\xa0years, in line with NICE's technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Lennox–Gastaut syndrome\n\nclobazam\n\nrufinamide\n\ntopiramate. In April 2022, these were off-label uses of clobazam as add-on therapy in children under 6\xa0months, rufinamide in children under 1\xa0year, and topiramate in children under 2\xa0years. See NICE's information on prescribing medicines.\n\n## Starting an add-on treatment\n\nWhen starting an add-on treatment in people with Lennox–Gastaut syndrome, carefully titrate the additional medicine and review treatment frequently, including monitoring for adverse effects such as sedation.\n\n## Further treatment options\n\nIf seizures continue with third-line treatments for Lennox–Gastaut syndrome, consider a ketogenic diet as an add-on treatment under the supervision of a ketogenic diet team.\n\nIf all other treatment options for Lennox–Gastaut syndrome are unsuccessful, consider felbamate as add-on treatment under the supervision of a neurologist with expertise in epilepsy. In April 2022, felbamate was not licensed for use in the UK. See NICE's information on prescribing medicines.\n\n## Other treatment considerations\n\nBe aware that the following medications may exacerbate seizures in people with Lennox–Gastaut syndrome:\n\ncarbamazepine\n\ngabapentin\n\nlacosamide\n\nlamotrigine\n\noxcarbazepine\n\nphenobarbital\n\npregabalin\n\ntiagabine\n\nvigabatrin.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on Lennox–Gastaut syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: effectiveness of antiseizure therapies in the treatment of Lennox-Gastaut syndrome.\n\nLoading. Please wait.\n\n# Infantile spasms syndrome\n\n## Specialist involvement\n\nIf a child under 2\xa0years has suspected or confirmed infantile spasms, within 24\xa0hours seek guidance from, and refer the child urgently to, a tertiary paediatric neurologist to ensure rapid assessment, including a sleep electroencephalogram (EEG), and rapid treatment to stop spasms.\n\n## Monitoring\n\nReview children under 2\xa0years with infantile spasms at least weekly during treatment and repeat sleep EEG at 2\xa0weeks after starting treatment.\n\nWhen infantile spasms have stopped, review children monthly and repeat sleep EEG if spasms recur or there are clinical concerns.\n\n## First-line treatment\n\nOffer combination therapy with high-dose oral prednisolone and vigabatrin as first-line treatment for infantile spasms that are not due to tuberous sclerosis, unless the child is at high risk of steroid-related side effects. In April 2022, this was an off-label use of vigabatrin in combination with prednisolone. See NICE's information on prescribing medicines.\n\nConsider vigabatrin alone as first-line treatment for infantile spasms in children at high risk of steroid-related side effects.\n\nOffer vigabatrin alone as first-line treatment for infantile spasms due to tuberous sclerosis. If vigabatrin is ineffective after 1\xa0week, add high-dose oral prednisolone.In April 2022, this was an off-label use of vigabatrin in combination with prednisolone. See NICE's information on prescribing medicines.\n\nBefore starting oral prednisolone for infantile spasms:\n\ndiscuss the possible side effects of steroid treatment with parents and carers\n\ntest whether the child has antibodies to the varicella zoster virus\n\ngive the parents and carers a steroid card and information about when to seek medical help for side effects.\n\nWhen using oral prednisolone to treat infantile spasms, follow the advice in the BNF for children on prednisolone dosages. Monitor blood pressure and urinary glucose weekly during treatment.\n\nWhen using vigabatrin to treat infantile spasms, increase the dose as outlined in the BNF for children on vigabatrin. Discuss further dose increases with a tertiary paediatric neurologist if the spasms do not stop (clinically and on EEG).\n\n## Second-line treatment\n\nIf first-line treatment for infantile spasms is unsuccessful, discuss further treatment with a tertiary paediatric epilepsy specialist.\n\nConsider the following as a second-line monotherapy or add-on treatment options for infantile spasms, guided by a ketogenic diet team or tertiary paediatric epilepsy specialist, as appropriate:\n\nketogenic diet\n\nlevetiracetam\n\nnitrazepam\n\nsodium valproate\n\ntopiramate.If the first choice is unsuccessful, consider the other second-line options.In April 2022, these were off-label uses of levetiracetam, nitrazepam and topiramate. See NICE's information on prescribing medicines.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on infantile spasms syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0P: effectiveness of antiseizure therapies for infantile spasms.\n\nLoading. Please wait.\n\n# Self-limited epilepsy with centrotemporal spikes\n\nFor more information on treatment in women and girls, see the section on antiseizure medications for women and girls. Follow the MHRA safety advice on antiepileptic drugs in pregnancy.\n\n## Discussing starting treatment\n\nDiscuss with children and young people with self-limited epilepsy with centrotemporal spikes, and their families or carers as appropriate, whether they wish to start treatment. In particular, discuss:\n\nfrequency and severity of seizures\n\npossible hazards of ongoing seizures (including the small risk of death)\n\npossible side effects of treatment.\n\n## First-line treatment\n\nConsider lamotrigine or levetiracetam as first-line treatment for self-limited epilepsy with centrotemporal spikes. If either lamotrigine or levetiracetam is unsuccessful, try the other of these options.In April 2022, these were off-label uses of lamotrigine in children under 13\xa0years, and levetiracetam in children under 16\xa0years. See NICE's information on prescribing medicines.\n\n## Second-line treatment\n\nIf first-line treatments for self-limited epilepsy with centrotemporal spikes are unsuccessful, consider the following as second-line monotherapy treatment options:\n\ncarbamazepine\n\noxcarbazepine\n\nzonisamide.If the first choice is unsuccessful, consider the other second-line monotherapy options.In April 2022, these were off-label uses for oxcarbazepine in children under 6\xa0years, and zonisamide in adults and children. See NICE's information on prescribing medicines.\n\n## Third-line treatment\n\nIf second-line treatments tried are unsuccessful for self-limited epilepsy with centrotemporal spikes, consider sulthiame as monotherapy or add-on treatment, but only after discussion with a tertiary paediatric neurologist.In April 2022, sulthiame was not licensed for use in the UK. See NICE's information on prescribing medicines.\n\n## Other treatment considerations\n\nBe aware that carbamazepine, oxcarbazepine and lamotrigine may rarely exacerbate seizures or the development of another epilepsy syndrome, or affect cognitive performance, in a small number of children and young people with self-limited epilepsy with centrotemporal spikes.\n\nIf there is concern about the school performance of a child or young person having antiseizure medication, seek guidance from an epilepsy specialist and consider:\n\nsleep electroencephalogram (EEG) to exclude exacerbation of epileptic activity (electrical status epilepticus during sleep) and\n\nneuropsychology assessment to review academic performance.\n\nIf a child or young person having antiseizure medication treatment develops other seizure types, consider a sleep EEG to exclude exacerbation of epileptic activity (developmental epileptic encephalopathy with spike-wave activation in sleep).\n\nOffer follow up at a frequency and with a healthcare professional appropriate to the child or young person's individual needs. Discuss discontinuing treatment if a child or young person with self-limited epilepsy with centrotemporal spikes is seizure-free for at least 2\xa0years or at age\xa014\xa0years.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on self-limited epilepsy with centrotemporal spikes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0Q: effectiveness of antiseizure medications for self-limited epilepsy with centrotemporal spikes.\n\nLoading. Please wait.\n\n# Epilepsy with myoclonic-atonic seizures (Doose syndrome)\n\nFor more information on treatment in women and girls, see the section on antiseizure medications for women and girls.\n\nFollow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy.\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section.\n\n## Specialist involvement\n\nDiscuss the treatment and management of epilepsy with myoclonic-atonic seizures in children with a tertiary paediatric neurologist.\n\n## First-line treatment\n\nConsider levetiracetam or sodium valproate as first-line treatments for epilepsy with myoclonic-atonic seizures. If either levetiracetam or sodium valproate is unsuccessful, try the other of these options.In April 2022, this was an off-label use of levetiracetam. See NICE's information on prescribing medicines.\n\nIf sodium valproate is started or continued for epilepsy with myoclonic-atonic seizures in girls or women able to have children (including young girls who are likely to need treatment when they are old enough to have children):\n\ndiscuss the risks and benefits of treatment, including the risks to an unborn child\n\ntake into account the likelihood of pregnancy and put in place a pregnancy prevention programme, if appropriate.Follow the MHRA safety advice on valproate use by women and girls.\n\n## Second-line treatment\n\nIf first-line treatments for epilepsy with myoclonic-atonic seizures are unsuccessful, consider a ketogenic diet as a second-line monotherapy or add-on treatment, under the supervision of a ketogenic diet team.\n\n## Third-line treatment\n\nFor guidance on safe prescribing and managing withdrawal of clobazam in adults, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nIf second-line treatment for epilepsy with myoclonic-atonic seizures is unsuccessful, consider the following as third-line monotherapy or add-on treatment options:\n\nclobazam\n\nethosuximide\n\ntopiramate\n\nzonisamide.If the first choice is unsuccessful, consider the other third-line options.In April 2022, these were off-label uses of clobazam as monotherapy in adults and children, and add-on therapy in children under 6\xa0months, and topiramate and zonisamide in adults and children. See NICE's information on prescribing medicines.\n\n## Other treatment considerations\n\nDo not use any of the following medications because they may exacerbate seizures in people with epilepsy with myoclonic-atonic seizures:\n\ncarbamazepine\n\ngabapentin\n\noxcarbazepine\n\nphenytoin\n\npregabalin\n\nvigabatrin.\n\n## Discontinuing medication\n\nConsider discontinuing antiseizure medication treatment in children with epilepsy with myoclonic-atonic seizures who are seizure-free for 2\xa0years.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on epilepsy with myoclonic-atonic seizures (Doose syndrome)\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0R: effectiveness of antiseizure therapies for epilepsy with myoclonic-atonic seizures (Doose syndrome).\n\nLoading. Please wait.", 'Treating status epilepticus, repeated or cluster seizures, and prolonged seizures': "# Status epilepticus\n\n## Initial treatment for generalised convulsive status epilepticus\n\nProvide resuscitation and immediate emergency treatment for children, young people and adults who have convulsive status epilepticus (seizures lasting 5\xa0minutes or more).\n\nIf the person with convulsive status epilepticus has an individualised emergency management plan that is immediately available, administer medication as detailed in the plan.\n\nIf the person with convulsive status epilepticus does not have an individualised emergency management plan immediately available:\n\ngive a benzodiazepine (buccal midazolam or rectal diazepam) immediately as first-line treatment in the community or\n\nuse intravenous lorazepam if intravenous access and resuscitation facilities are immediately available.\n\nBe aware of the possible underlying causes of status epilepticus, including hypoglycaemia, eclampsia and alcohol withdrawal, which may need to be treated with additional medication.\n\nBe alert to non-adherence to antiseizure medication, which can also be a cause of status epilepticus.\n\nBe aware that non-epileptic seizures (dissociative seizures) can be similar in presentation to convulsive status epilepticus.\n\n## Management if initial treatment is unsuccessful\n\nIf convulsive status epilepticus does not respond to the first dose of benzodiazepine:\n\ncall emergency services in the community or\n\nseek expert guidance in hospital.\n\nContinue to follow the person's individualised emergency management plan, if this is immediately available, or give a second dose of benzodiazepine if the seizure does not stop within 5\xa0to 10\xa0minutes of the first dose.\n\nIf convulsive status epilepticus does not respond to 2\xa0doses of a benzodiazepine, give any of the following medicines intravenously as a second-line treatment:\n\nlevetiracetam\n\nphenytoin\n\nsodium valproate. Take into account that levetiracetam may be quicker to administer and have fewer adverse effects than the alternative options.In April 2022, this was an off-label use of levetiracetam. See NICE's information on prescribing medicines. Follow the Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on valproate use by women and girls.\n\nIf convulsive status epilepticus does not respond to a second-line treatment, consider trying an alternative second-line treatment option under expert guidance.\n\nIf convulsive status epilepticus does not respond to the second-line treatment options tried, consider the following third-line options under expert guidance:\n\nphenobarbital or\n\ngeneral anaesthesia.\n\nAfter an episode of convulsive status epilepticus, agree an emergency management plan with the person if they do not already have one and there is concern that status epilepticus may recur.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on status epilepticus\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa09: antiseizure medication for status epilepticus.\n\nLoading. Please wait.\n\n# Repeated seizures or cluster seizures\n\nManage repeated or cluster seizures (typically 3\xa0or more self-terminating seizures in 24\xa0hours) as a medical emergency.\n\nIf a person has repeated or cluster seizures:\n\nfollow their individualised emergency management plan, if this is immediately available or\n\nconsider giving a benzodiazepine, such as clobazam or midazolam, immediately if they do not have an individualised emergency management plan immediately available.\n\nSeek expert guidance if the person has further episodes of repeated or cluster seizures.\n\nAgree an individualised emergency management plan with the person after repeated or cluster seizures if they do not have one already and there is concern that repeated or cluster seizures may recur.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on repeated or cluster seizures\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa010: antiseizure medications for repetitive/cluster seizures: monotherapy and add-on therapies.\n\nLoading. Please wait.\n\n# Prolonged seizures\n\nFor convulsive seizures that continue for 5\xa0minutes or more, follow the recommendations in the section on status epilepticus.\n\nManage prolonged convulsive seizures (any convulsive seizure that continues for more than 2\xa0minutes longer than a person's usual seizure) as a medical emergency.\n\nIf a person has a prolonged convulsive seizure:\n\nfollow their individualised emergency management plan if this is immediately available or\n\nconsider giving a benzodiazepine, such as midazolam or clobazam, immediately if they do not have an individualised emergency management plan immediately available.\n\nAfter a prolonged convulsive seizure, agree an emergency management plan with the person if they do not already have one and there is concern that prolonged convulsive seizures may recur.\n\nAfter a prolonged non-convulsive seizure (a non-convulsive seizure that continues for more than 2\xa0minutes longer than a person's usual seizure), agree an emergency management plan with the person if they do not already have one and there is concern that prolonged non-convulsive seizures may recur.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prolonged seizures\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa011: antiseizure medication for prolonged seizures: monotherapy.\n\nLoading. Please wait.", 'Non-pharmacological treatments': "# Ketogenic diet\n\nConsider a ketogenic diet under the guidance of a tertiary epilepsy specialist, in people with:\n\ncertain childhood-onset epilepsy syndromes (see also the section on treating childhood-onset epilepsies), for example:\n\n\n\nglucose transporter type\xa01 deficiency syndrome (GLUT1 deficiency syndrome)\n\nepilepsy associated with pyruvate dehydrogenase deficiency\n\ninfantile spasms syndrome\n\nepilepsy with myoclonic-atonic seizures (Doose syndrome)\n\nDravet syndrome\n\nLennox–Gastaut syndrome\n\n\n\ndrug-resistant epilepsy if other treatment options have been unsuccessful or are not appropriate.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on ketogenic diet\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa012: ketogenic diets for drug-resistant epilepsy.\n\nLoading. Please wait.\n\n# Resective epilepsy surgery\n\n## Referral for resective epilepsy surgery assessment\n\nDiscuss the options for assessment for resective epilepsy surgery with people who have drug-resistant epilepsy, and their families or carers if appropriate. Explain what the process of surgical assessment involves as well as the benefits and risks associated with surgical procedures.\n\nRefer people with drug-resistant epilepsy, including those without identified MRI abnormalities, for consideration of assessment for resective epilepsy surgery:\n\nFor adults, this should be to a tertiary epilepsy service.\n\nFor children and young people, this should be to a tertiary paediatric neurology service for consideration of referral to a children's epilepsy service surgery centre.\n\nFor people with MRI abnormalities that indicate a high risk of drug-resistant epilepsy, consider early referral to a tertiary epilepsy service for assessment, including an evaluation for resective epilepsy surgery if appropriate. Examples of specific lesions seen on MRI may include, but are not limited to, the following:\n\nhippocampal sclerosis\n\nmalformations of cortical development\n\nepilepsy-associated low-grade tumours\n\nhypothalamic hamartomas\n\nneuronal migrational disorders\n\ntuberous sclerosis complex\n\nvascular malformations, including Sturge–Weber syndrome\n\ncerebral contusions from previous head injury.\n\nDo not exclude people with learning disabilities or underlying genetic abnormalities from referral for resective epilepsy surgery assessment if it is indicated.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on resective epilepsy surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa013: referral and surgical interventions.\n\nLoading. Please wait.\n\n# Vagus nerve stimulation\n\nIf resective epilepsy surgery is not suitable for a person with drug-resistant seizures, consider vagus nerve stimulation as an add-on treatment to antiseizure medication. See also NICE's interventional procedures guidance on vagus nerve stimulation for refractory epilepsy in children.\n\nDiscuss with the person with epilepsy, and their family or carers if appropriate, the benefits and risks of vagus nerve stimulation before making a shared decision about having this procedure.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on vagus nerve stimulation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa014: vagus nerve stimulation.\n\nLoading. Please wait.", 'Psychological, neurobehavioural, cognitive and developmental comorbidities in epilepsy': "# Providing coordinated care\n\nBe aware that there is a higher prevalence of mental health difficulties, learning disabilities, neurodevelopmental comorbidities (for example, attention deficit hyperactivity disorder and autism spectrum disorder) and dementia, and a higher risk of suicide in people with epilepsy compared with the general population.\n\nProvide coordinated care for people with epilepsy who have a mental health condition or learning disability using a multidisciplinary team approach.\n\nBe aware that children and young people with a complex childhood epilepsy syndrome can have developmental difficulties and cognitive impairment, and may need additional support from a multidisciplinary team.\n\nEnsure effective communication and liaison between healthcare professionals across the relevant services involved in the care of people with epilepsy and a mental health condition to agree and plan care across services.\n\nFor people with epilepsy who have a learning disability, a mental health problem or challenging behaviour, or who have dementia, follow the recommendations on coordinating care in NICE's guidelines on mental health problems in people with learning disabilities, challenging behaviour and learning disabilities and dementia.\n\n# Support and treatment\n\nRecognise that a diagnosis of epilepsy can have a significant adverse impact on a person's mental health and that people with epilepsy may feel socially excluded and stigmatised.\n\nReview neurodevelopment, cognitive function, mental health, social and emotional wellbeing, and learning disabilities as part of the routine management for people with epilepsy.\n\nOffer assessment and provide mental health support and treatment for people with epilepsy and depression in line with NICE's guidelines on depression in adults with a chronic physical health problem and depression in children and young people.\n\nBe alert to anxiety, other mental health difficulties and the risk of suicide in people diagnosed with epilepsy. If mental health difficulties are suspected, consider referral and follow the recommendations in NICE's guidelines on:\n\nattention deficit hyperactivity disorder\n\nautism spectrum disorders in under\xa019s\n\nautism spectrum disorder in adults\n\ncommon mental health problems\n\nmental health problems in people with learning disabilities\n\ngeneralised anxiety disorder and panic disorder in adults\n\npsychosis and schizophrenia in adults\n\npsychosis and schizophrenia in children and young people.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychological, neurobehavioural, cognitive and developmental comorbidities in epilepsy\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 15: prevalence of psychological disorders in people with epilepsies\n\nevidence review 16: psychological treatments for people with epilepsies.\n\nLoading. Please wait.", 'Reducing the risk of epilepsy-related death including sudden unexpected death in epilepsy': "# Risk factors\n\nBe aware that epilepsy is associated with an increased risk of premature death, including a risk of sudden unexpected death in epilepsy (SUDEP).\n\nBe aware that potentially modifiable risk factors for SUDEP include:\n\nnon-adherence to medication\n\nalcohol and drug misuse\n\nhaving focal to bilateral tonic-clonic seizures or generalised tonic-clonic seizures\n\nhaving uncontrolled seizures\n\nliving alone\n\nsleeping alone without supervision.\n\nBe aware that the risk of epilepsy-related death is increased in people with:\n\nprevious brain injury\n\nprevious central nervous system infection\n\nmetastatic cancer\n\nprevious stroke\n\nabnormal neurological examination findings.\n\nDiscuss with people with epilepsy, and their families and carers if appropriate, their individual risk of epilepsy-related death, including SUDEP, from the time of diagnosis onwards. For young children, this discussion should be with the child's parents or carers. Discussion should include:\n\nsupporting them to understand the risks of epilepsy-related death, including SUDEP\n\nexploring and agreeing ways to reduce the risks.\n\nDiscuss the risk of SUDEP with people who have seizures during sleep and, if appropriate, include their families and carers. Provide information on minimising risks, including taking their medication as prescribed.\n\n# Interventions\n\nDiscuss the possibility of introducing or increasing night-time supervision, for example, a parent or carer may wish to use a night monitor for people with epilepsy who have seizures during sleep and have been assessed to be at higher risk of epilepsy-related death.\n\nSupport people with epilepsy to take their medications as prescribed to reduce seizures. Explain that uncontrolled seizures increase the risk of epilepsy-related death, particularly for people with generalised tonic-clonic seizures or focal to bilateral tonic-clonic seizures. Follow the recommendations in NICE's guideline on medicines adherence.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reducing the risk of epilepsy-related death including sudden unexpected death in epilepsy\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nevidence review 17: prediction of death, including SUDEP, in people with epilepsy\n\nevidence review 18: modifiable risk factors for epilepsy related mortality\n\nevidence review 19: reducing the risk of seizure-related mortality, including SUDEP.\n\nLoading. Please wait.", 'Service provision and transition': "# Epilepsy specialist nurses\n\nEnsure that all children, young people and adults with epilepsy have access to an epilepsy specialist nurse who:\n\nhas a central role in providing information, education and support (see box 1 for information that should be covered)\n\nsupports epilepsy specialists and healthcare professionals in primary and secondary care, and in educational, respite and social care settings\n\nis a point of contact for, and facilitates access to, other community and multi-agency services.\n\nOffer people with epilepsy an information and care-planning session with an epilepsy specialist nurse that includes emotional wellbeing and self-management strategies promoting inclusion and participation.\n\nFor people with epilepsy who continue to have seizures, offer epilepsy specialist nurse sessions:\n\nat least twice a year and\n\nafter A&E department visits.\n\nConsider epilepsy specialist nurse-led group sessions for education and information giving in young people and adults with epilepsy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on epilepsy specialist nurses\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0O: effectiveness of a nurse specialist in the management of epilepsy.\n\nLoading. Please wait.\n\n# Transition from children's to adults' epilepsy services\n\nInvolve young people with epilepsy in planning for their transition from children's to adult epilepsy services in line with the NICE guideline on transition from children's to adults' services for young people using health or social care services.\n\nEnsure transition from children's to adults' epilepsy services is individually tailored to the young person with epilepsy.\n\nBegin planning transition early for young people who have complex or additional health and social care needs, for example young people whose seizures are not yet controlled or those with learning disabilities.\n\nDuring transition of young people with epilepsy to adult services, the paediatric and adult multidisciplinary teams should jointly review the person's diagnosis and management plan, taking a person-centred approach that involves the young person, and their family or carers as appropriate, in planning and decisions about their care.\n\nEnsure that information about the young person's management plan and support for transition to adult services is discussed with the young person with epilepsy and shared in an accessible format that meets their needs and uses language they understand. Repeat this information at different time points to establish that the young person understands their care plan and the support that will be provided.\n\nWhen discussing transition to adult epilepsy services with the young person, cover any issues of concern to the person, including, but not limited to, the following:\n\nactivities of daily living, including driving and sports\n\nadherence to antiseizure medication\n\ncomorbidities, such as low mood or impaired memory\n\ncontinuing in education or work\n\nemotional health and psychological wellbeing\n\nliving independently\n\npossible effects of epilepsy and antiseizure medication on neurodevelopment, cognition and behaviour\n\nrisks associated with alcohol and illicit drugs\n\nsafety and risk (including sudden unexpected death in epilepsy [SUDEP])\n\nreproductive health, including contraception, pregnancy and teratogenicity\n\nsleep disturbance\n\nsocial aspects of epilepsy, including considering if or when to disclose epilepsy status and managing the impact of possible assumed limitations\n\nstigmatisation of epilepsy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on transition from children's to adults' epilepsy services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa020: transition from paediatric to adult epilepsy services.\n\nLoading. Please wait.", 'Terms used in this guideline': "This section defines terms that have been used in a particular way for this guideline.\n\nThe definitions for the epilepsy syndromes and seizure types are based on the International League Against Epilepsy's proposed new definitions and framework for classifying epilepsy.\n\n# Drug-resistant epilepsy\n\nEpilepsy in which seizures persist and seizure freedom is very unlikely to be attained with further manipulation of antiseizure medication. Defined by the International League Against Epilepsy as 'failure of adequate trials of 2 tolerated and appropriately chosen and used antiseizure medication schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom'.\n\n# MRI protocols\n\nAn MRI scan produces sets of images of the brain, or 'sequences', each with a particular appearance. An epilepsy MRI protocol is made up of a group of sequences, put together to improve the sensitivity and specificity in demonstrating possible structural abnormalities of the brain that cause epilepsy. The use of a regionally agreed, standardised protocol aims to maximise diagnostic quality and deliver consistency in scan quality.\n\n# Suboptimal MRI\n\nAn MRI scan would be deemed suboptimal if:\n\nit gives an inappropriate or inadequate set of sequences\n\nimage quality is poor, for example, because of patient movement.\n\n# Tertiary epilepsy service\n\nA service provided by epilepsy specialists who are adult or paediatric neurologists who undertake continuing professional development in the investigation, diagnosis and management of complex epilepsy. It offers:\n\nAccess to additional specialist assessments, including:\n\n\n\nneuropsychology\n\nneuropsychiatry\n\nspecialised neuroimaging, including 3T MRI\n\nspecialised neurophysiology, including video electroencephalogram (EEG) telemetry.\n\n\n\nSpecialised assessment and management of particular patient groups, including:\n\n\n\npeople with learning disability\n\npregnant women\n\npeople transitioning between services\n\nolder people with epilepsy.\n\n\n\nAccess to:\n\n\n\nspecialised non-surgical treatments, for example, cannabidiol, ketogenic diet\n\ngenetic diagnosis and counselling\n\nspecialised assessment for surgery\n\nvagus nerve stimulation\n\nparticipation in relevant clinical trials and research studies.\n\n\n\n# Unprovoked seizure\n\nA seizure that is not caused by a particular event such as a fever, head injury or consumption of alcohol or drugs.\n\n# Unsuccessful treatment\n\nTreatment is unsuccessful if it does not reduce or stop seizures, or if side effects are intolerable for the person with epilepsy.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Antibody testing\n\nWhat immunomodulation strategies are effective in people with defined autoimmune epilepsy syndromes?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on antibody testing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: antibody testing in epilepsy.\n\nLoading. Please wait.\n\n## Complex epilepsy syndromes\n\nWhat antiseizure therapies (alternative or add-on) are effective in the treatment of complex epilepsy syndromes (that is, Dravet syndrome, Lennox–Gastaut syndrome, infantile spams syndrome and epilepsy with myoclonic-atonic seizures [Doose syndrome]) when first-line therapy is unsuccessful or not tolerated?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on Dravet syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: effectiveness of antiseizure therapies in the treatment of Dravet syndrome.\n\nLoading. Please wait.\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on Lennox–Gastaut syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: effectiveness of antiseizure therapies in the treatment of Lennox-Gastaut syndrome.\n\nLoading. Please wait.\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on infantile spasms syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0P: effectiveness of antiseizure therapies for infantile spasms.\n\nLoading. Please wait.\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on epilepsy with myoclonic-atonic seizures (Doose syndrome)\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0R: effectiveness of antiseizure therapies for epilepsy with myoclonic-atonic seizures (Doose syndrome).\n\nLoading. Please wait.\n\n## Risk prediction tool for all-cause epilepsy-related death\n\nDevelopment of a risk prediction tool to detect all-cause mortality including sudden unexpected death in epilepsy (SUDEP) in people with epilepsy or those who have had a single seizure, and an external validation of a risk prediction tool to detect the probability of epilepsy-related death.\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on reducing the risk of epilepsy-related death including SUDEP\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa017: prediction of death, including SUDEP, in people with epilepsy.\n\nLoading. Please wait.\n\n## Vagus nerve stimulation\n\nWhat is the effectiveness of vagus nerve stimulation in treating epilepsy (including people with learning disabilities as a subgroup)?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on vagus nerve stimulation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa014: vagus nerve stimulation.\n\nLoading. Please wait.\n\n## Psychological treatments\n\nWhat is the cost effectiveness of providing tailored psychological treatments for people with epilepsy?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on psychological, neurobehavioural, cognitive and developmental comorbidities in epilepsy\xa0.\n\nFull details of the evidence and the committee's discussion are in in evidence review\xa016: psychological treatments for people with epilepsies.\n\nLoading. Please wait.\n\n## Monitoring antiseizure medications in women and girls\n\nWhat is the clinical and cost effectiveness of therapeutic drug monitoring in girls, young women and women with epilepsy?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on support and monitoring for women planning pregnancy or who are pregnant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa08: therapeutic drug monitoring in women and girls.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Digital health technologies\n\nWhat is the clinical and cost effectiveness of digital health technologies in people with epilepsy?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on new technologies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa05: new technologies.\n\nLoading. Please wait.\n\n## Antiseizure medication for repeated or cluster seizures\n\nWhat antiseizure medications (monotherapy or add-on) are effective in the treatment of repeated or cluster seizures?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on repeated or cluster seizures\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa010: antiseizure medications for repetitive/cluster seizures: monotherapy and add-on therapies.\n\nLoading. Please wait.\n\n## Risk prediction tool for second seizure\n\nDevelopment of a risk prediction tool for second seizures in people with a single seizure, and an external validation of a risk prediction tool to detect the probability of a second seizure in people with a single seizure at baseline.\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on referral after a first seizure or remission and assessing risk of a second seizure\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa01: prediction of second seizure.\n\nLoading. Please wait.\n\n## Ketogenic diets\n\nWhat is the short-term and long-term clinical and cost effectiveness of ketogenic diets in adults and children with drug-resistant epilepsy, and what factors affect the long-term maintenance and tolerability of ketogenic diets?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on ketogenic diet\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa012: ketogenic diets for drug-resistant epilepsy.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Referral after a first seizure or remission and assessing risk of a second seizure\n\nRecommendations 1.1.1 to 1.1.9\n\n## Why the committee made the recommendations\n\n## Referral after a first seizure\n\nThe committee agreed that people presenting with a suspected first seizure should be referred urgently to ensure that a specialist is involved early in diagnosing epilepsy. Diagnosing epilepsy can be complex and involving a specialist can help avoid misdiagnosis and ensure that the person receives the right care and support.\n\n## Assessing the risk of a second seizure\n\nThe evidence suggested that adults having a first seizure who have a mental health condition are almost 3\xa0times more likely to have a second seizure when compared with the general population. The risk was even higher for people with sepsis, who are 4.5\xa0times more likely to have a second seizure than people who do not have sepsis. The committee agreed that these are significant risk factors that could be modified to try to prevent second seizures. Evidence for vascular risk factors did not show a difference in risk. However, based on their knowledge and experience, the committee agreed that conditions such as diabetes, hypertension and atrial fibrillation are important risk factors for seizures in adults that may also be modified.\n\nIn children, the committee acknowledged that there was a lack of clarity in the evidence for risk associated with higher or lower temperature. A seizure because of a high temperature does not necessarily predispose a child to more seizures, but they agreed that increased temperature is important to take into consideration. Febrile seizures tend not to predispose to a second afebrile seizure. However, afebrile seizures may be associated with an increased risk of a second seizure. The committee agreed that parents and carers should be given information about the potential risk and how to self-refer should the child have a second seizure. Safety guidance should also be given so that parents and carers can take precautions to minimise the risk of injury.\n\nThe risk factors identified in the studies are not the only factors that affect a person's chances of having a second seizure. For this reason, the committee decided that assessment should include identifying any potential mental, physical and social risk factors, which should then be discussed with the person and their family or carers.\n\nThe committee discussed the evidence for prediction tools for a second seizure, but did not recommend using any of these tools because they were considered to carry the potential for harm. The evidence suggested that the tools had a poor capacity to discriminate between people at low and high risk of second seizure. Therefore, the committee made a recommendation for research on developing and testing a risk prediction tool for second seizure.\n\n## How the recommendations might affect practice\n\nThese recommendations are likely to mean a change in clinical practice for how adults are cared for after a first seizure. In current practice, only about 25% of adults are fully assessed for modifiable risk factors. Assessment includes checking for underlying mental health problems, vascular risk factors and sepsis. Although the recommendations for adults will result in a change in clinical practice, the assessment does not take long and is not expected to result in a substantial resource impact. A small increase in costs is likely for additional staff time to assess people presenting with a first seizure.\n\nThe recommendation made for children reflects current practice so the committee agreed there should be no substantial resource impact.\n\nReturn to recommendations\n\n# Specialist assessment and diagnosis\n\nRecommendations 1.2.1 to 1.2.10\n\n## Why the committee made the recommendations\n\nIn assessing the evidence for individual tests to diagnose epilepsy, the committee agreed that a diagnostic test would need to give the lowest possible level of false-positive and false-negative results. False-positive results may result in unnecessary treatment and anxiety, whereas false-negative results may result in people with epilepsy remaining undiagnosed and untreated. Given the seriousness of these harms, the committee agreed that a 10% rate for false negatives and a 10% rate for false positives were the highest acceptable rates (equating to a minimally acceptable value of 0.9 for both sensitivity and specificity). Most tests evaluated in the review did not meet this threshold.\n\nClinical history and examination provided by a specialist in epilepsy demonstrated levels of sensitivity and specificity for detecting epilepsy that were above the agreed threshold. Although the evidence was restricted to adults, the committee were confident that this could also be applied to diagnosis in children and young people. Witness reports and review of video footage were included as useful additional features of the clinical history. The evidence did not show sufficient diagnostic accuracy to warrant the use of witness reports or video footage independently, but the committee agreed that they increase the accuracy of expert clinical diagnosis.\n\nThe committee agreed, based on their knowledge and experience, that a positive electrocardiogram (ECG) can identify cardiac causes of seizure-like symptoms, and a negative ECG can support a further investigation of suspected epilepsy. Similarly, they agreed that the assessment of metabolic disturbances, such as hypoglycaemia can help to exclude alternative causes of a first seizure.\n\nAlthough none of the imaging modalities were sufficiently accurate for use as diagnostic tools, the committee agreed that neuroimaging should be used to investigate potential structural causes of epilepsy.\n\nThe evidence showed low sensitivity for routine interictal EEG, suggesting that many people with epilepsy will not demonstrate interictal EEG abnormalities. The committee therefore agreed that a negative routine interictal EEG should not be used to exclude an epilepsy diagnosis. However, the specificity was high enough for a positive EEG finding to support a provisional diagnosis of epilepsy. Most people without epilepsy will not have EEG abnormalities, so a person with a positive finding on EEG is more likely to have epilepsy than not. The committee agreed that routine EEG should therefore be considered to help support clinical diagnoses of epilepsy. The committee also agreed, based on clinical knowledge and experience, that EEG would provide more accurate results if done as soon as possible (ideally within 72\xa0hours) after the seizure.\n\nSome evidence also suggested that provoking manoeuvres or longer-term EEG (for example, during a period of sleep or ambulatory EEG over 48\xa0hours) could slightly increase sensitivity. Although this small increase in sensitivity would be insufficient to exclude diagnoses if EEG findings are negative, it might help to further support the overall clinical diagnosis of epilepsy. The committee agreed that provoking manoeuvres during an EEG or, for example, sleep deprivation to capture sleep EEG, could be offered if agreed with the person being tested (or their family or carers). If routine and sleep-deprived EEG are normal, the committee agreed that longer-term monitoring with ambulatory EEG could be considered for some people. This may be particularly indicated in people who are thought to have a focal epilepsy. The committee highlighted the potential harms of these methods and agreed that the risks and benefits should be fully discussed with the person and their families or carers before performing the relevant EEG test.\n\n## How the recommendations might affect practice\n\nNo impact on practice is expected, because these recommendations do not substantially change current practice.\n\nReturn to recommendations\n\n# Neuroimaging\n\nRecommendations 1.3.1 to 1.3.7\n\n## Why the committee made the recommendations\n\nNeuroimaging may help to identify the cause of epilepsy, inform prognosis and can give information to plan appropriate management. However, the committee agreed that it is unnecessary for people with epilepsy that is not associated with structural brain abnormalities, such as idiopathic generalised epilepsy or self-limited epilepsy with centrotemporal spikes.\n\nBased on the evidence and their experience, the committee agreed that MRI is the investigation of choice for people with epilepsy. The evidence for different protocols was not reviewed, so based on awareness of the wider literature, the committee decided that regionally agreed epilepsy protocols should be followed, using sequences available on most modern MRI scanners, to capture enough detail. The committee stressed the importance of carrying out scans early to inform timely management choices, and discussed variation in current practice, with some people having to wait several weeks. They agreed that imaging should take place as soon as possible and specified a wait of no longer than 6\xa0weeks from referral for the MRI, in line with the pledge on waiting times for diagnostic tests in the Handbook to the NHS Constitution for England.\n\nThe committee acknowledged that there may be situations when MRI is not suitable and CT should be offered instead, for example, if a person has severe claustrophobia or a non-MRI conditional pacemaker.\n\nSuccessful interpretation of MRI findings depends on the reader's proficiency, so the committee agreed, based on their experience, that scans should be reported by a radiologist with expertise in neuroradiology. Tertiary neuroradiology centres have expertise in performing and interpreting MRI scans, so further review by these specialist centres may be warranted if the diagnosis is in doubt or the person has drug-resistant epilepsy.\n\nBased on their experience, the committee agreed on certain situations for which repeat MRI in people with an established epilepsy diagnosis may be important. For example, to look for change in lesions in people with new symptoms, such as rapid cognitive decline or unexplained increase in seizure frequency. Repeat MRI may also be used to help locate the areas of the brain responsible for seizures if surgery is being considered.\n\nBased on their experience and expertise, the committee agreed that a CT scan can help determine whether a new-onset seizure is caused by an acute neurological lesion or illness in those with acute symptomatic seizures. However, being aware that people with an established diagnosis of epilepsy who present to an emergency department with a seizure often have a CT scan, the committee emphasised that this is not needed for those who have a typical seizure if there are no other clinical concerns.\n\n## How the recommendations might affect practice\n\nThe use of neuroimaging varies in current practice, and is not routinely used in all settings. The recommendations will reduce variation in current practice. There may be an increase in the number of people who have neuroimaging. However, with the use of regionally agreed protocols, the detection of abnormalities may avoid the need for more scans in the future.\n\nReturn to recommendations\n\n# Genetic testing\n\nRecommendations 1.4.1 to 1.4.5\n\n## Why the committee made the recommendations\n\nThe committee agreed that a discussion with a neurologist or geneticist may be needed to advise on who to test and which type of test to use if there are uncertainties. Access to genetic testing varies but is likely to increase. The committee noted that the NHS National Genomic Test Directory for rare and inherited disease lists the genetic tests for epilepsy that are nationally commissioned by the NHS in England, and when they should be performed.\n\nA genetic diagnosis can provide information about treatment options, related medical problems and prognosis. It can also inform genetic counselling for the person and their family members. The committee discussed the importance of genetic counselling to ensure that people, and their families or carers if appropriate, are supported to understand the possible results of testing and what they might mean for them and their family. Results can reveal information about the person who is being tested, but also their family members, which may have emotional and social consequences.\n\nThe committee agreed that a full discussion of the purpose and implications of genetic testing is needed before testing, so that the person, and their family or carers if appropriate, can make decisions about testing and give informed consent. Informed consent needs to be documented and it involves a full discussion about the benefits and possible limitations and risks of genetic testing, as well as consent to share information, where appropriate, about the results to advise the person's relatives.\n\nThe evidence did not support genetic testing for all people with epilepsy, so the committee took a pragmatic approach and agreed that testing should be considered in situations most likely to yield positive diagnostic results. The committee agreed that there was not enough evidence to recommend genetic testing at a specific point in the clinical pathway.\n\nPeople whose epilepsy started at an early age (under 2 years) and people whose epilepsy is associated with developmental disorders or certain clinical features are more likely to have epilepsy with a genetic cause. Therefore, based on their knowledge and experience, the committee agreed that whole-genome sequencing would be best targeted to this population. This is in line with the eligibility criteria that accompany the NHS National Genomic Test Directory (clinical indication R59: early-onset or syndromic epilepsy).\n\nThe diagnostic yield of genetic testing in people with epilepsy of unknown cause with onset between 2 and 3 years is affected by factors such as co-occurring conditions and MRI and EEG findings. The committee noted that a genetic diagnosis in this group of people can have a significant positive impact on outcomes and management, therefore, based on their knowledge and experience and as specified by the NHS National Genomic Test Directory, they agreed that whole-genome sequencing should be carried out if agreed by a specialist multidisciplinary team.\n\n## How the recommendations might affect practice\n\nThe use of genetic testing varies in current practice, and it is not routinely carried out even when a genetic cause is suspected. The recommendations clarify when genetic testing should be considered, which will reduce variation in current practice. There may be an increase in the number of people who have a genetic test and who are referred for genetic counselling. However, with the use of whole-genome sequencing, there may also be a reduction in the number of people having unnecessary tests that do not provide additional information on their diagnosis.\n\nReturn to recommendations\n\n# Antibody testing\n\nRecommendation 1.5.1\n\n## Why the committee made the recommendation\n\nThe evidence for antibody testing was limited and did not support routine antibody testing for people with epilepsy. However, the committee discussed antibody testing in the context of suspected autoimmune encephalitis in people with new-onset epilepsy because it is recognised that people with autoimmune encephalitis can present with seizures or status epilepticus with encephalopathy. Although not part of the evidence review, the committee was aware that treatment guided by antibody testing (immunotherapy) may improve outcomes in these people compared with standard antiseizure medication.\n\nThere is emerging evidence on 'autoimmune epilepsy', but the committee agreed that further research is needed to assess which immunomodulation strategies are effective in people with defined autoimmune epilepsy syndromes. The committee agreed that further research is needed and developed a recommendation for research on immunomodulation strategies for people with autoimmune epilepsy syndromes to help inform future guidance.\n\n## How the recommendation might affect practice\n\nSuspected autoimmune encephalitis is relatively rare and antibody testing is already current practice, so the recommendation reinforces current best practice.\n\nReturn to recommendation\n\n# Information and support\n\nRecommendations 2.1.1 to 2.1.11\n\n## Why the committee made the recommendations\n\nThe evidence showed that there are gaps in current practice in communication and in the information and support available to people with epilepsy.\n\nThe committee agreed that tailored information should be provided to people with epilepsy, and their parents and carers if appropriate, to enable them to be fully informed and involved in decisions about their care. The evidence reported that some people with epilepsy and some parents and carers felt that information was withheld, making it difficult to be fully involved in their care. It also showed that children and young people wanted to be involved but sometimes struggled to understand information inappropriate for their age, including information about sudden unexpected death in epilepsy (SUDEP). The committee stressed the importance of providing age-appropriate information to enable children to be involved in discussions about their care. Extra support and time in consultations for people with learning disabilities or complex needs, such as other comorbidities, were also highlighted by the committee.\n\nThe committee highlighted the important role that epilepsy specialist nurses play in information giving. This was supported by the evidence and recommendations on epilepsy specialist nurses.\n\nThe evidence showed that parents and carers struggled to find help from sources other than their doctor. The committee acknowledged that information on where and how people with epilepsy can access information and support for activities of daily living, such as local and national support groups, should be provided.\n\nThe committee stressed the importance of providing key information for self-managing epilepsy during the first appointment. Medicines adherence, mitigating epilepsy-related risk and avoiding potential provoking factors for seizures were identified as key topics from the evidence to enable the person to self-manage their epilepsy and maintain everyday activities. Based on their experience, the committee also included activities of daily living, including driving, as a key topic for discussion because it is commonly raised as a concern at the first appointment. The committee agreed that this key information should be repeated at subsequent appointments.\n\nThe committee recognised that people with epilepsy may have a range of worries and anxieties that may change over time, and that opportunities should be provided to discuss these at each appointment. They agreed on some topics that are often of concern to people with epilepsy and their families and carers, based on their experience and themes identified in the evidence, which could be used to help provide a framework for discussions.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice so the committee agreed there should be no substantial resource impact.\n\nReturn to recommendations\n\n# New technologies\n\n## Why the committee did not make any recommendations\n\nNo evidence was found on using digital health technologies, so the committee agreed that no recommendation could be made. The committee noted that people are already using devices, such as night monitors and alarms, as self-management tools, but that evidence is lacking to support this use, and these are not currently offered by the NHS. Based on their experience, the committee acknowledged that some monitoring tools may offer benefit to people with epilepsy.\n\nThere is a trend towards the use of digital health technologies and the committee were keen to encourage more research in this emerging and potentially important area. A recommendation for research on digital health technologies was developed to help determine their clinical and cost effectiveness for people with epilepsy in the hope that these interventions could lead to improvements in self-management.\n\nReturn to recommendation for research\n\n# Referral to tertiary specialist services\n\nRecommendations 3.1.1 to 3.1.4\n\n## Why the committee made the recommendations\n\nThere was a lack of evidence on referral to specialist services, so the committee based their recommendations on their clinical experience and expertise, and also used the NHS England 2019 guidance for referral pathways to specialist services for adults as a reference.\n\nChildren, young people and adults may need access to tertiary services at certain times during their care and these services should be available to everyone who needs them through their specialist. However, the committee acknowledged that some groups may need extra tertiary support to manage their epilepsy, even if they are already receiving care from other specialists for another condition. The committee noted that people with a learning disability or mental health problem may struggle to access tertiary services and may need help to get appropriate referrals. They may also need additional support to attend appointments, such as having a family member or carer accompany them.\n\nWith the number of referrals increasing, the committee agreed that clearer and more specific criteria for referral would help to ensure that people who will benefit most from specialist services are prioritised. The proposed criteria aim to ensure that people with epilepsy that is difficult to diagnose or manage receive the specialist care and treatment they need, including consideration for clinical trials. The committee recommended, based on their knowledge and expertise, that people with epilepsy meeting these criteria should be seen within 4 weeks. The committee agreed that these are people with substantial health needs, so prompt referral could have a significant positive impact on their prognosis. This is in line with current clinical practice and consistent with the previous version of the guideline, so it is not expected to have an impact on resources. The committee agreed to retain and update the recommendation from the previous guideline because it was important to continue to guide clinicians to improve care and to reduce variation in service provision and outcomes between services.\n\nThe committee also discussed particular groups of children that should be prioritised for more urgent referral within 2\xa0weeks. This was based on the committee's knowledge and experience, and on the probability that treatment from a tertiary paediatric epilepsy service would significantly benefit children meeting these criteria. They agreed that all children under 3\xa0years should be referred to tertiary services without delay, because of the risk of developmental problems with some paediatric syndromes with onset before this age. Children with myoclonic seizures presenting aged up to 4\xa0years should be referred because myoclonic seizures may start after 3\xa0years and could indicate an underlying neurodegenerative disorder that may be treatable. Children with a unilateral structural lesion should be prioritised for immediate referral because this is likely to lead to difficulties in seizure management and surgery may need to be considered early. The presence of deterioration in the child's behaviour, speech or learning (such as loss of previously acquired developmental milestones), particularly in the absence of an established diagnosis, should also be a priority for prompt investigation in tertiary services.\n\n## How the recommendations might affect practice\n\nThe recommendations will not change current practice, but will reinforce current best practice.\n\nReturn to recommendations\n\n# Treatment with antiseizure medications\n\nRecommendations 4.1.1 to 4.1.9\n\n## Why the committee made the recommendations\n\nThese recommendations are based on the committee's informal consensus on principles for the use of antiseizure medications for treating all epilepsy syndromes and seizure types. They are based on recommendations from the previous version of the guideline and have been retained and updated because the committee agreed it was important to include them to guide clinicians to improve care.\n\nThe committee agreed on some general factors to consider once the diagnosis of epilepsy is confirmed to ensure that the best treatment is started, balancing the risks and benefits of the medicine with the lifestyle and choices of the person. For example, if a person is starting university and the most effective medication can affect cognitive performance, they may wish to choose a different option without these side effects. For some people, their seizure type may mean that a medicine that is faster-acting to reduce seizures might be a priority. These factors should be discussed with the person with epilepsy (and their families and carers if appropriate) in all settings where antiseizure medications may be prescribed and managed, including primary, secondary and tertiary care.\n\nThe committee agreed on some particular issues that should additionally be taken into account when giving antiseizure medications in older people. This group presents with specific considerations because of differences in clinical presentation and aetiology when compared with younger people, particularly those with co-occurring conditions. Treatment can be more difficult because of drug interactions, therefore other medications the person may be taking should be taken into account. Additionally, care is needed in choosing the adequate initial dose and subsequent titration. The committee noted that following the NICE guideline on multimorbidity, which covers care optimisation in people with multiple long-term conditions, may benefit people with epilepsy and 1 or more mental or physical health condition.\n\nThe committee agreed that an antiseizure medication treatment strategy should take account of these factors and the special considerations for antiseizure medications in women and girls. The committee agreed that a shared decision should be made with the person to agree their individualised antiseizure medication treatment strategy.\n\nThe committee agreed on some principles if seizures continue after monotherapy treatment, which included reviewing the diagnosis and trying monotherapy with another antiseizure medication to ensure that the most effective treatment strategy is being used. The committee agreed that, when starting an alternative antiseizure medication, the dose of the new antiseizure medication should be slowly increased while the existing antiseizure medication is tapered off because this can reduce the risk of drug-related withdrawal symptoms of the first medication and clinicians can monitor the correct dose of the second medication.\n\nIf alternative antiseizure medications prove to be unsuccessful, an add-on treatment should be considered. Because of the possible interactions between antiseizure medications, for example sodium valproate and lamotrigine, the committee agreed that add-on therapies should be carefully titrated and people should be monitored for adverse effects and their medicines reviewed frequently.\n\nThe committee highlighted the importance of using the regimen that provides the best balance in terms of effectiveness and tolerability of side effects, and that the benefits of rationalising medications (using a single medicine if possible and what to consider if this monotherapy is unsuccessful) should be discussed with the person with epilepsy (and their families and carers if appropriate) to ensure people are not taking more medicines than is necessary to reduce the impact of side effects.\n\n## How the recommendations might affect practice\n\nThe recommendations will not change current practice, but will reinforce current best practice.\n\nReturn to recommendations\n\n# When to start antiseizure medication\n\nRecommendations 4.2.1 and 4.2.2\n\n## Why the committee made the recommendations\n\nThese recommendations are based on the committee's informal consensus on when to start treatment with antiseizure medication for all epilepsy syndromes and seizure types.\n\nThe committee agreed that treatment with antiseizure medication after a first unprovoked seizure should not be offered routinely. However, they agreed that some clinical features should prompt early treatment after a first unprovoked seizure, such as if an examination shows the person has a neurological deficit or the EEG shows unequivocal epileptic activity, which may indicate that the risk of recurrence is high. In some circumstances, for example if there is a risk of loss of employment, further seizures may be unacceptable, so the person or their family or carers may choose to start early treatment. A structural brain abnormality indicates that the brain is damaged, therefore prompt treatment may stop further seizures.\n\n## How the recommendations might affect practice\n\nThe recommendations will not change current practice, but will reinforce current best practice.\n\nReturn to recommendations\n\n# Safety considerations\n\nRecommendations 4.3.1 to 4.3.4\n\n## Why the committee made the recommendations\n\nThese recommendations are based on the committee's informal consensus on safety considerations for starting antiseizure medication to treat all epilepsy syndromes and seizure types with antiseizure medication.\n\nAntiseizure medications differ significantly in their characteristics, therefore the risk of switching between different manufacturer's products, different generic products or branded originator and generic products needs to be taken into account. The committee agreed that Medicines and Healthcare products Regulatory Agency (MHRA) advice on switching between different manufacturer's products needs to be followed.\n\nIn line with the BNF, the committee agreed clinicians should be aware of the risks of serious complications associated with phenytoin for people of Han Chinese or Thai family background, and the risks of serious complications associated with carbamazepine and potentially medicines with a similar chemical structure (such as oxcarbazepine and eslicarbazepine acetate) for people of Han Chinese, Thai, European or Japanese family background.\n\nIn line with the MHRA, the committee noted the antiseizure medicines most commonly reported to cause decreased bone mineral density and increased risk of osteomalacia. The committee agreed that appropriate supplementation should be considered for those at risk.\n\n## How the recommendations might affect practice\n\nThe recommendations will not change current practice, but will reinforce current best practice.\n\nReturn to recommendations\n\n# Antiseizure medications for women and girls\n\nRecommendations 4.4.1 to 4.4.8\n\n## Why the committee made the recommendations\n\nThe guideline committee wanted to ensure that women and girls with epilepsy had access to appropriate support and information about contraception, conception, pregnancy, breastfeeding and caring for children, and menopause. They stressed the importance of having regular reviews with women and girls to ensure they had access to further information and treatment as their circumstances change.\n\nThe committee referred to the MHRA's Public Assessment Report of antiepileptic drugs: review of safety of use during pregnancy to inform the recommendations.\n\nIn the absence of evidence, the committee made consensus recommendations for women and girls with epilepsy who were breastfeeding. They agreed women and girls should be supported to breastfeed if they wish, because the benefits of breastfeeding outweigh the small risk of the drug affecting the child.\n\n## Impact of the recommendations on practice\n\nWomen and girls with epilepsy do not currently have their concerns addressed adequately. Services providing reviews and support are thought to be under-commissioned at the present time and so the recommendations are likely to have an impact on practice with an increase in regular reviews. The MHRA safety advice may encourage women who are on antiseizure medications other than lamotrigine and levetiracetam to reconsider their treatment options.\n\nReturn to recommendations\n\n# Monitoring and review\n\nRecommendations 4.5.1 to 4.5.4\n\n## Why the committee made the recommendations\n\nMonitoring reviews are essential to reassess the clinical management plans of people with epilepsy as their needs change. Evidence comparing regular scheduled reviews with patient-initiated ad-hoc reviews did not suggest any differences in benefit or harm between these approaches. The committee discussed that patient-initiated review could help to ensure timely management of changes in a person's needs and support their sense of ownership of managing their epilepsy. However, it would have disadvantages for people with less independence or capacity to make decisions, and could lead to loss of contact with services, with potentially serious consequences. It might also be unsuitable for people with a serious or complex condition, for whom failing to contact services could be particularly harmful.\n\nThe committee agreed that patient-initiated review should be available to all people with epilepsy, but that regular reviews should be provided to groups that are less suited to a patient-initiated approach. Based on their experience, the committee agreed that groups scheduled for regular reviews should include people with reduced capacity for decision making, people with serious or complex epilepsy, those with serious comorbidities, and children and young people. They also identified people taking antiseizure medication associated with long-term side effects or drug interactions as a priority to check for any adverse effects. Long-term side effects may include adverse effects on blood parameters or bone health, or changes in lipid metabolism. Enzyme-inducing medications in particular are associated with reduced bone density. Regular review for women and girls who are able to have children and are taking valproate or other high-risk teratogenic medication was also recommended to allow a discussion of their treatment options and any plans for pregnancy. The committee commented that regular review is current practice for children and young people, typically with 2\xa0reviews a year and at least once every 12\xa0months.\n\nThe evidence comparing therapeutic drug monitoring with clinical review suggested there is little difference in benefit between these approaches. Based on their experience, the committee agreed that for most people with epilepsy, therapeutic drug monitoring is unnecessary, but that certain groups might gain particular benefit from it. These groups include people who need accurate titration of their medicine levels, such as those with side effects, whose seizures are not controlled with treatment and those in whom adherence is less assured. They also include people at particular risk from their medication, because of either the intrinsic nature of the medication or the increased risks of the medication in people with comorbidities or who are pregnant (for example, to monitor for changes in lamotrigine plasma levels during pregnancy and after birth).\n\n## How the recommendations might affect practice\n\nThe recommendations may change practice because regular review is currently standard practice for all people with epilepsy. There was some concern that specialist nurse services would need to be developed to coordinate patient-initiated reviews. However, the committee agreed that demand on services is likely to be manageable, provided that regular reviews are maintained for groups that might have additional need for coordination. Restricting therapeutic drug monitoring to a few specific groups will not place any extra burden on providers, and might even slightly reduce it.\n\nReturn to recommendations\n\n# Support and monitoring for women planning pregnancy or who are pregnant\n\nRecommendations 4.6.1 to 4.6.10\n\n## Why the committee made the recommendations\n\nThe committee acknowledged the potential importance of drug monitoring in pregnancy. However, the available evidence was limited to a single study. The committee agreed that the evidence was inconclusive, so the group based the recommendations on their own experience and guidance from the MHRA about monitoring levels of carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital or phenytoin if used in pregnancy. The committee noted that on-site testing is often available at tertiary epilepsy centres for some antiseizure medications, including carbamazepine, phenytoin and phenobarbital. They acknowledged that phenytoin and phenobarbital are not usually taken by girls and women who are planning pregnancy. The committee also agreed that pre-conception monitoring of antiseizure medication levels should be considered in women and girls at risk of their seizures worsening during pregnancy and made a recommendation based on committee consensus. The committee highlighted the importance of obtaining pre-conception levels of antiseizure medication as a baseline level to compare and titrate against when monitoring drug levels during pregnancy.\n\nThe committee expressed the need for robust evidence in this area and therefore suggested a recommendation for research on monitoring antiseizure medications in women and girls.\n\n## How the recommendations might affect practice\n\nThe committee noted that currently there would be some women with epilepsy who are planning pregnancy or who are pregnant who are not having their antiseizure medications monitored. The recommendations are in line with MHRA safety advice on monitoring in pregnancy, and may result in some increases in drug monitoring compared with current practice.\n\nReturn to recommendations\n\n# Discontinuing antiseizure medication\n\nRecommendations 4.7.1 to 4.7.7\n\n## Why the committee made the recommendations\n\nDecisions about stopping antiseizure medication are nuanced, based on the person's preferences and their individual risk of seizure recurrence. Although there was some evidence for independent risk factors associated with seizure recurrence, the committee agreed that the recommendations should be broader than listing risk factors, which could be misleading in isolation.\n\nOngoing risk and benefit assessment is important to take account of the evolving needs of the person with epilepsy. Based on their knowledge and experience, the committee agreed that an individualised assessment of the risk of seizure recurrence should be carried out in those who have been 2\xa0years without seizures. The committee stressed the importance of having a discussion with the person, and their family or carer if appropriate, about their personal preferences and the person's individual risk of seizure recurrence, in particular taking into account the type of epilepsy, so that the person is able to make an informed decision about their care. For example, stopping antiseizure medication in people with certain epileptic syndromes, such as juvenile myoclonic epilepsy, structural abnormalities or with co-existing neurodegenerative and other neurological conditions will pose a significant risk of seizure recurrence.\n\nThe committee agreed that guidance should be sought if there are doubts or concerns about the risks and benefits of discontinuing antiseizure medications. Because of the complexity and wide variation of epilepsy surgery techniques, the committee agreed that those who have undergone epilepsy surgery should have antiseizure medications discontinued under the guidance of the epilepsy surgery centre.\n\nThe committee highlighted the importance of stopping antiseizure medications slowly, especially benzodiazepines and barbiturates, because of the possibility of drug-related withdrawal symptoms. They also agreed that epilepsy specialist guidance would be needed if seizures recur.\n\n## How the recommendations might affect practice\n\nThe recommendations will not change current practice, but will reinforce current best practice.\n\nReturn to recommendations\n\n# Generalised tonic-clonic seizures\n\nRecommendations 5.1.1 to 5.1.8\n\n## Why the committee made the recommendations\n\nGeneralised tonic-clonic seizures rapidly involve both sides of the brain. During such seizures, consciousness is lost and muscles will stiffen before jerking rhythmically.\n\nThe evidence showed that, for time to treatment failure, no drugs performed better than sodium valproate, with sodium valproate showing clear benefits over lacosamide, phenobarbital, carbamazepine and topiramate. There was no clear difference between sodium valproate and all other drugs for remission or time to first seizure. The committee agreed that sodium valproate should be offered as first-line treatment, but because of the risks to unborn babies associated with sodium valproate use in pregnancy, they highlighted that it should not be used in women and girls who are able to have children unless other treatments are unsuccessful and the MHRA safety advice is followed.\n\nThe evidence suggested that, after sodium valproate, lamotrigine and levetiracetam had the next best time until treatment failure. For this reason, the committee recommended them as first-line monotherapy options for women and girls who can have children and second-line monotherapy options when sodium valproate is unsuccessful as first-line monotherapy.\n\nThe committee discussed the evidence on adverse events and their importance in making choices about drug treatment. However, these were reported inconsistently across the studies making comparisons between drugs difficult. The committee also agreed that for most drugs, adverse events could be managed by careful titration and dosage changes.\n\nFrom the evidence, it was difficult to determine the most effective add-on drug for generalised tonic-clonic seizures that have failed to respond to monotherapy. Therefore, a number of drugs were recommended as potential first-line add-on treatments. There was evidence that lamotrigine, levetiracetam, perampanel and topiramate performed better than placebo for achieving a 50% response rate. No evidence was identified for clobazam and sodium valproate, but the committee agreed to include them based on their experience and current use in practice. There was also some evidence that levetiracetam and perampanel were more effective than placebo at achieving seizure freedom, but there was a lot of uncertainty around these results.\n\nThe evidence also suggested that brivaracetam might be more effective than placebo at achieving more than 50% reduction in seizure frequency, and lacosamide was less effective than levetiracetam for the same outcome. The committee therefore recommended both brivaracetam and lacosamide, as well as phenobarbital, primidone and zonisamide, based on their experience and knowledge of current practice, as possible second-line add-on treatments.\n\nThe committee stressed again that women and girls able to have children should not be offered sodium valproate as a first-line add-on.\n\nThe committee highlighted that clinicians should take into account that some drugs used in clinical practice can exacerbate seizures in those with absence or myoclonic seizures, including in juvenile myoclonic epilepsy.\n\nIn line with the MHRA, the committee emphasised that long-term treatment with primidone and sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk.\n\n## How the recommendations might affect practice\n\nThe recommendations will reinforce current practice.\n\nReturn to recommendations\n\n# Focal seizures with or without evolution to bilateral tonic-clonic seizures\n\nRecommendations 5.2.1 to 5.2.7\n\n## Why the committee made the recommendations\n\nFocal-onset seizures originate in 1\xa0area on 1\xa0side of the brain and the person may have full or partial awareness. Symptoms vary widely depending on the area of the brain they originate from.\n\nThe evidence showed that lamotrigine and levetiracetam were continued for longer than other drugs for treating focal epilepsy, suggesting that they may be more effective and better tolerated. However, the evidence also suggested they were not more effective than other drugs in terms of remission at 6 and 12\xa0months, and the evidence for time to first seizure suggested they were less effective than carbamazepine.\n\nThe committee discussed the evidence on adverse events and their importance in making choices about drug treatment. The evidence suggested that lamotrigine, levetiracetam and gabapentin may have more tolerable adverse events than other drugs. However, adverse events were reported inconsistently across the studies making comparisons between drugs difficult. The committee also agreed that for most drugs, adverse events could be managed by careful titration and dosage changes.\n\nThe committee agreed that lamotrigine and levetiracetam should be considered as first-line monotherapy options, and this was supported by economic modelling. They agreed that if these treatments were unsuccessful, carbamazepine, oxcarbazepine or zonisamide could be considered for second-line monotherapy. The evidence was weaker for lacosamide, so this was included as a third-line option.\n\nFrom the evidence, it was difficult to determine the most effective add-on treatment for people with focal epilepsy that has failed to respond to monotherapy. The evidence showed that a number of antiseizure medications are effective compared with placebo for more than 50% reduction in seizure frequency rate: brivaracetam, carbamazepine, eslicarbazepine acetate, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, topiramate and zonisamide. Medications with the strongest evidence for this outcome were recommended as first-line options. The committee agreed the use of cenobamate as an add-on treatment, after at least 1 other add-on antiseizure medication has been unsuccessful, in line with NICE's technology appraisal guidance on cenobamate for treating focal onset seizures in epilepsy.\n\nAs with the evidence for monotherapy, the evidence on adverse events with add-on therapy was inconsistent and the committee were not able to use it to inform the recommendations.\n\nAlthough the evidence was less clear, the committee agreed that, based on their experience, sodium valproate can also be an effective option. Because of the risks to unborn babies associated with sodium valproate use in pregnancy, the committee highlighted that it should not be used in women and girls who are able to have children unless other treatments are unsuccessful and the MHRA safety advice is followed.\n\nThere was a lack of evidence for other antiseizure medications, but based on the committee's experience, phenobarbital, phenytoin and vigabatrin were recommended only when the previous treatments are not tolerated or are unsuccessful, for example because of the risk of particular adverse effects.\n\nThe committee noted that, in line with guidance from the MHRA, clinicians should be aware of the risks of serious complications associated with phenytoin for people of Han Chinese or Thai family background, and the risks of serious complications associated with carbamazepine, and potentially medicines with a similar chemical structure (such as oxcarbazepine and eslicarbazepine acetate) for people of Han Chinese, Thai, European or Japanese family background.\n\nIn addition, in line with the MHRA, the committee emphasised that long-term treatment with carbamazepine, phenytoin and sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk.\n\n## How the recommendations might affect practice\n\nThe recommendations will reinforce current practice. Previous NICE guidance recommended lamotrigine and carbamazepine for first-line monotherapy, with restrictions on the use of levetiracetam owing to costs. Levetiracetam is now significantly cheaper and widely prescribed in the NHS. These recommendations may lead to a small increase in the use of levetiracetam, but this will not lead to a significant increase in costs.\n\nAll drugs recommended as add-on treatments are already widely used. Gabapentin and clobazam are no longer recommended, which may lead to a small decrease in the use of these drugs. However, these drugs are not widely used and are likely to be continued in people who are already using them successfully.\n\nReturn to recommendations\n\n# Absence seizures\n\nRecommendations 5.3.1 to 5.3.9\n\n## Why the committee made the recommendations\n\nAbsence seizures are a form of generalised epileptic seizure, characterised by a lack of awareness, stopping moving or talking and staring blankly. They can occur in isolation, but can also be associated epilepsy syndromes, such as childhood absence epilepsy, juvenile absence epilepsy and juvenile myoclonic epilepsy. The evidence identified was only on children and young people; however, the committee agreed that it was appropriate to extrapolate from this evidence to the adult population because of the similar pathophysiology in children, young people and adults.\n\nThe limited evidence suggested that ethosuximide may improve outcomes for absence seizures (including childhood absence epilepsy). It also suggested that ethosuximide may increase the likelihood of remission, which is the main objective of treatment for people with these seizures. The committee agreed that, despite a lack of robust evidence, their expertise and experience supported the use of ethosuximide as first-line treatment for absence seizures. The committee noted that ethosuximide treatment may lead to improved cognitive outcomes and is already well established in clinical practice.\n\nThe committee agreed that sodium valproate should be offered as second-line monotherapy or add-on treatment for absence seizures because the evidence suggested that it may increase the likelihood of remission and it appears to be associated with fewer adverse events than other drugs reviewed. The committee acknowledged that sodium valproate should be used with caution in women and girls, only if the risks and benefits have been thoroughly discussed, other treatments are unsuccessful and MHRA safety advice is followed. However, they agreed that sodium valproate should be considered because absence seizures are usually self-limiting, so treatment is likely to be discontinued or an alternative sought if seizures continue beyond puberty. In line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk.\n\nThe evidence also suggested that lamotrigine and levetiracetam were effective in treating absence seizures. However, the evidence was limited and the committee agreed that these medications should only be considered as third-line monotherapy or add-on treatments.\n\nThe committee agreed that although other antiseizure medications are used in clinical practice and may benefit some people, it should be highlighted that some can exacerbate seizures.\n\nThe evidence showed that sodium valproate is associated with a higher likelihood of remission and is well tolerated, so the committee agreed that it should be considered as first-line treatment for absence seizures with other seizure types (or at risk of other seizure types). However, because of the risks to unborn babies associated with sodium valproate use in pregnancy, the committee decided that it should not be offered as first-line treatment for women and girls able to have children who experience absence seizures in addition to other seizure types. In addition, in line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk.\n\nThe evidence also indicated that lamotrigine and levetiracetam are effective, so the committee agreed that these could be considered as first-line options for women and girls able to have children and as second-line monotherapy or add-on treatment options for men, boys and women unable to have children.\n\nThe evidence on ethosuximide suggested that it may improve outcomes for absence seizures and increase the likelihood of remission, so the committee agreed that it could also be a possible second-line add-on treatment. Because ethosuximide only controls absence seizures, the committee noted that it should not be used as monotherapy treatment for absence seizures with other seizure types.\n\nThe committee agreed it is important to stress that for some women and girls who are able to have children, sodium valproate may still be an option, but only if the risks and benefits have been thoroughly discussed, other treatments are unsuccessful and safety advice from the MHRA is followed. This should be a shared decision taken by the person with epilepsy and their healthcare professional.\n\nThe committee agreed that although other antiseizure medications are used in clinical practice and may benefit some people, it should be highlighted that some can exacerbate seizures.\n\n## How the recommendations might affect practice\n\nThe recommendations will not change current practice, but will reinforce current best practice.\n\nReturn to recommendations\n\n# Myoclonic seizures\n\nRecommendations 5.4.1 to 5.4.8\n\n## Why the committee made the recommendations\n\nThere was very limited evidence on first-line treatment for myoclonic seizures, so the committee used their clinical expertise and expert opinion to inform the recommendations. The onset of myoclonic seizures before the age of 4\xa0years may indicate an underlying neurodegenerative disorder, therefore the committee agreed that these children should be referred to a tertiary paediatric neurologist.\n\nMyoclonic seizures are classified as generalised seizures. Because no evidence was identified on monotherapy or first-line treatments for myoclonic seizures, the committee agreed that it was appropriate to extrapolate from the evidence reviewed on generalised tonic-clonic seizures. Based on this, the committee agreed that sodium valproate is the most effective treatment option for myoclonic seizures compared with other antiseizure medications. However, because of the risks to unborn babies associated with sodium valproate use during pregnancy, the committee agreed that it was important to make separate recommendations for women and girls who are able to have children. In addition, in line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk.\n\nThere was some evidence that levetiracetam, when used as an add-on treatment, is effective in controlling seizures, so the committee agreed that it should be offered as the first-line treatment in women and girls who are able to have children, and for younger girls with epilepsy likely to continue beyond puberty. Based on this evidence, the committee agreed that levetiracetam should also be offered as a second-line add-on or monotherapy treatment for men and boys if sodium valproate is unsuccessful.\n\nThe committee agreed it is important to stress that for some women and girls who are able to have children, sodium valproate may still be an option, but only if the risks and benefits have been thoroughly discussed, other treatments are unsuccessful and safety advice from the MHRA is followed. This should be a shared decision taken by the person with epilepsy and their healthcare professional.\n\nIn the absence of robust evidence, the committee discussed their experience and knowledge of other antiseizure medications for myoclonic seizures and agreed that brivaracetam, clobazam, clonazepam, lamotrigine, phenobarbital, piracetam, topiramate and zonisamide may be effective as third-line treatments if second-line monotherapy or add-on treatment is not sufficient to stop seizures. The committee noted that doctors should use their knowledge and experience to determine which treatment is most appropriate for the person with myoclonic seizures, taking into account clinical factors and the person's preferences and choice. They noted that although lamotrigine is used in clinical practice and may benefit some people, it can sometimes exacerbate myoclonic seizures.\n\nThe committee wanted to make clear that carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine and vigabatrin should not be used because they are known to increase the frequency of myoclonic seizures.\n\n## How the recommendations might affect practice\n\nThe recommendations will not change current practice, but will reinforce current best practice.\n\nReturn to recommendations\n\n# Tonic or atonic seizures\n\nRecommendations 5.5.1 to 5.5.9\n\n## Why the committee made the recommendations\n\nTonic or atonic seizures are events that may cause a person to suddenly drop to the floor. These may be the result of atonic (generalised loss of tone) or tonic (sustained generalised body stiffening) seizures. Although these are characteristic of Lennox–Gastaut syndrome, they are also seen in other epilepsy syndromes and aetiologies. They often result in injury and can therefore have a significant impact on quality of life.\n\nBecause of the complexities associated with the treatment of tonic or atonic seizures and the range of syndromes of which they can be a feature, the committee agreed that a neurologist with expertise in epilepsy should assess people with these seizures in order to provide accurate diagnoses if possible and advise on further investigations as well as treatment.\n\nTonic or atonic seizures are classified as generalised seizures. Because no evidence was identified on monotherapy or first-line treatments for tonic or atonic seizures, the committee agreed that it was appropriate to extrapolate from the evidence on generalised tonic-clonic seizures. Based on this, the committee agreed that sodium valproate is the most effective treatment option for tonic or atonic seizures compared with other antiseizure medications. However, because of the risks to unborn babies associated with sodium valproate use during pregnancy, the committee agreed that it was important to make separate recommendations for women and girls who are able to have children. In addition, in line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk.\n\nThere was some evidence that lamotrigine, when used as an add-on therapy, is effective in controlling tonic and atonic seizures or drop attacks, so the committee agreed that it could be considered as first-line treatment for women and girls who are able to have children and as a second-line monotherapy or add-on treatment for boys and men, and women and girls unable to have children.\n\nHowever, the committee also agreed that for some women and girls who are able to have children, sodium valproate may still be an option, but only if the risks and benefits have been thoroughly discussed, other treatments are unsuccessful and safety advice from the MHRA is followed. This should be a shared decision taken by the person with epilepsy and their healthcare professional.\n\nThe evidence indicated that clobazam, rufinamide and topiramate can also be effective in the management of tonic and atonic seizures and the committee recommended that any of these antiseizure medications could be used as a third-line monotherapy or add-on treatment. In the absence of clear cost-effectiveness evidence of superiority between the different options, the committee agreed that clinicians should use their knowledge and experience to determine which treatment is most appropriate for the person with epilepsy, taking into account clinical factors and the person's preference.\n\nEvidence was identified for a number of other treatment options; however, the low quality and absence of direct comparisons meant that it was difficult for the committee to prioritise 1\xa0treatment over another. The committee agreed that a ketogenic diet can be considered as an add-on treatment and, if this is unsuccessful, felbamate may also be an option as an add-on treatment. However, these treatments should only be used under the supervision of a ketogenic diet team or a neurologist with expertise in epilepsy, respectively, because of the complex nature of the epilepsy.\n\nThe committee agreed that although other antiseizure medications are used in clinical practice and may benefit some people, it should be highlighted that some can exacerbate seizures.\n\n## How the recommendations might affect practice\n\nThe recommendations are not likely to change current practice, but should reinforce best practice.\n\nReturn to recommendations\n\n# Idiopathic generalised epilepsies\n\nRecommendations 5.6.1 to 5.6.5\n\n## Why the committee made the recommendations\n\nIdiopathic generalised epilepsies are 1 of the most common forms of epilepsy. These are well defined, and onset is usually in adolescence, although it can begin in childhood. Seizures will continue into middle age, after which there is some evidence that these will remit, but is not possible to predict in which people this will occur. Many have a good prognosis for seizure control with antiseizure medications and treatment goal is seizure freedom.\n\nThe evidence showed that sodium valproate is the most effective treatment for idiopathic generalised epilepsies compared with other antiseizure medications. However, because of the risks to unborn babies associated with sodium valproate use during pregnancy, the committee agreed that it was important to make separate recommendations for women and girls who are able to have children. In addition, in line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk.\n\nThe evidence showed that both lamotrigine and levetiracetam were effective at reducing seizures, and the committee agreed that they should be options for first-line treatment in women and girls who are able to have children, and for younger girls with epilepsy likely to continue beyond puberty.\n\nThe committee agreed it was important to stress that for some women and girls who are able to have children, sodium valproate may still be an option, but only if the risks and benefits have been thoroughly discussed, other treatments are unsuccessful and safety advice from the MHRA is followed. This should be a shared decision taken by the person with epilepsy and their healthcare professional.\n\nThere was some evidence that levetiracetam is of benefit as add-on therapy compared with placebo. The evidence also showed that lamotrigine was associated with fewer side effects leading to treatment stopping and better health-related quality of life than sodium valproate. Therefore, the committee agreed that these medications could be considered as monotherapy or add-on treatment if first-line treatment is unsuccessful.\n\nThe included studies did not show a clinically important benefit for topiramate when compared with placebo or valproate; however, the committee noted that this drug is useful in clinical practice. The evidence showed that add-on perampanel is effective for reducing seizures and therefore, based on their expert opinion and the evidence reviewed respectively, the committee agreed that these drugs should be available as a third-line add-on treatment option.\n\n## How the recommendations might affect practice\n\nThe committee agreed these recommendations will reinforce current best practice.\n\nReturn to recommendations\n\n# Dravet syndrome\n\nRecommendations 6.1.1 to 6.1.8\n\n## Why the committee made the recommendations\n\nOnset of Dravet syndrome is usually in the first year of life. Children present with prolonged febrile seizures, which may need admission to an intensive care unit. Dravet syndrome can be difficult to diagnose in the first year of life; therefore, the committee emphasised that these recommendations only apply once the diagnosis has been confirmed and discussed with a paediatric neurologist.\n\nDravet syndrome is complex to treat and the response to treatment is variable. Based on their experience and expertise, the committee agreed that the involvement of a neurologist with expertise in epilepsy is needed to guide the care of people with Dravet syndrome.\n\nThere was no evidence for first-line treatments, so the committee based their recommendations on clinical experience and expert opinion. The committee agreed that sodium valproate can be effective at reducing seizures in people with Dravet syndrome because it is successfully used in current practice to treat generalised epilepsies, including Dravet syndrome. The committee acknowledged that sodium valproate should be used with caution in women and girls, only after the risks and benefits have been thoroughly discussed and in line with safety advice from the MHRA. However, they agreed that sodium valproate should be considered as first-line treatment for all people with Dravet syndrome, because there are few effective treatment options and treatment is often started at a young age (under 2\xa0years). In line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk.\n\nThe evidence suggested that triple therapy with sodium valproate, clobazam and stiripentol was effective at reducing seizures in children and young people whose seizures were previously treated unsuccessfully with clobazam and sodium valproate in combination. Although the evidence was limited, the committee agreed that it supported this as first-line add-on therapy. The committee also highlighted that careful titration of doses and regular review are important because of possible adverse effects such as sedation.\n\nThe committee agreed that the NICE technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Dravet syndrome supports the use of this combination as a second-line treatment option.\n\nThere was an absence of evidence to guide further treatment if seizures continue. The committee recommended further treatment options based on their experience and expert opinion, and agreed that these should be considered only under the supervision of a neurologist with expertise in epilepsy or a ketogenic diet team, as appropriate. The use of potassium bromide is unusual in practice, but the committee noted that for some people with Dravet syndrome, it can be effective.\n\nThe committee were aware of ongoing trials, but agreed that further research on treating Dravet syndrome when first-line therapy is unsuccessful or not tolerated would be beneficial and they developed a recommendation for research on complex epilepsy syndromes to help inform future guidance.\n\n## How the recommendations might affect practice\n\nThe recommendations will not change current practice, but will reinforce best practice.\n\nReturn to recommendations\n\n# Lennox–Gastaut syndrome\n\nRecommendations 6.2.1 to 6.2.9\n\n## Why the committee made the recommendations\n\nLennox–Gastaut syndrome is a severe developmental and epileptic encephalopathy with onset in childhood. It can be difficult to diagnose, so children may be started on antiseizure medication before a final diagnosis is established.\n\nLennox–Gastaut syndrome is complex to treat and the response to treatment is variable. Based on their experience and expertise, the committee agreed that the involvement of a neurologist with expertise in epilepsy is needed to guide the care of people with Lennox–Gastaut syndrome.\n\nThere was no evidence for first-line treatments, so the committee based the recommendations on clinical experience and expert opinion. The committee agreed that sodium valproate can be effective in suppressing seizures in people with Lennox–Gastaut syndrome because it is successfully used in current practice to treat generalised epilepsy, including Lennox–Gastaut syndrome. They acknowledged that sodium valproate should be used with caution in women and girls, and only if the risks and benefits have been thoroughly discussed and safety advice from the MHRA is followed. However, they agreed that it should be considered as first-line treatment for all people with Lennox–Gastaut syndrome because there are few effective treatment options and treatment is often started at a young age (under 2\xa0years). In line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk.\n\nThe evidence showed that when used as an add-on treatment, lamotrigine is effective for reducing seizures and drop attacks, therefore the committee agreed that it could be used as second-line therapy, as either an add-on or monotherapy treatment if treatment was not successful or first-line therapy is not tolerated. If used as an add-on therapy, the committee recommended lower initial doses and caution in titration, in line with the BNF. This is because of interactions between sodium valproate and lamotrigine.\n\nThere was some evidence that clobazam, rufinamide and topiramate were of benefit in reducing seizure frequency and drop attacks when used as add-on therapy compared with a placebo. In addition, the NICE technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Lennox–Gastaut syndrome supports the use of this combination as a further treatment option. Therefore, the committee agreed that any of these treatment options could be considered as an add-on treatment if first- and second-line therapy are not tolerated or if seizures continue.\n\nThere was an absence of robust evidence to guide further treatment if seizures continue. The committee discussed possible alternative treatment options and, based on their expert opinion and knowledge, agreed that a ketogenic diet or felbamate could be considered, but only under the supervision of a ketogenic diet team or neurologist with expertise in epilepsy, respectively.\n\nThe committee noted that although other drugs are used in clinical practice and may benefit some people with Lennox–Gastaut syndrome, it should be highlighted that they can exacerbate seizures in some people.\n\nGiven the paucity of published drug trial data in this population, the committee decided to prioritise a recommendation for research on complex epilepsy syndromes including the effectiveness of antiseizure therapies in people with Lennox–Gastaut syndrome when first-line therapy is unsuccessful or not tolerated.\n\n## How the recommendations might affect practice\n\nThe recommendations are not likely to change current practice, but should reinforce best practice.\n\nReturn to recommendations\n\n# Infantile spasms syndrome\n\nRecommendations 6.3.1 to 6.3.11\n\n## Why the committee made the recommendations\n\nInfantile spasms are a severe developmental and epileptic encephalopathy that need urgent care. Based on experience and expertise, the committee agreed that guidance should be sought immediately from a tertiary paediatric neurologist, followed by referral if needed. If untreated, long-term risks of infantile spasms include poor neurodevelopmental outcomes, which could be a serious safety concern. Based on their experience and expertise, the committee stressed that prompt diagnosis and treatment is associated with an improved prognosis. Based on best practice and monitoring strategies used in the studies included in the review, the committee agreed that these children should be monitored both during and after treatment for the relapse of spasms and the emergence of other seizure types, as well as for possible side effects related to treatment.\n\nThe evidence suggested that first-line treatment combining steroids with vigabatrin is more effective than either steroids or vigabatrin alone in stopping spasms. There was no clear evidence about whether oral or injectable steroids were better, but the committee agreed that oral steroids would be easier to use.\n\nBased on their expert opinion, the committee agreed that steroids may not be suitable for all children under 2\xa0years and that vigabatrin alone should be considered for those at high risk from the side effects of steroid treatment, such as those with neurological impairments and other comorbidities.\n\nThere was evidence that vigabatrin alone is effective for children with infantile spasms associated with tuberous sclerosis, so the committee agreed that it should be used as first-line treatment in these children, with high-dose oral prednisolone added on if vigabatrin is ineffective after 1\xa0week.\n\nThe committee agreed that there should be a discussion between parents and carers of children under 2\xa0years taking steroids and their healthcare professional, and that information should be given about possible side effects, such as the increased risk of infection, high blood pressure and high blood sugar levels. Information should include, for example, how to reduce exposure to infections such as chickenpox and what to do if the child may have been exposed.\n\nThe evidence showed that higher doses of both vigabatrin and oral steroids gave improved freedom from spasms, so the committee agreed that dosages should be increased in line with the guidance in the BNF for children. Based on their expert opinion, the committee agreed that it may be necessary to go above the specified doses of vigabatrin if the spasms do not stop, but this should be carried out with specialist supervision.\n\nThere was an absence of robust evidence to guide second-line treatments. The committee agreed possible options based on expert opinion and experience, which should be guided and supervised by a tertiary paediatric neurologist experienced in the care of these children.\n\nThe committee agreed to prioritise a recommendation for research on complex epilepsy syndromes including the effectiveness of antiseizure therapies for infantile spasms when first-line therapy is unsuccessful, because there is no controlled trial data to support evidence-based therapy decisions when first-line treatment fails to stop the spasms.\n\n## How the recommendations might affect practice\n\nThe recommendations will not change current practice, but will reinforce best practice.\n\nReturn to recommendations\n\n# Self-limited epilepsy with centrotemporal spikes\n\nRecommendations 6.4.1 to 6.4.8\n\n## Why the committee made the recommendations\n\nChildren will grow out of self-limited epilepsy with centrotemporal spikes by their early teens. Some only have infrequent seizures, which have little impact on wellbeing. Therefore, not all children and young people and their families will choose antiseizure medication treatment. The committee acknowledged the importance of discussing the balance of risks and benefits of treatment compared with no treatment, with the child or young person and their family or carers, and agreed on some important factors that should form part of a full discussion about treatment. They also agreed that the risk of sudden unexpected death in epilepsy (SUDEP) should be discussed, and reassurance given that this is very rare.\n\nThe committee members were confident, based on their experience and knowledge, that current practice using antiseizure medications is effective at controlling seizures in children and young people with self-limited epilepsy with centrotemporal spikes.\n\nThere was a lack of evidence on antiseizure medications for self-limited epilepsy with centrotemporal spikes, but because these children and young people usually have focal seizures, the committee agreed to use the evidence on monotherapy for treating focal seizures to inform the recommendations for first- and second-line treatments. This evidence showed that lamotrigine and levetiracetam were continued for longer than other drugs for treating focal epilepsy, suggesting that they may be more effective and better tolerated. However, the evidence also suggested they were not more effective than other drugs in terms of remission at 6 and 12\xa0months, and the evidence for time to first seizure suggested they were less effective than carbamazepine.\n\nThe evidence on focal seizures suggested that lamotrigine, levetiracetam and gabapentin may have more tolerable adverse events than other drugs. However, adverse events were reported inconsistently across the studies making comparisons between drugs difficult. The committee also agreed that, for most drugs, adverse events could be managed by careful titration and dosage changes.\n\nBased on the evidence for focal seizures, the committee agreed that lamotrigine and levetiracetam should be considered as first-line treatment options, and carbamazepine, oxcarbazepine or zonisamide as second-line monotherapy treatments.\n\nThe committee noted that, in line with guidance from the MHRA, clinicians should be aware of the risks of serious complications associated with carbamazepine and potentially medicines with a similar chemical structure (such as oxcarbazepine and eslicarbazepine acetate) for people of Han Chinese, Thai, European or Japanese family background.\n\nIn addition, in line with the MHRA, the committee emphasised that long-term treatment with carbamazepine can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk.\n\nThe evidence on self-limited epilepsy with centrotemporal spikes showed that sulthiame is effective for reducing seizures, and so the committee agreed that it should also be available. However, the evidence was limited in quantity and sulthiame is not currently licensed in the UK, so the committee decided that it should be considered as a third-line treatment if licensed options are unsuccessful, and only in consultation with a tertiary paediatric neurologist.\n\nThe committee noted that in their experience, carbamazepine, oxcarbazepine and lamotrigine are sometimes associated with increased seizures or the development of another epilepsy syndrome. The committee recognised that only a small number of children are likely to be affected by these problems, but agreed that any change should prompt a sleep electroencephalogram (EEG) to exclude developmental epileptic encephalopathy with spike-wave activation in sleep, which may indicate an atypical form of self-limited epilepsy with centrotemporal spikes. The committee agreed that poor school performance should also prompt a neuropsychology assessment.\n\nBased on their experience, the committee agreed that these children and young people will have varied needs for review, for example, depending on frequency of seizures and choice of treatment. Regular reviews are important to prevent children and young people continuing on unnecessary treatment and allow discussion of stopping treatment. The committee agreed that this should usually happen when the child has been seizure-free for 2\xa0years or at age\xa014\xa0years.\n\n## How the recommendations might affect practice\n\nThe recommendations are not likely to change current practice, but should reinforce best practice.\n\nReturn to recommendations\n\n# Epilepsy with myoclonic-atonic seizures (Doose syndrome)\n\nRecommendations 6.5.1 to 6.5.7\n\n## Why the committee made the recommendations\n\nEpilepsy with myoclonic-atonic seizures is a rare condition in young children. Successful treatment depends on accurate diagnosis, so based on their experience and expertise, the committee agreed that a tertiary paediatric neurologist should advise on management.\n\nNo evidence was identified on treating epilepsy with myoclonic-atonic seizures. Based on their experience, the committee agreed that levetiracetam and sodium valproate should be considered as first-line treatment options because they are used effectively in current practice to treat generalised epilepsy, including epilepsy with myoclonic-atonic seizures. The committee acknowledged that sodium valproate should be used with caution in women and girls, only after the risks and benefits have been thoroughly discussed, other treatments are unsuccessful and MHRA safety advice is followed. However, they agreed that sodium valproate should be considered as a first-line treatment option for girls and women with epilepsy with myoclonic-atonic seizures, with regular review of the risks and benefits, because there are few effective treatment options available, treatment is often started at a young age and most children will outgrow their seizures by their teenage years. In line with the MHRA, the committee emphasised that long-term treatment with sodium valproate can cause decreased bone mineral density and increased risk of osteomalacia. The committee noted that appropriate supplementation should be considered for those at risk.\n\nThe committee were aware of studies that showed benefits of a ketogenic diet in these children, and based on this knowledge and their experience, agreed that this should be considered as a second-line add-on or alternative treatment, under the supervision of a ketogenic diet team.\n\nIn the absence of evidence, the committee discussed their experience and knowledge of other antiseizure medications for epilepsy with myoclonic-atonic seizures. They agreed that clobazam, ethosuximide, topiramate and zonisamide may be effective. However, these medicines are less commonly used than the first-line treatments, so the committee decided that they could be considered only if first- and second-line options are unsuccessful.\n\nThe committee wanted to make it clear that carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin and vigabatrin should not be used for epilepsy with myoclonic-atonic seizures, because they are known to increase the frequency of seizures in this type of epilepsy.\n\nChildren can grow out of epilepsy with myoclonic-atonic seizures, so the committee discussed discontinuing treatment. Based on their experience, they agreed that this should be considered if the child is seizure-free for 2\xa0years.\n\nThe committee agreed that further research is needed on treating epilepsy with myoclonic-atonic seizures when first-line therapy is unsuccessful or not tolerated and developed a recommendation for research on complex epilepsy syndromes to help inform future guidance.\n\n## How the recommendations might affect practice\n\nThe recommendations are not likely to change practice.\n\nReturn to recommendations\n\n# Status epilepticus\n\nRecommendations 7.1.1 to 7.1.12\n\n## Why the committee made the recommendations\n\nConvulsive status epilepticus is a medical emergency that needs immediate treatment with antiseizure medication. The committee noted the importance of an agreed, individualised emergency management plan for people with epilepsy that should be followed for people experiencing status epilepticus. The management plan should include details of any emergency medicine that has been prescribed, who is trained to use it and when to give it.\n\nThe evidence showed an overall benefit for benzodiazepines, but no clear evidence to support a particular drug. The committee agreed that the speed of delivery is more important than the type of benzodiazepine, and that the route of administration is likely to depend on whether the drug is being given in the community or in a hospital. In community settings, medicines are usually given in buccal or rectal forms because intravenous access is not available. The committee discussed that intravenous lorazepam is routinely given in hospitals and agreed that it should be the first-choice treatment in this setting because of its rapid action and because it causes less respiratory depression and sedation than other drugs. Buccal midazolam is currently used in the community, and based on their experience and the evidence, the committee agreed that it should remain as the first choice, with rectal diazepam as an alternative if agreed, based on previous use or if buccal midazolam is unavailable.\n\nThe committee agreed that the evidence for further antiseizure medication, if seizures continue after 2 doses of a benzodiazepine, showed a benefit for the intravenous administration of levetiracetam, phenytoin or valproate, but did not favour 1\xa0specific medication over the others. However, based on their experience, the committee agreed that levetiracetam can be quicker to prepare, easier to administer and may be associated with fewer adverse effects than the alternative options, so it is likely to become the preferred second-line treatment. However, because the evidence showed no difference in efficacy, the committee agreed that phenytoin or valproate can also be considered. If status epilepticus does not respond to 1\xa0of these medications, the committee agreed that another second-line medication should be considered.\n\nA small amount of evidence showed benefit for general anaesthesia and phenobarbital if status epilepticus continues after second-line treatment. The committee agreed that these should be considered as third-line treatment options, but cautioned that guidance should be sought from an expert in administering these drugs.\n\nThe committee discussed concerns that some causes of status epilepticus may need additional treatment and agreed that awareness of the different circumstances that can cause status epilepticus should be promoted. They also highlighted the need to differentiate non-epileptic attacks from convulsive status epilepticus.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations reflect current practice and are not likely to involve a significant change in practice or have a substantial resource impact.\n\nReturn to recommendations\n\n# Repeated or cluster seizures\n\nRecommendations 7.2.1 to 7.2.4\n\n## Why the committee made the recommendations\n\nThe committee discussed the limited evidence available for repeated or clusters of seizures. There was some evidence that benzodiazepines are effective, and the committee agreed that they should be an option. Clobazam and midazolam were given as examples, reflecting the committee's experience and knowledge of current practice. Rectal diazepam is not preferred owing to the route of administration. The committee agreed that further research using clear, consistent definitions for repeated or cluster seizures are needed and developed a recommendation for research on antiseizure medication for repeated or cluster seizures to inform future guidance.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations reflect current practice and are not likely to involve a significant change in practice or have a substantial resource impact.\n\nReturn to recommendations\n\n# Prolonged seizures\n\nRecommendations 7.3.1 to 7.3.4\n\n## Why the committee made the recommendations\n\nNo evidence was found on treating prolonged convulsive seizures, defined as seizures that last less than 5 minutes but are more than 2\xa0minutes longer than the person's usual seizures. The committee noted that the definition of prolonged convulsive seizures used to include those longer than 5\xa0minutes, because status epilepticus was defined as seizures that persist for 30\xa0minutes. The International League Against Epilepsy (ILAE) proposed a new definition of status epilepticus meaning that all seizures lasting longer than 5\xa0minutes constitute status epilepticus.\n\nThe committee noted that prolonged convulsive seizures should be managed as an emergency. Based on their experience and knowledge, they agreed that benzodiazepines should be a treatment option and that midazolam is often used in current practice.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations reflect current practice and are not likely to involve a significant change in practice or have a substantial resource impact.\n\nReturn to recommendations\n\n# Ketogenic diet\n\nRecommendation 8.1.1\n\n## Why the committee made the recommendation\n\nThe committee were unable to ascertain clear benefits for ketogenic diets in either adults or children with drug-resistant epilepsy from the evidence available. The committee were also mindful of the potential long-term health drawbacks of ketogenic diets, as well as the high-cost implication of providing ketogenic diets. However, from their experience and knowledge, the committee were also aware that benefits are sometimes seen in clinical practice for a small number of people with drug-resistant epilepsy, including children with certain childhood epilepsy syndromes.\n\nThe committee decided against recommending ketogenic diets routinely, but did not wish to remove them completely as an option for specialist consideration in people with few further treatment options. They highlighted the need for high-quality clinical data in this area and agreed that a recommendation for research for children and adults on the effectiveness and long-term tolerability of ketogenic diets would help to inform future guidance.\n\n## How the recommendation might affect practice\n\nKetogenic diets are not routinely offered and so the recommendations are unlikely to have an impact on current practice.\n\nReturn to recommendation\n\n# Resective epilepsy surgery\n\nRecommendations 8.2.1 to 8.2.4\n\n## Why the committee made the recommendations:\n\nThe evidence on surgical interventions showed that resective epilepsy surgery is the most clinically effective treatment for children, young people and adults with drug-resistant focal epilepsy. This was based on the evidence showing better quality of life and lower rates of recurrence after surgery compared with medical care. The committee also considered the relative harms of surgery, such as higher rates of postoperative cognitive deficits and other adverse events. The benefits of surgery were agreed to outweigh these harms, because in many cases, the cognitive effects did not cause significant dysfunction in everyday life, and many of the other adverse events (perioperative infection, bleeding and postoperative changes in mood) were self-limiting. In addition, the committee noted that the risk of harm from surgery needed to be balanced against the risks of ongoing seizures, which include injury, head injury and sudden unexpected death in epilepsy (SUDEP). The committee accepted that the risk of harm may increase as the surgical complexity increases, but agreed that the overall balance in favour of a benefit is likely to apply across most types of epilepsy surgery for both children and adults.\n\nOriginal health economic modelling was undertaken to assess the cost effectiveness of resective epilepsy surgery in adults. However, insufficient data were available to model cost effectiveness in children. The results of the analysis indicated that resective epilepsy surgery was cost effective in adults. Overall, the committee concluded that resective epilepsy surgery was also highly likely to be cost effective for children because they typically have better outcomes after surgery than adults, and the benefits of surgery are experienced for longer. The committee did note that the cost of assessment for resective epilepsy surgery may be higher in children, but these costs would likely be offset by later savings in the form of fewer outpatient appointments and the benefits observed from resective epilepsy surgery.\n\nNo evidence was found on the most effective criteria for referral. However, the committee agreed that because benefits from surgery would outweigh harms across all the populations considered, including improvement in seizure control, potential seizure freedom, better quality of life and reduced risk of epilepsy-related death, all people with drug-resistant epilepsy would benefit from a referral to a tertiary centre for consideration of resective surgery, including those without identified MRI abnormalities.\n\nThe committee also discussed whether there were other groups that might benefit from a referral for consideration of surgery. The committee agreed, by consensus, that people with specific MRI abnormalities that might indicate future resistance to antiseizure medication, should be referred to a tertiary centre at diagnosis, rather than waiting until treatment is unsuccessful.\n\nIn addition, the committee discussed that, in their experience, people with genetic abnormalities or learning disabilities can sometimes be excluded from referral to a tertiary centre for consideration of surgery. This may happen because it is thought that surgery is not suitable for them, or they might be erroneously considered unable to cope with surgical assessment. The committee agreed they should have treatment in the same way as other people with epilepsy and be referred if indicated.\n\n## How the recommendations might affect practice\n\nOnly a proportion of people with drug-resistant epilepsy are referred for resective surgery currently, because of relatively low levels of epilepsy surgical treatment provision, as well as lengthy waiting times for presurgical assessments. Therefore, referral of all people with drug-resistant epilepsy to surgical centres will probably lead to an increase in presurgical investigations and surgical procedures. This may necessitate the need for more epilepsy surgical training and a greater investment in epilepsy surgery programmes.\n\nReferral of people whose epilepsy is not drug resistant might increase the burden on tertiary centres, but the number of people in these groups is likely to be relatively small.\n\nReturn to recommendations\n\n# Vagus nerve stimulation\n\nRecommendations 8.3.1 and 8.3.2\n\n## Why the committee made the recommendations\n\nThere was no long-term robust evidence on vagus nerve stimulation in epilepsy. The committee noted that there is variation in current use, but that it tends to be offered when antiseizure medications have failed to control seizures and epilepsy surgery is not suitable or has not been successful. There was no evidence to suggest that use of vagus nerve stimulation should stop for this small group with complex needs and few management options. The committee agreed that the benefits and harms should be discussed with the person because the intervention does not work in all people and is not a risk-free procedure. NICE has published interventional procedures guidance on the use of vagus nerve stimulation in children with refractory epilepsy. The committee agreed that more research is needed in this area and drafted a recommendation for research on the effectiveness of vagus nerve stimulation.\n\n## How the recommendations might affect practice\n\nThe use of vagus nerve stimulation in practice is currently quite varied. It tends to be a palliative procedure for people with epilepsy that is resistant to treatment and who are not candidates for surgery. The recommendations are not expected to lead to a large change in current practice.\n\nReturn to recommendations\n\n# Psychological, neurobehavioural, cognitive and developmental comorbidities in epilepsy\n\nRecommendations 9.1.1 to 9.1.5 and 9.2.1 to 9.2.4\n\n## Why the committee made the recommendations\n\nThe committee felt it was important to address the higher prevalence of mental health comorbidities, learning disabilities and dementia in people with epilepsy. They also acknowledged the gap in communication and knowledge between the different specialities involved in managing epilepsy and these comorbidities, and thus the need for joint multidisciplinary working relationships. The committee highlighted the importance of active and ongoing liaison between the different specialist teams and people with epilepsy (and their families and carers if appropriate) to ensure the adequate support and treatment is in place. The committee agreed the recommendations reflected current good practice.\n\nThere is variability in the evidence in terms of the different types of psychological interventions, the healthcare professionals who delivered the therapies and the characteristics of people included in the studies. The analyses showed that the differences in psychological treatments and populations did not affect the epilepsy-related quality-of-life outcome significantly, but the committee acknowledged that making recommendations for specific subgroups of people for specific interventions would not be possible from the pooled evidence. The committee also agreed that the clinical evidence for children and young people was extremely limited and very uncertain. However, the committee acknowledged the importance of recognising neurodevelopmental comorbidities in children, particularly those with complex syndromes that may need additional support from the multidisciplinary team.\n\nCoupled with the lack of health economic evidence, it was not possible to make recommendations for tailored psychological interventions with any confidence. The committee noted the need for health economic research in this area.\n\nPeople with epilepsy are at higher risk of experiencing depression. Anxiety is also associated with epilepsy, along with psychosis to a lesser degree. The increased risk of dying from suicide was also noted. The committee highlighted that healthcare professionals should be alert to these psychological comorbidities and check for them in people with epilepsy as part of regular review. The committee agreed to refer to existing NICE guidance on depression. They also agreed to make a recommendation for research on the cost effectiveness of tailored psychological therapy for people with epilepsy.\n\n## How the recommendations might affect practice\n\nThe recommendations on providing coordinated care do not reflect routine practice, and therefore will involve a change of practice for the majority of providers.\n\nThe guideline committee acknowledged the lack of psychological therapies available to people with epilepsy in current practice, especially children and young people. Although some centres have access to neuropsychology services, this varies across the country and there are often long waiting lists. An improvement in access to psychological services for people with epilepsy and depression or anxiety may result from highlighting existing NICE guidance. No significant resource impact is expected as a consequence of the recommendations on support and treatment.\n\nReturn to recommendations\n\n# Reducing the risk of epilepsy-related death including sudden unexpected death in epilepsy\n\nRecommendations 10.1.1 to 10.1.5 and 10.2.1 and 10.2.2\n\n## Why the committee made the recommendations\n\nThere was a lack of evidence for tools predicting sudden unexpected death in epilepsy (SUDEP) and other causes of epilepsy-related death. Sparse data for the SUDEP-7 and SUDEP-7 revised tools suggested good accuracy, but the level of imprecision was very high because of the small number of SUDEP events recorded. Similarly, although there was some evidence for 3 tools for predicting all-cause mortality, it was from a single study with insufficient data to make recommendations.\n\nThe committee agreed that more research is needed and that this should focus on the development of a tool, as well as its validation (see the recommendation for research on risk prediction tool for all-cause epilepsy-related death). The new tool should not focus entirely on SUDEP but should look at other causes of epilepsy-related death, such as suicide, injury and drowning. Large national or international registries recording SUDEP, all causes of death and a wide range of risk factors are needed to produce data of sufficient detail to inform a useful tool. These would need to collect data over a long period of time to provide useful numbers of outcomes.\n\nThe committee also acknowledged that the SUDEP-7 tool showed some promise, despite the uncertainties in the data, and agreed that further larger-scale validation studies of SUDEP-7 should be conducted in the shorter term.\n\nThe committee agreed it was important to highlight the increased risk of premature death, including SUDEP, for people with epilepsy. The lifetime risk of SUDEP is estimated to be between 7% and 12%. This risk is increased in people with severe drug-resistant epilepsy, and is particularly high among those with uncontrolled tonic-clonic seizures. To help prevent premature death, people with epilepsy and their families or carers should be supported to understand their individualised risk as well as what they can do to reduce the risk of SUDEP.\n\nBased on the evidence and their experience in clinical practice, the committee decided to highlight non-adherence to medication, alcohol and drug misuse, living alone, sleeping alone without supervision, and generalised tonic-clonic, focal to bilateral tonic-clonic and uncontrolled seizures, as important risk factors. Non-adherence to medications may also cause the person to experience more seizures and increase their risk of physical injury and premature death. The committee acknowledged that the type of seizures the person has and how often they have them can be modified through medication, significantly reducing the risk of death from seizures. The evidence showed that living alone or sleeping without supervision increased a person's risk of dying. By modifying these risk factors with support from family, carers and clinicians, a person can directly reduce their risk of premature death or SUDEP. The committee did acknowledge that it may not be possible to provide night-time supervision to adults living independently. They highlighted the use of monitors and alarms to prevent risk in children living with their parents. The committee also acknowledged that it may not be possible to remove all risk related to epilepsy.\n\nThe evidence demonstrated that several comorbidities could contribute to the risk of epilepsy-related death. Therefore, the committee agreed that from a person's clinical history, a person's individual risk of premature death including SUDEP should be assessed and should include a history of abnormal neurological findings, neurological conditions and cancer.\n\nThe committee noted that other risk factors may increase the risk of premature death in a person with epilepsy, and that these should also be discussed with the person to help them fully understand their individual risk.\n\nThere was a lack of evidence for interventions to reduce seizure-related death including SUDEP. The committee agreed that the evidence on supervising people with nocturnal seizures was not of sufficient quantity or quality to warrant making a recommendation. However, based on their clinical experience and expertise, the committee agreed it was important to discuss risk factors with people who have nocturnal seizures to minimise the risk of seizures and promote safe practice (such as adherence to medication and improving sleep hygiene) as much as possible. Although limited, the evidence for nocturnal supervision did show some benefit, and based on their knowledge and experience, the committee agreed that this might be discussed alongside other support and information on minimising risks, for example if a carer wishes to use a night monitor or a parent wishes to sleep in the same room as a child.\n\nThe committee agreed that every effort should be made to reduce epilepsy-related risk, particularly the risk of mortality, and emphasised the importance of supporting people with epilepsy to take their medications as prescribed to reduce seizures. Although this applies to all people with epilepsy, the committee noted that this is particularly the case for people with generalised tonic-clonic seizures and focal to bilateral tonic-clonic seizures, because these seizure types are associated with higher risk.\n\n## How the recommendations might affect practice\n\nThe committee highlighted that there is variation in the information currently discussed about the risk of premature death including SUDEP. The recommendations will have an impact on clinical practice by focusing on specific modifiable risk factors and working with people to reduce risk and prevent premature death. The recommendations will create a framework for discussions between healthcare professionals and the person with epilepsy and their families and carers to help inform decisions.\n\nThe recommendation on night-time supervision reflects current good practice and is unlikely to change current practice.\n\nReturn to recommendations\n\n# Epilepsy specialist nurses\n\nRecommendations 11.1.1 to 11.1.4\n\n## Why the committee made the recommendations\n\nThe clinical evidence on epilepsy specialist nurses was limited in quality and quantity, and the committee acknowledged that research in this area can be challenging because of limited funding and difficulties conducting high-quality randomised studies, given that epilepsy specialist nurses are already embedded in many services. However, because there was economic evidence of cost savings both long term and within the first year, the committee agreed that people with epilepsy should have access to an epilepsy specialist nurse. Epilepsy specialist nurses are already embedded in practice and the committee agreed that they play a vital role in supporting other healthcare professionals in primary, secondary and tertiary care, as well as educational and social care settings. They are specialised in supporting children, young people and adults with all aspects of living with epilepsy, providing support with information giving, advice on administering medications, care planning, management of side effects and the impact of epilepsy on daily activities. In addition, epilepsy specialist nurses may identify problems that had been previously unnoticed, such as long-standing side effects of antiseizure medications.\n\nThe committee used the evidence to determine the common features of clinically and cost-effective epilepsy specialist nurse interventions. Based on the clinical evidence, they agreed that interventions should include emotional wellbeing and self-management strategies to support improvements to day-to-day living and health. Based on economic evidence and their own expertise, the committee agreed that people's needs for information and care planning may vary over time and more contact may be needed when seizures are ongoing. The economic evidence showed that epilepsy specialist nurse-led interventions are likely to be cost saving and cost effective when delivered twice a year to people with epilepsy and after attending an emergency department. The committee recommended this approach for people with ongoing seizures or after an emergency department visit. Although it was a wider population (approximately 300,000 people in England) to that explored in the economic analyses, they are much more likely to be in regular contact with healthcare services, with a quarter of this group making at least 1\xa0emergency department visit per year. Nearly all will have some sort of outpatient appointment in a hospital setting, often with an epilepsy specialist nurse where these are available. Therefore, a large number of these epilepsy specialist nurse appointments will already be taking place or will replace appointments with other healthcare practitioners. Although there will be additional total healthcare appointments as a result of these recommendations, the increase would be much smaller in this group than for all people with epilepsy, and costs would be potentially regained within the first year.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice available in some services, but there is variation in epilepsy specialist nurses' involvement across different settings. Some services may need to make changes to practice, such as hiring epilepsy specialist nurses or changing how they work, but this should lead to a number of advantages, including improved patient satisfaction and emotional wellbeing, greater consistency in provision and care, improved access to epilepsy specialist nurses and potentially cost savings.\n\nThe involvement of an epilepsy specialist nurse is likely to result in cost savings by reducing the overall use of healthcare services especially in terms of reduced emergency department visits and the subsequent length of hospital stay.\n\nReturn to recommendations\n\n# Transition from children's to adults' epilepsy services\n\nRecommendations 11.2.1 to 11.2.6\n\n## Why the committee made the recommendations\n\nThe committee acknowledged that many of the recommendations in the NICE guideline on transition from children's to adults' services for young people using health or social care services are directly applicable to young people with epilepsy and their families or carers. So, they reviewed the evidence on identified themes specific to people with epilepsy that are not covered by that guideline.\n\nThe committee noted that a young person's transition should be tailored to their needs and that this should be recognised by both paediatric and adult services. The committee discussed the value of reviewing diagnosis and management at transition and agreed that this should involve both paediatric and adult multidisciplinary teams working together with the young person and their family or carers. The evidence found that young people who engaged with a multidisciplinary team felt more confident and able to communicate their needs, so the committee stressed that planning and decision making should be patient-centred, with young people and their families and carers (if appropriate) fully involved in discussions about their transition and ongoing care.\n\nThe committee acknowledged that transition can be a distressing time for young people with epilepsy and their families and carers. The evidence showed a lack of clarity in communication and the information given to young people and their families and carers at transition, for example they lacked clear information about the risks of SUDEP and unplanned pregnancy. The committee agreed that clear and balanced information is vital during transition and, based on their experience, listed some key areas that should be covered in discussions. In particular, stigma around epilepsy was highlighted as an important topic to raise so as to give the young person the opportunity to discuss their experiences and for support to be provided. The evidence showed that stigma can have a significant impact on young people's everyday activities, educational achievement and engagement with healthcare professionals. The evidence also suggested that repeating information at intervals during transition would help young people understand and retain key information. Based on the evidence and their experience, the committee highlighted the importance of providing information in a suitable format for the person, using language they understand and that is appropriate for their developmental age, and avoiding technical terms.\n\nThe evidence showed that young people with epilepsy and a learning disability, and their parents, often struggled with transition, and had difficulty finding information and understanding the changes in service provision. They noted that transition was often not planned or happened much later than for young people without learning disabilities. Young people with learning disabilities may have complex needs, and transition to adult services may need more planning and involve other specialties, such as a learning disabilities multidisciplinary team and child and adolescent mental health services. Based on their experience, the committee agreed that it would be beneficial to start transition planning earlier than usual for young people with complex health or social care needs, including people whose seizures were not fully controlled by their treatment or those with a learning disability, to allow time for care packages to be set up. They agreed that the timeframe would depend on individual circumstances.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current best practice so the committee agreed there should be no resource impact.\n\nReturn to recommendations", 'Context': 'Epilepsy is one of the most common serious neurological disorders, affecting around 50\xa0million people worldwide and about 533,000 in England and Wales. Of these, around 112,000 are children and young people. The incidence of epilepsy is estimated to be 50\xa0per 100,000\xa0per year and the prevalence of active epilepsy in the UK is estimated to be 5\xa0to 10\xa0people per 1,000. Epilepsy is also a common cause of people attending A&E departments. Epileptic seizures can result in injury, and may also be associated with mortality, for example, because of sudden unexpected death in epilepsy (SUDEP).\n\nMost people with active epilepsy (60% to 70%) have their seizures satisfactorily controlled with antiseizure medications. Other treatment options may include surgery, vagus nerve stimulation, and psychological and dietary therapies. Optimal management improves health and wellbeing, including reducing the impact of epilepsy on social activities, education and career choices, and reduces the risk of SUDEP.\n\nThe original NICE guideline on epilepsy (2004) stated that the annual estimated cost of established epilepsy was £2\xa0billion (direct and indirect costs). However, newer and more expensive antiseizure medications are now being prescribed. With an increase in treatment costs likely in coming years, it is essential to ensure that antiseizure medications with proven clinical and cost effectiveness are identified.\n\nThe 2004 NICE guideline on epilepsies, the 2004 NICE technology appraisal guidance and the subsequent 2012 pharmacological review on newer drugs for epilepsy, failed to show a difference in effectiveness between newer and older antiseizure medications, or between the newer drugs (as monotherapy) for seizure control. The International League Against Epilepsy has proposed new definitions and a framework for classifying epilepsy, and diagnosis and investigation have become more focused on aetiology. This guideline update reflects this and considers new evidence on managing epilepsies.'}	https://www.nice.org.uk/guidance/ng217	This guideline covers diagnosing and managing epilepsy in children, young people and adults in primary and secondary care, and referral to tertiary services. It aims to improve diagnosis and treatment for different seizure types and epilepsy syndromes, and reduce the risks for people with epilepsy.
18d304ce7af07bc17582d2d96865710c005b598c	nice	Tucatinib with trastuzumab and capecitabine for treating HER2-positive advanced breast cancer after 2 or more anti-HER2 therapies	Tucatinib with trastuzumab and capecitabine for treating HER2-positive advanced breast cancer after 2 or more anti-HER2 therapies Evidence-based recommendations on tucatinib (TUKYSA) for HER2‑positive locally advanced or metastatic breast cancer in adults after 2 or more anti‑HER2 treatment therapies. # Recommendations Tucatinib with trastuzumab and capecitabine is recommended, within its marketing authorisation, as an option for treating HER2‑positive locally advanced or metastatic breast cancer in adults after 2 or more anti‑HER2 treatment therapies, only if the company provides tucatinib according to the commercial arrangement. Why the committee made these recommendations Current treatment for HER2‑positive locally advanced or metastatic breast cancer after 2 or more anti‑HER2 regimens is chemotherapy. Tucatinib with trastuzumab and capecitabine (tucatinib combination) is another anti‑HER2 therapy that could be used after 2 or more anti‑HER2 regimens. Trastuzumab can be given subcutaneously or intravenously, but the subcutaneous injection is easier to administer. Clinical trial evidence shows that tucatinib combination increases the time people have before their cancer gets worse and how long they live compared with trastuzumab with capecitabine. But trastuzumab with capecitabine is not standard care in the NHS. Comparing tucatinib combination indirectly with chemotherapy suggests it may increase the time people have before their cancer gets worse and how long they live. It is likely that tucatinib combination improves people's quality of life before and after their cancer gets worse compared with chemotherapy. The economic model does not take into account all of the benefits of tucatinib combination, particularly for people with brain metastases. Taking this into account, the cost-effectiveness estimates for tucatinib combination are likely to be within what NICE normally considers an acceptable use of NHS resources. So, tucatinib combination is recommended.# Information about tucatinib # Marketing authorisation indication Tucatinib (TUKYSA, Seagen UK) has a marketing authorisation for use 'in combination with trastuzumab and capecitabine for the treatment of adult patients with HER2-positive locally advanced or metastatic breast cancer who have received at least 2 prior anti-HER2 treatment regimens'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for tucatinib. # Price The list price is £5,636.84 per 84 pack of 150 mg film-coated tablets (excluding VAT; BNF online accessed February 2022). The average cost of a course of combination treatment at list price is £7,016.91 for the loading dose and £6,677.14 for the following cycles (company submission). The company has a commercial arrangement. This makes tucatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Seagen UK, a review of this submission by the evidence review group (ERG), responses from stakeholders and comments on the first appraisal consultation document. See the committee papers for full details of the evidence. The committee discussed the following issues. # Clinical need and treatment pathway ## HER2-positive breast cancer has a high disease burden Some breast cancer cells have higher levels of a protein called HER2 on their surface, which stimulates them to grow. This is known as HER2‑positive breast cancer. Around 1 in 5 breast cancers are HER2‑positive. Patient experts explained that being diagnosed with locally advanced or metastatic breast cancer is extremely difficult for people and their family and friends. It can cause considerable anxiety and fear, with the uncertainty being the hardest part for many people. These feelings can negatively affect mental health. People with metastatic breast cancer must organise their lives around hospital appointments, which constrains their everyday activities. Brain metastases may develop in up to half of people with HER2‑positive cancer, which negatively affects people's prognosis and quality of life. The patient experts explained they were not able to drive or work, and lost their independence. The committee concluded that there is a high disease burden for people with HER2‑positive metastatic breast cancer, especially for those with brain metastases. ## There is a need for anti-HER2 therapies after second-line treatment, especially for people with brain metastases There is no cure for metastatic breast cancer. Treatment aims to stop progression of the disease, extend life, and maintain or improve quality of life for as long as possible. Treatment is continued for as long as it works. First-line treatment of HER2‑positive metastatic breast cancer includes the anti‑HER2 therapies pertuzumab with trastuzumab and docetaxel, or trastuzumab with paclitaxel (see NICE's technology appraisal guidance on pertuzumab with trastuzumab and docetaxel for treating HER2-positive breast cancer and trastuzumab for treating advanced breast cancer). Trastuzumab emtansine is an anti‑HER2 therapy used at second line (see NICE's technology appraisal guidance on trastuzumab emtansine for treating HER2-positive advanced breast cancer after trastuzumab and a taxane; from now referred to as TA458). Clinical experts explained that HER2‑positive metastatic breast cancer that has progressed after 2 or more anti‑HER2 regimens has a high symptom burden and is resistant to previous lines of therapy. The committee noted that, although some NHS trusts may offer third-line anti‑HER2 therapy, it is not available across the NHS and cannot be considered standard care. Trastuzumab deruxtecan is only available through the Cancer Drugs Fund so is not considered standard care (see NICE's technology appraisal guidance on trastuzumab deruxtecan for treating HER2-positive unresectable or metastatic breast cancer after 2 or more anti-HER2 therapies; from now referred to as TA704). Instead, standard care for people whose disease has progressed on or after 2 anti‑HER2 therapies is non-targeted chemotherapy, including capecitabine, vinorelbine or eribulin (see NICE's guideline on advanced breast cancer: diagnosis and treatment and NICE's technology appraisal guidance on eribulin for treating locally advanced or metastatic breast cancer after 2 or more chemotherapy regimens, from now referred to as TA423). Brain metastases can be treated with stereotactic radiosurgery or radiotherapy (see NICE's guideline on brain tumours and metastases in over 16s). The clinical experts explained that there is a limit to the number of these treatments, and most people cannot have more than 2 courses of radiotherapy because of its neurological toxicity. Currently there are no further treatment options that target brain metastases because most chemotherapy treatments have very limited capacity to cross from the blood into the brain. The committee concluded that there is a high unmet need for anti‑HER2 treatment after second-line anti-HER2 treatment. This is particularly important for the significant proportion of people who have brain metastases, because tucatinib can cross an intact blood-brain barrier and treat brain metastases. ## The relevant comparators are capecitabine, vinorelbine and eribulin In its initial submission, the company used eribulin as its base-case comparator. It stated that eribulin is the only third-line treatment approved by NICE for HER2‑positive locally advanced or metastatic breast cancer and has clinical equivalence to capecitabine and vinorelbine. The ERG noted that CG81 recommends that people may also have treatment with other non‑HER2‑targeted chemotherapies such as capecitabine or vinorelbine. The clinical experts confirmed that current NHS third-line standard care is non-targeted chemotherapy, including capecitabine, vinorelbine or eribulin. The clinical experts explained that although some people have trastuzumab with capecitabine, there is wide regional variation in its availability. As it is not available to all patients in the NHS, the committee agreed that trastuzumab with capecitabine is not a relevant comparator. The committee concluded that the relevant comparators for tucatinib with trastuzumab and capecitabine (from now referred to as tucatinib combination) are capecitabine, vinorelbine and eribulin. # Clinical evidence ## The HER2CLIMB population is generalisable to UK clinical practice The clinical evidence was based on HER2CLIMB, a randomised, double-blind, placebo-controlled, active comparator trial for HER2‑positive locally advanced or metastatic breast cancer previously treated with trastuzumab, pertuzumab and trastuzumab emtansine. Approximately 50% of people in HER2CLIMB had brain metastases. The clinical experts explained that HER2CLIMB represents patients in the NHS in terms of characteristics and previous treatment, including the proportion of people who will go on to develop brain metastases. The committee concluded that the population in HER2CLIMB was generalisable to the eligible population in clinical practice in the UK. ## Tucatinib combination is more effective than trastuzumab with capecitabine, but this comparison does not reflect NHS practice HER2CLIMB assessed tucatinib combination compared with placebo plus trastuzumab and capecitabine (from now referred to as placebo combination). However, trastuzumab with capecitabine is not used in NHS practice (see section 3.3). People who had tucatinib combination had a median progression-free survival of 7.8 months compared with 5.6 months for people who had placebo combination. The hazard ratio for disease progression or death was 0.54 (95% confidence interval , 0.42 to 0.71; p<0.001). People who had tucatinib combination had a median overall survival of 21.9 months compared with 17.4 months for people who had placebo combination. The hazard ratio for death was 0.66 (95% CI, 0.50 to 0.88; p=0.005). An improvement in progression-free and overall survival was observed in people with and without brain metastases. The clinical experts explained that this is because, unlike existing treatments, tucatinib is a small molecule that can pass through an intact blood-brain barrier. The clinical experts also explained that the clinical data in the company submission was supported by some longer follow-up data from the trial, which was presented at the American Society of Clinical Oncology annual meeting. The committee concluded that tucatinib combination is more effective than trastuzumab with capecitabine, but that this comparison does not reflect NHS practice. The committee also noted that the impact on brain metastases is important because brain metastases are associated with a poor prognosis and reduced quality of life (see section 3.1 and section 3.2). # Indirect treatment comparison ## Results of the network meta-analysis are uncertain because of heterogeneity across trials There was no head-to-head evidence comparing tucatinib combination against the relevant comparators, capecitabine, vinorelbine or eribulin (see section 3.3). Therefore, the company did a network meta-analysis to allow for an indirect treatment comparison. The results showed increased progression-free and overall survival for tucatinib combination compared with other treatments (the exact numbers are academic in confidence and cannot be reported here). However, the ERG explained that these results are uncertain because there were differences between patient populations in the trials included. The HER2CLIMB trial included people with and without brain metastases. Approximately 29% had active brain metastases (that is, either treated and progressing, or untreated) and 19% had stable brain metastases. None of the comparator trials included people with active brain metastases. All but one included people with stable or inactive brain metastases, but the proportion was usually not reported or was lower than in HER2CLIMB (see section 3.8 and section 3.9 for further discussion of brain metastases). Other differences between patient populations were the number of previous therapies, prior anti‑HER2 treatment, HER2 positivity status, Eastern Cooperative Oncology Group performance status and family background. The committee concluded that tucatinib is likely to improve clinical outcomes relative to eribulin, capecitabine and vinorelbine, but the size of the effect is uncertain. This is because there was clinical heterogeneity in several areas, particularly that people with active brain metastases were included in the HER2CLIMB trial but not in the other trials. ## A random effects model is appropriate because of heterogeneity in the network, but does not account for systematic differences between trials In its initial submission, the company used a fixed effects model for the network meta-analysis. This was because random effects modelling had limitations such as convergence issues and a higher degree of uncertainty. The ERG used a random effects model, explaining that it better accounted for heterogeneity in the network meta-analysis and is preferred to fixed effects modelling, despite its limitations. The company agreed with the ERG's approach in its response to consultation and updated its base case accordingly. The committee noted that the results from using the 2 methods were similar, although the random effects model gave wider confidence intervals. The committee concluded that the random effects methodology was more appropriate because of heterogeneity in the network, and acknowledged it was used by the company in its updated base case. However, it noted that using a random effects model did not account for any systematic bias in the network related to differences in the proportions of people with brain metastases. ## Network meta-analysis results should be adjusted for a treatment-modifying effect of brain metastases The clinical experts explained that people with brain metastases have a poorer prognosis than those without. The committee noted that an anchored indirect treatment comparison can account for differences in prognostic factors between trials, but only if they have no effect on relative treatment outcomes (that is, they are not treatment effect modifiers). The clinical experts explained that tucatinib is the only treatment shown to cross the blood-brain barrier with demonstrated activity in brain metastases. But they highlighted that the impact of other treatment options on brain metastases is complex. Although comparator drugs generally cannot cross an intact blood-brain barrier, small amounts can cross when the barrier is compromised, for example, after whole-brain radiation therapy. The clinical experts also noted that good control of disease and metastases in other parts of the body may delay the time to developing brain metastases or them reoccurring. This means that treatments that are more effective in controlling other metastases, such as trastuzumab with capecitabine, are also believed to be more effective for people with brain metastases compared with single-agent non-targeted chemotherapy. They also noted that lapatinib with capecitabine (not a relevant comparator but included in the network) was shown to have at least some activity for brain metastases. The committee understood that the network meta-analysis results may be biased because the presence of brain metastases may affect how well comparator treatments work for people with breast cancer. That is, had people with active brain metastases been included in the comparator trials, the outcomes would be expected to be worse. In its response to consultation, the company presented the results of a literature review suggesting that the trastuzumab component alone in both arms of the HER2CLIMB trial may give a survival benefit in people with brain metastases compared with no treatment or non‑HER2‑targeted therapy. Therefore, the non-tucatinib control arm in the trial may itself have had better outcomes than the 3 individual non‑HER2‑targeted therapies considered as comparators in this appraisal. However, the company acknowledged this represents a naive comparison between different populations in different studies. The committee concluded that the network meta-analysis results could be adjusted for a treatment-modifying effect of brain metastases. It noted that this analysis is still likely to be highly uncertain, but nevertheless useful for decision making (see section 3.9). ## Adjustment based on HER2CLIMB data is preferred, but may be conservative The company used 2 approaches to estimate how much worse outcomes would have been if the same proportion of people with brain metastases as in HER2CLIMB had been included in the comparator monotherapy trials. In its preferred approach, the company asked 10 clinicians to estimate overall survival at 1, 2, 3 and 5 years for single-agent chemotherapies if their respective trials had included the same proportion of people with brain metastases as HER2CLIMB. These estimates were lower than predicted by the ERG model (see section 3.11). Comparing the 2 sets of estimates, the company calculated by how much the network meta-analysis results would need to be adjusted to align with the survival predictions given by clinicians. In the alternative approach, the company used individual patient data from HER2CLIMB to estimate a treatment-modifying effect of brain metastases.The ERG noted that the company's preferred approach (using clinician estimates) resulted in an upward kink in the survival estimates at year 2, which was unrealistic. It preferred the alternative, data-driven approach, using HER2CLIMB data. The company explained that the upward kink in survival estimates was because it relied on clinician predictions at specific timepoints, without smoothing out between these timepoints. However, it noted that if it had done so, the cost-effectiveness estimates would decrease slightly. The company explained that the approach using the HER2CLIMB data did not capture any additional treatment effect from HER2‑targeted therapy (trastuzumab) in the placebo arm of the trial. The ERG recognised that its approach may be conservative. The committee noted that neither approach was robust. There was uncertainty about how much the comparator arms should be adjusted to account for the discrepancy in the proportion of people with brain metastases. However, despite its limitations, the committee's preference was for the HER2CLIMB data-driven approach, over the clinician's estimations. It concluded that this approach did not account for any benefit from trastuzumab and may be conservative, and acknowledged that the true cost-effectiveness estimates are likely to be lower than those estimated using the data-driven approach. # Cost-effectiveness evidence ## The company's economic model is suitable for decision making The company submitted a partitioned survival model to estimate the cost effectiveness of tucatinib combination compared with eribulin, capecitabine and vinorelbine. It had 3 health states: progression-free, progressed, and death. The committee considered that the partitioned survival model is a standard approach to estimate the cost effectiveness of cancer drugs and is suitable for decision making. ## Directly extrapolating HER2CLIMB data is most appropriate for estimating progression-free and overall survival for tucatinib and the comparators In its initial submission, the company chose lapatinib with capecitabine as a reference treatment to model progression-free and overall survival, because this was the most commonly used treatment in the network meta-analysis. It explained that lapatinib with capecitabine data was generated using an average of the evidence in the network. It used fractional polynomial curves to extrapolate survival data for the reference arm. It then used hazard ratios from its network meta-analysis to estimate survival for other treatments. The ERG explained that the company approach resulted in estimated survival data for tucatinib combination that had a poor visual fit to data from the HER2CLIMB trial, particularly for overall survival. Instead, it preferred to fit survival curves directly to the HER2CLIMB data using trastuzumab with capecitabine as the reference treatment. It chose the Weibull curve because it provided better visual fit and the best statistical fit. The company explained the ERG's approach created bias against tucatinib because HER2CLIMB included more people with brain metastases than the comparator trials (see section 3.6), and because these people have poorer outcomes than people without brain metastases (see section 3.8). The committee noted that because the HER2CLIMB population was representative of that in clinical practice (see section 3.4), while the populations of other trials were not, it should be used to model survival that would be expected in NHS practice. It also noted that lapatinib with capecitabine is not a relevant comparator in this appraisal (see section 3.3). The committee agreed that the curves fitted to the HER2CLIMB data better fitted the outcomes observed in the trial and more closely matched the clinical expert estimates of progression-free survival and overall survival. However, it acknowledged that this did not address the underlying issues with the network meta-analysis (see sections 3.6 to 3.9). In its response to consultation, the company agreed with the ERG approach. It updated its base case to directly extrapolate HER2CLIMB data for progression-free and overall survival for trastuzumab with capecitabine. It applied hazard ratios from its network meta-analysis, adjusted for the treatment-modifying effect of brain metastases, to estimate survival for the other treatments. The committee acknowledged that the revised company approach aligned with its preference to directly extrapolate survival data from the HER2CLIMB trial. ## The subgroup analyses have methodological limitations and are not appropriate for decision making The company did not model the cost effectiveness of tucatinib combination relative to its comparators separately for people with and without brain metastases because there was limited evidence on the efficacy of comparators in people with brain metastases. The ERG agreed that there was a lack of evidence for the comparators in people with brain metastases. The committee noted that the subgroup of people without brain metastases from HER2CLIMB better corresponded to the patient populations in the other trials included in the network meta-analysis (see section 3.6). It considered that modelling survival for tucatinib combination and its comparators separately for people with and without brain metastases could help to better understand the uncertainty in the cost effectiveness of tucatinib. This is because the presence of brain metastases may be a prognostic factor and have a treatment-modifying effect. So, the shape and extrapolation of survival curves would be likely to differ for people with and without brain metastases (see sections 3.6 to 3.9). In response to consultation, the company did a subgroup analysis for people with brain metastases, by directly extrapolating progression-free and overall survival data from the corresponding HER2CLIMB subgroup. It stated that this analysis showed that tucatinib combination is more cost effective in people with brain metastases than in those without brain metastases. However, it cautioned that the HER2CLIMB trial was not powered to show a significant benefit in overall survival in subgroups. The ERG noted that the company did not provide sufficient information on how the analysis was done and was unable to replicate the company's results. In particular, the company did not justify its selection of survival extrapolation curves, nor did it explore alternative survival extrapolations, so it was unclear if the method it chose was appropriate. The ERG ran exploratory analyses using the same assumptions as the company, and the results were generally aligned with the company estimates. The company further stated that it was not able to do subgroup analyses for people without brain metastases because of time constraints. Instead, it used a weighted average approach to estimate cost effectiveness in this subgroup. The ERG explained these estimates were not accurate because the survival curves were likely to differ between the 2 subgroups, which was not explored. It also explained that incremental cost-effectiveness ratios (ICERs) are ratios and cannot be directly used to estimate weighted averages. Instead, weighted averages of the total costs and total quality-adjusted life years would need to be estimated and used to calculate the ICER for the non-brain-metastases subgroup. It also noted that the results did not account for the cost of screening people for brain metastases. The committee concluded that the subgroup analyses had methodological limitations and were not described in sufficient detail for adequate scrutiny. Therefore, it concluded that the subgroup analyses were not appropriate for decision making. ## Differences in health state utilities before progression are plausible, but the exact values are uncertain For tucatinib combination, the company used EQ‑5D‑5L health-related quality of life data collected in HER2CLIMB, mapped to the EQ‑5D‑3L with UK preference weighting. Utilities for the comparator therapies were from TA423. This resulted in higher utility values for tucatinib combination compared with comparators in both pre- and post-progression health states. The company explained that tucatinib has better efficacy and safety profiles than eribulin or vinorelbine. It noted that in TA423, eribulin had higher pre-progression utilities than other single-agent chemotherapies. The ERG explained the company approach was inappropriate because the differences in utilities between tucatinib and comparators were not based on comparative evidence. It preferred to use the same utility values for all treatments for each health state, and to derive them all from HER2CLIMB data. The ERG noted that in the HER2CLIMB trial, there was no difference in utility values between the 2 trial arms. The clinical experts explained that the safety profile of tucatinib is good, but it is difficult to separate the effects on quality of life of disease progression and toxicity. The clinical experts also noted that disease control could support different pre-progression utility values because treatments offer different levels of overall response rate. The committee concluded that different pre-progression utility values are plausible, but noted the values used by the company were not evidence based, so were uncertain. ## Differences in health state utilities after progression are plausible, but their extent is probably overestimated In addition to the limitations of the company's approach highlighted in section 3.13, the ERG explained that the utility value used by the company was not accepted by the TA423 committee because it was too low. In response to consultation, the company corrected its post-progression utility value to align with the value the committee agreed on in TA423. It also provided a literature review and results of a survey with clinicians to support differences in post-progression utilities between tucatinib combination, HER2‑directed therapies, and standard single-agent chemotherapy. The ERG explained that the company's justification was reasonable, but it still had concerns about using different sources for post-progression utilities for different treatments. It noted that this resulted in large differences in post-progression utilities for tucatinib combination and the comparators, which may have overestimated the benefit of tucatinib combination. The clinical experts explained that: Brain metastases affect people's quality of life to a greater extent than metastases to other organs. So, it is likely that if it takes longer for the disease to progress because of brain metastases, someone's quality of life after progression will be better than if the disease had progressed quickly. People with disease that is better controlled would have better quality of life before and after progression than those with disease that is less well controlled. This is because the decline in quality of life related to progression will start from a higher level than in people with disease that is less well controlled and with lower quality of life before progression. Some toxic effects of chemotherapy can be long lasting and affect a person's quality of life after progression.The committee noted that: Differences in quality of life after progression between tucatinib combination and comparators were plausible. However, it noted that this difference may decrease once people's disease (and therefore quality of life) deteriorates further with time after progression on tucatinib combination. The toxicity of capecitabine on its own is expected to be similar or lower than the toxicity of tucatinib combination. Therefore, differences in toxicity may not explain the large difference in utilities after disease progression between capecitabine and tucatinib combination. The company's approach was not methodologically robust because it used utility values from 2 different sources: the HER2CLIMB trial for tucatinib combination and TA423 for the comparators, in a 'naive comparison', that is, without adjusting for any differences between populations in these sources that might have affected the utility values. It also noted that the value from TA423 was based on the midpoint of 2 utility estimates from 2 different studies. Therefore, the results from the company's approach were uncertain. The company's approach may overestimate the extent of difference in post-progression utilities between tucatinib and comparators, so it may overestimate the benefit of tucatinib combination. The alternative approach of assuming equal post-progression utility after tucatinib and single-agent chemotherapy is most likely pessimistic.The committee concluded that some differences in post-progression health state utilities are plausible, but uncertain. Although the ERG incorporated the company's revised utilities in its base case, the committee remained concerned that if the difference in post-progression utility was overestimated, the cost-effectiveness estimates would be slightly higher than those estimated by the company. It noted that in future it would prefer evidence-based utilities and additional scenarios to be explored. ## Standard NHS practice is subcutaneous trastuzumab In HER2CLIMB, trastuzumab (as part of tucatinib combination) was administered either intravenously or subcutaneously, as allowed for in tucatinib's summary of product characteristics. But the initial company model assumed only intravenous administration of trastuzumab. The clinical experts explained that intravenous trastuzumab is no longer standard NHS practice. The clinical and patient experts explained that subcutaneous administration is preferred because people can self-administer, avoiding unnecessary hospital visits. Both the clinical and patient experts explained that if subcutaneous administration was not possible, they would accept intravenous administration if it meant people could have tucatinib combination. In its response to consultation, the company presented scenario analyses assuming different levels of subcutaneous trastuzumab usage. The ERG provided an additional scenario analysis assuming 100% use of subcutaneous trastuzumab. The Cancer Drugs Fund clinical lead explained that over 90% of patients have trastuzumab subcutaneously in the NHS. Some people may choose to have intravenous trastuzumab if subcutaneous administration is not appropriate for them. He also noted that chemotherapy units have capacity issues with intravenous administration. The clinical experts noted that there are additional benefits from subcutaneous administration that have not been captured in the current modelling, such as fewer hospital visits, and convenience and quality-of-life benefits for patients. Fewer hospital visits may also help reduce COVID‑19 transmission. The committee concluded that subcutaneous trastuzumab is standard care in the NHS and could have unaccounted-for benefits for patients and service delivery. ## Drug wastage should be included in the analysis In its initial submission, the company did not include drug wastage for intravenous trastuzumab in its base case because it is packaged in multi-use vials. The ERG preferred to include this because some wastage is expected in clinical practice. It noted this has a very small effect on overall costs and the cost-effectiveness estimates. It also noted that this applied to intravenous administration only and was not relevant for analyses assuming subcutaneous administration of trastuzumab. The company agreed with the ERG in its response to consultation and updated its base case accordingly. The committee concluded that drug wastage should be included in the analysis and acknowledged this was done appropriately by the company in its revised base case. # End of life ## Tucatinib combination meets the end of life criteria The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The clinical experts and the ERG agreed that the life expectancy for people with HER2‑positive locally advanced or metastatic breast cancer having third-line treatment is less than 24 months. They also agreed that the gain in life expectancy with tucatinib combination is expected to be greater than 3 months. The committee also noted that the end of life criteria were accepted in TA423 and TA704 in a third-line setting, and in TA458 in a second-line setting. The committee concluded that tucatinib meets the end of life criteria. # Cost-effectiveness results ## Tucatinib with trastuzumab and capecitabine is likely to be cost effective Because of confidential commercial arrangements for tucatinib, trastuzumab, eribulin and post-progression therapies, the ICERs cannot be reported here. The company addressed a number of the committee's concerns in its response to consultation, including: using a random effects network meta-analysis (see section 3.7) exploring a treatment-modifying effect of brain metastases (see section 3.8 and section 3.9) extrapolating progression-free and overall survival directly from HER2CLIMB data ('within-trial' approach; see section 3.11) assuming different pre-progression utility values for tucatinib and its comparators (see section 3.13) justifying differences in post-progression utility values for tucatinib and its comparators (see section 3.14) adjusting utility values for ageing including drug wastage for trastuzumab and capecitabine (see section 3.16).However, the committee noted that the company's updated base case was not fully aligned with its preferences and instead considered ERG scenarios in its decision making that: used HER2CLIMB data to derive a treatment-modifying effect for tucatinib combination (see section 3.9) assumed 100% subcutaneous administration of trastuzumab (see section 3.15) assumed different post-progression utility values for tucatinib combination or assumed the same post-progression utility values for tucatinib combination (see section 3.14).Taking into account all of the confidential discounts, the committee concluded that, compared with chemotherapy, the cost-effectiveness estimates for tucatinib combination are likely to be within the range that NICE considers a cost-effective use of NHS resources. # Innovation ## Tucatinib has a novel mechanism of action and not all of its benefits are captured in the model The company and the clinical and patient experts considered tucatinib combination to be innovative. They explained this is because of its improved efficacy and tolerability in people with HER2‑positive metastatic breast cancer, including those with brain metastases, which are common at this stage of disease. The committee agreed that tucatinib combination has significant potential benefits. It acknowledged that not all of the potential benefits in relation to its effect on brain metastases were captured in the analyses (see section 3.9). # Conclusion ## Tucatinib with trastuzumab and capecitabine is recommended for routine use Having concluded that tucatinib combination is likely to be a cost-effective use of NHS resources, the committee recommended it for routine use.	{'Recommendations': "Tucatinib with trastuzumab and capecitabine is recommended, within its marketing authorisation, as an option for treating HER2‑positive locally advanced or metastatic breast cancer in adults after 2 or more anti‑HER2 treatment therapies, only if the company provides tucatinib according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nCurrent treatment for HER2‑positive locally advanced or metastatic breast cancer after 2 or more anti‑HER2 regimens is chemotherapy. Tucatinib with trastuzumab and capecitabine (tucatinib combination) is another anti‑HER2 therapy that could be used after 2 or more anti‑HER2 regimens. Trastuzumab can be given subcutaneously or intravenously, but the subcutaneous injection is easier to administer.\n\nClinical trial evidence shows that tucatinib combination increases the time people have before their cancer gets worse and how long they live compared with trastuzumab with capecitabine. But trastuzumab with capecitabine is not standard care in the NHS. Comparing tucatinib combination indirectly with chemotherapy suggests it may increase the time people have before their cancer gets worse and how long they live. It is likely that tucatinib combination improves people's quality of life before and after their cancer gets worse compared with chemotherapy.\n\nThe economic model does not take into account all of the benefits of tucatinib combination, particularly for people with brain metastases. Taking this into account, the cost-effectiveness estimates for tucatinib combination are likely to be within what NICE normally considers an acceptable use of NHS resources. So, tucatinib combination is recommended.", 'Information about tucatinib': "# Marketing authorisation indication\n\nTucatinib (TUKYSA, Seagen UK) has a marketing authorisation for use 'in combination with trastuzumab and capecitabine for the treatment of adult patients with HER2-positive locally advanced or metastatic breast cancer who have received at least 2 prior anti-HER2 treatment regimens'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for tucatinib.\n\n# Price\n\nThe list price is £5,636.84 per 84 pack of 150 mg film-coated tablets (excluding VAT; BNF online accessed February 2022). The average cost of a course of combination treatment at list price is £7,016.91 for the loading dose and £6,677.14 for the following cycles (company submission).\n\nThe company has a commercial arrangement. This makes tucatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Seagen UK, a review of this submission by the evidence review group (ERG), responses from stakeholders and comments on the first appraisal consultation document. See the committee papers for full details of the evidence.\n\nThe committee discussed the following issues.\n\n# Clinical need and treatment pathway\n\n## HER2-positive breast cancer has a high disease burden\n\nSome breast cancer cells have higher levels of a protein called HER2 on their surface, which stimulates them to grow. This is known as HER2‑positive breast cancer. Around 1\xa0in 5\xa0breast cancers are HER2‑positive. Patient experts explained that being diagnosed with locally advanced or metastatic breast cancer is extremely difficult for people and their family and friends. It can cause considerable anxiety and fear, with the uncertainty being the hardest part for many people. These feelings can negatively affect mental health. People with metastatic breast cancer must organise their lives around hospital appointments, which constrains their everyday activities. Brain metastases may develop in up to half of people with HER2‑positive cancer, which negatively affects people's prognosis and quality of life. The patient experts explained they were not able to drive or work, and lost their independence. The committee concluded that there is a high disease burden for people with HER2‑positive metastatic breast cancer, especially for those with brain metastases.\n\n## There is a need for anti-HER2 therapies after second-line treatment, especially for people with brain metastases\n\nThere is no cure for metastatic breast cancer. Treatment aims to stop progression of the disease, extend life, and maintain or improve quality of life for as long as possible. Treatment is continued for as long as it works. First-line treatment of HER2‑positive metastatic breast cancer includes the anti‑HER2 therapies pertuzumab with trastuzumab and docetaxel, or trastuzumab with paclitaxel (see NICE's technology appraisal guidance on pertuzumab with trastuzumab and docetaxel for treating HER2-positive breast cancer and trastuzumab for treating advanced breast cancer). Trastuzumab emtansine is an anti‑HER2 therapy used at second line (see NICE's technology appraisal guidance on trastuzumab emtansine for treating HER2-positive advanced breast cancer after trastuzumab and a taxane; from now referred to as TA458). Clinical experts explained that HER2‑positive metastatic breast cancer that has progressed after 2 or more anti‑HER2 regimens has a high symptom burden and is resistant to previous lines of therapy. The committee noted that, although some NHS trusts may offer third-line anti‑HER2 therapy, it is not available across the NHS and cannot be considered standard care. Trastuzumab deruxtecan is only available through the Cancer Drugs Fund so is not considered standard care (see NICE's technology appraisal guidance on trastuzumab deruxtecan for treating HER2-positive unresectable or metastatic breast cancer after 2 or more anti-HER2 therapies; from now referred to as TA704). Instead, standard care for people whose disease has progressed on or after 2 anti‑HER2 therapies is non-targeted chemotherapy, including capecitabine, vinorelbine or eribulin (see NICE's guideline on advanced breast cancer: diagnosis and treatment [from now referred to as CG81] and NICE's technology appraisal guidance on eribulin for treating locally advanced or metastatic breast cancer after 2 or more chemotherapy regimens, from now referred to as TA423). Brain metastases can be treated with stereotactic radiosurgery or radiotherapy (see NICE's guideline on brain tumours and metastases in over 16s). The clinical experts explained that there is a limit to the number of these treatments, and most people cannot have more than 2\xa0courses of radiotherapy because of its neurological toxicity. Currently there are no further treatment options that target brain metastases because most chemotherapy treatments have very limited capacity to cross from the blood into the brain. The committee concluded that there is a high unmet need for anti‑HER2 treatment after second-line anti-HER2 treatment. This is particularly important for the significant proportion of people who have brain metastases, because tucatinib can cross an intact blood-brain barrier and treat brain metastases.\n\n## The relevant comparators are capecitabine, vinorelbine and eribulin\n\nIn its initial submission, the company used eribulin as its base-case comparator. It stated that eribulin is the only third-line treatment approved by NICE for HER2‑positive locally advanced or metastatic breast cancer and has clinical equivalence to capecitabine and vinorelbine. The ERG noted that CG81 recommends that people may also have treatment with other non‑HER2‑targeted chemotherapies such as capecitabine or vinorelbine. The clinical experts confirmed that current NHS third-line standard care is non-targeted chemotherapy, including capecitabine, vinorelbine or eribulin. The clinical experts explained that although some people have trastuzumab with capecitabine, there is wide regional variation in its availability. As it is not available to all patients in the NHS, the committee agreed that trastuzumab with capecitabine is not a relevant comparator. The committee concluded that the relevant comparators for tucatinib with trastuzumab and capecitabine (from now referred to as tucatinib combination) are capecitabine, vinorelbine and eribulin.\n\n# Clinical evidence\n\n## The HER2CLIMB population is generalisable to UK clinical practice\n\nThe clinical evidence was based on HER2CLIMB, a randomised, double-blind, placebo-controlled, active comparator trial for HER2‑positive locally advanced or metastatic breast cancer previously treated with trastuzumab, pertuzumab and trastuzumab emtansine. Approximately 50% of people in HER2CLIMB had brain metastases. The clinical experts explained that HER2CLIMB represents patients in the NHS in terms of characteristics and previous treatment, including the proportion of people who will go on to develop brain metastases. The committee concluded that the population in HER2CLIMB was generalisable to the eligible population in clinical practice in the UK.\n\n## Tucatinib combination is more effective than trastuzumab with capecitabine, but this comparison does not reflect NHS practice\n\nHER2CLIMB assessed tucatinib combination compared with placebo plus trastuzumab and capecitabine (from now referred to as placebo combination). However, trastuzumab with capecitabine is not used in NHS practice (see section 3.3). People who had tucatinib combination had a median progression-free survival of 7.8\xa0months compared with 5.6\xa0months for people who had placebo combination. The hazard ratio for disease progression or death was 0.54 (95% confidence interval [CI], 0.42 to 0.71; p<0.001). People who had tucatinib combination had a median overall survival of 21.9\xa0months compared with 17.4\xa0months for people who had placebo combination. The hazard ratio for death was 0.66 (95% CI, 0.50 to 0.88; p=0.005). An improvement in progression-free and overall survival was observed in people with and without brain metastases. The clinical experts explained that this is because, unlike existing treatments, tucatinib is a small molecule that can pass through an intact blood-brain barrier. The clinical experts also explained that the clinical data in the company submission was supported by some longer follow-up data from the trial, which was presented at the American Society of Clinical Oncology annual meeting. The committee concluded that tucatinib combination is more effective than trastuzumab with capecitabine, but that this comparison does not reflect NHS practice. The committee also noted that the impact on brain metastases is important because brain metastases are associated with a poor prognosis and reduced quality of life (see section 3.1 and section 3.2).\n\n# Indirect treatment comparison\n\n## Results of the network meta-analysis are uncertain because of heterogeneity across trials\n\nThere was no head-to-head evidence comparing tucatinib combination against the relevant comparators, capecitabine, vinorelbine or eribulin (see section 3.3). Therefore, the company did a network meta-analysis to allow for an indirect treatment comparison. The results showed increased progression-free and overall survival for tucatinib combination compared with other treatments (the exact numbers are academic in confidence and cannot be reported here). However, the ERG explained that these results are uncertain because there were differences between patient populations in the trials included. The HER2CLIMB trial included people with and without brain metastases. Approximately 29% had active brain metastases (that is, either treated and progressing, or untreated) and 19% had stable brain metastases. None of the comparator trials included people with active brain metastases. All but one included people with stable or inactive brain metastases, but the proportion was usually not reported or was lower than in HER2CLIMB (see section 3.8 and section 3.9 for further discussion of brain metastases). Other differences between patient populations were the number of previous therapies, prior anti‑HER2 treatment, HER2 positivity status, Eastern Cooperative Oncology Group performance status and family background. The committee concluded that tucatinib is likely to improve clinical outcomes relative to eribulin, capecitabine and vinorelbine, but the size of the effect is uncertain. This is because there was clinical heterogeneity in several areas, particularly that people with active brain metastases were included in the HER2CLIMB trial but not in the other trials.\n\n## A random effects model is appropriate because of heterogeneity in the network, but does not account for systematic differences between trials\n\nIn its initial submission, the company used a fixed effects model for the network meta-analysis. This was because random effects modelling had limitations such as convergence issues and a higher degree of uncertainty. The ERG used a random effects model, explaining that it better accounted for heterogeneity in the network meta-analysis and is preferred to fixed effects modelling, despite its limitations. The company agreed with the ERG's approach in its response to consultation and updated its base case accordingly. The committee noted that the results from using the 2\xa0methods were similar, although the random effects model gave wider confidence intervals. The committee concluded that the random effects methodology was more appropriate because of heterogeneity in the network, and acknowledged it was used by the company in its updated base case. However, it noted that using a random effects model did not account for any systematic bias in the network related to differences in the proportions of people with brain metastases.\n\n## Network meta-analysis results should be adjusted for a treatment-modifying effect of brain metastases\n\nThe clinical experts explained that people with brain metastases have a poorer prognosis than those without. The committee noted that an anchored indirect treatment comparison can account for differences in prognostic factors between trials, but only if they have no effect on relative treatment outcomes (that is, they are not treatment effect modifiers). The clinical experts explained that tucatinib is the only treatment shown to cross the blood-brain barrier with demonstrated activity in brain metastases. But they highlighted that the impact of other treatment options on brain metastases is complex. Although comparator drugs generally cannot cross an intact blood-brain barrier, small amounts can cross when the barrier is compromised, for example, after whole-brain radiation therapy. The clinical experts also noted that good control of disease and metastases in other parts of the body may delay the time to developing brain metastases or them reoccurring. This means that treatments that are more effective in controlling other metastases, such as trastuzumab with capecitabine, are also believed to be more effective for people with brain metastases compared with single-agent non-targeted chemotherapy. They also noted that lapatinib with capecitabine (not a relevant comparator but included in the network) was shown to have at least some activity for brain metastases. The committee understood that the network meta-analysis results may be biased because the presence of brain metastases may affect how well comparator treatments work for people with breast cancer. That is, had people with active brain metastases been included in the comparator trials, the outcomes would be expected to be worse. In its response to consultation, the company presented the results of a literature review suggesting that the trastuzumab component alone in both arms of the HER2CLIMB trial may give a survival benefit in people with brain metastases compared with no treatment or non‑HER2‑targeted therapy. Therefore, the non-tucatinib control arm in the trial may itself have had better outcomes than the 3\xa0individual non‑HER2‑targeted therapies considered as comparators in this appraisal. However, the company acknowledged this represents a naive comparison between different populations in different studies. The committee concluded that the network meta-analysis results could be adjusted for a treatment-modifying effect of brain metastases. It noted that this analysis is still likely to be highly uncertain, but nevertheless useful for decision making (see section 3.9).\n\n## Adjustment based on HER2CLIMB data is preferred, but may be conservative\n\nThe company used 2\xa0approaches to estimate how much worse outcomes would have been if the same proportion of people with brain metastases as in HER2CLIMB had been included in the comparator monotherapy trials.\n\nIn its preferred approach, the company asked 10\xa0clinicians to estimate overall survival at 1, 2, 3 and 5\xa0years for single-agent chemotherapies if their respective trials had included the same proportion of people with brain metastases as HER2CLIMB. These estimates were lower than predicted by the ERG model (see section 3.11). Comparing the 2\xa0sets of estimates, the company calculated by how much the network meta-analysis results would need to be adjusted to align with the survival predictions given by clinicians.\n\nIn the alternative approach, the company used individual patient data from HER2CLIMB to estimate a treatment-modifying effect of brain metastases.The ERG noted that the company's preferred approach (using clinician estimates) resulted in an upward kink in the survival estimates at year\xa02, which was unrealistic. It preferred the alternative, data-driven approach, using HER2CLIMB data. The company explained that the upward kink in survival estimates was because it relied on clinician predictions at specific timepoints, without smoothing out between these timepoints. However, it noted that if it had done so, the cost-effectiveness estimates would decrease slightly. The company explained that the approach using the HER2CLIMB data did not capture any additional treatment effect from HER2‑targeted therapy (trastuzumab) in the placebo arm of the trial. The ERG recognised that its approach may be conservative. The committee noted that neither approach was robust. There was uncertainty about how much the comparator arms should be adjusted to account for the discrepancy in the proportion of people with brain metastases. However, despite its limitations, the committee's preference was for the HER2CLIMB data-driven approach, over the clinician's estimations. It concluded that this approach did not account for any benefit from trastuzumab and may be conservative, and acknowledged that the true cost-effectiveness estimates are likely to be lower than those estimated using the data-driven approach.\n\n# Cost-effectiveness evidence\n\n## The company's economic model is suitable for decision making\n\nThe company submitted a partitioned survival model to estimate the cost effectiveness of tucatinib combination compared with eribulin, capecitabine and vinorelbine. It had 3\xa0health states: progression-free, progressed, and death. The committee considered that the partitioned survival model is a standard approach to estimate the cost effectiveness of cancer drugs and is suitable for decision making.\n\n## Directly extrapolating HER2CLIMB data is most appropriate for estimating progression-free and overall survival for tucatinib and the comparators\n\nIn its initial submission, the company chose lapatinib with capecitabine as a reference treatment to model progression-free and overall survival, because this was the most commonly used treatment in the network meta-analysis. It explained that lapatinib with capecitabine data was generated using an average of the evidence in the network. It used fractional polynomial curves to extrapolate survival data for the reference arm. It then used hazard ratios from its network meta-analysis to estimate survival for other treatments. The ERG explained that the company approach resulted in estimated survival data for tucatinib combination that had a poor visual fit to data from the HER2CLIMB trial, particularly for overall survival. Instead, it preferred to fit survival curves directly to the HER2CLIMB data using trastuzumab with capecitabine as the reference treatment. It chose the Weibull curve because it provided better visual fit and the best statistical fit. The company explained the ERG's approach created bias against tucatinib because HER2CLIMB included more people with brain metastases than the comparator trials (see section 3.6), and because these people have poorer outcomes than people without brain metastases (see section 3.8). The committee noted that because the HER2CLIMB population was representative of that in clinical practice (see section 3.4), while the populations of other trials were not, it should be used to model survival that would be expected in NHS practice. It also noted that lapatinib with capecitabine is not a relevant comparator in this appraisal (see section 3.3). The committee agreed that the curves fitted to the HER2CLIMB data better fitted the outcomes observed in the trial and more closely matched the clinical expert estimates of progression-free survival and overall survival. However, it acknowledged that this did not address the underlying issues with the network meta-analysis (see sections 3.6 to 3.9). In its response to consultation, the company agreed with the ERG approach. It updated its base case to directly extrapolate HER2CLIMB data for progression-free and overall survival for trastuzumab with capecitabine. It applied hazard ratios from its network meta-analysis, adjusted for the treatment-modifying effect of brain metastases, to estimate survival for the other treatments. The committee acknowledged that the revised company approach aligned with its preference to directly extrapolate survival data from the HER2CLIMB trial.\n\n## The subgroup analyses have methodological limitations and are not appropriate for decision making\n\nThe company did not model the cost effectiveness of tucatinib combination relative to its comparators separately for people with and without brain metastases because there was limited evidence on the efficacy of comparators in people with brain metastases. The ERG agreed that there was a lack of evidence for the comparators in people with brain metastases. The committee noted that the subgroup of people without brain metastases from HER2CLIMB better corresponded to the patient populations in the other trials included in the network meta-analysis (see section 3.6). It considered that modelling survival for tucatinib combination and its comparators separately for people with and without brain metastases could help to better understand the uncertainty in the cost effectiveness of tucatinib. This is because the presence of brain metastases may be a prognostic factor and have a treatment-modifying effect. So, the shape and extrapolation of survival curves would be likely to differ for people with and without brain metastases (see sections 3.6 to 3.9). In response to consultation, the company did a subgroup analysis for people with brain metastases, by directly extrapolating progression-free and overall survival data from the corresponding HER2CLIMB subgroup. It stated that this analysis showed that tucatinib combination is more cost effective in people with brain metastases than in those without brain metastases. However, it cautioned that the HER2CLIMB trial was not powered to show a significant benefit in overall survival in subgroups. The ERG noted that the company did not provide sufficient information on how the analysis was done and was unable to replicate the company's results. In particular, the company did not justify its selection of survival extrapolation curves, nor did it explore alternative survival extrapolations, so it was unclear if the method it chose was appropriate. The ERG ran exploratory analyses using the same assumptions as the company, and the results were generally aligned with the company estimates. The company further stated that it was not able to do subgroup analyses for people without brain metastases because of time constraints. Instead, it used a weighted average approach to estimate cost effectiveness in this subgroup. The ERG explained these estimates were not accurate because the survival curves were likely to differ between the 2\xa0subgroups, which was not explored. It also explained that incremental cost-effectiveness ratios (ICERs) are ratios and cannot be directly used to estimate weighted averages. Instead, weighted averages of the total costs and total quality-adjusted life years would need to be estimated and used to calculate the ICER for the non-brain-metastases subgroup. It also noted that the results did not account for the cost of screening people for brain metastases. The committee concluded that the subgroup analyses had methodological limitations and were not described in sufficient detail for adequate scrutiny. Therefore, it concluded that the subgroup analyses were not appropriate for decision making.\n\n## Differences in health state utilities before progression are plausible, but the exact values are uncertain\n\nFor tucatinib combination, the company used EQ‑5D‑5L health-related quality of life data collected in HER2CLIMB, mapped to the EQ‑5D‑3L with UK preference weighting. Utilities for the comparator therapies were from TA423. This resulted in higher utility values for tucatinib combination compared with comparators in both pre- and post-progression health states. The company explained that tucatinib has better efficacy and safety profiles than eribulin or vinorelbine. It noted that in TA423, eribulin had higher pre-progression utilities than other single-agent chemotherapies. The ERG explained the company approach was inappropriate because the differences in utilities between tucatinib and comparators were not based on comparative evidence. It preferred to use the same utility values for all treatments for each health state, and to derive them all from HER2CLIMB data. The ERG noted that in the HER2CLIMB trial, there was no difference in utility values between the 2\xa0trial arms. The clinical experts explained that the safety profile of tucatinib is good, but it is difficult to separate the effects on quality of life of disease progression and toxicity. The clinical experts also noted that disease control could support different pre-progression utility values because treatments offer different levels of overall response rate. The committee concluded that different pre-progression utility values are plausible, but noted the values used by the company were not evidence based, so were uncertain.\n\n## Differences in health state utilities after progression are plausible, but their extent is probably overestimated\n\nIn addition to the limitations of the company's approach highlighted in section 3.13, the ERG explained that the utility value used by the company was not accepted by the TA423 committee because it was too low. In response to consultation, the company corrected its post-progression utility value to align with the value the committee agreed on in TA423. It also provided a literature review and results of a survey with clinicians to support differences in post-progression utilities between tucatinib combination, HER2‑directed therapies, and standard single-agent chemotherapy. The ERG explained that the company's justification was reasonable, but it still had concerns about using different sources for post-progression utilities for different treatments. It noted that this resulted in large differences in post-progression utilities for tucatinib combination and the comparators, which may have overestimated the benefit of tucatinib combination. The clinical experts explained that:\n\nBrain metastases affect people's quality of life to a greater extent than metastases to other organs. So, it is likely that if it takes longer for the disease to progress because of brain metastases, someone's quality of life after progression will be better than if the disease had progressed quickly.\n\nPeople with disease that is better controlled would have better quality of life before and after progression than those with disease that is less well controlled. This is because the decline in quality of life related to progression will start from a higher level than in people with disease that is less well controlled and with lower quality of life before progression.\n\nSome toxic effects of chemotherapy can be long lasting and affect a person's quality of life after progression.The committee noted that:\n\nDifferences in quality of life after progression between tucatinib combination and comparators were plausible. However, it noted that this difference may decrease once people's disease (and therefore quality of life) deteriorates further with time after progression on tucatinib combination.\n\nThe toxicity of capecitabine on its own is expected to be similar or lower than the toxicity of tucatinib combination. Therefore, differences in toxicity may not explain the large difference in utilities after disease progression between capecitabine and tucatinib combination.\n\nThe company's approach was not methodologically robust because it used utility values from 2\xa0different sources: the HER2CLIMB trial for tucatinib combination and TA423 for the comparators, in a 'naive comparison', that is, without adjusting for any differences between populations in these sources that might have affected the utility values. It also noted that the value from TA423 was based on the midpoint of 2\xa0utility estimates from 2\xa0different studies. Therefore, the results from the company's approach were uncertain.\n\nThe company's approach may overestimate the extent of difference in post-progression utilities between tucatinib and comparators, so it may overestimate the benefit of tucatinib combination.\n\nThe alternative approach of assuming equal post-progression utility after tucatinib and single-agent chemotherapy is most likely pessimistic.The committee concluded that some differences in post-progression health state utilities are plausible, but uncertain. Although the ERG incorporated the company's revised utilities in its base case, the committee remained concerned that if the difference in post-progression utility was overestimated, the cost-effectiveness estimates would be slightly higher than those estimated by the company. It noted that in future it would prefer evidence-based utilities and additional scenarios to be explored.\n\n## Standard NHS practice is subcutaneous trastuzumab\n\nIn HER2CLIMB, trastuzumab (as part of tucatinib combination) was administered either intravenously or subcutaneously, as allowed for in tucatinib's summary of product characteristics. But the initial company model assumed only intravenous administration of trastuzumab. The clinical experts explained that intravenous trastuzumab is no longer standard NHS practice. The clinical and patient experts explained that subcutaneous administration is preferred because people can self-administer, avoiding unnecessary hospital visits. Both the clinical and patient experts explained that if subcutaneous administration was not possible, they would accept intravenous administration if it meant people could have tucatinib combination. In its response to consultation, the company presented scenario analyses assuming different levels of subcutaneous trastuzumab usage. The ERG provided an additional scenario analysis assuming 100% use of subcutaneous trastuzumab. The Cancer Drugs Fund clinical lead explained that over 90% of patients have trastuzumab subcutaneously in the NHS. Some people may choose to have intravenous trastuzumab if subcutaneous administration is not appropriate for them. He also noted that chemotherapy units have capacity issues with intravenous administration. The clinical experts noted that there are additional benefits from subcutaneous administration that have not been captured in the current modelling, such as fewer hospital visits, and convenience and quality-of-life benefits for patients. Fewer hospital visits may also help reduce COVID‑19 transmission. The committee concluded that subcutaneous trastuzumab is standard care in the NHS and could have unaccounted-for benefits for patients and service delivery.\n\n## Drug wastage should be included in the analysis\n\nIn its initial submission, the company did not include drug wastage for intravenous trastuzumab in its base case because it is packaged in multi-use vials. The ERG preferred to include this because some wastage is expected in clinical practice. It noted this has a very small effect on overall costs and the cost-effectiveness estimates. It also noted that this applied to intravenous administration only and was not relevant for analyses assuming subcutaneous administration of trastuzumab. The company agreed with the ERG in its response to consultation and updated its base case accordingly. The committee concluded that drug wastage should be included in the analysis and acknowledged this was done appropriately by the company in its revised base case.\n\n# End of life\n\n## Tucatinib combination meets the end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The clinical experts and the ERG agreed that the life expectancy for people with HER2‑positive locally advanced or metastatic breast cancer having third-line treatment is less than 24\xa0months. They also agreed that the gain in life expectancy with tucatinib combination is expected to be greater than 3\xa0months. The committee also noted that the end of life criteria were accepted in TA423 and TA704 in a third-line setting, and in TA458 in a second-line setting. The committee concluded that tucatinib meets the end of life criteria.\n\n# Cost-effectiveness results\n\n## Tucatinib with trastuzumab and capecitabine is likely to be cost effective\n\nBecause of confidential commercial arrangements for tucatinib, trastuzumab, eribulin and post-progression therapies, the ICERs cannot be reported here. The company addressed a number of the committee's concerns in its response to consultation, including:\n\nusing a random effects network meta-analysis (see section 3.7)\n\nexploring a treatment-modifying effect of brain metastases (see section 3.8 and section 3.9)\n\nextrapolating progression-free and overall survival directly from HER2CLIMB data ('within-trial' approach; see section 3.11)\n\nassuming different pre-progression utility values for tucatinib and its comparators (see section 3.13)\n\njustifying differences in post-progression utility values for tucatinib and its comparators (see section 3.14)\n\nadjusting utility values for ageing\n\nincluding drug wastage for trastuzumab and capecitabine (see section 3.16).However, the committee noted that the company's updated base case was not fully aligned with its preferences and instead considered ERG scenarios in its decision making that:\n\nused HER2CLIMB data to derive a treatment-modifying effect for tucatinib combination (see section 3.9)\n\nassumed 100% subcutaneous administration of trastuzumab (see section 3.15)\n\nassumed different post-progression utility values for tucatinib combination or assumed the same post-progression utility values for tucatinib combination (see section 3.14).Taking into account all of the confidential discounts, the committee concluded that, compared with chemotherapy, the cost-effectiveness estimates for tucatinib combination are likely to be within the range that NICE considers a cost-effective use of NHS resources.\n\n# Innovation\n\n## Tucatinib has a novel mechanism of action and not all of its benefits are captured in the model\n\nThe company and the clinical and patient experts considered tucatinib combination to be innovative. They explained this is because of its improved efficacy and tolerability in people with HER2‑positive metastatic breast cancer, including those with brain metastases, which are common at this stage of disease. The committee agreed that tucatinib combination has significant potential benefits. It acknowledged that not all of the potential benefits in relation to its effect on brain metastases were captured in the analyses (see section 3.9).\n\n# Conclusion\n\n## Tucatinib with trastuzumab and capecitabine is recommended for routine use\n\nHaving concluded that tucatinib combination is likely to be a cost-effective use of NHS resources, the committee recommended it for routine use."}	https://www.nice.org.uk/guidance/ta786	Evidence-based recommendations on tucatinib (TUKYSA) for HER2‑positive locally advanced or metastatic breast cancer in adults after 2 or more anti‑HER2 treatment therapies.
ef5403cb6840a3cf74eb3645092079ef84b3589b	nice	Venetoclax with low dose cytarabine for untreated acute myeloid leukaemia when intensive chemotherapy is unsuitable	Venetoclax with low dose cytarabine for untreated acute myeloid leukaemia when intensive chemotherapy is unsuitable Evidence-based recommendations on venetoclax (Venclyxto) with low dose cytarabine for untreated acute myeloid leukaemia in adults when intensive chemotherapy is unsuitable. # Recommendations Venetoclax with low dose cytarabine is recommended as an option for untreated acute myeloid leukaemia in adults when intensive chemotherapy is unsuitable, only if: they have over 30% bone marrow blasts the company provides venetoclax according to the commercial arrangement. This is not intended to affect treatment with venetoclax with low dose cytarabine that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations When intensive chemotherapy is unsuitable, treatment for untreated acute myeloid leukaemia is usually azacitidine or low dose cytarabine. The clinical trial evidence shows that people with untreated acute myeloid leukaemia with over 30% bone marrow blasts (from here, blasts) having venetoclax plus low dose cytarabine live longer than people having low dose cytarabine alone. The company did not submit any evidence for the 20% to 30% blast group. Venetoclax plus low dose cytarabine meets NICE's criteria for a life-extending treatment at the end of life. The likely cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources. Therefore, for people with untreated acute myeloid leukaemia with over 30% blasts, venetoclax plus low dose cytarabine is recommended.# Information about venetoclax # Marketing authorisation indication Venetoclax (Venclyxto, AbbVie) in combination with low dose cytarabine is indicated for 'the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for venetoclax. # Price The cost of venetoclax is £299.34 for 7×100‑mg tablets (excluding VAT; BNF online accessed September 2021). The cost of cytarabine is £6.29 per 1‑g/10‑ml vial (excluding VAT; electronic market information tool online, accessed November 2021). Costs may vary in different settings because of negotiated procurement discounts. The company has a commercial arrangement. This makes venetoclax available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that: The general population mortality adjustment should be removed from the transition to the progression/relapse health state in the model (issue 2, see ERG report, section 4.2.6). The company's updated approach to modelling time to treatment discontinuation is acceptable (issue 3, see ERG report, section 4.2.6). It is acceptable in this case for adverse event data in the model to be sourced from a separate study to the VIALE trials, because it is unlikely to have a big impact on the cost-effectiveness results (issue 4, see ERG report, section 4.2.7). It is acceptable in this case for treatment-independent utility values in the model to be derived from pooled data from both VIALE‑A and VIALE‑C, because it is unlikely to have a big impact on the cost-effectiveness results (issue 4, see ERG report, section 4.2.7). Seven days' wastage for venetoclax should be included in the model to account for tablets that are prescribed but not used because of treatment discontinuation or death during a cycle (issue 6, see ERG report, section 4.2.8). The committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed issues 1, 5 and an additional issue identified at technical engagement, issue 7, which were outstanding after the technical engagement stage. # New treatment option ## People with acute myeloid leukaemia for whom intensive chemotherapy is unsuitable would welcome a new treatment option Intensive chemotherapy is unsuitable for about 40% of people with untreated acute myeloid leukaemia. This may be because of fitness status, age or presence of comorbidities. The patient expert explained that patients in this group feel that treatment options for them are very limited. They value increased survival as much as increased quality of life, and the possibility of long-term remission with venetoclax plus low dose cytarabine is appealing. Clinical experts also stated that there is a significant unmet need for new treatments for this population because outcomes with currently available treatments are poor. Venetoclax is an oral treatment that can be taken at home, so the time patients need to be in hospital might be significantly reduced. Patients would also appreciate being able to manage side effects at home when possible. The committee concluded that people with acute myeloid leukaemia for whom intensive chemotherapy is unsuitable would welcome a new treatment option. ## Venetoclax plus low dose cytarabine would be a valuable option Venetoclax is also available with azacitidine for people with acute myeloid leukaemia for whom intensive chemotherapy is unsuitable. The company stated that for people with acute myeloid leukaemia, whether to have venetoclax plus azacitidine or venetoclax plus low dose cytarabine would be an individual choice for patients and clinicians. The clinical experts stated that venetoclax plus low dose cytarabine may be preferrable for some people, such as those with NPM1 mutations or people who are older and more frail. They stated that low dose cytarabine was less toxic than azacitidine and could be administered at home. The committee concluded that venetoclax plus low dose cytarabine would be a valuable option for some people with acute myeloid leukaemia when intensive chemotherapy is unsuitable. # Comparators ## Splitting the trial population by blast cell count is necessary to compare venetoclax plus low dose cytarabine with the relevant comparator but increases uncertainty The evidence for venetoclax plus low dose cytarabine came from a randomised controlled trial, VIALE‑C (n=211), which compared venetoclax plus low dose cytarabine with low dose cytarabine alone in people with untreated acute myeloid leukaemia who could not have intensive chemotherapy because of age or comorbidities. The clinical experts considered that the population in the trial would be generalisable to people who would be eligible for venetoclax plus low dose cytarabine in England. In the NHS in England, when intensive chemotherapy is unsuitable, acute myeloid leukaemia is treated with either azacitidine or low dose cytarabine. NICE's technology appraisal guidance on azacitidine recommends azacitidine only for acute myeloid leukaemia with 20% to 30% bone marrow blasts (from here, blasts). In practice, this means that low dose cytarabine is used for acute myeloid leukaemia with over 30% blasts. Therefore, the company did a post-hoc subgroup analysis to split the trial population by blast count. It used the data from the subgroup with over 30% blasts to compare venetoclax plus low dose cytarabine with low dose cytarabine alone. The company did not submit any analyses of venetoclax plus low dose cytarabine for acute myeloid leukaemia with 20% to 30% blasts. The committee concluded that it was necessary to use the subgroup data to compare venetoclax plus low dose cytarabine with the relevant comparator in clinical practice in England, but that the subgroup analysis increased uncertainty in the results. # Clinical efficacy ## Venetoclax plus low dose cytarabine increases overall survival compared with low dose cytarabine alone The post-hoc subgroup analysis splitting the trial population by blast count showed that venetoclax plus low dose cytarabine statistically significantly increased overall survival compared with low dose cytarabine alone in the subgroup with over 30% blasts. The company considers the exact results to be academic in confidence, so they cannot be reported here. The committee concluded that venetoclax plus low dose cytarabine increases overall survival compared with low dose cytarabine alone. # Economic model ## The company's economic model included a cure health state The company presented a cohort-level state transition model to assess the cost effectiveness of venetoclax plus low dose cytarabine. The model included 5 health states: remission, non-remission, cure, progressive disease or relapse, and death. In the company's original model, patients having venetoclax who were alive after 2 years of being in the remission health state moved into the cure state. Patients having low dose cytarabine alone could not transition to the cure state. ## The evidence for including a cure state in the model is uncertain The company stated that the results from VIALE‑A (a separate trial comparing venetoclax plus azacitidine with azacitidine alone) showed that complete remission rates with venetoclax plus azacitidine were similar to those seen in patients over 60 receiving intensive chemotherapy, and that rates of sustained deep remission were higher with venetoclax plus azacitidine than with azacitidine alone. It argued that there was an established relationship between complete remission and long-term survival, and that it was therefore plausible to assume that some patients having venetoclax plus azacitidine, and venetoclax plus low dose cytarabine, could be considered cured. It cited clinical advice that the rate of relapse after 2 years in remission is low and commented that there was a plateau in the Kaplan–Meier curve for venetoclax plus azacitidine at 2 years. The ERG noted that there was a lack of long-term data to validate a cure assumption because the maximum follow up in VIALE‑A was 2.56 years. It highlighted that, historically, non-intensive treatments such as low dose cytarabine have not been considered curative in this population, and that the Kaplan–Meier curve was based on very few patients by 2 years. The clinical experts stated that it was plausible that there could be a proportion of patients who are cured after having venetoclax, but that it was difficult to specify a time frame and there was a lack of evidence to inform this. At technical engagement, a professional organisation highlighted a small study by Chyn Chua et al. (2021) comparing stopping venetoclax treatment while in remission with continuing it until relapse. It considered that the results suggested that venetoclax could be stopped after 2 years in remission without a negative impact on outcomes. However, the committee noted that in this study, a number of relapses occurred after 2 years. During the consultation on the appraisal consultation document for venetoclax plus azacitidine, the authors of the study commented that most of the late relapses were associated with new molecular or cytogenetic abnormalities, suggesting they were not relapses of the original disease. The company highlighted that a cure assumption had been included in NICE's technology appraisal guidance on gilteritinib for treating relapsed or refractory acute myeloid leukaemia. However, the committee noted that this appraisal was in a different population and that although the committee had accepted a cure assumption applied to all patients alive at between 2 and 3 years in the gilteritinib model, a substantial proportion of people in the trial had received a stem cell transplant. The committee also noted that the cure assumption in the gilteritinib model applied to both the gilteritinib and salvage chemotherapy arms, whereas in the venetoclax model it only applied to the venetoclax arm. The committee agreed that any cure state in the venetoclax model should have been applied to both arms. However, the ERG presented scenario analyses applying the cure state to the low dose cytarabine arm, and this only had a small impact on the cost-effectiveness results. After the first committee meeting, the company updated its base-case model so that people moved into the cure state after 3 years of being in remission, instead of 2 years. It also presented scenario analyses in which only a proportion of people in remission transitioned to the cure state. The rest remained in the remission state with a continuing disease-related risk of relapse and death. The ERG presented further scenario analyses with alternative proportions and noted that the cost-effectiveness results were not sensitive to the different proportions explored in these scenarios. The clinical experts explained that around 30% of people in this population have acute myeloid leukaemia with an NPM1, IDH1 or IDH2 mutation, and that these patients may be more likely to be cured. At the first committee meeting, the committee noted that cure fractions estimated from a mixture cure model may have been helpful to provide some basis for validating the proportion of patients remaining in the remission health state over time. After the first committee meeting, the company presented the proportion of people remaining in remission at various time points, based on removing the cure state and applying mixture cure models to separate transitions (from remission to relapse and from remission to death) to validate the proportion of the overall cohort who were in remission at different time points. The committee noted that it would have preferred to see the cure fraction reported from a mixture cure model fitted to the overall population. The committee noted that the company's evidence for a cure assumption related to venetoclax plus azacitidine and that it had not presented any evidence for a cure with venetoclax plus low dose cytarabine. The committee concluded that the evidence for including a cure state in the model was uncertain. ## Using the remission state utility value in the cure state does not affect the cost-effectiveness results In the cure health state, patients were assumed to have the same utility value as that of the general population. The clinical experts stated that most people would return to the same level of quality of life after treatment as could be expected in the general population, but that a small number would not. The committee did not consider it plausible that patients in the cure state would experience the same level of quality of life as the general population. However, after the first committee meeting, the company stated that because of the age of patients in the model at the point of cure, the age-adjusted general population utility was always lower than the remission health state utility. Therefore, using the remission utility value in the cure state, capped by general population utility, had no effect on the cost-effectiveness results. The committee accepted that using the remission state utility value in the cure state did not affect the cost-effectiveness results. ## The company's updated assumptions about the proportions of people having subsequent gilteritinib are acceptable In the company's original model, 3% of people in the venetoclax plus low dose cytarabine arm had gilteritinib after venetoclax plus low dose cytarabine, and all others who had subsequent treatment had hydroxycarbamide. The ERG suggested this proportion should be higher, based on clinical advice. At technical engagement, clinical experts and professional groups agreed that around 10% of people may have FLT3‑mutation-positive disease and be eligible for gilteritinib after venetoclax plus low dose cytarabine or low dose cytarabine alone. The company cited clinical advice that suggested more people who had venetoclax with low dose cytarabine would be able to have subsequent treatment with gilteritinib than people who had low dose cytarabine alone, because it was more likely their disease would go into complete remission. The company updated its base case to include 5% of people having gilteritinib after venetoclax plus low dose cytarabine and 3% having gilteritinib after low dose cytarabine. It also presented a scenario analysis showing that increasing the proportions to 15% after venetoclax plus low dose cytarabine and 10% after low dose cytarabine had a small impact on the cost-effectiveness results. The ERG's clinical expert considered that the company's updated base-case assumptions were plausible. The committee agreed that the company's updated base-case assumptions were acceptable to use in the model. ## The company's updated modelling of dose intensity reflects clinical practice The dose of venetoclax in the summary of product characteristics in VIALE‑C and in the company's model was 600 mg daily, after treatment initiation. The company applied a lower dose intensity to venetoclax in its model, which was the dose intensity seen in VIALE‑C. The company considers the exact dose intensity to be academic in confidence so it cannot be reported here. At technical engagement, clinical experts stated that in clinical practice in England, almost all patients with acute myeloid leukaemia would have concomitant treatment with azoles such as posaconazole as antifungal prophylaxis. Azoles are strong CYP3A inhibitors, which affect the metabolism of venetoclax and increase its plasma level. Therefore, in line with the summary of product characteristics advice on managing potential venetoclax interactions with CYP3A inhibitors, the dose of venetoclax used in clinical practice would be much lower than in the trial, usually 100 mg a day rather than 600 mg. The clinical experts also stated that they would often only give venetoclax for 14 days from the second cycle onwards, rather than 28 days, to limit toxicity. The company highlighted the summary of product characteristics for venetoclax, which notes that in most cases this should be considered once the person's disease is in remission. The committee agreed that the dose intensity in the NHS in England would likely be 16.7% of the full licensed dose for the first cycle, and 8.3% from cycle 2 onwards. After the first committee meeting, the company updated its model to use a dose intensity for venetoclax of 16.7% for the first cycle and 8.3% from cycle 2 onwards. It also presented a pharmacokinetic study that showed that a 100 mg dose of venetoclax given with a strong CYP3A inhibitor led to drug exposure between that of a 400 mg dose and the safe maximum dose of 1,200 mg per day. The company also presented a post-hoc analysis of VIALE‑A data showing that complete remission rates were similar when an adjusted dose was given with a CYP3A inhibitor, compared with the licensed dose and no CYP3A inhibitor. The committee concluded that the company's updated modelling was appropriate and reflected clinical practice. # End of life ## Venetoclax meets the criteria to be considered a life-extending treatment at the end of life The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Median overall survival in VIALE‑C for people having low dose cytarabine in the over 30% blast count group was under 24 months. The company considers the exact figure to be academic in confidence so it cannot be reported here. The mean undiscounted life years in the model were 0.84 years for the low dose cytarabine (over 30% blast count) arm. The committee agreed that the short life expectancy criterion was met. The increase in median overall survival from VIALE‑C for venetoclax plus low dose cytarabine compared with low dose cytarabine alone in the over 30% blast count group was over 3 months. The company considers the exact figure to be academic in confidence so it cannot be reported here. The mean incremental undiscounted life years in the model were more than 3 months across all scenarios for venetoclax plus low dose cytarabine compared with low dose cytarabine alone (over 30% blast count). The committee agreed that the extension to life criterion was met. It therefore concluded that venetoclax plus low dose cytarabine met the criteria to be considered a life-extending treatment at the end of life. # Cost-effectiveness results ## All the plausible ICERs presented are below £50,000 per QALY gained All analyses included the patient access scheme for venetoclax. After technical engagement, the company's base-case incremental cost-effectiveness ratio (ICER) was £36,995 per quality-adjusted life year (QALY) gained for venetoclax plus low dose cytarabine compared with low dose cytarabine alone in the over 30% blasts population. This included a cure point at 2 years. In its exploratory analyses, the ERG preferred to use alternative costs for adverse events in the model, to account for long-stay admissions. It also corrected an error in the cost of subsequent treatment. After the first committee meeting, the company presented a revised base case for venetoclax plus low dose cytarabine, which included: the ERG's correction and alternative costs for adverse events a cure state at 3 years instead of 2 (see section 3.6) the dose intensity of venetoclax that reflects clinical practice (see section 3.9).This resulted in an updated base-case ICER of £10,948 per QALY gained for venetoclax plus low dose cytarabine compared with low dose cytarabine alone in the over 30% blasts population. The company and ERG presented scenario analyses in which only a proportion of people who were in remission at 3 years were assumed to be cured. The committee noted that the ICER remained below £50,000 per QALY gained even when no patients in remission at 3 years were considered cured. When the ERG included the confidential discount for gilteritinib subsequent treatment in its analyses, the ICERs decreased slightly. Because of the confidentiality of this discount, the exact ICERs cannot be reported here. The committee concluded that all the plausible ICERs presented were below £50,000 per QALY gained. ## Venetoclax with low dose cytarabine is recommended for routine use in the NHS Because all of the plausible ICERs were within the range that NICE normally considers to be a cost-effective use of NHS resources for a life-extending treatment at the end of life, the committee recommended venetoclax plus low dose cytarabine as an option for untreated acute myeloid leukaemia with over 30% blasts in adults when intensive chemotherapy is unsuitable. Because the company did not submit any analyses for the 20% to 30% blast group (see section 3.3) the committee could not make any recommendations for this group. # Equality and innovation ## There are no equality issues relevant to the recommendations A committee member highlighted that venetoclax could provide an effective treatment option for older people who have not benefitted from other recent advances in treatment, and that anyone who cannot easily travel to a major hospital may particularly benefit from being able to take venetoclax at home. The committee considered these potential issues but noted that recommendations would apply to all patients, regardless of age or location. It concluded that no equality issues relevant to the recommendations had been identified. ## The benefits of venetoclax are captured in the cost-effectiveness analysis The company, professional organisations and clinical experts considered that venetoclax was innovative because it was a targeted therapy, was different to currently available therapies, led to increased overall survival and rates of complete and deep remissions, and decreased the need for blood transfusions. The committee agreed that these were important benefits of venetoclax, but concluded that it had not been presented with evidence of any additional benefits that were not captured in the QALY calculation.	{'Recommendations': "Venetoclax with low dose cytarabine is recommended as an option for untreated acute myeloid leukaemia in adults when intensive chemotherapy is unsuitable, only if:\n\nthey have over 30% bone marrow blasts\n\nthe company provides venetoclax according to the commercial arrangement.\n\nThis is not intended to affect treatment with venetoclax with low dose cytarabine that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nWhen intensive chemotherapy is unsuitable, treatment for untreated acute myeloid leukaemia is usually azacitidine or low dose cytarabine. The clinical trial evidence shows that people with untreated acute myeloid leukaemia with over 30% bone marrow blasts (from here, blasts) having venetoclax plus low dose cytarabine live longer than people having low dose cytarabine alone. The company did not submit any evidence for the 20% to 30% blast group.\n\nVenetoclax plus low dose cytarabine meets NICE's criteria for a life-extending treatment at the end of life. The likely cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources. Therefore, for people with untreated acute myeloid leukaemia with over 30% blasts, venetoclax plus low dose cytarabine is recommended.", 'Information about venetoclax': "# Marketing authorisation indication\n\nVenetoclax (Venclyxto, AbbVie) in combination with low dose cytarabine is indicated for 'the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for venetoclax.\n\n# Price\n\nThe cost of venetoclax is £299.34 for 7×100‑mg tablets (excluding VAT; BNF online accessed September\xa02021). The cost of cytarabine is £6.29 per 1‑g/10‑ml vial (excluding VAT; electronic market information tool online, accessed November\xa02021). Costs may vary in different settings because of negotiated procurement discounts.\n\nThe company has a commercial arrangement. This makes venetoclax available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nThe general population mortality adjustment should be removed from the transition to the progression/relapse health state in the model (issue\xa02, see ERG report, section\xa04.2.6).\n\nThe company's updated approach to modelling time to treatment discontinuation is acceptable (issue\xa03, see ERG report, section\xa04.2.6).\n\nIt is acceptable in this case for adverse event data in the model to be sourced from a separate study to the VIALE trials, because it is unlikely to have a big impact on the cost-effectiveness results (issue\xa04, see ERG report, section\xa04.2.7).\n\nIt is acceptable in this case for treatment-independent utility values in the model to be derived from pooled data from both VIALE‑A and VIALE‑C, because it is unlikely to have a big impact on the cost-effectiveness results (issue\xa04, see ERG report, section\xa04.2.7).\n\nSeven\xa0days' wastage for venetoclax should be included in the model to account for tablets that are prescribed but not used because of treatment discontinuation or death during a cycle (issue\xa06, see ERG report, section\xa04.2.8).\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed issues\xa01,\xa05 and an additional issue identified at technical engagement, issue\xa07, which were outstanding after the technical engagement stage.\n\n# New treatment option\n\n## People with acute myeloid leukaemia for whom intensive chemotherapy is unsuitable would welcome a new treatment option\n\nIntensive chemotherapy is unsuitable for about 40% of people with untreated acute myeloid leukaemia. This may be because of fitness status, age or presence of comorbidities. The patient expert explained that patients in this group feel that treatment options for them are very limited. They value increased survival as much as increased quality of life, and the possibility of long-term remission with venetoclax plus low dose cytarabine is appealing. Clinical experts also stated that there is a significant unmet need for new treatments for this population because outcomes with currently available treatments are poor. Venetoclax is an oral treatment that can be taken at home, so the time patients need to be in hospital might be significantly reduced. Patients would also appreciate being able to manage side effects at home when possible. The committee concluded that people with acute myeloid leukaemia for whom intensive chemotherapy is unsuitable would welcome a new treatment option.\n\n## Venetoclax plus low dose cytarabine would be a valuable option\n\nVenetoclax is also available with azacitidine for people with acute myeloid leukaemia for whom intensive chemotherapy is unsuitable. The company stated that for people with acute myeloid leukaemia, whether to have venetoclax plus azacitidine or venetoclax plus low dose cytarabine would be an individual choice for patients and clinicians. The clinical experts stated that venetoclax plus low dose cytarabine may be preferrable for some people, such as those with NPM1 mutations or people who are older and more frail. They stated that low dose cytarabine was less toxic than azacitidine and could be administered at home. The committee concluded that venetoclax plus low dose cytarabine would be a valuable option for some people with acute myeloid leukaemia when intensive chemotherapy is unsuitable.\n\n# Comparators\n\n## Splitting the trial population by blast cell count is necessary to compare venetoclax plus low dose cytarabine with the relevant comparator but increases uncertainty\n\nThe evidence for venetoclax plus low dose cytarabine came from a randomised controlled trial, VIALE‑C (n=211), which compared venetoclax plus low dose cytarabine with low dose cytarabine alone in people with untreated acute myeloid leukaemia who could not have intensive chemotherapy because of age or comorbidities. The clinical experts considered that the population in the trial would be generalisable to people who would be eligible for venetoclax plus low dose cytarabine in England. In the NHS in England, when intensive chemotherapy is unsuitable, acute myeloid leukaemia is treated with either azacitidine or low dose cytarabine. NICE's technology appraisal guidance on azacitidine recommends azacitidine only for acute myeloid leukaemia with 20% to 30% bone marrow blasts (from here, blasts). In practice, this means that low dose cytarabine is used for acute myeloid leukaemia with over 30% blasts. Therefore, the company did a post-hoc subgroup analysis to split the trial population by blast count. It used the data from the subgroup with over 30% blasts to compare venetoclax plus low dose cytarabine with low dose cytarabine alone. The company did not submit any analyses of venetoclax plus low dose cytarabine for acute myeloid leukaemia with 20%\xa0to 30% blasts. The committee concluded that it was necessary to use the subgroup data to compare venetoclax plus low dose cytarabine with the relevant comparator in clinical practice in England, but that the subgroup analysis increased uncertainty in the results.\n\n# Clinical efficacy\n\n## Venetoclax plus low dose cytarabine increases overall survival compared with low dose cytarabine alone\n\nThe post-hoc subgroup analysis splitting the trial population by blast count showed that venetoclax plus low dose cytarabine statistically significantly increased overall survival compared with low dose cytarabine alone in the subgroup with over 30% blasts. The company considers the exact results to be academic in confidence, so they cannot be reported here. The committee concluded that venetoclax plus low dose cytarabine increases overall survival compared with low dose cytarabine alone.\n\n# Economic model\n\n## The company's economic model included a cure health state\n\nThe company presented a cohort-level state transition model to assess the cost effectiveness of venetoclax plus low dose cytarabine. The model included 5\xa0health states: remission, non-remission, cure, progressive disease or relapse, and death. In the company's original model, patients having venetoclax who were alive after 2\xa0years of being in the remission health state moved into the cure state. Patients having low dose cytarabine alone could not transition to the cure state.\n\n## The evidence for including a cure state in the model is uncertain\n\nThe company stated that the results from VIALE‑A (a separate trial comparing venetoclax plus azacitidine with azacitidine alone) showed that complete remission rates with venetoclax plus azacitidine were similar to those seen in patients over\xa060 receiving intensive chemotherapy, and that rates of sustained deep remission were higher with venetoclax plus azacitidine than with azacitidine alone. It argued that there was an established relationship between complete remission and long-term survival, and that it was therefore plausible to assume that some patients having venetoclax plus azacitidine, and venetoclax plus low dose cytarabine, could be considered cured. It cited clinical advice that the rate of relapse after 2\xa0years in remission is low and commented that there was a plateau in the Kaplan–Meier curve for venetoclax plus azacitidine at 2\xa0years. The ERG noted that there was a lack of long-term data to validate a cure assumption because the maximum follow up in VIALE‑A was 2.56\xa0years. It highlighted that, historically, non-intensive treatments such as low dose cytarabine have not been considered curative in this population, and that the Kaplan–Meier curve was based on very few patients by 2\xa0years. The clinical experts stated that it was plausible that there could be a proportion of patients who are cured after having venetoclax, but that it was difficult to specify a time frame and there was a lack of evidence to inform this. At technical engagement, a professional organisation highlighted a small study by Chyn Chua et al. (2021) comparing stopping venetoclax treatment while in remission with continuing it until relapse. It considered that the results suggested that venetoclax could be stopped after 2\xa0years in remission without a negative impact on outcomes. However, the committee noted that in this study, a number of relapses occurred after 2\xa0years. During the consultation on the appraisal consultation document for venetoclax plus azacitidine, the authors of the study commented that most of the late relapses were associated with new molecular or cytogenetic abnormalities, suggesting they were not relapses of the original disease. The company highlighted that a cure assumption had been included in NICE's technology appraisal guidance on gilteritinib for treating relapsed or refractory acute myeloid leukaemia. However, the committee noted that this appraisal was in a different population and that although the committee had accepted a cure assumption applied to all patients alive at between 2 and 3\xa0years in the gilteritinib model, a substantial proportion of people in the trial had received a stem cell transplant. The committee also noted that the cure assumption in the gilteritinib model applied to both the gilteritinib and salvage chemotherapy arms, whereas in the venetoclax model it only applied to the venetoclax arm. The committee agreed that any cure state in the venetoclax model should have been applied to both arms. However, the ERG presented scenario analyses applying the cure state to the low dose cytarabine arm, and this only had a small impact on the cost-effectiveness results. After the first committee meeting, the company updated its base-case model so that people moved into the cure state after 3\xa0years of being in remission, instead of 2\xa0years. It also presented scenario analyses in which only a proportion of people in remission transitioned to the cure state. The rest remained in the remission state with a continuing disease-related risk of relapse and death. The ERG presented further scenario analyses with alternative proportions and noted that the cost-effectiveness results were not sensitive to the different proportions explored in these scenarios. The clinical experts explained that around 30% of people in this population have acute myeloid leukaemia with an NPM1, IDH1 or IDH2 mutation, and that these patients may be more likely to be cured. At the first committee meeting, the committee noted that cure fractions estimated from a mixture cure model may have been helpful to provide some basis for validating the proportion of patients remaining in the remission health state over time. After the first committee meeting, the company presented the proportion of people remaining in remission at various time points, based on removing the cure state and applying mixture cure models to separate transitions (from remission to relapse and from remission to death) to validate the proportion of the overall cohort who were in remission at different time points. The committee noted that it would have preferred to see the cure fraction reported from a mixture cure model fitted to the overall population. The committee noted that the company's evidence for a cure assumption related to venetoclax plus azacitidine and that it had not presented any evidence for a cure with venetoclax plus low dose cytarabine. The committee concluded that the evidence for including a cure state in the model was uncertain.\n\n## Using the remission state utility value in the cure state does not affect the cost-effectiveness results\n\nIn the cure health state, patients were assumed to have the same utility value as that of the general population. The clinical experts stated that most people would return to the same level of quality of life after treatment as could be expected in the general population, but that a small number would not. The committee did not consider it plausible that patients in the cure state would experience the same level of quality of life as the general population. However, after the first committee meeting, the company stated that because of the age of patients in the model at the point of cure, the age-adjusted general population utility was always lower than the remission health state utility. Therefore, using the remission utility value in the cure state, capped by general population utility, had no effect on the cost-effectiveness results. The committee accepted that using the remission state utility value in the cure state did not affect the cost-effectiveness results.\n\n## The company's updated assumptions about the proportions of people having subsequent gilteritinib are acceptable\n\nIn the company's original model, 3% of people in the venetoclax plus low dose cytarabine arm had gilteritinib after venetoclax plus low dose cytarabine, and all others who had subsequent treatment had hydroxycarbamide. The ERG suggested this proportion should be higher, based on clinical advice. At technical engagement, clinical experts and professional groups agreed that around 10% of people may have FLT3‑mutation-positive disease and be eligible for gilteritinib after venetoclax plus low dose cytarabine or low dose cytarabine alone. The company cited clinical advice that suggested more people who had venetoclax with low dose cytarabine would be able to have subsequent treatment with gilteritinib than people who had low dose cytarabine alone, because it was more likely their disease would go into complete remission. The company updated its base case to include 5% of people having gilteritinib after venetoclax plus low dose cytarabine and 3% having gilteritinib after low dose cytarabine. It also presented a scenario analysis showing that increasing the proportions to 15% after venetoclax plus low dose cytarabine and 10% after low dose cytarabine had a small impact on the cost-effectiveness results. The ERG's clinical expert considered that the company's updated base-case assumptions were plausible. The committee agreed that the company's updated base-case assumptions were acceptable to use in the model.\n\n## The company's updated modelling of dose intensity reflects clinical practice\n\nThe dose of venetoclax in the summary of product characteristics in VIALE‑C and in the company's model was 600\xa0mg daily, after treatment initiation. The company applied a lower dose intensity to venetoclax in its model, which was the dose intensity seen in VIALE‑C. The company considers the exact dose intensity to be academic in confidence so it cannot be reported here. At technical engagement, clinical experts stated that in clinical practice in England, almost all patients with acute myeloid leukaemia would have concomitant treatment with azoles such as posaconazole as antifungal prophylaxis. Azoles are strong CYP3A inhibitors, which affect the metabolism of venetoclax and increase its plasma level. Therefore, in line with the summary of product characteristics advice on managing potential venetoclax interactions with CYP3A inhibitors, the dose of venetoclax used in clinical practice would be much lower than in the trial, usually 100\xa0mg a day rather than 600\xa0mg. The clinical experts also stated that they would often only give venetoclax for 14\xa0days from the second cycle onwards, rather than 28\xa0days, to limit toxicity. The company highlighted the summary of product characteristics for venetoclax, which notes that in most cases this should be considered once the person's disease is in remission. The committee agreed that the dose intensity in the NHS in England would likely be 16.7% of the full licensed dose for the first cycle, and 8.3% from cycle\xa02 onwards. After the first committee meeting, the company updated its model to use a dose intensity for venetoclax of 16.7% for the first cycle and 8.3% from cycle\xa02 onwards. It also presented a pharmacokinetic study that showed that a 100\xa0mg dose of venetoclax given with a strong CYP3A inhibitor led to drug exposure between that of a 400\xa0mg dose and the safe maximum dose of 1,200\xa0mg per day. The company also presented a post-hoc analysis of VIALE‑A data showing that complete remission rates were similar when an adjusted dose was given with a CYP3A inhibitor, compared with the licensed dose and no CYP3A inhibitor. The committee concluded that the company's updated modelling was appropriate and reflected clinical practice.\n\n# End of life\n\n## Venetoclax meets the criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Median overall survival in VIALE‑C for people having low dose cytarabine in the over 30% blast count group was under 24\xa0months. The company considers the exact figure to be academic in confidence so it cannot be reported here. The mean undiscounted life\xa0years in the model were 0.84\xa0years for the low dose cytarabine (over 30% blast count) arm. The committee agreed that the short life expectancy criterion was met. The increase in median overall survival from VIALE‑C for venetoclax plus low dose cytarabine compared with low dose cytarabine alone in the over 30% blast count group was over 3\xa0months. The company considers the exact figure to be academic in confidence so it cannot be reported here. The mean incremental undiscounted life\xa0years in the model were more than 3\xa0months across all scenarios for venetoclax plus low dose cytarabine compared with low dose cytarabine alone (over 30% blast count). The committee agreed that the extension to life criterion was met. It therefore concluded that venetoclax plus low dose cytarabine met the criteria to be considered a life-extending treatment at the end of life.\n\n# Cost-effectiveness results\n\n## All the plausible ICERs presented are below £50,000 per QALY gained\n\nAll analyses included the patient access scheme for venetoclax. After technical engagement, the company's base-case incremental cost-effectiveness ratio (ICER) was £36,995 per quality-adjusted life\xa0year (QALY) gained for venetoclax plus low dose cytarabine compared with low dose cytarabine alone in the over 30% blasts population. This included a cure point at 2\xa0years. In its exploratory analyses, the ERG preferred to use alternative costs for adverse events in the model, to account for long-stay admissions. It also corrected an error in the cost of subsequent treatment. After the first committee meeting, the company presented a revised base case for venetoclax plus low dose cytarabine, which included:\n\nthe ERG's correction and alternative costs for adverse events\n\na cure state at 3\xa0years instead of 2 (see\xa0section\xa03.6)\n\nthe dose intensity of venetoclax that reflects clinical practice (see\xa0section\xa03.9).This resulted in an updated base-case ICER of £10,948 per QALY gained for venetoclax plus low dose cytarabine compared with low dose cytarabine alone in the over 30% blasts population. The company and ERG presented scenario analyses in which only a proportion of people who were in remission at 3\xa0years were assumed to be cured. The committee noted that the ICER remained below £50,000 per QALY gained even when no patients in remission at 3\xa0years were considered cured. When the ERG included the confidential discount for gilteritinib subsequent treatment in its analyses, the ICERs decreased slightly. Because of the confidentiality of this discount, the exact ICERs cannot be reported here. The committee concluded that all the plausible ICERs presented were below £50,000 per QALY gained.\n\n## Venetoclax with low dose cytarabine is recommended for routine use in the NHS\n\nBecause all of the plausible ICERs were within the range that NICE normally considers to be a cost-effective use of NHS resources for a life-extending treatment at the end of life, the committee recommended venetoclax plus low dose cytarabine as an option for untreated acute myeloid leukaemia with over 30% blasts in adults when intensive chemotherapy is unsuitable. Because the company did not submit any analyses for the 20% to 30% blast group (see section\xa03.3) the committee could not make any recommendations for this group.\n\n# Equality and innovation\n\n## There are no equality issues relevant to the recommendations\n\nA committee member highlighted that venetoclax could provide an effective treatment option for older people who have not benefitted from other recent advances in treatment, and that anyone who cannot easily travel to a major hospital may particularly benefit from being able to take venetoclax at home. The committee considered these potential issues but noted that recommendations would apply to all patients, regardless of age or location. It concluded that no equality issues relevant to the recommendations had been identified.\n\n## The benefits of venetoclax are captured in the cost-effectiveness analysis\n\nThe company, professional organisations and clinical experts considered that venetoclax was innovative because it was a targeted therapy, was different to currently available therapies, led to increased overall survival and rates of complete and deep remissions, and decreased the need for blood transfusions. The committee agreed that these were important benefits of venetoclax, but concluded that it had not been presented with evidence of any additional benefits that were not captured in the QALY calculation."}	https://www.nice.org.uk/guidance/ta787	Evidence-based recommendations on venetoclax (Venclyxto) with low dose cytarabine for untreated acute myeloid leukaemia in adults when intensive chemotherapy is unsuitable.
12fdc3fb20a5614733ad93d9fdab92c4e3edde86	nice	Intramedullary distraction for upper limb lengthening	Intramedullary distraction for upper limb lengthening Evidence-based recommendations on intramedullary distraction for upper limb lengthening in children, young people and adults. This involves surgically inserting a metal lengthening device in the shorter arm. # Recommendations Evidence on the safety and efficacy of intramedullary distraction for upper limb lengthening is inadequate in quantity and quality. But because this is a rare condition with limited alternative treatments, the procedure can be considered as long as special arrangements for clinical governance, consent, and audit or research are in place. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to use intramedullary distraction for upper limb lengthening should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Make sure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Make sure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. This technically challenging procedure should only be done in specialist centres by surgeons with specific training and experience in upper limb lengthening techniques, using a multidisciplinary approach. Report any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme. Further research, which could be registry data, should report details of patient selection, device selection, technique used, procedural outcomes, long-term outcomes including quality of life, the need for repeat interventions or surgery, and complication rates.# The condition, current treatments and procedure # The condition People may have different limb lengths caused by trauma or infection or, more rarely, hypoplasia or dysplasia (congenital conditions such as achondroplasia, Ollier's disease, and brachial plexus palsy). The condition can be unilateral or bilateral. Unequal limb lengths can lead to disability and limit functional ability. # Current treatments Lengthening of a short upper limb can be attempted using external fixation devices, which exert force along the long axis of bone to induce new bone formation (called distraction osteogenesis). The main potential problems with external fixation include infection of the pin tracts, and external frames that are impractical and aesthetically unpleasant. In some people with an underlying bone pathology, once the external fixation is removed, the new bone is augmented by either an internal plate fixation or an intramedullary nail. # The procedure Intramedullary distraction systems are intramedullary devices that are similar to intramedullary nails used for managing fractures. Once inserted and fixed, they can be mechanically lengthened over time using different techniques, resulting in a controlled lengthening of the bone. The device can be inserted into the humerus from the top (antegrade), though this may cause damage to the shoulder muscles, or the lower end (retrograde). Under general anaesthesia, a humeral osteotomy is done avoiding damage to the periosteum and its blood supply. The adjustable nail-like intramedullary device is then implanted into the intramedullary canal, and the proximal and distal sections of the device are fixed to the appropriate section of the humerus with sterile locking screws. Once implanted and fixed, the length of the device can be adjusted to provide an appropriate amount of compression and allow bony alignment at the osteotomy site. The device exerts a force along the long axis of the bone, which stimulates new bone formation (distraction osteogenesis) in the gap, causing bone lengthening. Over a period of days, weeks or months, sequential distractions are used to produce the target limb length. Different devices achieve distraction in different ways. For example, some work mechanically by releasing a preloaded spring or using a motor. Others use an external electromagnetic device. The intramedullary device remains implanted until bone consolidation is completed. When there is radiological evidence of adequate bone consolidation across the gap, full function and limb use (weight bearing) is permitted. The device can usually be removed using standard surgical techniques or may be left in place indefinitely.	{'Recommendations': "Evidence on the safety and efficacy of intramedullary distraction for upper limb lengthening is inadequate in quantity and quality. But because this is a rare condition with limited alternative treatments, the procedure can be considered as long as special arrangements for clinical governance, consent, and audit or research are in place. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to use intramedullary distraction for upper limb lengthening should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nMake sure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nMake sure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nThis technically challenging procedure should only be done in specialist centres by surgeons with specific training and experience in upper limb lengthening techniques, using a multidisciplinary approach.\n\nReport any problems with a medical device using the\xa0Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.\n\nFurther research, which could be registry data, should report details of patient selection, device selection, technique used, procedural outcomes, long-term outcomes including quality of life, the need for repeat interventions or surgery, and complication rates.", 'The condition, current treatments and procedure': "# The condition\n\nPeople may have different limb lengths caused by trauma or infection or, more rarely, hypoplasia or dysplasia (congenital conditions such as achondroplasia, Ollier's disease, and brachial plexus palsy). The condition can be unilateral or bilateral. Unequal limb lengths can lead to disability and limit functional ability.\n\n# Current treatments\n\nLengthening of a short upper limb can be attempted using external fixation devices, which exert force along the long axis of bone to induce new bone formation (called distraction osteogenesis). The main potential problems with external fixation include infection of the pin tracts, and external frames that are impractical and aesthetically unpleasant. In some people with an underlying bone pathology, once the external fixation is removed, the new bone is augmented by either an internal plate fixation or an intramedullary nail.\n\n# The procedure\n\nIntramedullary distraction systems are intramedullary devices that are similar to intramedullary nails used for managing fractures. Once inserted and fixed, they can be mechanically lengthened over time using different techniques, resulting in a controlled lengthening of the bone. The device can be inserted into the humerus from the top (antegrade), though this may cause damage to the shoulder muscles, or the lower end (retrograde).\n\nUnder general anaesthesia, a humeral osteotomy is done avoiding damage to the periosteum and its blood supply. The adjustable nail-like intramedullary device is then implanted into the intramedullary canal, and the proximal and distal sections of the device are fixed to the appropriate section of the humerus with sterile locking screws. Once implanted and fixed, the length of the device can be adjusted to provide an appropriate amount of compression and allow bony alignment at the osteotomy site. The device exerts a force along the long axis of the bone, which stimulates new bone formation (distraction osteogenesis) in the gap, causing bone lengthening. Over a period of days, weeks or months, sequential distractions are used to produce the target limb length.\n\nDifferent devices achieve distraction in different ways. For example, some work mechanically by releasing a preloaded spring or using a motor. Others use an external electromagnetic device.\n\nThe intramedullary device remains implanted until bone consolidation is completed. When there is radiological evidence of adequate bone consolidation across the gap, full function and limb use (weight bearing) is permitted. The device can usually be removed using standard surgical techniques or may be left in place indefinitely."}	https://www.nice.org.uk/guidance/ipg722	Evidence-based recommendations on intramedullary distraction for upper limb lengthening in children, young people and adults. This involves surgically inserting a metal lengthening device in the shorter arm.
f532721e4c41e3e2f7950d9cfe7fe8ef885217fb	nice	Medicines associated with dependence or withdrawal symptoms: safe prescribing and withdrawal management for adults	Medicines associated with dependence or withdrawal symptoms: safe prescribing and withdrawal management for adults This guideline covers general principles for prescribing and managing withdrawal from opioids, benzodiazepines, gabapentinoids, Z‑drugs and antidepressants in primary and secondary care. # Context Medicines associated with dependence include benzodiazepines, Z‑drugs (such as zopiclone and zolpidem), opioids, gabapentin and pregabalin. Antidepressants, although historically not classified as dependence-forming medicines, can nevertheless cause withdrawal symptoms when they are stopped. This guideline focuses on medicines that are usually used for conditions that are chronic, complex and difficult to treat, such as anxiety and insomnia, chronic pain including neuropathic pain, depression and generalised anxiety disorder. It also covers medicines that were initially prescribed for acute pain but continue to be prescribed over a longer term. These medicines can provide lasting symptom management with a favourable balance of benefits and adverse effects for many people. But like all medicines, they do not work for everyone and can have negative consequences that outweigh their benefits. Even when people are not getting clinical benefit, these medicines may sometimes continue to be prescribed for various reasons, including concerns about the risk of unpleasant withdrawal symptoms or fear of worsening of the underlying condition. Dependence is characterised by both tolerance (the need for increasing doses to maintain the same effect) and withdrawal symptoms. Dependence is a common and well described property of a number of medicines and is not in itself a contraindication to continued or new prescribing. Dependence becomes clinically important if treatment reduction or cessation is needed. Dependence is different from addiction. Addiction also features tolerance and withdrawal but is accompanied by additional characteristics of cravings, lack of control, overuse and continued use despite harm. Addiction is also associated with problematic behaviours including unsanctioned dose escalations and seeking early prescriptions or prescriptions from multiple prescribers. There is considerable debate about these definitions and in practice the terms are often used interchangeably. This guideline uses the term 'problems associated with dependence' to refer to these behaviours; the term 'addiction' has not been used because of its potential to stigmatise. This guideline applies to people prescribed a medicine associated with dependence and withdrawal symptoms, and is not limited to people at high risk of developing problems associated with dependence. There is wide variation in the prescribing of medicines associated with dependence or withdrawal symptoms. People with a dependence on prescribed medicines may be reluctant to seek help from their healthcare professionals because of a perceived stigma of dependence, which they may associate with illicit drug use or alcohol misuse. Professional and policy bodies have issued guidelines on the clinical use of medicines associated with dependence or withdrawal symptoms. However, there are few guidelines that focus on avoiding dependence and managing withdrawal from prescribed medicines. This guideline aims to meet the need for evidence-based advice in these areas. It supports safe practice in all settings in which medicines associated with dependence or withdrawal are prescribed.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Supporting people taking a dependence-forming medicine or antidepressant Aim to foster collaborative, trusting and supportive relationships with people considering taking, and at all stages of prescribing and withdrawal management of, an opioid, benzodiazepine, gabapentinoid, Z‑drug or antidepressant. Follow the recommendations in the NICE guideline on patient experience in adult NHS services, particularly those relating to: continuity of care and relationships enabling patients to actively participate in their care tailoring healthcare services to each person. Ask people whether they would like to have support during appointments from a family member, carer, advocate or other person close to them. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting people taking a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in evidence review A: patient information and support. Loading. Please wait. # Making decisions about prescribing and taking a dependence-forming medicine or antidepressant Before starting or continuing treatment with an opioid, benzodiazepine, gabapentinoid, Z‑drug or antidepressant, ensure that all suitable management options, including non-pharmacological approaches and watchful waiting, have been discussed with and offered to the person. When making decisions about prescribing medicines, determine whether there are any factors that might increase the person's risk of developing problems associated with dependence, but do not withhold the medicine solely on the basis of one of these factors. Explain and discuss the risk with the person. Factors that might increase risk include: a comorbid mental health diagnosis a history of drug or alcohol misuse not having a clear, defined diagnosis to support the prescription taking an opioid together with a benzodiazepine. During the first discussion about prescribing, give the person information and advice (in their preferred format) to help them balance the potential benefit of the medicine and other treatment options with the risk of long-term consequences. Use the NICE guidelines on shared decision making and decision making and mental capacity to support people when making decisions. Recognise and acknowledge that decisions about medicines can be difficult for a person who is in distress. Acknowledge that these decisions are also difficult for the prescriber particularly when supporting a person who is distressed, and in the presence of risk factors for developing problems associated with dependence, and that additional time may be required to consider options and consult with colleagues. Consider delaying prescribing if the person needs more time to think about their options or the prescriber needs to consult with other members of the healthcare team. If prescribing is delayed, ensure that a follow-up appointment is arranged. If a prescriber thinks that a medicine is not in the person's best interests but a shared decision about starting or continuing a medicine cannot be reached with the person, the prescriber should follow the advice on 'handling patient requests for medicines you don't think will benefit them' in the General Medical Council guidance: good practice in prescribing and managing medicines and devices. The prescriber should: not prescribe a medicine if they believe it is not in the person's best interests explain the reasons for their decision to the person document all discussions carefully and give a copy to the person -ffer the person a second opinion. For people who find it difficult to communicate their symptoms, for example people with a learning disability or cognitive impairment: explore a range of methods to understand the person's symptoms, including discussion with family members, carers or an advocate if appropriate make necessary reasonable adjustments, for example increasing the appointment length, using short clear sentences or alternative methods of communication and visual aids during consultations, to help the person understand their options for treatment and the associated risks and benefits of each, and to express their view ensure that family members or carers are aware of the properties of any medicine prescribed, if appropriate. For more information, see the NICE guidelines on shared decision making, care and support of people growing older with learning disabilities and dementia. Ensure that people with a learning disability or mental health problem have had a full assessment before prescribing a dependence-forming medicine or antidepressant, to ensure that they do not have other unmet needs and that prescribing is the appropriate option. Consider involving the relevant specialist teams.For more information, see the NICE guideline on challenging behaviour and learning disabilities. Prescribers must understand and take into account the principles set out in the Mental Capacity Act 2005 when working with individuals who may lack capacity to make decisions. For more information, see the NICE guideline on decision making and mental capacity. Prescribers should use the Royal Pharmaceutical Society's Competency framework for all prescribers to support safe and effective prescribing and improve prescribing practice. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on making decisions about prescribing and taking a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in: evidence review A: patient information and support evidence review B: prescribing strategies evidence review E: risk factors. Loading. Please wait. # Starting a dependence-forming medicine or antidepressant ## Information and support for people starting a medicine Before starting treatment with an opioid, benzodiazepine, gabapentinoid, Z‑drug or antidepressant, give the person verbal and written information (in their preferred format) about the medicine. Ensure that the information is evidence-based and understandable by the person. Explain to the person: the potential side effects of the medicine, whether these are likely to be temporary or permanent and whether they might improve or worsen over time any additional implications of taking the medicine if the person is pregnant or planning pregnancy what the options might be if the medicine does not work how difficult it might be to stop the medicine later and how that might be managed (see the section on withdrawing a dependence-forming medicine or antidepressant) that missing doses may lead to symptoms of withdrawal how to store medicines safely (for more information, see the NICE guideline on controlled drugs). Before starting treatment with an opioid, benzodiazepine, gabapentinoid or Z‑drug, explain and discuss with the person: that dependence is an expected effect of these medicines and is not a reason in itself to avoid the medicine the potential for developing problems associated with dependence the symptoms that suggest the development of problems associated with dependence and, if appropriate, the importance of making family members, carers or other people close to them aware of these symptoms. Before starting treatment with an antidepressant or gabapentinoid, explain and discuss with the person: that any beneficial effect of the medicine may occur slowly, and they might experience side effects before noticing any benefit that many side effects are likely to ease over time. Consider supplementing verbal and written information with details of peer support networks or online forums suitable for the person. ## Management planning Discuss and agree a management plan with the person. Document the plan in the person's medical record and give them a copy in their preferred format. Include: what the medicine has been prescribed for, the intended outcomes of treatment and how these might be assessed the starting dose and intervals between dose adjustments or titrations who to contact if problems occur information about how long the medicine will take to work and how long they might be taking it for the duration of each prescription that will be issued the risks of taking more than the prescribed dose the symptoms and signs of an overdose and what they should do if this happens the plans for reviewing the medicine (including where and by whom this will be done) and the date of their next review. Think about a strategy for regular reviews and include these in the management plan. Use regular reviews to: ensure that the benefits of the medicine continue to outweigh the potential harms check whether the dose needs to be adjusted and, if so, how to do this safely. ## Prescribing strategies Take steps to reduce the risk of developing problems associated with dependence, for example starting at a low dose, and consider avoiding modified-release opioids. Explain the importance of these steps to the person. Discuss with the person the range of doses likely to be safe and effective. Start with a low dose and agree frequent, regular reviews to ensure that timely adjustments can be made to test effectiveness, safety and acceptability and to find the lowest effective dose. Once an effective dose has been established, avoid automatically increasing the dose if the response is not sustained. If the person's individual circumstances or the setting (for example, a secure setting) mean that usual prescribing practices are not suitable, adjust the prescription to ensure that: the medicine can be administered safely as part of the setting's routine the medicine does not pose a risk to the person or to others living in that setting. For more information, see the NICE guideline on physical health of people in prison. The duration of each individual prescription: should reflect the management plan (see recommendation 1.3.5) should comply with best practice in controlled drugs prescribing must comply with relevant legislation (for more information, see the NICE guideline on controlled drugs). ## Working with other healthcare professionals When starting a prescription suggested by another healthcare professional, taking over a person's care, or deciding whether to continue a prescription made by another healthcare professional: take the same level of care you would take if you were starting the prescription follow the section on supporting people taking a dependence-forming medicine or antidepressant to help establish the new relationship ensure that you have sufficient knowledge of the person's health and preferences to determine whether continued prescribing is in their best interests or whether careful withdrawal (in discussion with the person) would be more beneficial for them. Healthcare professionals in secondary care who recommend a dependence-forming medicine or antidepressant to be started or continued in primary care should explain to the person that: the medicine will be prescribed by their primary care team the primary care team will need to review the medicine if the primary care team declines to prescribe the medicine, or wishes to delay it, the secondary and primary care teams will discuss the medicine and involve the person in these discussions, explaining the reasons for any delay the secondary care team might not continue to manage and provide the medicine if this is agreed after discussions. When transferring responsibility for prescribing from secondary to primary care, ensure that all relevant healthcare professionals have access to the management plan in the person's medical record. If possible, ensure that 1 person has overall responsibility for a prescription. If the initial prescriber is unable to review the medicine, ensure there are arrangements for review by another healthcare professional and that effective communication, including sharing the person's records and management plan as needed, is in place to support this. Pharmacists working in primary care may play a key role in supporting prescribing. See the section on medication review in the NICE guideline on medicines optimisation. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on starting a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in: evidence review A: patient information and support evidence review B: prescribing strategies evidence review E: risk factors evidence review F: monitoring. Loading. Please wait. # Reviewing a dependence-forming medicine or antidepressant ## Frequency of reviews Offer regular reviews (by phone, video or face to face) to people taking an opioid, benzodiazepine, gabapentinoid, Z‑drug or antidepressant. Base the frequency of reviews on: the person's preferences and circumstances the type of medicine they are taking and the dose factors that might indicate a need for frequent reviews, for example if: the person has additional care needs (such as people with a learning disability or cognitive impairment) the person is taking the medicine for the first time there are potential adverse effects or problems associated with dependence the medicine is being used outside its licensed indications there is potential for misuse of the medicine.For more information on antidepressants, see the NICE guidelines on depression in adults and depression in adults with a chronic physical health problem. Consider increasing the frequency of reviews during dose adjustment. Take into account the person's clinical and support needs when agreeing review frequency. Offer extra, unscheduled reviews when needed, for example if the person: reports adverse effects from the medicine becomes pregnant or is planning pregnancy has a change in their physical or mental health condition, or social circumstances starts taking medicines from a different prescriber requests a change in dose. For guidance on reviewing medicines, see the section on medication review in the NICE guideline on medicines optimisation and the section on reviewing medicines in the NICE guideline on medicines adherence. ## Content of reviews During the review, discuss with the person the benefits and risks of continuing the current dose, adjusting the dose or stopping the medicine. Base decisions on this discussion, taking into account, for example: the benefits or harms the person is experiencing from continuing the medicine any signs that the person is developing problems associated with dependence (such as running out of a medicine early, making frequent requests for dose increases or reporting loss of efficacy of a medicine that was previously working well) the person's preferences. Agree and update the management plan with the person after each review, and give them a copy (see recommendation 1.3.5). Check that they know who to contact if they have problems or concerns. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reviewing a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in evidence review F: monitoring. Loading. Please wait. # Withdrawing a dependence-forming medicine or antidepressant ## Making shared decisions about withdrawing medicines Discuss withdrawing an opioid, benzodiazepine, gabapentinoid, Z‑drug or antidepressant with the person if: it is no longer benefiting the person problems associated with dependence have developed the condition for which the medicine was prescribed has resolved the harms of the medicine outweigh the benefits the person wants to stop taking the medicine. Explain the benefits the person can expect from reducing the medicine and aim to reach agreement using a shared decision-making approach. Allow enough time to explore the person's circumstances and preferences. Understand that the person might be reluctant or anxious about discussing problems associated with dependence. Reassure them that dependence is an expected effect of these medicines and that problems associated with dependence sometimes develop. Be sensitive to the use of terminology that may apportion blame to the person or be perceived adversely. Acknowledge and discuss with the person any differences between their views and your own about the risks and benefits of the medicine. Be prepared for queries about prescribing decisions made previously. Explain that our understanding of the balance of risks and benefits of a medicine can change over time. If sufficient clinical detail is available, discuss the possibility that past prescribing was done in the person's best interests using the knowledge available at the time. Do not stop a medicine abruptly (complete cessation with immediate effect) unless there are exceptional medical circumstances, such as the occurrence of serious side effects (for example, upper gastrointestinal bleeding from an antidepressant, respiratory depression from an opioid or severe ataxia from a gabapentinoid). In these circumstances, consider: scheduling more frequent reviews short-term use of medicines to treat the physical symptoms of withdrawal (for example, abdominal cramps and diarrhoea during withdrawal of an opioid). When planning withdrawal from an opioid, benzodiazepine, gabapentinoid, Z‑drug or antidepressant, take into account: the urgency of the withdrawal, for example gradual withdrawal of a medicine that is no longer effective or necessary, or more rapid withdrawal of a medicine that is causing significant harm (the speed of rapid withdrawal depends on the type of medicine and the person's circumstances, see recommendation 1.5.6) whether the initial goal should be complete withdrawal or, for people who find complete withdrawal too difficult, whether dose reduction with ongoing review is a more realistic initial aim which medicine to reduce first, if the person will be withdrawing from more than 1 medicine factors that might increase the person's risk of problems during withdrawal, including: long duration of medicine use high dose of medicine history of withdrawal symptoms history of problems associated with dependence taking an antidepressant with a short half-life any concurrent medicines and how these might affect the person's response to withdrawal factors that might influence the timing of the start of the dose reduction, such as the person's circumstances and available support. ## Information and support for people withdrawing from a medicine Before starting withdrawal: give the person information about the process of withdrawal that is tailored to their situation and the medicine they are taking explain how the withdrawal will be carried out consider providing details of sources of peer support, national and local support groups for people who are withdrawing from a medicine. Discuss withdrawal symptoms with the person and tell them about the support that is available. When discussing withdrawal symptoms, explain that: withdrawal can be difficult, and may take several months or more support will be available throughout the withdrawal process withdrawal symptoms do not affect everyone, and it is not possible to predict who will be affected withdrawal symptoms vary widely in type and severity, can affect both physical and mental health, may occur at any time during withdrawal or be delayed in onset and can change over time or persist over a prolonged period there are options for managing withdrawal symptoms (see the section on identifying and managing withdrawal symptoms and the section on interventions to support withdrawal) some people may experience withdrawal symptoms that can be difficult to distinguish from a re‑emergence of their original symptoms or a new disorder, and it is important to discuss these with a healthcare professional if they occur (see recommendation 1.5.17). ## Dose reduction When agreeing a dose reduction schedule with the person: explain the risk of abrupt discontinuation and that the rate of safe withdrawal varies between people and can vary over time for the same person balance the risk of adverse events from continued exposure to the medicine with minimising the risk of withdrawal symptoms by slow dose reduction and withdrawal ensure that the planned rate of reduction is acceptable to the person explain that although withdrawal symptoms are to be expected, the reduction schedule can be modified to allow intolerable withdrawal symptoms to improve before making the next reduction consider giving the person additional control over the process of dose reduction (for example, by issuing their usual daily dose in a form that allows them to reduce the amount in small decrements at a pace of their choosing, rather than issuing successive prescriptions for reduced daily doses) agree regular intervals for reviewing and adjusting the reduction schedule as needed ensure the person knows who to contact if problems occur. If the person is withdrawing from an opioid, benzodiazepine, Z‑drug or antidepressant, suggest a slow, stepwise rate of reduction proportionate to the existing dose, so that decrements become smaller as the dose is lowered, unless clinical risk is such that rapid withdrawal is needed (see recommendation 1.5.6). If the person is withdrawing from a gabapentinoid, reduce the dose by a fixed amount at each decrement, unless clinical risk is such that rapid withdrawal is needed (see recommendation 1.5.6). If the person is withdrawing from a benzodiazepine with a short half-life, consider switching to a benzodiazepine with a longer half-life. If using a published withdrawal schedule, apply it flexibly to accommodate the person's preferences, changes to their circumstances and the response to dose reductions. During withdrawal, offer continued management of the underlying condition for which the medicine was prescribed, if needed. Ensure the plan for dose reduction or withdrawal is clearly recorded in the overall management plan. ## Identifying and managing withdrawal symptoms Be aware that it can be difficult to distinguish between the re‑emergence of underlying conditions and the emergence of withdrawal symptoms. The following may indicate withdrawal symptoms rather than symptoms of an underlying condition: rapid or early onset of symptoms after a dose reduction or cessation of the medicine symptoms of the underlying illness that the person reports as qualitatively different or more intense than before new symptoms that the person has not experienced before. Follow recommendation 1.2.8 for people who find it difficult to communicate their symptoms, for example people with a learning disability or cognitive impairment. Use clinical judgement to determine the need for further investigation to rule out new pathology. If distressing symptoms occur or worsen after a dose reduction: determine whether they are withdrawal symptoms or a re‑emergence of symptoms that were relieved by the medicine if the symptoms are new, think about delaying the next dose reduction, trying a smaller dose reduction or reverting to the previous dose. ## Interventions to support withdrawal Do not treat withdrawal symptoms with another medicine that is associated with dependence or withdrawal symptoms. Do not offer sodium valproate or buspirone to aid withdrawal from a benzodiazepine. Consider group cognitive behavioural therapy (CBT) when withdrawing from a benzodiazepine. Discuss the timing of referral for CBT with the person. ## Strategies if withdrawal cannot be agreed or is unsuccessful Follow recommendation 1.2.7 if a shared decision to withdraw cannot be reached and continuing the current prescription is not in the person's best interests. Be aware that medicines associated with dependence and withdrawal symptoms should not be stopped abruptly in most cases (see recommendation 1.5.6) and need to be reduced in line with the section on withdrawing medicines. If continued use of the medicine may be particularly harmful for the person or others (for example, in a secure setting) and a dose reduction, or a more rapid reduction than the person wishes, is the safest option, consider: scheduling more frequent reviews short-term use of medicines to treat the physical symptoms of withdrawal (for example, abdominal cramps and diarrhoea during withdrawal of an opioid). If dose reduction has been unsuccessful (for example because of intolerable withdrawal symptoms or a change in the person's physical, mental or social circumstances) and the current prescription needs to be continued: aim to stop any further escalation in dose make a plan to attempt dose reduction again at a later date clearly record the advice given to the person about the potential harms of continuing the medicine, and the reasons for continuing without a reduction, in the management plan. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on withdrawing a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in: evidence review A: patient information and support evidence review C: safe withdrawal evidence review D: withdrawal symptoms. Loading. Please wait.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Multicomponent withdrawal interventions What are the key components of an effective multicomponent intervention to support dose reduction during withdrawal of opioids? For a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in evidence review C: safe withdrawal. Loading. Please wait. ## Psychological interventions to support withdrawal What are the most effective psychological interventions to support withdrawal and help people cope with withdrawal symptoms? For a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in evidence review C: safe withdrawal. Loading. Please wait. ## Service models for withdrawal interventions What service models are most effective in supporting withdrawal from medicines associated with dependence and withdrawal symptoms? For a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in evidence review C: safe withdrawal. Loading. Please wait. ## Individual circumstances and the risk of dependence Do individual circumstances such as social distress, low income or limited access to alternative sources of support lead to an increased risk of problems associated with dependence on prescribed medicines? For a short explanation of why the committee made the recommendation for research, see the rationale section on making decisions about prescribing and taking a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in evidence review E: risk factors. Loading. Please wait. ## Information for family members or carers What information and support are needed by family members or carers of people having treatment with an opioid, benzodiazepine, Z‑drug, antidepressant or gabapentinoid? For a short explanation of why the committee made the recommendation for research, see the rationale section on starting a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in evidence review A: patient information and support. Loading. Please wait. # Other recommendations for research ## System-level factors and the risk of dependence Do system-level factors, such as training received by prescribers alter the risk of developing problems associated with dependence on prescribed medicines? For a short explanation of why the committee made the recommendation for research, see the rationale section on making decisions about prescribing and taking a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in evidence review E: risk factors. Loading. Please wait. ## Converting to a medicine with a different half‑life to aid withdrawal What is the clinical and cost effectiveness of converting to medicines with a longer half‑life to aid withdrawal from benzodiazepines or antidepressants? For a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in evidence review C: safe withdrawal. Loading. Please wait. ## Cognitive behavioural therapy (CBT) to support withdrawal from benzodiazepines What is the most effective model of CBT, including timing of CBT, to support withdrawal from benzodiazepines? For a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in evidence review C: safe withdrawal. Loading. Please wait. ## Acupuncture to support withdrawal from opioids What is the clinical and cost effectiveness of acupuncture (including electroacupuncture) as an adjunct to aid withdrawal from opioids? For a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in evidence review C: safe withdrawal. Loading. Please wait. ## Withdrawal interventions for gabapentinoids What are the most clinically and cost-effective strategies or interventions to aid withdrawal of gabapentinoids? For a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in evidence review C: safe withdrawal. Loading. Please wait. ## Aids to support withdrawal What is the effectiveness of equipment, technologies, practical aids and medicine formulations in supporting people to manage dose reductions, compared with usual practice? For a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant . Full details of the evidence and the committee's discussion are in evidence review C: safe withdrawal. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Supporting people taking a dependence-forming medicine or antidepressant Recommendations 1.1.1 and 1.1.2 ## Why the committee made the recommendations Qualitative evidence was available from studies on opioids, benzodiazepines and antidepressants. Most of the participants were people prescribed these medicines, although some studies included prescribers (GPs, nurses and pharmacists). The evidence highlighted that some people experience dissatisfaction with treatment and a poor relationship with healthcare professionals. The committee agreed that continuity of care, a tailored approach for each person, and the formation of good relationships are particularly important in this population. The recommendations in the NICE guideline on patient experience in adult NHS services will help to achieve this. Evidence and the committee's experience showed that the presence of a family member, carer, advocate or other person at appointments can be helpful, especially for people who are older, or who are distressed or find it difficult to take in and remember information. ## How the recommendations might affect practice The recommendations reflect best practice but are not implemented consistently and might involve changes in practice for some providers. Return to recommendations # Making decisions about prescribing and taking a dependence-forming medicine or antidepressant Recommendations 1.2.1 to 1.2.11 ## Why the committee made the recommendations Evidence from qualitative studies of people taking opioids showed that they want the opportunity to discuss all management options before starting the medicine. The evidence also highlighted people's need for support when making decisions about taking prescribed medicines. The committee agreed that reaching a shared decision about a medicine is beneficial for both the prescriber and the person taking the medicine, and that the NICE guideline on shared decision making should be used to support people when making decisions. Based on the evidence and their experience, the committee agreed that specific factors can increase a person's risk of developing problems associated with dependence. Prognostic evidence from studies of opioids and benzodiazepines demonstrated an increased risk in people diagnosed with mental health problems including depression, anxiety, post-traumatic stress disorder, bipolar disorder, alcohol-use disorder or drug-misuse disorder. The committee agreed, based on their experience, that this also applies to Z‑drugs and gabapentinoids, but not to antidepressants, which are not dependence-forming medicines. They noted that a comorbid mental health diagnosis can have a profound impact on people and increase their desire for medicines, and that people with a history of drug misuse may need higher drug doses to obtain the desired effect. There was evidence indicating that, for people prescribed opioids, concurrent use of benzodiazepines increases the risk of problems associated with dependence, as does the presence of painful conditions without a clear, defined diagnosis. The committee agreed that it is important for healthcare professionals to be mindful of these factors when making prescribing decisions, but the needs of each person should be taken into account when balancing benefits and harms, and these factors alone should not be seen as barriers to prescribing. The committee noted other factors that were not captured by the evidence but might influence the development of problems associated with dependence, including social distress, access to alternative sources of support and system-level factors such as training or supervision of prescribers. They made a recommendation for research on individual circumstances and the risk of problems associated with dependence, and a recommendation for research on system-level factors and the risk of problems associated with dependence. The committee noted that, in their experience, people can often present in distress and may be focused on immediate relief of their symptoms. They also noted the pressure to prescribe that is sometimes felt by healthcare professionals and agreed that in some circumstances, it is advantageous to delay prescribing until after the first discussion about prescribing. They agreed that a short delay would not disadvantage the person and would be beneficial in allowing both the person and the healthcare professional time to reflect on the options. The committee acknowledged that on occasion, a healthcare professional may not think that prescribing or continuing a medicine is in the person's best interests, but the person disagrees, and a shared decision cannot be reached. In this circumstance, it is the responsibility of the healthcare professional not to prescribe the medicine and to follow General Medical Council guidance. The committee noted that there are some people with communication difficulties, for example those with a learning disability or cognitive impairment, who may have difficulties describing their symptoms, which can lead to medicines being prescribed inappropriately, or not at all. The committee agreed that, in their experience, additional consideration and support is needed to ensure prescribing decisions are made in the person's best interests, and that the person is able to share in those decisions. ## How the recommendations might affect practice The recommendations are expected to reduce the number of people who develop dependence on medicines by raising awareness of the risk factors and ensuring shared decisions are made based on fully informed discussions of the risks and benefits. This will benefit the healthcare system and improve the health of people taking these medicines. Return to recommendations # Starting a dependence-forming medicine or antidepressant Recommendations 1.3.1 to 1.3.14 ## Why the committee made the recommendations Evidence from study participants showed that they were often not given sufficient information about their medicine before starting treatment, particularly the risks of dependence and withdrawal symptoms. Participants also reported a lack of information about side effects, how well the medicine is expected to work, how long it will take to work and the likely duration of treatment. This evidence reflected the committee's experience. The recommendations aim to ensure that all of this information is provided before people begin treatment. The committee also agreed that it is important to make people aware of how to safely store their medicines and included a cross reference to the NICE guideline on controlled drugs, which covers storage of medicines. The evidence also showed discrepancies between the information people reported being given and the information their healthcare professionals reported giving them, highlighting the importance of providing both verbal and written information in the person's preferred format that they can take home for later reference. There was no evidence on the views of family members or carers, so the committee made a recommendation for research on information for family members or carers. Within the evidence, peer support (for example, through online forums) was identified as a valuable complement to information provided by healthcare professionals. The committee agreed with this finding and recommended that prescribers should consider supplementing information with details of peer support networks. Evidence and the committee's experience demonstrated the value of agreeing a management plan with the person. The plan should include practical information about the medicine, including how to take it safely, and set out when the medicine will be reviewed. The importance of giving a copy of the plan to the person was highlighted both in the evidence and the committee's experience. The committee's experience and evidence from studies on opioids indicated that long-term treatment is a risk factor for dependence, and that higher doses taken long term increase this risk further. Therefore, the management plan should be reviewed regularly to ensure that the dosage remains optimal, the benefits of the medicine continue to outweigh the potential harms and the medicine is not continued when it is no longer needed. Although the evidence was limited, the committee agreed that there was some indication that starting a medicine at a low dose may reduce the risk of problems associated with dependence and the risk of withdrawal symptoms. This was supported by evidence in the risk factor review showing a dose–response association between higher doses of opioids and incident addiction to opioids when taken long term. Evidence and the committee's experience also showed that standard-release opioids are less frequently associated with problems compared with modified-release opioids unless clinical considerations or the person's circumstances dictate otherwise. The committee noted this only applied to opioid formulations and not to the other medicines considered. The committee agreed, based on their experience, that it is important to take particular care during dose adjustments. Although pharmacological tolerance is a property of medicines described in this guideline, if a person has an initially favourable response that then diminishes, it is rarely helpful to increase the dose to try to restore the clinical benefit. This is because such an approach increases the risk of harmful prescribing, and also because the loss of benefit is rarely due to pharmacological tolerance, but due to other factors. In the committee's experience, there may be individual circumstances in which adjustments are needed to the prescription to ensure it is safe and practical. If it is not possible for people to hold their own medicines, in secure settings for example, twice-daily administration may be difficult. To avoid unnecessary long-term use of a medicine, prescribers should ensure that each prescription is in line with the management plan and complies with good practice guidance and relevant legislation. The committee based these recommendations on their experience. They agreed that standardised prescribing practice can help to ensure continuity of care. The committee's recommendations emphasise the importance of clear communication between primary and secondary care. They also stress the importance of giving clear explanations to people about arrangements for their care across services. The committee agreed that it is vital that a new prescriber taking over a person's care acquires sufficient knowledge about the person to determine whether the prescription should be continued, establishes a therapeutic relationship with the person and takes the same care they would if they had been the original prescriber. Primary and secondary care prescribers should ensure that they discuss and agree medicines to be prescribed or continued in primary care, and ensure that the person is kept involved and informed about these discussions. The committee noted that this is consistent with NHS England's guidance on responsibility for prescribing between primary and secondary/tertiary care (2018). The committee recognised the difficulties involved in achieving and maintaining continuity of care and communication across settings, and agreed that it is helpful to have 1 prescriber take overall responsibility for a person's prescribing. It was noted that pharmacists may play an important role here. ## How the recommendations might affect practice The recommendations reflect best practice, but there are variations in their implementation, and they may involve a change of practice for some providers. Longer consultations or additional follow up may be needed to allow for full discussion of treatments and treatment options when starting or reviewing a medicine. However, enabling effective conversations about risks and benefits could reduce unnecessary prescribing, which would have large health benefits for the person and economic benefits for the healthcare service, for example, by preventing unplanned hospital admissions from harms caused by the medicines and reducing the need for additional healthcare support for people with dependence. Return to recommendations # Reviewing a dependence-forming medicine or antidepressant Recommendations 1.4.1 to 1.4.6 ## Why the committee made the recommendations There was no evidence on the frequency of reviews, so the committee based the recommendations on their experience. They agreed that prescribing is an ongoing process that should be monitored with regular reviews. The frequency of these reviews should be tailored to the person, the medicine they are taking and the presence of any risk factors. They could be held by phone, video or face to face. The committee also agreed that the frequency of reviews could be increased during dose adjustments, to ensure safety and early identification of any withdrawal symptoms. Evidence and the committee's experience highlighted the importance of weighing up the benefits and risks of continuing or stopping the medicine as part of each review, and of updating the management plan after every review. ## How the recommendations might affect practice Tailored review schedules should reduce unnecessary appointment time and increase the efficiency of treatment monitoring. Although the frequency of reviews may be increased for some people, the cost is expected to be mitigated by the current move to online, phone and video consultations. Moreover, upfront costs of more frequent tailored reviews could be offset by downstream savings such as reducing the number of people needing help from addiction services and reducing the number of medicines being prescribed, with potential health benefits because of fewer adverse events and less clinical harm caused by prescribed medicines. Return to recommendations # Withdrawing a dependence-forming medicine or antidepressant Recommendations 1.5.1 to 1.5.26 ## Why the committee made the recommendations The committee agreed that withdrawal should be considered when a medicine is no longer beneficial, the harms outweigh the benefits, or the person would like to withdraw. A small amount of evidence indicated that including the benefits of withdrawal and information about the process in discussions with the person can increase the likelihood that their withdrawal will be successful. Qualitative evidence highlighted that people can be reluctant or anxious about discussing dependence and report feelings of fear, worry or anxiety surrounding discontinuation. The committee agreed that, in their experience, this can be addressed by explaining that dependence is an expected effect of the medicine, and some people experience problems associated with dependence. They also agreed it was important to avoid using language that ascribes blame to the person. The committee also thought it important to acknowledge and discuss differences of opinion and to be prepared for queries about the reasons for past prescribing. Evidence from studies on benzodiazepines and antidepressants showed that a gradual, stepwise dose reduction is more beneficial than abrupt discontinuation. The committee agreed that this evidence can be extrapolated to opioids, Z‑drugs and gabapentinoids, and that none of these medicines should be stopped abruptly. However, the committee acknowledged clinical experience of exceptional circumstances in which stopping treatment abruptly might be necessary, for example if a serious side effect has occurred. In their experience, this would usually be done within a hospital setting. Based on their experience, the committee agreed that individual factors can affect the withdrawal process and should be taken into account when planning withdrawal. The plan for withdrawal should also take into account the urgency of withdrawal. Based on both the qualitative evidence and their experience, the committee agreed that the provision of information and support is vital for people withdrawing from a medicine. Knowing what to expect, and having reassurance that they will have support and help with managing withdrawal symptoms, will increase the likelihood of a successful withdrawal. There was some qualitative evidence, reflected in the committee's experience, that support groups can be beneficial for people during the withdrawal process. The evidence comparing different speeds of dose reduction was inconclusive and the committee agreed that most of the studies did not reflect clinical practice. The committee are aware there are different terms used to describe reduction schedules. Based on their experience, they agreed that flexibility in schedules is needed, and tolerability is the most important factor to take into account when deciding the speed of dose reduction, and therefore a descriptive schedule incorporating these factors should be recommended. Although tolerability varies across individuals, most people find a stepwise, decremental dose reduction process tolerable and effective. With opioids, benzodiazepines, Z‑drugs and antidepressants, a rate of reduction proportionate to the existing dose is suggested. For gabapentinoids, the dose can be reduced by a fixed amount at each decrement, with the amount of reduction tailored to the person. In the committee's experience, people who have some control over their own dose reduction schedule often have a more successful withdrawal than those whose schedule is decided for them. The committee also agreed that a flexible reduction schedule that is regularly reviewed and revised when needed is an important contributor to a successful outcome. The committee noted that there was evidence for converting treatment from lorazepam to diazepam before withdrawal. This is because diazepam has a longer half‑life and is therefore considered to allow better management of the pace of reduction, and potentially reduce withdrawal symptoms. Withdrawing from a short-acting benzodiazepine such as lorazepam can be difficult because withdrawal symptoms can occur very quickly. The committee agreed that switching to a benzodiazepine with a longer half‑life is common practice and can be considered for people withdrawing from a benzodiazepine. Despite being common practice, there is a lack of evidence to support conversion to a preparation with a longer half‑life, so the committee made a recommendation for research on converting to a medicine with a different half-life to aid withdrawal. The committee agreed this recommendation for research should also apply to antidepressants. The committee recognised that it can be difficult to differentiate withdrawal symptoms from symptoms of a new or existing underlying condition. They agreed that withdrawal symptoms are often characterised by rapid onset after the dose of a medicine is reduced or the medicine is stopped, or there are qualitative differences from previous symptoms of the underlying illness, or there are new symptoms that have not previously occurred. The committee agreed that if symptoms occur or worsen after a dose reduction, it is important to try to determine whether they are withdrawal symptoms or a re‑emergence of symptoms of the original condition. If they are likely to be withdrawal symptoms, the committee agreed that the next dose reduction may need to be delayed, or the person may need to revert to the previous dose. The evidence did not inform of the frequency or prevalence of symptoms, and the committee agreed that withdrawal symptoms could vary widely between individuals in terms of which symptoms were experienced, but also in terms of their intensity and duration. The committee also agreed that, based on the current evidence, it would not be helpful to include a list of symptoms in the recommendation because this could be misleading and result in symptoms being overlooked if they are not on the list or wrongly implying new symptoms do not need further investigation. There was little evidence on psychological interventions to support withdrawal or relieve withdrawal symptoms. Health economic analysis showed that group cognitive behavioural therapy (CBT) alongside dose reduction can improve discontinuation rates and quality of life for people during withdrawal from benzodiazepines and reduce costs for the NHS. There was no clear evidence on the most effective model or timing of CBT, so the committee also made a recommendation for research on CBT to support withdrawal from benzodiazepines. Evidence on other psychological interventions, or psychological interventions for other medicines, was too limited to inform recommendations, so the committee made a recommendation for research on psychological interventions to support withdrawal. The committee agreed, based on their experience, that using another medicine associated with dependence and withdrawal symptoms to treat withdrawal symptoms does not aid withdrawal and can lead to harms. The evidence did not support the use of pharmacological interventions to aid withdrawal, but was very limited for most pharmacological interventions. The committee agreed that sodium valproate and buspirone taken during withdrawal from a benzodiazepine are not only ineffective but are associated with harm and should not be used. There was some evidence that a multicomponent intervention is beneficial during withdrawal from an opioid. However, the relative effectiveness of each component was not clear, so the committee made a recommendation for research on multicomponent withdrawal interventions. Although acupuncture is commonly used in addiction services to manage dependence on illicit opioids, and there is some evidence supporting its use to aid withdrawal from opioids, evidence on its overall effectiveness is lacking. The committee made a recommendation for research on acupuncture to support withdrawal from opioids. There was no evidence on the effectiveness of any withdrawal strategies or interventions to aid withdrawal from a gabapentinoid, so the committee made a recommendation for research on withdrawal interventions for gabapentinoids. The committee were aware of specific equipment, practical aids and technologies used to support withdrawal but there was no evidence on these. They made a recommendation for research on aids to support withdrawal. The committee discussed whether different service models, such as virtual clinics or specialist pharmacy input, would be effective in helping people withdraw from medicines. No evidence was identified in these areas and the committee made a recommendation for research on service models for withdrawal interventions. The committee recognised that it may not be possible to reach a shared decision with the person about withdrawal and referred to the General Medical Council guidance for advice on how to handle this. They acknowledged particular difficulties if continued use of the medicine is especially hazardous, for example in a secure setting, and recommended steps that can be taken to manage withdrawal in this situation. The committee recognised that dose reduction may sometimes be too difficult and agreed, based on their experience, that in this circumstance the aim should be to stop any further dose escalation and to make a plan to try again later. They stressed the importance of recording the reasons for continuing the medicine and the advice given to the person in the management plan. ## How the recommendations might affect practice At present, there is limited provision of services within the NHS specifically to support withdrawal from prescribed medicines. There are some local centres that have established good practice in this area, but they are not widely available. It is expected that implementing these recommendations will increase the number of people needing specialist withdrawal services. Additional resources will be needed to increase the provision of these services by expanding existing centres or creating additional ones in areas where these services are not available. This should be balanced by savings accrued from a reduction in unplanned hospitalisations to treat adverse drug events, fewer medicines prescribed and hence fewer medicine reviews. Providing CBT to people during withdrawal from benzodiazepines would initially need additional resources, but in the long term will generate savings and improve quality of life. Return to recommendations	{'Context': "Medicines associated with dependence include benzodiazepines, Z‑drugs (such as zopiclone and zolpidem), opioids, gabapentin and pregabalin. Antidepressants, although historically not classified as dependence-forming medicines, can nevertheless cause withdrawal symptoms when they are stopped. This guideline focuses on medicines that are usually used for conditions that are chronic, complex and difficult to treat, such as anxiety and insomnia, chronic pain including neuropathic pain, depression and generalised anxiety disorder. It also covers medicines that were initially prescribed for acute pain but continue to be prescribed over a longer term.\n\nThese medicines can provide lasting symptom management with a favourable balance of benefits and adverse effects for many people. But like all medicines, they do not work for everyone and can have negative consequences that outweigh their benefits. Even when people are not getting clinical benefit, these medicines may sometimes continue to be prescribed for various reasons, including concerns about the risk of unpleasant withdrawal symptoms or fear of worsening of the underlying condition.\n\nDependence is characterised by both tolerance (the need for increasing doses to maintain the same effect) and withdrawal symptoms. Dependence is a common and well described property of a number of medicines and is not in itself a contraindication to continued or new prescribing. Dependence becomes clinically important if treatment reduction or cessation is needed.\n\nDependence is different from addiction. Addiction also features tolerance and withdrawal but is accompanied by additional characteristics of cravings, lack of control, overuse and continued use despite harm. Addiction is also associated with problematic behaviours including unsanctioned dose escalations and seeking early prescriptions or prescriptions from multiple prescribers. There is considerable debate about these definitions and in practice the terms are often used interchangeably. This guideline uses the term 'problems associated with dependence' to refer to these behaviours; the term 'addiction' has not been used because of its potential to stigmatise.\n\nThis guideline applies to people prescribed a medicine associated with dependence and withdrawal symptoms, and is not limited to people at high risk of developing problems associated with dependence.\n\nThere is wide variation in the prescribing of medicines associated with dependence or withdrawal symptoms. People with a dependence on prescribed medicines may be reluctant to seek help from their healthcare professionals because of a perceived stigma of dependence, which they may associate with illicit drug use or alcohol misuse.\n\nProfessional and policy bodies have issued guidelines on the clinical use of medicines associated with dependence or withdrawal symptoms. However, there are few guidelines that focus on avoiding dependence and managing withdrawal from prescribed medicines. This guideline aims to meet the need for evidence-based advice in these areas. It supports safe practice in all settings in which medicines associated with dependence or withdrawal are prescribed.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Supporting people taking a dependence-forming medicine or antidepressant\n\nAim to foster collaborative, trusting and supportive relationships with people considering taking, and at all stages of prescribing and withdrawal management of, an opioid, benzodiazepine, gabapentinoid, Z‑drug or antidepressant. Follow the recommendations in the NICE guideline on patient experience in adult NHS services, particularly those relating to:\n\ncontinuity of care and relationships\n\nenabling patients to actively participate in their care\n\ntailoring healthcare services to each person.\n\nAsk people whether they would like to have support during appointments from a family member, carer, advocate or other person close to them.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting people taking a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: patient information and support.\n\nLoading. Please wait.\n\n# Making decisions about prescribing and taking a dependence-forming medicine or antidepressant\n\nBefore starting or continuing treatment with an opioid, benzodiazepine, gabapentinoid, Z‑drug or antidepressant, ensure that all suitable management options, including non-pharmacological approaches and watchful waiting, have been discussed with and offered to the person.\n\nWhen making decisions about prescribing medicines, determine whether there are any factors that might increase the person's risk of developing problems associated with dependence, but do not withhold the medicine solely on the basis of one of these factors. Explain and discuss the risk with the person. Factors that might increase risk include:\n\na comorbid mental health diagnosis\n\na history of drug or alcohol misuse\n\nnot having a clear, defined diagnosis to support the prescription\n\ntaking an opioid together with a benzodiazepine.\n\nDuring the first discussion about prescribing, give the person information and advice (in their preferred format) to help them balance the potential benefit of the medicine and other treatment options with the risk of long-term consequences. Use the NICE guidelines on shared decision making and decision making and mental capacity to support people when making decisions.\n\nRecognise and acknowledge that decisions about medicines can be difficult for a person who is in distress.\n\nAcknowledge that these decisions are also difficult for the prescriber particularly when supporting a person who is distressed, and in the presence of risk factors for developing problems associated with dependence, and that additional time may be required to consider options and consult with colleagues.\n\nConsider delaying prescribing if the person needs more time to think about their options or the prescriber needs to consult with other members of the healthcare team. If prescribing is delayed, ensure that a follow-up appointment is arranged.\n\nIf a prescriber thinks that a medicine is not in the person's best interests but a shared decision about starting or continuing a medicine cannot be reached with the person, the prescriber should follow the advice on 'handling patient requests for medicines you don't think will benefit them' in the General Medical Council guidance: good practice in prescribing and managing medicines and devices. The prescriber should:\n\nnot prescribe a medicine if they believe it is not in the person's best interests\n\nexplain the reasons for their decision to the person\n\ndocument all discussions carefully and give a copy to the person\n\noffer the person a second opinion.\n\nFor people who find it difficult to communicate their symptoms, for example people with a learning disability or cognitive impairment:\n\nexplore a range of methods to understand the person's symptoms, including discussion with family members, carers or an advocate if appropriate\n\nmake necessary reasonable adjustments, for example increasing the appointment length, using short clear sentences or alternative methods of communication and visual aids during consultations, to help the person understand their options for treatment and the associated risks and benefits of each, and to express their view\n\nensure that family members or carers are aware of the properties of any medicine prescribed, if appropriate. For more information, see the NICE guidelines on shared decision making, care and support of people growing older with learning disabilities and dementia.\n\nEnsure that people with a learning disability or mental health problem have had a full assessment before prescribing a dependence-forming medicine or antidepressant, to ensure that they do not have other unmet needs and that prescribing is the appropriate option. Consider involving the relevant specialist teams.For more information, see the NICE guideline on challenging behaviour and learning disabilities.\n\nPrescribers must understand and take into account the principles set out in the Mental Capacity Act 2005 when working with individuals who may lack capacity to make decisions. For more information, see the NICE guideline on decision making and mental capacity.\n\nPrescribers should use the Royal Pharmaceutical Society's Competency framework for all prescribers to support safe and effective prescribing and improve prescribing practice.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on making decisions about prescribing and taking a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: patient information and support\n\nevidence review\xa0B: prescribing strategies\n\nevidence review\xa0E: risk factors.\n\nLoading. Please wait.\n\n# Starting a dependence-forming medicine or antidepressant\n\n## Information and support for people starting a medicine\n\nBefore starting treatment with an opioid, benzodiazepine, gabapentinoid, Z‑drug or antidepressant, give the person verbal and written information (in their preferred format) about the medicine. Ensure that the information is evidence-based and understandable by the person. Explain to the person:\n\nthe potential side effects of the medicine, whether these are likely to be temporary or permanent and whether they might improve or worsen over time\n\nany additional implications of taking the medicine if the person is pregnant or planning pregnancy\n\nwhat the options might be if the medicine does not work\n\nhow difficult it might be to stop the medicine later and how that might be managed (see the section on withdrawing a dependence-forming medicine or antidepressant)\n\nthat missing doses may lead to symptoms of withdrawal\n\nhow to store medicines safely (for more information, see the NICE guideline on controlled drugs).\n\nBefore starting treatment with an opioid, benzodiazepine, gabapentinoid or Z‑drug, explain and discuss with the person:\n\nthat dependence is an expected effect of these medicines and is not a reason in itself to avoid the medicine\n\nthe potential for developing problems associated with dependence\n\nthe symptoms that suggest the development of problems associated with dependence and, if appropriate, the importance of making family members, carers or other people close to them aware of these symptoms.\n\nBefore starting treatment with an antidepressant or gabapentinoid, explain and discuss with the person:\n\nthat any beneficial effect of the medicine may occur slowly, and they might experience side effects before noticing any benefit\n\nthat many side effects are likely to ease over time.\n\nConsider supplementing verbal and written information with details of peer support networks or online forums suitable for the person.\n\n## Management planning\n\nDiscuss and agree a management plan with the person. Document the plan in the person's medical record and give them a copy in their preferred format. Include:\n\nwhat the medicine has been prescribed for, the intended outcomes of treatment and how these might be assessed\n\nthe starting dose and intervals between dose adjustments or titrations\n\nwho to contact if problems occur\n\ninformation about how long the medicine will take to work and how long they might be taking it for\n\nthe duration of each prescription that will be issued\n\nthe risks of taking more than the prescribed dose\n\nthe symptoms and signs of an overdose and what they should do if this happens\n\nthe plans for reviewing the medicine (including where and by whom this will be done) and the date of their next review.\n\nThink about a strategy for regular reviews and include these in the management plan. Use regular reviews to:\n\nensure that the benefits of the medicine continue to outweigh the potential harms\n\ncheck whether the dose needs to be adjusted and, if so, how to do this safely.\n\n## Prescribing strategies\n\nTake steps to reduce the risk of developing problems associated with dependence, for example starting at a low dose, and consider avoiding modified-release opioids. Explain the importance of these steps to the person.\n\nDiscuss with the person the range of doses likely to be safe and effective. Start with a low dose and agree frequent, regular reviews to ensure that timely adjustments can be made to test effectiveness, safety and acceptability and to find the lowest effective dose. Once an effective dose has been established, avoid automatically increasing the dose if the response is not sustained.\n\nIf the person's individual circumstances or the setting (for example, a secure setting) mean that usual prescribing practices are not suitable, adjust the prescription to ensure that:\n\nthe medicine can be administered safely as part of the setting's routine\n\nthe medicine does not pose a risk to the person or to others living in that setting. For more information, see the NICE guideline on physical health of people in prison.\n\nThe duration of each individual prescription:\n\nshould reflect the management plan (see recommendation 1.3.5)\n\nshould comply with best practice in controlled drugs prescribing\n\nmust comply with relevant legislation (for more information, see the NICE guideline on controlled drugs).\n\n## Working with other healthcare professionals\n\nWhen starting a prescription suggested by another healthcare professional, taking over a person's care, or deciding whether to continue a prescription made by another healthcare professional:\n\ntake the same level of care you would take if you were starting the prescription\n\nfollow the section on supporting people taking a dependence-forming medicine or antidepressant to help establish the new relationship\n\nensure that you have sufficient knowledge of the person's health and preferences to determine whether continued prescribing is in their best interests or whether careful withdrawal (in discussion with the person) would be more beneficial for them.\n\nHealthcare professionals in secondary care who recommend a dependence-forming medicine or antidepressant to be started or continued in primary care should explain to the person that:\n\nthe medicine will be prescribed by their primary care team\n\nthe primary care team will need to review the medicine\n\nif the primary care team declines to prescribe the medicine, or wishes to delay it, the secondary and primary care teams will discuss the medicine and involve the person in these discussions, explaining the reasons for any delay\n\nthe secondary care team might not continue to manage and provide the medicine if this is agreed after discussions.\n\nWhen transferring responsibility for prescribing from secondary to primary care, ensure that all relevant healthcare professionals have access to the management plan in the person's medical record.\n\nIf possible, ensure that 1\xa0person has overall responsibility for a prescription. If the initial prescriber is unable to review the medicine, ensure there are arrangements for review by another healthcare professional and that effective communication, including sharing the person's records and management plan as needed, is in place to support this. Pharmacists working in primary care may play a key role in supporting prescribing. See the section on medication review in the NICE guideline on medicines optimisation.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on starting a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: patient information and support\n\nevidence review\xa0B: prescribing strategies\n\nevidence review\xa0E: risk factors\n\nevidence review\xa0F: monitoring.\n\nLoading. Please wait.\n\n# Reviewing a dependence-forming medicine or antidepressant\n\n## Frequency of reviews\n\nOffer regular reviews (by phone, video or face to face) to people taking an opioid, benzodiazepine, gabapentinoid, Z‑drug or antidepressant. Base the frequency of reviews on:\n\nthe person's preferences and circumstances\n\nthe type of medicine they are taking and the dose\n\nfactors that might indicate a need for frequent reviews, for example if:\n\n\n\nthe person has additional care needs (such as people with a learning disability or cognitive impairment)\n\nthe person is taking the medicine for the first time\n\nthere are potential adverse effects or problems associated with dependence\n\nthe medicine is being used outside its licensed indications\n\nthere is potential for misuse of the medicine.For more information on antidepressants, see the NICE guidelines on depression in adults and depression in adults with a chronic physical health problem.\n\n\n\nConsider increasing the frequency of reviews during dose adjustment. Take into account the person's clinical and support needs when agreeing review frequency.\n\nOffer extra, unscheduled reviews when needed, for example if the person:\n\nreports adverse effects from the medicine\n\nbecomes pregnant or is planning pregnancy\n\nhas a change in their physical or mental health condition, or social circumstances\n\nstarts taking medicines from a different prescriber\n\nrequests a change in dose.\n\nFor guidance on reviewing medicines, see the section on medication review in the NICE guideline on medicines optimisation and the section on reviewing medicines in the NICE guideline on medicines adherence.\n\n## Content of reviews\n\nDuring the review, discuss with the person the benefits and risks of continuing the current dose, adjusting the dose or stopping the medicine. Base decisions on this discussion, taking into account, for example:\n\nthe benefits or harms the person is experiencing from continuing the medicine\n\nany signs that the person is developing problems associated with dependence (such as running out of a medicine early, making frequent requests for dose increases or reporting loss of efficacy of a medicine that was previously working well)\n\nthe person's preferences.\n\nAgree and update the management plan with the person after each review, and give them a copy (see recommendation\xa01.3.5). Check that they know who to contact if they have problems or concerns.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reviewing a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: monitoring.\n\nLoading. Please wait.\n\n# Withdrawing a dependence-forming medicine or antidepressant\n\n## Making shared decisions about withdrawing medicines\n\nDiscuss withdrawing an opioid, benzodiazepine, gabapentinoid, Z‑drug or antidepressant with the person if:\n\nit is no longer benefiting the person\n\nproblems associated with dependence have developed\n\nthe condition for which the medicine was prescribed has resolved\n\nthe harms of the medicine outweigh the benefits\n\nthe person wants to stop taking the medicine.\n\nExplain the benefits the person can expect from reducing the medicine and aim to reach agreement using a shared decision-making approach. Allow enough time to explore the person's circumstances and preferences.\n\nUnderstand that the person might be reluctant or anxious about discussing problems associated with dependence. Reassure them that dependence is an expected effect of these medicines and that problems associated with dependence sometimes develop. Be sensitive to the use of terminology that may apportion blame to the person or be perceived adversely.\n\nAcknowledge and discuss with the person any differences between their views and your own about the risks and benefits of the medicine.\n\nBe prepared for queries about prescribing decisions made previously. Explain that our understanding of the balance of risks and benefits of a medicine can change over time. If sufficient clinical detail is available, discuss the possibility that past prescribing was done in the person's best interests using the knowledge available at the time.\n\nDo not stop a medicine abruptly (complete cessation with immediate effect) unless there are exceptional medical circumstances, such as the occurrence of serious side effects (for example, upper gastrointestinal bleeding from an antidepressant, respiratory depression from an opioid or severe ataxia from a gabapentinoid). In these circumstances, consider:\n\nscheduling more frequent reviews\n\nshort-term use of medicines to treat the physical symptoms of withdrawal (for example, abdominal cramps and diarrhoea during withdrawal of an opioid).\n\nWhen planning withdrawal from an opioid, benzodiazepine, gabapentinoid, Z‑drug or antidepressant, take into account:\n\nthe urgency of the withdrawal, for example gradual withdrawal of a medicine that is no longer effective or necessary, or more rapid withdrawal of a medicine that is causing significant harm (the speed of rapid withdrawal depends on the type of medicine and the person's circumstances, see recommendation 1.5.6)\n\nwhether the initial goal should be complete withdrawal or, for people who find complete withdrawal too difficult, whether dose reduction with ongoing review is a more realistic initial aim\n\nwhich medicine to reduce first, if the person will be withdrawing from more than 1\xa0medicine\n\nfactors that might increase the person's risk of problems during withdrawal, including:\n\n\n\nlong duration of medicine use\n\nhigh dose of medicine\n\nhistory of withdrawal symptoms\n\nhistory of problems associated with dependence\n\ntaking an antidepressant with a short half-life\n\n\n\nany concurrent medicines and how these might affect the person's response to withdrawal\n\nfactors that might influence the timing of the start of the dose reduction, such as the person's circumstances and available support.\n\n## Information and support for people withdrawing from a medicine\n\nBefore starting withdrawal:\n\ngive the person information about the process of withdrawal that is tailored to their situation and the medicine they are taking\n\nexplain how the withdrawal will be carried out\n\nconsider providing details of sources of peer support, national and local support groups for people who are withdrawing from a medicine.\n\nDiscuss withdrawal symptoms with the person and tell them about the support that is available. When discussing withdrawal symptoms, explain that:\n\nwithdrawal can be difficult, and may take several months or more\n\nsupport will be available throughout the withdrawal process\n\nwithdrawal symptoms do not affect everyone, and it is not possible to predict who will be affected\n\nwithdrawal symptoms vary widely in type and severity, can affect both physical and mental health, may occur at any time during withdrawal or be delayed in onset and can change over time or persist over a prolonged period\n\nthere are options for managing withdrawal symptoms (see the section on identifying and managing withdrawal symptoms and the section on interventions to support withdrawal)\n\nsome people may experience withdrawal symptoms that can be difficult to distinguish from a re‑emergence of their original symptoms or a new disorder, and it is important to discuss these with a healthcare professional if they occur (see recommendation\xa01.5.17).\n\n## Dose reduction\n\nWhen agreeing a dose reduction schedule with the person:\n\nexplain the risk of abrupt discontinuation and that the rate of safe withdrawal varies between people and can vary over time for the same person\n\nbalance the risk of adverse events from continued exposure to the medicine with minimising the risk of withdrawal symptoms by slow dose reduction and withdrawal\n\nensure that the planned rate of reduction is acceptable to the person\n\nexplain that although withdrawal symptoms are to be expected, the reduction schedule can be modified to allow intolerable withdrawal symptoms to improve before making the next reduction\n\nconsider giving the person additional control over the process of dose reduction (for example, by issuing their usual daily dose in a form that allows them to reduce the amount in small decrements at a pace of their choosing, rather than issuing successive prescriptions for reduced daily doses)\n\nagree regular intervals for reviewing and adjusting the reduction schedule as needed\n\nensure the person knows who to contact if problems occur.\n\nIf the person is withdrawing from an opioid, benzodiazepine, Z‑drug or antidepressant, suggest a slow, stepwise rate of reduction proportionate to the existing dose, so that decrements become smaller as the dose is lowered, unless clinical risk is such that rapid withdrawal is needed (see recommendation 1.5.6).\n\nIf the person is withdrawing from a gabapentinoid, reduce the dose by a fixed amount at each decrement, unless clinical risk is such that rapid withdrawal is needed (see recommendation 1.5.6).\n\nIf the person is withdrawing from a benzodiazepine with a short half-life, consider switching to a benzodiazepine with a longer half-life.\n\nIf using a published withdrawal schedule, apply it flexibly to accommodate the person's preferences, changes to their circumstances and the response to dose reductions.\n\nDuring withdrawal, offer continued management of the underlying condition for which the medicine was prescribed, if needed.\n\nEnsure the plan for dose reduction or withdrawal is clearly recorded in the overall management plan.\n\n## Identifying and managing withdrawal symptoms\n\nBe aware that it can be difficult to distinguish between the re‑emergence of underlying conditions and the emergence of withdrawal symptoms. The following may indicate withdrawal symptoms rather than symptoms of an underlying condition:\n\nrapid or early onset of symptoms after a dose reduction or cessation of the medicine\n\nsymptoms of the underlying illness that the person reports as qualitatively different or more intense than before\n\nnew symptoms that the person has not experienced before.\n\nFollow recommendation\xa01.2.8 for people who find it difficult to communicate their symptoms, for example people with a learning disability or cognitive impairment.\n\nUse clinical judgement to determine the need for further investigation to rule out new pathology.\n\nIf distressing symptoms occur or worsen after a dose reduction:\n\ndetermine whether they are withdrawal symptoms or a re‑emergence of symptoms that were relieved by the medicine\n\nif the symptoms are new, think about delaying the next dose reduction, trying a smaller dose reduction or reverting to the previous dose.\n\n## Interventions to support withdrawal\n\nDo not treat withdrawal symptoms with another medicine that is associated with dependence or withdrawal symptoms.\n\nDo not offer sodium valproate or buspirone to aid withdrawal from a benzodiazepine.\n\nConsider group cognitive behavioural therapy (CBT) when withdrawing from a benzodiazepine. Discuss the timing of referral for CBT with the person.\n\n## Strategies if withdrawal cannot be agreed or is unsuccessful\n\nFollow recommendation 1.2.7 if a shared decision to withdraw cannot be reached and continuing the current prescription is not in the person's best interests. Be aware that medicines associated with dependence and withdrawal symptoms should not be stopped abruptly in most cases (see recommendation\xa01.5.6) and need to be reduced in line with the section on withdrawing medicines.\n\nIf continued use of the medicine may be particularly harmful for the person or others (for example, in a secure setting) and a dose reduction, or a more rapid reduction than the person wishes, is the safest option, consider:\n\nscheduling more frequent reviews\n\nshort-term use of medicines to treat the physical symptoms of withdrawal (for example, abdominal cramps and diarrhoea during withdrawal of an opioid).\n\nIf dose reduction has been unsuccessful (for example because of intolerable withdrawal symptoms or a change in the person's physical, mental or social circumstances) and the current prescription needs to be continued:\n\naim to stop any further escalation in dose\n\nmake a plan to attempt dose reduction again at a later date\n\nclearly record the advice given to the person about the potential harms of continuing the medicine, and the reasons for continuing without a reduction, in the management plan.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on withdrawing a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: patient information and support\n\nevidence review\xa0C: safe withdrawal\n\nevidence review\xa0D: withdrawal symptoms.\n\nLoading. Please wait.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Multicomponent withdrawal interventions\n\nWhat are the key components of an effective multicomponent intervention to support dose reduction during withdrawal of opioids?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: safe withdrawal.\n\nLoading. Please wait.\n\n## Psychological interventions to support withdrawal\n\nWhat are the most effective psychological interventions to support withdrawal and help people cope with withdrawal symptoms?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: safe withdrawal.\n\nLoading. Please wait.\n\n## Service models for withdrawal interventions\n\nWhat service models are most effective in supporting withdrawal from medicines associated with dependence and withdrawal symptoms?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: safe withdrawal.\n\nLoading. Please wait.\n\n## Individual circumstances and the risk of dependence\n\nDo individual circumstances such as social distress, low income or limited access to alternative sources of support lead to an increased risk of problems associated with dependence on prescribed medicines?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on making decisions about prescribing and taking a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: risk factors.\n\nLoading. Please wait.\n\n## Information for family members or carers\n\nWhat information and support are needed by family members or carers of people having treatment with an opioid, benzodiazepine, Z‑drug, antidepressant or gabapentinoid?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on starting a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: patient information and support.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## System-level factors and the risk of dependence\n\nDo system-level factors, such as training received by prescribers alter the risk of developing problems associated with dependence on prescribed medicines?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on making decisions about prescribing and taking a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: risk factors.\n\nLoading. Please wait.\n\n## Converting to a medicine with a different half‑life to aid withdrawal\n\nWhat is the clinical and cost effectiveness of converting to medicines with a longer half‑life to aid withdrawal from benzodiazepines or antidepressants?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: safe withdrawal.\n\nLoading. Please wait.\n\n## Cognitive behavioural therapy (CBT) to support withdrawal from benzodiazepines\n\nWhat is the most effective model of CBT, including timing of CBT, to support withdrawal from benzodiazepines?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: safe withdrawal.\n\nLoading. Please wait.\n\n## Acupuncture to support withdrawal from opioids\n\nWhat is the clinical and cost effectiveness of acupuncture (including electroacupuncture) as an adjunct to aid withdrawal from opioids?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: safe withdrawal.\n\nLoading. Please wait.\n\n## Withdrawal interventions for gabapentinoids\n\nWhat are the most clinically and cost-effective strategies or interventions to aid withdrawal of gabapentinoids?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: safe withdrawal.\n\nLoading. Please wait.\n\n## Aids to support withdrawal\n\nWhat is the effectiveness of equipment, technologies, practical aids and medicine formulations in supporting people to manage dose reductions, compared with usual practice?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on withdrawing a dependence-forming medicine or antidepressant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: safe withdrawal.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Supporting people taking a dependence-forming medicine or antidepressant\n\nRecommendations 1.1.1 and 1.1.2\n\n## Why the committee made the recommendations\n\nQualitative evidence was available from studies on opioids, benzodiazepines and antidepressants. Most of the participants were people prescribed these medicines, although some studies included prescribers (GPs, nurses and pharmacists).\n\nThe evidence highlighted that some people experience dissatisfaction with treatment and a poor relationship with healthcare professionals. The committee agreed that continuity of care, a tailored approach for each person, and the formation of good relationships are particularly important in this population. The recommendations in the NICE guideline on patient experience in adult NHS services will help to achieve this.\n\nEvidence and the committee's experience showed that the presence of a family member, carer, advocate or other person at appointments can be helpful, especially for people who are older, or who are distressed or find it difficult to take in and remember information.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect best practice but are not implemented consistently and might involve changes in practice for some providers.\n\nReturn to recommendations\n\n# Making decisions about prescribing and taking a dependence-forming medicine or antidepressant\n\nRecommendations 1.2.1 to 1.2.11\n\n## Why the committee made the recommendations\n\nEvidence from qualitative studies of people taking opioids showed that they want the opportunity to discuss all management options before starting the medicine. The evidence also highlighted people's need for support when making decisions about taking prescribed medicines. The committee agreed that reaching a shared decision about a medicine is beneficial for both the prescriber and the person taking the medicine, and that the NICE guideline on shared decision making should be used to support people when making decisions.\n\nBased on the evidence and their experience, the committee agreed that specific factors can increase a person's risk of developing problems associated with dependence. Prognostic evidence from studies of opioids and benzodiazepines demonstrated an increased risk in people diagnosed with mental health problems including depression, anxiety, post-traumatic stress disorder, bipolar disorder, alcohol-use disorder or drug-misuse disorder. The committee agreed, based on their experience, that this also applies to Z‑drugs and gabapentinoids, but not to antidepressants, which are not dependence-forming medicines. They noted that a comorbid mental health diagnosis can have a profound impact on people and increase their desire for medicines, and that people with a history of drug misuse may need higher drug doses to obtain the desired effect. There was evidence indicating that, for people prescribed opioids, concurrent use of benzodiazepines increases the risk of problems associated with dependence, as does the presence of painful conditions without a clear, defined diagnosis.\n\nThe committee agreed that it is important for healthcare professionals to be mindful of these factors when making prescribing decisions, but the needs of each person should be taken into account when balancing benefits and harms, and these factors alone should not be seen as barriers to prescribing.\n\nThe committee noted other factors that were not captured by the evidence but might influence the development of problems associated with dependence, including social distress, access to alternative sources of support and system-level factors such as training or supervision of prescribers. They made a recommendation for research on individual circumstances and the risk of problems associated with dependence, and a recommendation for research on system-level factors and the risk of problems associated with dependence.\n\nThe committee noted that, in their experience, people can often present in distress and may be focused on immediate relief of their symptoms. They also noted the pressure to prescribe that is sometimes felt by healthcare professionals and agreed that in some circumstances, it is advantageous to delay prescribing until after the first discussion about prescribing. They agreed that a short delay would not disadvantage the person and would be beneficial in allowing both the person and the healthcare professional time to reflect on the options.\n\nThe committee acknowledged that on occasion, a healthcare professional may not think that prescribing or continuing a medicine is in the person's best interests, but the person disagrees, and a shared decision cannot be reached. In this circumstance, it is the responsibility of the healthcare professional not to prescribe the medicine and to follow General Medical Council guidance.\n\nThe committee noted that there are some people with communication difficulties, for example those with a learning disability or cognitive impairment, who may have difficulties describing their symptoms, which can lead to medicines being prescribed inappropriately, or not at all. The committee agreed that, in their experience, additional consideration and support is needed to ensure prescribing decisions are made in the person's best interests, and that the person is able to share in those decisions.\n\n## How the recommendations might affect practice\n\nThe recommendations are expected to reduce the number of people who develop dependence on medicines by raising awareness of the risk factors and ensuring shared decisions are made based on fully informed discussions of the risks and benefits. This will benefit the healthcare system and improve the health of people taking these medicines.\n\nReturn to recommendations\n\n# Starting a dependence-forming medicine or antidepressant\n\nRecommendations 1.3.1 to 1.3.14\n\n## Why the committee made the recommendations\n\nEvidence from study participants showed that they were often not given sufficient information about their medicine before starting treatment, particularly the risks of dependence and withdrawal symptoms. Participants also reported a lack of information about side effects, how well the medicine is expected to work, how long it will take to work and the likely duration of treatment. This evidence reflected the committee's experience. The recommendations aim to ensure that all of this information is provided before people begin treatment.\n\nThe committee also agreed that it is important to make people aware of how to safely store their medicines and included a cross reference to the NICE guideline on controlled drugs, which covers storage of medicines.\n\nThe evidence also showed discrepancies between the information people reported being given and the information their healthcare professionals reported giving them, highlighting the importance of providing both verbal and written information in the person's preferred format that they can take home for later reference.\n\nThere was no evidence on the views of family members or carers, so the committee made a recommendation for research on information for family members or carers.\n\nWithin the evidence, peer support (for example, through online forums) was identified as a valuable complement to information provided by healthcare professionals. The committee agreed with this finding and recommended that prescribers should consider supplementing information with details of peer support networks.\n\nEvidence and the committee's experience demonstrated the value of agreeing a management plan with the person. The plan should include practical information about the medicine, including how to take it safely, and set out when the medicine will be reviewed. The importance of giving a copy of the plan to the person was highlighted both in the evidence and the committee's experience.\n\nThe committee's experience and evidence from studies on opioids indicated that long-term treatment is a risk factor for dependence, and that higher doses taken long term increase this risk further. Therefore, the management plan should be reviewed regularly to ensure that the dosage remains optimal, the benefits of the medicine continue to outweigh the potential harms and the medicine is not continued when it is no longer needed.\n\nAlthough the evidence was limited, the committee agreed that there was some indication that starting a medicine at a low dose may reduce the risk of problems associated with dependence and the risk of withdrawal symptoms. This was supported by evidence in the risk factor review showing a dose–response association between higher doses of opioids and incident addiction to opioids when taken long term. Evidence and the committee's experience also showed that standard-release opioids are less frequently associated with problems compared with modified-release opioids unless clinical considerations or the person's circumstances dictate otherwise. The committee noted this only applied to opioid formulations and not to the other medicines considered.\n\nThe committee agreed, based on their experience, that it is important to take particular care during dose adjustments. Although pharmacological tolerance is a property of medicines described in this guideline, if a person has an initially favourable response that then diminishes, it is rarely helpful to increase the dose to try to restore the clinical benefit. This is because such an approach increases the risk of harmful prescribing, and also because the loss of benefit is rarely due to pharmacological tolerance, but due to other factors.\n\nIn the committee's experience, there may be individual circumstances in which adjustments are needed to the prescription to ensure it is safe and practical. If it is not possible for people to hold their own medicines, in secure settings for example, twice-daily administration may be difficult.\n\nTo avoid unnecessary long-term use of a medicine, prescribers should ensure that each prescription is in line with the management plan and complies with good practice guidance and relevant legislation.\n\nThe committee based these recommendations on their experience. They agreed that standardised prescribing practice can help to ensure continuity of care.\n\nThe committee's recommendations emphasise the importance of clear communication between primary and secondary care. They also stress the importance of giving clear explanations to people about arrangements for their care across services.\n\nThe committee agreed that it is vital that a new prescriber taking over a person's care acquires sufficient knowledge about the person to determine whether the prescription should be continued, establishes a therapeutic relationship with the person and takes the same care they would if they had been the original prescriber.\n\nPrimary and secondary care prescribers should ensure that they discuss and agree medicines to be prescribed or continued in primary care, and ensure that the person is kept involved and informed about these discussions. The committee noted that this is consistent with NHS England's guidance on responsibility for prescribing between primary and secondary/tertiary care (2018).\n\nThe committee recognised the difficulties involved in achieving and maintaining continuity of care and communication across settings, and agreed that it is helpful to have 1\xa0prescriber take overall responsibility for a person's prescribing. It was noted that pharmacists may play an important role here.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect best practice, but there are variations in their implementation, and they may involve a change of practice for some providers. Longer consultations or additional follow up may be needed to allow for full discussion of treatments and treatment options when starting or reviewing a medicine. However, enabling effective conversations about risks and benefits could reduce unnecessary prescribing, which would have large health benefits for the person and economic benefits for the healthcare service, for example, by preventing unplanned hospital admissions from harms caused by the medicines and reducing the need for additional healthcare support for people with dependence.\n\nReturn to recommendations\n\n# Reviewing a dependence-forming medicine or antidepressant\n\nRecommendations 1.4.1 to 1.4.6\n\n## Why the committee made the recommendations\n\nThere was no evidence on the frequency of reviews, so the committee based the recommendations on their experience. They agreed that prescribing is an ongoing process that should be monitored with regular reviews. The frequency of these reviews should be tailored to the person, the medicine they are taking and the presence of any risk factors. They could be held by phone, video or face to face. The committee also agreed that the frequency of reviews could be increased during dose adjustments, to ensure safety and early identification of any withdrawal symptoms.\n\nEvidence and the committee's experience highlighted the importance of weighing up the benefits and risks of continuing or stopping the medicine as part of each review, and of updating the management plan after every review.\n\n## How the recommendations might affect practice\n\nTailored review schedules should reduce unnecessary appointment time and increase the efficiency of treatment monitoring. Although the frequency of reviews may be increased for some people, the cost is expected to be mitigated by the current move to online, phone and video consultations. Moreover, upfront costs of more frequent tailored reviews could be offset by downstream savings such as reducing the number of people needing help from addiction services and reducing the number of medicines being prescribed, with potential health benefits because of fewer adverse events and less clinical harm caused by prescribed medicines.\n\nReturn to recommendations\n\n# Withdrawing a dependence-forming medicine or antidepressant\n\nRecommendations 1.5.1 to 1.5.26\n\n## Why the committee made the recommendations\n\nThe committee agreed that withdrawal should be considered when a medicine is no longer beneficial, the harms outweigh the benefits, or the person would like to withdraw. A small amount of evidence indicated that including the benefits of withdrawal and information about the process in discussions with the person can increase the likelihood that their withdrawal will be successful.\n\nQualitative evidence highlighted that people can be reluctant or anxious about discussing dependence and report feelings of fear, worry or anxiety surrounding discontinuation. The committee agreed that, in their experience, this can be addressed by explaining that dependence is an expected effect of the medicine, and some people experience problems associated with dependence. They also agreed it was important to avoid using language that ascribes blame to the person. The committee also thought it important to acknowledge and discuss differences of opinion and to be prepared for queries about the reasons for past prescribing.\n\nEvidence from studies on benzodiazepines and antidepressants showed that a gradual, stepwise dose reduction is more beneficial than abrupt discontinuation. The committee agreed that this evidence can be extrapolated to opioids, Z‑drugs and gabapentinoids, and that none of these medicines should be stopped abruptly. However, the committee acknowledged clinical experience of exceptional circumstances in which stopping treatment abruptly might be necessary, for example if a serious side effect has occurred. In their experience, this would usually be done within a hospital setting.\n\nBased on their experience, the committee agreed that individual factors can affect the withdrawal process and should be taken into account when planning withdrawal. The plan for withdrawal should also take into account the urgency of withdrawal.\n\nBased on both the qualitative evidence and their experience, the committee agreed that the provision of information and support is vital for people withdrawing from a medicine. Knowing what to expect, and having reassurance that they will have support and help with managing withdrawal symptoms, will increase the likelihood of a successful withdrawal. There was some qualitative evidence, reflected in the committee's experience, that support groups can be beneficial for people during the withdrawal process.\n\nThe evidence comparing different speeds of dose reduction was inconclusive and the committee agreed that most of the studies did not reflect clinical practice. The committee are aware there are different terms used to describe reduction schedules. Based on their experience, they agreed that flexibility in schedules is needed, and tolerability is the most important factor to take into account when deciding the speed of dose reduction, and therefore a descriptive schedule incorporating these factors should be recommended. Although tolerability varies across individuals, most people find a stepwise, decremental dose reduction process tolerable and effective. With opioids, benzodiazepines, Z‑drugs and antidepressants, a rate of reduction proportionate to the existing dose is suggested. For gabapentinoids, the dose can be reduced by a fixed amount at each decrement, with the amount of reduction tailored to the person.\n\nIn the committee's experience, people who have some control over their own dose reduction schedule often have a more successful withdrawal than those whose schedule is decided for them. The committee also agreed that a flexible reduction schedule that is regularly reviewed and revised when needed is an important contributor to a successful outcome.\n\nThe committee noted that there was evidence for converting treatment from lorazepam to diazepam before withdrawal. This is because diazepam has a longer half‑life and is therefore considered to allow better management of the pace of reduction, and potentially reduce withdrawal symptoms. Withdrawing from a short-acting benzodiazepine such as lorazepam can be difficult because withdrawal symptoms can occur very quickly. The committee agreed that switching to a benzodiazepine with a longer half‑life is common practice and can be considered for people withdrawing from a benzodiazepine. Despite being common practice, there is a lack of evidence to support conversion to a preparation with a longer half‑life, so the committee made a recommendation for research on converting to a medicine with a different half-life to aid withdrawal. The committee agreed this recommendation for research should also apply to antidepressants.\n\nThe committee recognised that it can be difficult to differentiate withdrawal symptoms from symptoms of a new or existing underlying condition. They agreed that withdrawal symptoms are often characterised by rapid onset after the dose of a medicine is reduced or the medicine is stopped, or there are qualitative differences from previous symptoms of the underlying illness, or there are new symptoms that have not previously occurred.\n\nThe committee agreed that if symptoms occur or worsen after a dose reduction, it is important to try to determine whether they are withdrawal symptoms or a re‑emergence of symptoms of the original condition. If they are likely to be withdrawal symptoms, the committee agreed that the next dose reduction may need to be delayed, or the person may need to revert to the previous dose.\n\nThe evidence did not inform of the frequency or prevalence of symptoms, and the committee agreed that withdrawal symptoms could vary widely between individuals in terms of which symptoms were experienced, but also in terms of their intensity and duration. The committee also agreed that, based on the current evidence, it would not be helpful to include a list of symptoms in the recommendation because this could be misleading and result in symptoms being overlooked if they are not on the list or wrongly implying new symptoms do not need further investigation.\n\nThere was little evidence on psychological interventions to support withdrawal or relieve withdrawal symptoms. Health economic analysis showed that group cognitive behavioural therapy (CBT) alongside dose reduction can improve discontinuation rates and quality of life for people during withdrawal from benzodiazepines and reduce costs for the NHS. There was no clear evidence on the most effective model or timing of CBT, so the committee also made a recommendation for research on CBT to support withdrawal from benzodiazepines. Evidence on other psychological interventions, or psychological interventions for other medicines, was too limited to inform recommendations, so the committee made a recommendation for research on psychological interventions to support withdrawal.\n\nThe committee agreed, based on their experience, that using another medicine associated with dependence and withdrawal symptoms to treat withdrawal symptoms does not aid withdrawal and can lead to harms.\n\nThe evidence did not support the use of pharmacological interventions to aid withdrawal, but was very limited for most pharmacological interventions. The committee agreed that sodium valproate and buspirone taken during withdrawal from a benzodiazepine are not only ineffective but are associated with harm and should not be used.\n\nThere was some evidence that a multicomponent intervention is beneficial during withdrawal from an opioid. However, the relative effectiveness of each component was not clear, so the committee made a recommendation for research on multicomponent withdrawal interventions.\n\nAlthough acupuncture is commonly used in addiction services to manage dependence on illicit opioids, and there is some evidence supporting its use to aid withdrawal from opioids, evidence on its overall effectiveness is lacking. The committee made a recommendation for research on acupuncture to support withdrawal from opioids.\n\nThere was no evidence on the effectiveness of any withdrawal strategies or interventions to aid withdrawal from a gabapentinoid, so the committee made a recommendation for research on withdrawal interventions for gabapentinoids.\n\nThe committee were aware of specific equipment, practical aids and technologies used to support withdrawal but there was no evidence on these. They made a recommendation for research on aids to support withdrawal.\n\nThe committee discussed whether different service models, such as virtual clinics or specialist pharmacy input, would be effective in helping people withdraw from medicines. No evidence was identified in these areas and the committee made a recommendation for research on service models for withdrawal interventions.\n\nThe committee recognised that it may not be possible to reach a shared decision with the person about withdrawal and referred to the General Medical Council guidance for advice on how to handle this. They acknowledged particular difficulties if continued use of the medicine is especially hazardous, for example in a secure setting, and recommended steps that can be taken to manage withdrawal in this situation.\n\nThe committee recognised that dose reduction may sometimes be too difficult and agreed, based on their experience, that in this circumstance the aim should be to stop any further dose escalation and to make a plan to try again later. They stressed the importance of recording the reasons for continuing the medicine and the advice given to the person in the management plan.\n\n## How the recommendations might affect practice\n\nAt present, there is limited provision of services within the NHS specifically to support withdrawal from prescribed medicines. There are some local centres that have established good practice in this area, but they are not widely available. It is expected that implementing these recommendations will increase the number of people needing specialist withdrawal services. Additional resources will be needed to increase the provision of these services by expanding existing centres or creating additional ones in areas where these services are not available. This should be balanced by savings accrued from a reduction in unplanned hospitalisations to treat adverse drug events, fewer medicines prescribed and hence fewer medicine reviews. Providing CBT to people during withdrawal from benzodiazepines would initially need additional resources, but in the long term will generate savings and improve quality of life.\n\nReturn to recommendations"}	https://www.nice.org.uk/guidance/ng215	This guideline covers general principles for prescribing and managing withdrawal from opioids, benzodiazepines, gabapentinoids, Z‑drugs and antidepressants in primary and secondary care.

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